Imidazole-pyrazole derivatives with antibacterial properties

Abstract

The present invention provides novel imidazole-pyrazole derivatives having the general formula (I), and pharmaceutically acceptable salts thereof, wherein R 1 ~R 7 is as described herein: (I) TIFF2023540307000209.tif6985 Further provided are pharmaceutical compositions comprising the compounds of the invention, processes for making the compounds of the invention, and methods of using the compounds of the invention as medicines, particularly methods of using the compounds of the invention as antibiotics for the treatment or prevention of bacterial infections and diseases resulting therefrom.

Description

[Technical Field]

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

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

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

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

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

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

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

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

[0009] Summary of the Invention In the first aspect, the present invention relates to formula (I) [ka] We provide compounds of or pharmaceutically acceptable salts thereof, in which R 1 ~R 7 This is as described herein.

[0010] In one embodiment, the present invention provides a process for producing a compound of formula (I) described herein.

[0011] In a further embodiment, the present invention provides a compound of formula (I) as described herein, when produced according to the process described herein.

[0012] In a further embodiment, the present invention provides compounds of formula (I) described herein or pharmaceutically acceptable salts thereof for use as therapeutic active substances.

[0013] In a further embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof and a therapeutically inactive carrier.

[0014] In a further embodiment, the present invention provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, for use as antibiotics.

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

[0016] In a further embodiment, the present invention provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, for use in the treatment or prevention of infections caused by Gram-negative bacteria and diseases resulting therefrom.

[0017] In a further embodiment, the present invention provides compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, for use in the treatment or prevention of infections and diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof. [Modes for carrying out the invention]

[0018] Detailed description of the invention definition Features, integers, characteristics, compounds, chemical parts, or groups described in relation to specific aspects, embodiments, or examples of the present invention should be understood to be applicable to any other aspects, embodiments, or examples described herein, unless they are incompatible. All features disclosed herein (including any appended claims, abstract, and drawings) and / or all steps of any method or process so so disclosed may be combined in any combination, except for combinations in which at least some of such features and / or steps are mutually exclusive. The present invention is not limited to the details of any of the embodiments described above. The present invention extends to any novel features or any novel combination of features disclosed herein (including any appended claims, abstract, and drawings) and any novel steps of any method or process so so disclosed.

[0019] The term "alkyl" refers to a monovalent or polyvalent, linear or branched saturated hydrocarbon group ("C1-C6-alkyl") having 1 to 6 carbon atoms, e.g., 1, 2, 3, 4, 5, or 6 carbon atoms. In some embodiments, alkyl groups include 1 to 3 carbon atoms, e.g., 1, 2, or 3 carbon atoms. Some non-limiting examples of alkyl groups include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, isobutyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. A particularly preferred but non-limiting example of alkyl is methyl.

[0020] As used herein, the term "alkyldiyl" refers to a saturated linear or branched divalent hydrocarbon group with approximately 1 to 6 carbon atoms (C1-C6). Examples of alkyldiyl groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), and propylene (-CH2CH2CH2-). Alkyldiyl groups are sometimes also called "alkylene" groups.

[0021] The term "alkoxy" refers to the alkyl group described above, bonded to the parent molecule 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 yet other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. A particularly preferred but non-limiting example of an alkoxy is methoxy.

[0022] The term "halogen" or "halo" refers to fluoro(F), chloro(Cl), bromo(Br), or iodine(I). Preferably, the term "halogen" or "halo" refers to fluoro(F), chloro(Cl), or bromo(Br). Particularly preferred but non-limiting examples of "halogen" or "halo" are fluoro(F) and chloro(Cl).

[0023] The adjective "aminoalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group is replaced by an amino group. Preferably, "aminoalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms of the alkyl group are replaced by an amino group. Preferred, but non-limiting, examples of aminoalkyls are aminomethyl and 1-aminoethyl.

[0024] The term "aminoalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group is replaced by an amino group. Preferably, "aminoalkoxy" refers to an alkoxy group in which one, two, or three hydrogen atoms of the alkoxy group are replaced by amino groups. Preferred but non-limiting examples of aminoalkoxy are aminomethoxy and 1-aminoethoxy.

[0025] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or bicyclic ring system, preferably having 3 to 10 ring atoms, preferably 3 to 8 ring atoms, where 1, 2, or 3 of the ring atoms are heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. Preferably, 1 to 2 of the ring atoms are selected from N and O, and the remaining ring atoms are carbon. A "bicyclic heterocyclyl" refers to a heterocyclic portion consisting of two rings having two common ring atoms, i.e., a spirocyclic portion where the two rings are joined via a single common ring atom, with the bridging separating the two rings being either a single bond or a chain of one or two ring atoms. Some non-limiting examples of heterocyclyl groups include azetidine-3-yl, azetidine-2-yl, oxetan-3-yl, oxetan-2-yl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, pyrrolidinyl (e.g., pyrrolidine-2-yl), morpholino, morpholin-2-yl, morpholin-3-yl, pyrrolidinyl (e.g., pyrrolidine-3-yl), piperazinyl (e.g., piperazine-1-yl), 3-azabicyclo[3.1.0]hexane-6-yl, or 2,5-diazabicyclo[2.2.1]heptan-2-yl. Particularly preferred, but non-limiting, examples of heterocyclyls include piperidyl, piperazinyl, pyrrolidinyl, and 3-azabicyclo[3.1.0]hexane-6-yl.

[0026] The term "heteroaryl" refers to a monovalent or polyvalent, monocyclic or bicyclic, preferably bicyclic, ring system having a total of 5 to 14 ring members, preferably 5 to 12 ring members, more preferably 5 to 10 ring members, wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms. Preferably, "heteroaryl" refers to a 5 to 10-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms independently selected from O, S, and N. Most preferably, "heteroaryl" refers to a 5 to 10-membered heteroaryl containing 1 to 2 heteroatoms independently selected from O and N. Some preferred but non-limiting examples of heteroaryls include pyrimidinyl, pyrazolyl, pyridyl, pyrazinyl, imidazolyl, pyridazinyl, thiazolyl, and 1H-pyrazolo[3,4-d]pyrimidine-6-yl. A particularly preferred but non-limiting example of a heteroaryl is pyridyl.

[0027] The term "hydroxy" refers to the -OH group.

[0028] The term "amino" refers to the -NH2 group.

[0029] The term "cyano" refers to the -CN (nitrile) group.

[0030] The term "nitro" refers to the group -NO2.

[0031] The term "carbamoyl" refers to the -C(O)NH2 group.

[0032] The term "carbonyl" refers to a carbon radical that has two of the four covalent bonds shared with the oxygen atom (C=O).

[0033] The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a halogen atom, preferably a fluoro atom. Preferably, "haloalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms of the alkyl group are replaced by a halogen atom, most preferably a fluoro atom. Preferred but non-limiting examples of haloalkyls are trifluoromethyl, trifluoroethyl, 2-fluoroethyl, and 2,2-difluoroethyl. A particularly preferred but non-limiting example of a haloalkoxy is trifluoromethyl.

[0034] The term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group is replaced by a halogen atom, preferably a fluoro atom. Preferably, "haloalkoxy" refers to an alkoxy group in which one, two, or three hydrogen atoms of the alkoxy group are replaced by halogen atoms, most preferably a fluoro atom. Particularly preferred but non-limiting examples of haloalkoxys are difluoromethoxy and trifluoromethoxy.

[0035] 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 methoxy. 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 methoxy. A particularly preferred but non-limiting example of alkoxyalkoxy is 2-methoxyethoxy.

[0036] The term "alkoxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by an alkoxy group. Preferably, "alkoxyalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms of the alkyl group are replaced by an alkoxy group. A specific non-limiting example of an alkoxyalkyl group is methoxyethyl.

[0037] The term "hydroxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a hydroxyl group. Preferably, "hydroxyalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms, most preferably one hydrogen atom, of the alkyl group are replaced by a hydroxyl group. Preferred, but non-limiting, examples of hydroxyalkyls are hydroxymethyl, hydroxyethyl (e.g., 2-hydroxyethyl), and 3-hydroxy-3-methylbutyl.

[0038] The term "carbamoylalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a carbamoyl group. Preferably, "carbamoylalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms, most preferably one hydrogen atom, of the alkyl group are replaced by a carbamoyl group. Preferred but non-limiting examples of carbamoylalkyls are 2-amino-2-oxo-ethyl, 3-amino-3-oxo-propyl, and 4-amino-4-oxo-butyl.

[0039] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy and properties of a free base or free acid, and is not biologically or otherwise undesirable. Salts are formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, particularly hydrochloric acid, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, lactic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and N-acetylcysteine. In addition, these salts can be prepared by adding an inorganic base or organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts that can be derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, and polyimine resins. Specific pharmaceutically acceptable salts of the compound of formula (I) are hydrochloride, fumarate, lactate (especially derived from L-(+)-lactic acid), tartrate (especially derived from L-(+)-tartaric acid), and trifluoroacetate.

[0040] The compound of formula (I) may contain several chiral centers and may exist as an optically pure enantiomer, a mixture of enantiomers such as a racemate, an optically pure diastereoisomer, a mixture of diastereoisomers, a diastereoisomer racemate, or a mixture of diastereoisomer racemates.

[0041] According to the Cahn-Ingold-Prelog rule, an asymmetric carbon atom can have either an "R" or "S" configuration.

[0042] The term “treatment,” as used herein, includes: (1) suppressing a symptom, disorder, or condition (e.g., in the case of maintenance treatment, stopping, reducing, or delaying the onset or recurrence of at least one clinical symptom or asymptomatic disease); and / or (2) alleviating a condition (i.e., causing regression of a symptom, disorder, or condition, or at least one of its clinical symptoms or asymptomatics). The benefit to the patient to be treated is either statistically significant or at least recognizable to the patient or physician. However, it will be understood that when a medicine is administered to a patient to treat a disease, the outcome does not necessarily have to be an effective treatment.

[0043] As used herein, the term “prevention” includes preventing or delaying the onset of clinical symptoms of a condition, disorder, or condition in mammals, particularly in humans who are suffering from or susceptible to a condition, disorder, or condition but have not yet experienced or shown any clinical symptoms or asymptomatic symptoms of that condition, disorder, or condition.

[0044] As used herein, the term “mammal” includes both humans and non-humans, and includes, but is not limited to, humans, non-human primates, dogs, cats, mice, cattle, horses, and pigs. In particularly preferred embodiments, the term “mammal” refers to humans.

[0045] The term "hospital-acquired infection" refers to hospital-acquired infections (HAIs), which are infections acquired in hospitals or other healthcare facilities. They are sometimes called healthcare-associated infections (HAIs or HCAIs) to emphasize both hospital and non-hospital settings. Such infections can be acquired in hospitals, nursing homes, rehabilitation facilities, outpatient clinics, or other clinical settings.

[0046] Compound of the present invention In the first aspect, the present invention relates to formula (I) [ka] (wherein, R 1 and R 2 together with the nitrogen atom to which they are attached form a group of formula (II), (III) or (IV) [Chemical formula] or; R 1 is C1-C6-alkyl, amino-C1-C6-alkyl, amino-C1-C6-alkoxy-C1-C6-alkyl, and the group [Chemical formula] selected from; R 2 is selected from hydrogen and C1-C6-alkyl; R 3 is selected from hydrogen, halogen, C1-C6-alkyl and C1-C6-alkoxy; R 4 and R 6 are each independently selected from hydrogen, C1-C6-alkyl, C1-C6-alkoxy, cyano, halo-C1-C6-alkyl and halo-C1-C6-alkoxy; R 5a R 5b and R 5c are each independently selected from hydrogen, halogen, hydroxy, C1-C6-alkyl, C1-C6-alkoxy, amino-C1-C6-alkoxy, hydroxy-C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl-, C1-C6-alkoxy-C1-C6-alkoxy-, amino, C1-C6-alkyl-NH-, (C1-C6-alkyl)2N-, C1-C6-alkyl-NH-C(O)-, amino-C1-C6-alkyl-NH-, C1-C6-alkoxy-C1-C6-alkyl-NH-, carbamoyl-C1-C6-alkyl-NH-, (3- to 14-membered heterocyclyl)-C(O)-NH-, carbamoyl and nitro; R 7This is selected from hydrogen, C1-C6-alkyl, and halo-C1-C6-alkyl; R 8a These are hydrogen, C1-C6-alkyl, carbamoyl-C1-C6-alkyl, and group [ka] Selected from; R 8b The group consists of hydrogen, hydroxy, oxo, hydroxy-C1-C6-alkyl, and [ka] Selected from; R 8c These are selected from hydrogen, C1-C6-alkyl, amino-C1-C6-alkyl, amino, C1-C6-alkyl-NH-, and C1-C6-alkoxy-C1-C6-alkyl; R 8d is hydrogen or C1-C6-alkyl; R 9a , R 9b , R 10a , R 10b , R 12a and R 12b Each of these is independently selected from hydrogen, halogen, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, amino, nitro, and hydroxy; R 11a and R 11b These are, independently, hydrogen, halogen, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, amino-C1-C6-alkyl, hydroxy-C1-C6-alkyl, halo-C1-C6-alkoxy, amino, nitro, hydroxy and group [ka] Selected from; Y is a carbonyl group, and X is selected from covalent bonds, NH, N(C1-C6-alkyl), NH-C1-C6-alkyldiyl, and C1-C6-alkyldiyl; or X is a carbonyl group, and Y is selected from covalent bonds, NH, N(C1-C6-alkyl), NH-C1-C6-alkyldiyl, and C1-C6-alkyldiyl groups; X is a C1-C6 alkyldiyl, and Y is a covalent bond; L 1 and L 3 Each of these is independently selected from covalent bonds, -C(O)-NH-C1-C6-alkyldiyl-, -C1-C6-alkyldiyl-NH-C(O)-, -C(O)-NH-C1-C6-alkoxy-C1-C6-alkyldiyl-, -C1-C6-alkoxy-C1-C6-alkyldiyl-NH-C(O)-, carbonyl, and C1-C6-alkyldiyl; L 2 and L 4 Each of these is independently selected from covalent, carbonyl, -O-, -NH-C(O)-, -C(O)-NH-, -C(O)-NH-C1-C6-alkyldiyl-, -C1-C6-alkyldiyl-NH-C(O)-, and C1-C6-alkyldiyl; A is a 5- to 14-membered heteroaryl; B, C, D, E, and G were each independently selected from 3- to 14-membered heterocyclyls and 5- to 14-membered heteroaryls; F consists of 3-14 member heterocyclyl and C3-C 10 The present invention provides compounds (selected from cycloalkyl groups) or pharmaceutically acceptable salts thereof.

[0047] In one embodiment, the present invention is R 1 and R 2 However, together with the nitrogen atom to which they are bonded, they form the base of formula (II), (III), or (IV) [ka] Forming; or R 1 However, C1-C6-alkyl, amino-C1-C6-alkyl, amino-C1-C6-alkoxy-C1-C6-alkyl, and group [ka] Selected from; R 2 However, it is selected from hydrogen and C1-C6-alkyl; R 9a However, it is hydrogen or hydroxyl; R 9b , R 10b , and R 12b However, each of them is hydrogen; R 8a However, hydrogen, C1-C6-alkyl, carbamoyl-C1-C6-alkyl, and group [ka] Selected from; R 8b However, hydrogen, hydroxy, oxo, hydroxy-C1-C6-alkyl and group [ka] Selected from; R 8c However, these are selected from hydrogen, C1-C6-alkyl, amino-C1-C6-alkyl, amino, C1-C6-alkyl-NH-, and C1-C6-alkoxy-C1-C6-alkyl; R 8d However, it is hydrogen or C1-C6-alkyl; R 10a However, they are selected from amino and nitro; R 11a However, hydrogen, amino-C1-C6-alkyl, hydroxy-C1-C6-alkyl, amino, hydroxy and group [ka] Selected from; R 11b However, these are selected from hydrogen, halo-C1-C6-alkyl, and hydroxy-C1-C6-alkyl; R 12a However, selected from hydrogen and hydroxyl; X is a carbonyl group and Y is a covalent group or a C1-C6 alkyldiyl group; or X is selected from NH, N(C1-C6-alkyl) and NH-C1-C6-alkyldiyl; Y is carbonyl; or X is a C1-C6 alkyldiyl, and Y is a covalent bond; L 1 is C1-C6-alkyldiyl; L 2 is -O-; L 3 However, these are selected from covalent bonds, C(O)-NH-C1-C6-alkyldiyl-, -C(O)-NH-C1-C6-alkoxy-C1-C6-alkyldiyl-, and C1-C6-alkyldiyl; L 4 However, these are selected from carbonyl, -C(O)-NH-, and -C(O)-NH-C1-C6-alkyldiyl-; B, C, D, and G are each independently 3- to 14-membered heterocyclines; E is a 5- to 14-membered heteroaryl; F is a 5-14 member heteroaryl, C3-C 10 - Selected from cycloalkyl and 3-14 membered heterocyclyl, This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0048] In a preferred embodiment, the present invention is R 1 and R 2 However, together with the nitrogen atom to which they are bonded, they form the base of formula (II), (III), or (IV) [ka] Forming; or R 1 is the basis [ka] And; R 2 It is a C1-C6 alkyl group; R 8a However, it is selected from hydrogen and C1-C6-alkyl; R 8b However, selected from hydrogen and hydroxyl; R 8c However, it is hydrogen or C1-C6-alkyl-NH-; R 8d is hydrogen; R 11a is the basis [ka] and; R 11b is hydrogen; R 12a is hydroxyl; R 12b is hydrogen; X is a carbonyl group; Y is a covalent bond or a C1-C6 alkyldiyl; L 3 The bond is covalent; L 4 is a carbonyl group; B, C, F, and G are each independently 3- to 14-membered heterocyclines. This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0049] In a particularly preferred embodiment, the present invention is R 1 and R 2 However, together with the nitrogen atom to which they are bonded, they form the base of formula (II), (III), or (IV) [ka] Forming; or R 1 is the basis [ka] And; R 2 is methyl; R 8aHowever, hydrogen and methyl are selected; R 8b However, selected from hydrogen and hydroxyl; R 8c However, it is hydrogen or methyl-NH-; R 8d is hydrogen; R 11a is the basis [ka] and; R 11b is hydrogen; R 12a is hydroxyl; R 12b is hydrogen; X is a carbonyl group; Y is a covalent bond or -CH2-; L 3 The bond is covalent; L 4 However, it is a carbonyl group; B is selected from piperazinil, piperidyl, and 2,8-diazaspiro[4.5]decane-8-yl; C is selected from piperidil and pyrrolidinil; F is piperidil; G is pyrrolidinyl. This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0050] In one embodiment, the present invention is A is a 5- to 14-membered heteroaryl; R 5aHowever, these are selected from hydrogen, halogen, C1-C6-alkyl, C1-C6-alkoxy, amino-C1-C6-alkoxy, hydroxy-C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl-, C1-C6-alkoxy-C1-C6-alkoxy-, amino, C1-C6-alkyl-NH-, (C1-C6-alkyl)2N-, C1-C6-alkyl-NH-C(O)-, amino-C1-C6-alkyl-NH-, C1-C6-alkoxy-C1-C6-alkyl-NH-, carbamoyl-C1-C6-alkyl-NH-, (3-14 member heterocyclyl)-C(O)-NH-, carbamoyl and nitro; R 5b However, these are selected from hydrogen, halogens, and amino acids; R 5c That is hydrogen. This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0051] In a preferred embodiment, the present invention is A is a 5- to 14-membered heteroaryl; R 5a However, these are selected from halogens, C1-C6-alkyl, C1-C6-alkoxy, hydroxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkyl-NH-, amino-C1-C6-alkyl-NH-, and amino; R 5b However, it is hydrogen or amino acid; R 5c That is hydrogen. This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0052] In a particularly preferred embodiment, the present invention is A is pyridyl; R 5a However, these are selected from fluoro, methyl, methoxy, hydroxymethyl, methylamino, 2-aminoethyl-NH-, and amino; R 5b However, it is hydrogen or amino acid; R5c is hydrogen, There is provided a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof.

[0053] In one embodiment, the present invention provides R 1 and R 2 together with the nitrogen atom to which they are attached form a group of formula (II), (III) or (IV)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0054] In a preferred embodiment, the present invention is R 1 and R 2 However, together with the nitrogen atom to which they are bonded, they form the base of formula (II), (III), or (IV) [ka] Forming; or R 1 is the basis [ka] And; R2 is C1-C6-alkyl; R 3 is halogen; R 4 is halo-C1-C6-alkyl; R 5a is selected from halogen, C1-C6-alkyl, C1-C6-alkoxy, hydroxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkyl-NH-, amino-C1-C6-alkyl-NH- and amino; R 5b is hydrogen or amino; R 5c and R 6 are hydrogen; R 7 is C1-C6-alkyl; R 8a is selected from hydrogen and C1-C6-alkyl; R 8b is selected from hydrogen and hydroxy; R 8c is hydrogen or C1-C6-alkyl-NH-; R 8d is hydrogen; R 11a is the group

Chemical formula

[0055] In a particularly preferred embodiment, the present invention is R 1 and R 2 However, together with the nitrogen atom to which they are bonded, they form the base of formula (II), (III), or (IV) [ka] Forming; or R 1 is the basis [ka] And; R 2 is methyl; R 3 is chloro; R 4 CF3 is; R 5a However, these are selected from fluoro, methyl, methoxy, hydroxymethyl, methylamino, 2-aminoethyl-NH-, and amino; R 5b However, it is hydrogen or amino acid; R 5c and R 6 is hydrogen; R 7 is methyl; R 8a However, hydrogen and methyl are selected; R 8b However, selected from hydrogen and hydroxyl; R 8c However, it is hydrogen or methyl-NH-; R 8d is hydrogen; R 11a is the basis [ka] and; R 11b is hydrogen; R 12ais hydroxyl; R 12b is hydrogen; X is a carbonyl group; Y is a covalent bond or -CH2-; L 3 The bond is covalent; L 4 However, it is a carbonyl group; A is pyridyl; B is selected from piperazinil, piperidyl, and 2,8-diazaspiro[4.5]decane-8-yl; C is selected from piperidil and pyrrolidinil; F is piperidil; G is pyrrolidinyl. This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0056] In one embodiment, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof as described herein, the compounds of formula (I) are, in particular, provided herein in specific examples. N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pyrimidine-2-yl-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(4-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(5-chloro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxypyrimidine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid; 5-[1-(5-aminopyrimidine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(2-methoxyethoxy)pyrimidine-2-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(2-methoxyethoxy)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(5-fluoropyrimidine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(1h-pyrazolo[3,4-d]pyrimidine-6-yl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[3-(trifluoromethyl)-1-[3-(trifluoromethyl)-2-pyridyl]pyrazole-4-yl]imidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(4-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid; 5-[1-[4-(2-aminoethoxy)pyrimidine-2-yl]-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid; 5-[1-(4-aminopyrimidine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 2,2,2-trifluoroacetic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[4-(methylamino)pyrimidine-2-yl]-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; 2,2,2-trifluoroacetic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[4-(dimethylamino)pyrimidine-2-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 2,2,2-trifluoroacetic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[4-(dimethylamino)pyrimidine-2-yl]-5-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 2,2,2-trifluoroacetic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[4-(2-methoxyethylamino)pyrimidine-2-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 2,2,2-trifluoroacetic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pyrazine-2-yl-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; 2,2,2-trifluoroacetic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(dimethylamino)pyrimidine-2-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid; 5-[1-[5-(2-aminoethylamino)pyrimidine-2-yl]-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[6-(dimethylamino)pyridazin-3-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(2-methoxyethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid; 5-[1-[5-[(3-amino-3-oxopropyl)amino]-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(4-methoxypyrimidine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(2-methoxypyrimidine-4-yl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[[1-(piperidine-4-carbonyl)-4-piperidyl]methylcarbamoyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-[(3S)-morpholine-3-carbonyl]piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid; 5-[1-(5-amino-2-pyridyl)-3-(difluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-methoxypyrazole-4-yl]-N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-cyanopyrazole-4-yl]-N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-methyl-pyrazole-4-yl]-N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-ethyl-pyrazole-4-yl]-N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 2,2,2-trifluoroacetic acid; 5-[1-(6-aminopyridazine-3-yl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 2,2,2-trifluoroacetic acid; N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(4-methyl-1H-pyrazole-3-yl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; 2,2,2-trifluoroacetic acid; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-[2-(3-hydroxypyrrolidine-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-[(2S,3S)-3-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid; 5-[1-[5-(2-aminoethylamino)pyrimidine-2-yl]-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-[(2S,3S)-3-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-[2-(3-hydroxypyrrolidine-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid; 1-Methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-methyl-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]imidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid arbthylamino)-2-py; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[1-(2-methoxyethyl)pyrazole-4-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[1-(2-methoxyethyl)-5-methylpyrazole-4-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[1-(2-methoxyethyl)imidazole-4-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(1-methylimidazole-4-yl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-methyl-1H-pyrazole-4-yl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-methyl-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(4-methyl-1H-pyrazole-5-yl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; 2,2,2-trifluoroacetic acid; N-[4-[4-[(1R,5S)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]-3-chlorophenyl]-1-methyl-5-[1-pyrimidine-2-yl-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid; N-[3-chloro-4-[[(1R,5S)-3-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]-3-azabicyclo[3.1.0]hexane-6-yl]carbamoyl]phenyl]-1-methyl-5-[1-pyrimidine-2-yl-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid; N-[3-chloro-4-[[(1S,5R)-3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexane-6-yl]carbamoyl]phenyl]-1-methyl-5-[1-pyrimidine-2-yl-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-[(3S,4R)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid; N-[4-[4-[1-(azetidine-3-ylmethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chlorophenyl]-1-methyl-5-[1-pyrimidine-2-yl-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperazine-1-carbonyl)piperidine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-[3-(hydroxymethyl)piperazine-1-carbonyl]piperidine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-[(2-oxopiperazine-1-yl)methyl]piperidine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(1H-pyrazole-3-ylmethylcarbamoyl)phenyl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S)-4-hydroxypiperidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(ethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid; N-[4-[(3R)-3-(aminomethyl)pyrroridine-1-carbonyl]-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; N-[4-(3-aminopropylcarbamoyl)-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(4-piperidylmethylcarbamoyl)phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(4-piperidylmethylcarbamoyl)phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(methylamino)piperidine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[(3-methylolpyrrolidine-3-yl)carbamoyl]phenyl]-1-methylimidazole-2-carboxamide; N-[4-[[1-(aminomethyl)cyclopropyl]carbamoyl]-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; N-[4-[(3S)-3-(aminomethyl)pyrroridine-1-carbonyl]-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(2,8-diazaspiro[4.5]decane-8-carbonyl)phenyl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[4-(methoxymethyl)-1H-pyrazole-3-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 5-[1-(6-amino-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]-1-methylimidazole-2-carboxamide; N-[4-[cis-(3-aminocyclobutyl)carbamoyl]-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; N-[4-(2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carbonyl)-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[methyl(4-piperidyl)carbamoyl]phenyl]-1-methylimidazole-2-carboxamide; N-[4-[4-(aminomethyl)piperidine-1-carbonyl]-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; N-[4-[[3-(aminomethyl)-3-(chloromethyl)cyclobutyl]carbamoyl]-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; N-[4-[[(trans-3-aminocyclopentyl]carbamoyl]-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; N-[4-(2-aminoethylcarbamoyl)-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; N-[4-[(2-aminocyclopropyl)methylcarbamoyl]-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; N-[4-[trans-(3-aminocyclobutyl)carbamoyl]-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; N-[4-(4-aminopiperidine-1-carbonyl)-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[2-[(2S,4R)-4-hydroxyprolyl]-2,8-diazaspiro[4.5]decane-8-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[[(1R,3R)-3-[[(2S,4R)-4-hydroxyprolyl]amino]cyclopentyl]carbamoyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-[[(2S,4R)-4-hydroxyprolyl]amino]piperidine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[6-[[(2S,4R)-4-hydroxyprolyl]amino]-2-azaspiro[3,3]heptan-2-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[3-[[(2S,4R)-4-hydroxyprolyl]amino]propylcarbamoyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-aminopyridine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl]-#N!-[3-chloro-4-[[4-(hydroxymethyl)-1-[#rac!-(2#R!4#S!)-4-hydroxypyrrolidine-2-carbonyl]pyrrolidine-3-yl]carbamoyl]phenyl]-1-methylimidazole-2-carboxamide; N-[4-(5-aminopentylcarbamoyl)-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 5-[1-(5-aminopyrazine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxyprolyl]piperazine-1-carbonyl]phenyl]-5-[1-(6-chloro-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]-5-[1-(6-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[2-[[(2S,4R)-4-hydroxyprolyl]amino]ethylcarbamoyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[[1-[(2S,4R)-4-hydroxyprolyl]-4-piperidyl]methylcarbamoyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[[1-[(2S,4R)-4-hydroxyprolyl]-4-piperidyl]-methyl-carbamoyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[[2-[[(2S,4R)-4-hydroxyprolyl]amino]cyclopropyl]methylcarbamoyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[5-[(2S,4R)-4-hydroxyprolyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-2-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[trans[3-[[(2S,4R)-4-hydroxyprolyl]amino]cyclobutyl]carbamoyl]phenyl]1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[(3S)-3-[[(2S,4R)-4-hydroxyprolyl]amino]methyl]pyrrolidine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[2-[2-[[(2S,4R)-4-hydroxyprolyl]amino]ethoxy]ethylcarbamoyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[[(7S)-2-[(2S,4R)-4-hydroxyprolyl]-5-oxa-2-azaspiro[3,4]octan-7-yl]carbamoyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[cis-[3-[[(2S,4R)-4-hydroxyprolyl]amino]cyclobutyl]carbamoyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[[1-[[(2S,4R)-4-hydroxyprolyl]amino]cyclopropyl]methylcarbamoyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[(3R)-3-[[(2S,4R)-4-hydroxyprolyl]amino]methyl]pyrrolidine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-[[(2S,4R)-4-hydroxyprolyl]amino]methyl]piperidine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-[[(2S,4R)-4-hydroxyprolyl]-methyl-amino]piperidine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[[3-[[(2S,4R)-4-hydroxyprolyl]amino]-1-bicyclo[1.1.1]pentanyl]carbamoyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[[(1S,3S)-3-[[(2S,4R)-4-hydroxyprolyl]amino]cyclopentyl]carbamoyl]phenyl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]-5-[1-(6-methoxypyrimidine-4-yl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(2-chloropyridine-4-yl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(4,7-diazaspiro[2.5]octane-7-carbonyl)phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[(3R)-3-methyl-1,4-diazepan-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(3,9-diazabicyclo[3.3.1]nonane-3-carbonyl)phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[(2S,6R)-2,6-dimethylpiperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(3,6-diazabicyclo[3.1.1]heptan-6-carbonyl)phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[(2S)-2-methylpiperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(3,3-dimethylpiperazine-1-carbonyl)phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[(3S)-3-isopropylpiperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(3,6-diazabicyclo[3.2.0]heptan-3-carbonyl)phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(1,4-diazepan-1-carbonyl)phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[(3S)-3-methylpiperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(3,8-diazabicyclo[3.2.1]octane-8-carbonyl)phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[(2R)-2-ethylpiperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[(2S)-2-ethylpiperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(2-piperazinoethylcarbamoyl)phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[(1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(4,7-diazaspiro[2.5]octane-4-carbonyl)phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[(2S,3R)-2,3-dimethylpiperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[3-(methoxymethyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[(1R,5R)-3,6-diazabicyclo[3.2.0]heptan-3-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-3-fluoro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-6-fluoro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]-5-[1-(2-methoxy-4-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 5-[1-(6-amino-5-fluoro-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]-5-[1-(6-methoxy-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(diethylcarbamoyl)phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(6-amino-5-methyl-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(6-amino-4-methyl-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(6-amino-2-methyl-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-4-chloro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-4-chloro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-3-methyl-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-4-methyl-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-fluoro-4-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(6-amino-2-fluoro-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(4-amino-5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-6-methylpyridine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl]-#N!-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(4,5-diamino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; N-[6-[4-[2-[[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]carbamoyl]-3-methylimidazole-4-yl]-3-(trifluoromethyl)pyrazole-1-yl]-3-pyridyl]isonipecotamide; and 5-[1-[5-(2-aminoethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]-1-methylimidazole-2-carboxamide To provide.

[0057] In one embodiment, the present invention is R 1 and R 2 However, together with the atoms to which they are bonded, they form the base of formula (II) or (III). [ka] To form: or R 1 is the base [ka] And R 2 The elements are selected from hydrogen and C1-C6-alkyl groups; R 3 These are selected from hydrogen, halogens, C1-C6-alkyl and C1-C6-alkoxy; R 4 and R6 Each of these is independently selected from hydrogen, C1-C6-alkyl, C1-C6-alkoxy, cyano, halo-C1-C6-alkyl, and halo-C1-C6-alkoxy; R 5a , R 5b and R 5c Each is independently selected from hydrogen, halogen, hydroxyl, C1-C6-alkyl, C1-C6-alkoxy, amino-C1-C6-alkoxy, hydroxyl-C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl-, C1-C6-alkoxy-C1-C6-alkoxy-, amino, C1-C6-alkyl-NH-, (C1-C6-alkyl)2N-, C1-C6-alkyl-NH-C(O)-, amino-C1-C6-alkyl-NH-, C1-C6-alkoxy-C1-C6-alkyl-NH-, carbamoyl-C1-C6-alkyl-NH-, carbamoyl and nitro; R 7 This is selected from hydrogen, C1-C6-alkyl, and halo-C1-C6-alkyl; R 8a These are hydrogen, C1-C6-alkyl, carbamoyl-C1-C6-alkyl, and group [ka] Selected from; R 8b The group consists of hydrogen, hydroxy, oxo, hydroxy-C1-C6-alkyl, and [ka] Selected from; R 9a , R 9b , R 10a , R 10b , R 12a and R 12b Each of these is independently selected from hydrogen, halogen, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, amino, nitro, and hydroxy; R 11aand R 11b These are, independently, hydrogen, halogen, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, amino, nitro, hydroxy and group [ka] Selected from; X is a carbonyl group and Y is a covalent group or a C1-C6 alkyldiyl group; or X is a C1-C6 alkyldiyl, and Y is a covalent bond; L 1 and L 3 However, each is independently selected from covalent bonds, carbonyl, and C1-C6 alkyldiyl; L 2 and L 4 However, each is independently selected from covalent, carbonyl, -O-, -NH-C(O)-, -C(O)-NH-, and C1-C6-alkyldiyl; A is a 5- to 14-membered heteroaryl; B, C, D, E, F, and G are each independently selected from 3- to 14-membered heterocyclyls and 5- to 14-membered heteroaryls. This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0058] In one embodiment, the compound of formula (I) is of formula (II). [ka] (In the formula, R 13 is, [ka] or base [ka] and; A, C, R 3 , R 4 , R 5a, R 5b , R 5c , R 6 , R 7 , R 8a and R 8b (As described herein) It is a compound of [the compound].

[0059] In one embodiment, the compound of formula (I) is of formula (I-II) [ka] (In the formula, R 13 is, [ka] or base [ka] and; A, C, R 3 , R 5a , R 5b , R 5c , R 8a and R 8b (As described herein) It is a compound of [the compound].

[0060] In one embodiment, the compound of formula (I) is of formula (I-III) [ka] (In the formula, R 13 is, [ka] or base [ka] and; A, C, R 3 , R 5a , R 5b , R 5c , R 8a and R8b (As described herein) It is a compound of [the compound].

[0061] In one embodiment, the present invention is R 1 and R 2 However, together with the atoms to which they are bonded, they form the base of formula (II) or (III). [ka] To form: or R 1 is the basis [ka] And R 2 is hydrogen; R 9a , R 9b , R 10b , R 11b and R 12b However, each of them is hydrogen; R 8a However, hydrogen, C1-C6-alkyl, carbamoyl-C1-C6-alkyl, and group [ka] Selected from; R 8b However, hydrogen, hydroxy, oxo, hydroxy-C1-C6-alkyl and group [ka] Selected from; R 10a However, they are selected from amino and nitro; R 11a is the basis [ka] and; R 12a However, selected from hydrogen and hydroxyl; X is a carbonyl group and Y is a covalent group or a C1-C6 alkyldiyl group; or X is a C1-C6 alkyldiyl, and Y is a covalent bond; L 1 is C1-C6-alkyldiyl; L 2 is -O-; L 3 However, these are selected from covalent bonds and C1-C6-alkyldiyl; L 4 However, it is a carbonyl group; B, C, D, and G are each independently 3- to 14-membered heterocyclines; E is a 5- to 14-membered heteroaryl; F is selected from 5-14 member heteroaryls and 3-14 member heterocyclines. This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0062] In a preferred embodiment, the present invention is R 1 and R 2 However, together with the atoms to which they are bonded, they form the base of formula (II) or (III). [ka] Forming, R 8a However, it is selected from hydrogen and C1-C6-alkyl; R 8b However, selected from hydrogen and hydroxyl; X is a carbonyl group; Y is a covalent bond or a C1-C6 alkyldiyl; B and C are independently 3- to 14-membered heterocyclines. This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0063] In a particularly preferred embodiment, the present invention is R 1 and R2 However, together with the atoms to which they are bonded, they form the base of formula (II) or (III). [ka] form; R 8a However, hydrogen and methyl are selected; R 8b However, selected from hydrogen and hydroxyl; X is a carbonyl group; Y is a covalent bond or -CH2-; B is piperazinyl; C is selected from piperidyl and pyrrolidinyl. This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0064] In one embodiment, the present invention is R 3 The present specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein the compound is a halogen or a C1-C6-alkyl.

[0065] In a preferred embodiment, the present invention is R 3 This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein is a halogen.

[0066] In a particularly preferred embodiment, the present invention is R 3 This specification provides compounds of formula (I) described herein or pharmaceutically acceptable salts thereof, wherein the compound is chloro.

[0067] In one embodiment, the present invention is R 4 However, these are selected from C1-C6-alkyl, C1-C6-alkoxy, cyano, and halo-C1-C6-alkyl; R 6 However, selected from hydrogen and halo-C1-C6-alkyl, This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0068] In a preferred embodiment, the present invention is R 4 It is a halo-C1-C6-alkyl; R 6 That is hydrogen. This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0069] In a particularly preferred embodiment, the present invention is R 4 CF3 is; R 6 That is hydrogen. This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0070] In preferred embodiments, the present invention provides compounds of formula (I) as described herein or pharmaceutically acceptable salts thereof, wherein A is a 5- to 9-membered heteroaryl and the other substituents of formula (I) are as described in any other embodiment herein.

[0071] In a more preferred embodiment, the present invention provides compounds of formula (I) as described herein or pharmaceutically acceptable salts thereof, wherein A is a 5- to 9-membered heteroaryl selected from pyrimidinyl, pyrazolyl, pyridyl, pyrazinyl, imidazolyl, pyridadinyl, thiazolyl and 1H-pyrazolo[3,4-d]pyrimidine-6-yl, and the other substituents of formula (I) are as described in any other embodiment herein.

[0072] In particularly preferred embodiments, the present invention provides compounds of formula (I) as described herein or pharmaceutically acceptable salts thereof, wherein A is a 5- to 9-membered heteroaryl selected from pyrimidinyl, pyrazolyl, pyridyl, pyrazinyl, imidazolyl, pyridazinyl and 1H-pyrazolo[3,4-d]pyrimidine-6-yl, and the other substituents of formula (I) are as described in any other embodiment herein.

[0073] In one embodiment, the present invention is A is a 5- to 14-membered heteroaryl; R 5a However, these are selected from hydrogen, halogen, C1-C6-alkyl, C1-C6-alkoxy, amino-C1-C6-alkoxy, hydroxy-C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl-, C1-C6-alkoxy-C1-C6-alkoxy-, amino, C1-C6-alkyl-NH-, (C1-C6-alkyl)2N-, C1-C6-alkyl-NH-C(O)-, amino-C1-C6-alkyl-NH-, C1-C6-alkoxy-C1-C6-alkyl-NH-, carbamoyl-C1-C6-alkyl-NH-, carbamoyl and nitro; R 5b and R 5c Both are hydrogen. This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0074] In a preferred embodiment, the present invention is A is a 5- to 14-membered heteroaryl; R 5a However, these are selected from C1-C6-alkoxy, hydroxy-C1-C6-alkyl, C1-C6-alkyl-NH-, and amino; R 5b and R 5c Both are hydrogen. This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0075] In a particularly preferred embodiment, the present invention is A is pyridyl; R 5a However, selected from methoxy, hydroxymethyl, methylamino, and amino; R 5b and R 5c Both are hydrogen. This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0076] The present invention is R 7 This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein is a C1-C6 alkyl group.

[0077] In a particularly preferred embodiment, the present invention is R 7 This specification provides compounds of formula (I) described herein, wherein the compound is methyl, or pharmaceutically acceptable salts thereof.

[0078] In one embodiment, the present invention is R 1 and R 2 However, together with the atoms to which they are bonded, they form the base of formula (II) or (III). [ka] Forming; or R 1 is the basis [ka] And R 2 is hydrogen; R 3 However, these are halogens or C1-C6 alkyl groups; R 4 However, these are selected from C1-C6-alkyl, C1-C6-alkoxy, cyano, and halo-C1-C6-alkyl; R 5a However, these are selected from hydrogen, halogen, C1-C6-alkyl, C1-C6-alkoxy, amino-C1-C6-alkoxy, hydroxy-C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl-, C1-C6-alkoxy-C1-C6-alkoxy-, amino, C1-C6-alkyl-NH-, (C1-C6-alkyl)2N-, C1-C6-alkyl-NH-C(O)-, amino-C1-C6-alkyl-NH-, C1-C6-alkoxy-C1-C6-alkyl-NH-, carbamoyl-C1-C6-alkyl-NH-, carbamoyl and nitro; R 5b , R 5c, R 9a , R 9b , R 10b , R 11b and R 12b Each of them is hydrogen; R 6 However, it is selected from hydrogen and halo-C1-C6-alkyl; R 7 It is a C1-C6 alkyl group; R 8a However, hydrogen, C1-C6-alkyl, carbamoyl-C1-C6-alkyl, and group [ka] Selected from; R 8b However, hydrogen, hydroxy, oxo, hydroxy-C1-C6-alkyl and group [ka] Selected from; R 10a However, they are selected from amino and nitro; R 11a is the basis [ka] and; R 12a However, selected from hydrogen and hydroxyl; X is a carbonyl group and Y is a covalent group or a C1-C6 alkyldiyl group; or X is a C1-C6 alkyldiyl, and Y is a covalent bond; L 1 is C1-C6-alkyldiyl; L 2 is -O-; L 3 However, these are selected from covalent bonds and C1-C6-alkyldiyl; L 4 However, it is a carbonyl, A is a 5- to 14-membered heteroaryl; B, C, D, and G are each independently 3- to 14-membered heterocyclines; E is a 5- to 14-membered heteroaryl; F is selected from 5-14 member heteroaryls and 3-14 member heterocyclines. This specification provides compounds of formula (I) as described herein.

[0079] In a preferred embodiment, the present invention is R 1 and R 2 However, together with the atoms to which they are bonded, they form the base of formula (II) or (III). [ka] form; R 3 is a halogen; R 4 It is a halo-C1-C6-alkyl; R 5a However, these are selected from C1-C6-alkoxy, hydroxy-C1-C6-alkyl, C1-C6-alkyl-NH-, and amino; R 5b , R 5c and R 6 is hydrogen; R 7 It is a C1-C6 alkyl group; R 8a However, it is selected from hydrogen and C1-C6-alkyl; R 8b However, selected from hydrogen and hydroxyl; X is a carbonyl group; Y is a covalent bond or a C1-C6 alkyldiyl; A is a 5- to 14-membered heteroaryl; B and C are independently 3- to 14-membered heterocyclines. This specification provides compounds of formula (I) as described herein.

[0080] In a particularly preferred embodiment, the present invention is R 1 and R2 However, together with the atoms to which they are bonded, they form the base of formula (II) or (III). [ka] form; R 3 is chloro; R 4 CF3 is; R 5a However, selected from methoxy, hydroxymethyl, methylamino, and amino; R 5b , R 5c and R 6 is hydrogen; R 8a However, hydrogen and methyl are selected; R 8b However, selected from hydrogen and hydroxyl; X is a carbonyl group; Y is a covalent bond or -CH2-; A is pyridyl; B is piperazinyl; C is selected from piperidyl and pyrrolidinyl. This specification provides compounds of formula (I) as described herein.

[0081] In one embodiment, the present invention relates to a compound of formula (I) described herein, wherein the compound of formula (I) is

[0082] Example A1 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pyrimidine-2-yl-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid

[0083] Example A2 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(4-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid

[0084] Example A3 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(5-chloro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid

[0085] Example A4 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxypyrimidine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid

[0086] Example A5 5-[1-(5-aminopyrimidine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid

[0087] Example A6 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(2-methoxyethoxy)pyrimidine-2-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid

[0088] Example A7 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(2-methoxyethoxy)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid

[0089] Example A8 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(5-fluoropyrimidine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid

[0090] Example A9 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(1h-pyrazolo[3,4-d]pyrimidine-6-yl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid

[0091] Example A10 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[3-(trifluoromethyl)-1-[3-(trifluoromethyl)-2-pyridyl]pyrazole-4-yl]imidazole-2-carboxamide; formic acid

[0092] Example A11 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid

[0093] Example A12 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(4-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid

[0094] Example A13 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid

[0095] Example A14 5-[1-[4-(2-aminoethoxy)pyrimidine-2-yl]-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid

[0096] Example A15 5-[1-(4-aminopyrimidine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 2,2,2-trifluoroacetic acid

[0097] Example A16 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[4-(methylamino)pyrimidine-2-yl]-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; 2,2,2-trifluoroacetic acid

[0098] Example A17 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[4-(dimethylamino)pyrimidine-2-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 2,2,2-trifluoroacetic acid

[0099] Example A18 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[4-(dimethylamino)pyrimidine-2-yl]-5-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 2,2,2-trifluoroacetic acid

[0100] Example A19 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[4-(2-methoxyethylamino)pyrimidine-2-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 2,2,2-trifluoroacetic acid

[0101] Example A20 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pyrazine-2-yl-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; 2,2,2-trifluoroacetic acid

[0102] Example B1 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(dimethylamino)pyrimidine-2-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid

[0103] Example B2 5-[1-[5-(2-aminoethylamino)pyrimidine-2-yl]-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid

[0104] Example B3 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[6-(dimethylamino)pyridazin-3-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid

[0105] Example C1 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid

[0106] Example C2 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(2-methoxyethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid

[0107] Example C3 5-[1-[5-[(3-amino-3-oxopropyl)amino]-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid

[0108] Example C4 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid

[0109] Example C5 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(4-methoxypyrimidine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid

[0110] Example C6 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(2-methoxypyrimidine-4-yl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid

[0111] Example C7 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[[1-(piperidine-4-carbonyl)-4-piperidyl]methylcarbamoyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid

[0112] Example C8 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-[(3S)-morpholine-3-carbonyl]piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid;

[0113] Example C9 5-[1-(5-amino-2-pyridyl)-3-(difluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide

[0114] Example C10 5-[1-(5-amino-2-pyridyl)-3-methoxypyrazole-4-yl]-N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide

[0115] Example C11 5-[1-(5-amino-2-pyridyl)-3-cyanopyrazole-4-yl]-N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide

[0116] Example C12 5-[1-(5-amino-2-pyridyl)-3-methylpyrazole-4-yl]-N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide

[0117] Example C13 5-[1-(5-amino-2-pyridyl)-3-ethyl-pyrazole-4-yl]-N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 2,2,2-trifluoroacetic acid

[0118] Example C14 5-[1-(6-aminopyridazine-3-yl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 2,2,2-trifluoroacetic acid

[0119] Example C15 N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(4-methyl-1H-pyrazole-3-yl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; 2,2,2-trifluoroacetic acid

[0120] Example C16 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-[2-(3-hydroxypyrrolidine-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid

[0121] Example C17 N-[3-chloro-4-[4-[(2S,3S)-3-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide

[0122] Example D1 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid

[0123] Example D2 5-[1-[5-(2-aminoethylamino)pyrimidine-2-yl]-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid

[0124] Example D3 N-[3-chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid

[0125] Example D4 N-[3-chloro-4-[4-[(2S,3S)-3-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid;

[0126] Example D5 N-[3-chloro-4-[4-[2-(3-hydroxypyrrolidine-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid

[0127] Example D6 1-Methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-methyl-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]imidazole-2-carboxamide; Formic acid

[0128] Example D7 N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid arbthylamino)-2-py

[0129] Example E1 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[1-(2-methoxyethyl)pyrazole-4-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid

[0130] Example E2 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[1-(2-methoxyethyl)-5-methylpyrazole-4-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid

[0131] Example E3 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[1-(2-methoxyethyl)imidazole-4-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid

[0132] Example E4 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(1-methylimidazole-4-yl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid

[0133] Example E5 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-methyl-1H-pyrazole-4-yl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid

[0134] Example E6 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-methyl-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid

[0135] Example E7 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(4-methyl-1H-pyrazole-5-yl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; 2,2,2-trifluoroacetic acid

[0136] Example F1 N-[4-[4-[(1R,5S)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]-3-chlorophenyl]-1-methyl-5-[1-pyrimidine-2-yl-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid

[0137] Example F2 N-[3-chloro-4-[[(1R,5S)-3-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]-3-azabicyclo[3.1.0]hexane-6-yl]carbamoyl]phenyl]-1-methyl-5-[1-pyrimidine-2-yl-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid

[0138] Example F3 N-[3-chloro-4-[[(1S,5R)-3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexane-6-yl]carbamoyl]phenyl]-1-methyl-5-[1-pyrimidine-2-yl-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid

[0139] Example F4 N-[3-chloro-4-[4-[(3S,4R)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid

[0140] Example G1 N-[4-[4-[1-(azetidine-3-ylmethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chlorophenyl]-1-methyl-5-[1-pyrimidine-2-yl-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid

[0141] Example H1 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperazine-1-carbonyl)piperidine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid

[0142] Example H2 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-[3-(hydroxymethyl)piperazine-1-carbonyl]piperidine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid

[0143] Example I1 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-[(2-oxopiperazine-1-yl)methyl]piperidine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid

[0144] Example I2 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(1H-pyrazole-3-ylmethylcarbamoyl)phenyl]-1-methylimidazole-2-carboxamide

[0145] Example J1 N-[3-chloro-4-[4-[(2S)-4-hydroxypiperidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid; and

[0146] Example K1 The present invention provides a compound selected from N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(ethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; and formic acid.

[0147] In preferred embodiments, the present invention provides compounds of formula (I) described herein or pharmaceutically acceptable salts thereof, wherein the compounds of formula (I) are

[0148] Example A7 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(2-methoxyethoxy)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid

[0149] Example B3 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[6-(dimethylamino)pyridazin-3-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid

[0150] Example C1 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid

[0151] Example C16 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-[2-(3-hydroxypyrrolidine-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid

[0152] Example D1 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid

[0153] Example D3 N-[3-chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid

[0154] Example D7 N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid arbthylamino)-2-py

[0155] Example E6 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-methyl-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid; and

[0156] Example F4 The present invention provides a compound selected from N-[3-chloro-4-[4-[(3S,4R)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; and formic acid.

[0157] In one embodiment, the present invention provides pharmaceutically acceptable salts of the compounds of formula (I) described herein, particularly pharmaceutically acceptable salts selected from hydrochloride, fumarate, lactate (particularly derived from L-(+)-lactic acid), tartrate (particularly derived from L-(+)-tartaric acid), and trifluoroacetate. In further specific embodiments, the present invention provides the compounds of formula (I) described herein (i.e., as “free base” or “free acid,” respectively).

[0158] In some embodiments, compounds of formula (I) are isotope-labeled by replacing one or more atoms with atoms having different atomic masses or mass numbers. Such isotope-labeled (i.e., radioactively labeled) compounds of formula (I) are considered to be within the scope of this disclosure. Examples of isotopes that can be incorporated into compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, for example, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Examples include, but are not limited to, formula (I). Certain isotope-labeled compounds of formula (I), for example, those incorporating radioactive isotopes, are useful for studying the tissue distribution of drugs and / or substrates. Radioactive isotope tritium, i.e., 3 H and carbon-14, that is, 14 C is particularly useful for this purpose, considering its ease of incorporation and immediate detection means. For example, the compound of formula (I) can be enriched at 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99% of a given isotope.

[0159] Heavier isotopes, such as deuterium, 2 Substitution with H, etc., can lead to increased metabolic stability, potentially resulting in certain therapeutic benefits, such as a longer in vivo half-life or a reduced required dose.

[0160] 1 1 C, 18 F, 15 O and 13Substitution with positron-emitting isotopes such as 1N may be useful in positron emission tomography (PET) studies to examine the receptor occupancy of a substrate. Compounds of formula (I) labeled with isotope can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the examples below, using appropriate isotope-labeled reagents instead of previously used unlabeled reagents.

[0161] Manufacturing process In one embodiment, the present invention provides a process for producing a compound of formula (I) described herein.

[0162] In a further embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, when prepared according to the process described herein.

[0163] The compounds of formula (I) of the present invention can be prepared by sequential or convergent synthetic routes. The synthesis of the compounds of the present invention is shown in the following scheme. The skills required to carry out the reactions and the purification of the resulting products are known to those skilled in the art. The substituents and indicators used in the following description of the process have the significance set forth herein unless otherwise noted. More specifically, the compounds of formula (I) can be prepared by the methods shown below, the methods shown in the examples, or similar methods. Appropriate reaction conditions for each reaction step are known to those skilled in the art. For reaction conditions described in the literature that may affect the reactions described, see, for example, the following: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition, Richard C. Larock, John Wiley & Sons, New York, NY. 2018). The inventors have found it convenient to carry out the reactions in or without a solvent. The properties of the solvent used are not particularly limited, as long as it does not adversely affect the reagents involved in the reaction and can dissolve the reagents to at least some extent. The described reactions can occur over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. It is convenient to carry out the described reactions in a temperature range between -78°C and reflux temperature. The time required for the reaction can also vary considerably, depending on many factors, particularly the reaction temperature and the properties of the reagents. However, a period of 0.5 hours to several days will usually be sufficient to obtain the described intermediates and compounds. The reaction sequence is not limited to that shown in the scheme, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivity. The starting materials can be commercially available or prepared by methods similar to those shown below, by methods described in the references or examples cited herein, or by methods known in the art.

[0164] The following abbreviations are used herein: CN or MeCN acetonitrile BINAP 2,2'-bis(diphenylphosphin)-1,1'-binaphthalene CFU Colony Formation Unit d day DCM Dichloromethane DIPEA N,N-diisopropylethylamine HCl or EA ethyl acetate FA Formic Acid h or hr time HATU:1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC: High-Performance Liquid Chromatography HPLC-UV: High-performance liquid chromatography with ultraviolet detector IC50 Maximum Half-Dose Inhibitory Concentration IC90 90% inhibitory concentration NaBH3CN Sodium borocyanohydride PE (Petroleum Ether) PdCl2(DPPF)[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0) PG protecting group Precat pre-catalyst Prep-HPLC: Preparative High-Performance Liquid Chromatography rt room temperature sat saturation SEM 2-Methoxyethyl(trimethyl)silane FA Formic Acid TEMPO(2,2,6,6-tetramethylpiperidine-1-yl)oxyl TFA (Trifluoroacetic Acid) wt weight X-PHOS 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0165] Scheme 1 [ka] In the ceremony, P.G. 1 is a protecting group, for example, the Boc protecting group; R 3 and R 7 This is as described in this specification.

[0166] The compound of formula intermediate B1 can be prepared according to scheme 1. 3 When substituted 4-nitrobenzoic acid A is protected with, for example, (Boc)2O, compound B is obtained. Reduction of the nitro group of compound B can be achieved under various conditions, such as obtaining amine C using an ammonium chloride / iron system at room temperature. Coupling of D and amine C using a coupling agent such as HATU / DIPEA in DMSO yields the compound of formula intermediate B1.

[0167] Scheme 2 [ka] In the ceremony, P.G. 1 PG 2 and PG 3 is a protecting group, such as a Boc group; R 1a and R 2a Together with the nitrogen atom to which they are bonded, they form the base of formula (IV), (V), or (VI). [ka] Forming; or R 1a is the base [ka] and; R 2a These are selected from hydrogen and C1-C6-alkyl; R 3 , R 7 , R 8a , R 8b , R 11a , R 11b , B, C, F, X, Y and L 3 This is as described in this specification.

[0168] The compound of intermediate B can be prepared according to scheme 2. Hydrolysis of intermediate B1 yields acid E, which can be coupled with various amines using a coupling agent, such as HATU / DIPEA in a solvent like DMSO, to obtain intermediate B.

[0169] Scheme 3 [ka] In the ceremony, P.G. 1 PG 2 and PG 3 is a protecting group, such as a Boc group; R 1a and R 2a Together with the nitrogen atom to which they are bonded, they form the base of formula (IV), (V), or (VI). [ka] Forming; or R 1a is the base [ka] and; R 2a These are selected from hydrogen and C1-C6-alkyl; R 3 , R 4 , R 5a , R 5b , R 5c , R 6 , R 7 , R 8a , R 8b , R 11a , R 11b A, B, C, F, X, Y and L 3 This is as described in this specification.

[0170] Compounds of formula intermediates C and D can be prepared according to Scheme 3. The Suzuki coupling of intermediate B with pyrazole bronic ester can be achieved by obtaining intermediate C using conditions known in the art, for example, by using a palladium precatalyst and a phosphine ligand. This intermediate can be further coupled with a halogen-substituted heteroaryl by microwave heating in a solvent such as MeCN and in the presence of a base such as K2CO3, under conditions known in the art, to obtain intermediate D (route 1 in Scheme 3). Alternatively, this coupling can also be achieved by a well-known palladium or copper-catalyzed cross-coupling. Another method is to use a halogen-substituted heteroaryl in the presence of 2-(2,6-dimethylanilino)-2-oxoacetic acid and a copper(I) source such as copper(I) iodide and a suitable base such as potassium phosphate.

[0171] Alternatively, intermediate D can also be prepared by ChanLam-type coupling using the corresponding boronate-substituted heteroaryl in the presence of a copper(II) source and an oxidizing agent such as oxygen.

[0172] Intermediate D can also be prepared by the Suzuki coupling reaction of intermediate B with a heteroaryl-substituted pyrazole bronn ester (route 2 in scheme 3).

[0173] In some cases, it is used. [ka] It is not commercially available and must be synthesized. One possibility is R5 a-c The process begins with compounds containing precursors and modifies them, for example, by substitution with benzophenone imines. This provides a clear procedure for preparing intermediate Y3.

[0174] In some cases, it is used. [ka] R5 can be further modified a-c This may include precursors. One example is a protecting group such as a Boc or SEM group, which can be cleaved by various known methods. Another example is a nitro group, which can then be reduced by a generally known method such as palladium-catalyzed hydrogenation using zinc or iron powder in the presence of a strong acid such as HCl or a weak acid such as ammonium chloride, or by a procedure such as the "Bechamp" method. The resulting amino group can be further modified by methods such as alkylation, amidation, or reductive amination to finally obtain the desired R5 a-c It can generate.

[0175] Scheme 3a In some examples, [ka] It is not commercially available and can be prepared in various appropriate sequences by the following process. An example is shown in scheme 3a. [ka]

[0176] The corresponding "A" ring is halogenated by deprotonation using a suitable strong base such as LDA, and then halogenated with a suitable X electrophile. Subsequent conversion of the X substituent to the corresponding boronic acid or boronic acid ester by palladium-catalyzed borylation yields the A ring boronic acid. Then, [ka] The resulting boronate can be N-arylated, for example, using the Chan-Lam procedure with a copper(II) source under oxygen. Subsequently, borylation as described above yields the desired components for use in Scheme 3.

[0177] An explicit example of such a process is given by the intermediate Y2.

[0178] It goes without saying that the method described in Scheme 3a can also be used for the transformation of Scheme 3.

[0179] In some examples, the order of the arylation reaction in Scheme 3 and the saponification and / or amidation reaction in Scheme 2 could be reversed.

[0180] Scheme 4 [ka] In the ceremony, P.G. 1 PG 2 and PG 3 is a protecting group, such as a Boc group; R 1a and R 2a Together with the nitrogen atom to which they are bonded, they form the base of formula (IV), (V), or (VI). [ka] Forming; or R 1a is the base [ka] and; R 2a These are selected from hydrogen and C1-C6-alkyl; R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 5c , R 6 , R 7 , R 8a , R 8b , R 11a , R 11b A, B, C, F, X, Y and L 3 This is as described in this specification.

[0181] The compounds of formula examples A to L can be prepared according to scheme 4 by removing the protecting group in intermediate D.

[0182] Use of the compound of the present invention As shown in the experimental section, the compound of formula (I) and its pharmaceutically acceptable salts possess valuable pharmacological properties for the treatment or prevention of infections and diseases caused by pathogens, particularly bacteria, more specifically by Acinetobacter species, and most specifically by Acinetobacter baumannii, in particular bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections.

[0183] The compounds of formula (I) and their pharmaceutically acceptable salts are active as antibiotics, particularly as antibiotics against Acinetobacter species, more specifically as antibiotics against Acinetobacter baumanni, and most specifically as pathogen-specific antibiotics against Acinetobacter baumanni.

[0184] Compounds of formula (I) and their pharmaceutically acceptable salts may be used as antibiotics, i.e., as appropriate antimicrobial agents in the treatment and prevention of bacterial infections, particularly in the treatment and prevention of bacterial infections caused by Acinetobacter species, and more specifically in the treatment and prevention of bacterial infections caused by Acinetobacter baumannii.

[0185] The compounds of the present invention may be used alone or in combination with other drugs for the treatment or prevention of infections and diseases caused by pathogens, particularly bacteria, more specifically by Acinetobacter species, most specifically by Acinetobacter baumanni, in particular bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections.

[0186] In one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof for use as a therapeutically active substance.

[0187] In a further embodiment, the present invention provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, for use as antibiotics.

[0188] In a further embodiment, the present invention provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, for use in the treatment or prevention of hospital-acquired infections and diseases resulting therefrom.

[0189] In certain embodiments, the hospital-acquired infection and the resulting illness are selected from bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections, or a combination thereof.

[0190] In a further embodiment, the present invention provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, for use in the treatment or prevention of infections caused by Gram-negative bacteria and diseases resulting therefrom.

[0191] In certain embodiments, the infections and resulting diseases caused by Gram-negative bacteria are selected from bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections, or a combination thereof.

[0192] In a further embodiment, the present invention provides compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, for use in the treatment or prevention of infections and diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof.

[0193] In a further embodiment, the present invention provides a method for the treatment or prevention of infections and diseases resulting from infections caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli or combinations thereof, comprising administering a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof to a mammal.

[0194] In a further embodiment, the present invention provides for the use of a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof as an antibiotic.

[0195] In a further embodiment, the present invention provides the use of compounds of formula (I) described herein or pharmaceutically acceptable salts thereof for the treatment or prevention of infections and diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli or combinations thereof.

[0196] In a further embodiment, the present invention provides the use of compounds of formula (I) described herein or pharmaceutically acceptable salts thereof for the preparation of pharmaceuticals useful for the treatment or prevention of infections and diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli or combinations thereof.

[0197] In certain embodiments, the infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof, are selected from bacteremia, pneumonia, meningitis, urinary tract infections and wound infections, or combinations thereof.

[0198] In a further embodiment, the present invention provides compounds of formula (I) defined above, or pharmaceutically acceptable salts thereof, for use in the treatment or prevention of infections and diseases caused by pathogens, particularly bacteria, more specifically Acinetobacter species, most specifically Acinetobacter baumanni, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0199] In a further embodiment, the present invention provides a method for the treatment or prevention of infections and diseases caused by pathogens, particularly bacteria, more specifically Acinetobacter species, most specifically Acinetobacter baumanni, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections, comprising administering a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof to a mammal.

[0200] In a further embodiment, the present invention provides the use of compounds of formula (I) defined above, or pharmaceutically acceptable salts thereof, for the treatment or prevention of infections and diseases caused by pathogens, particularly bacteria, more specifically Acinetobacter species, most specifically Acinetobacter baumanni, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0201] In a further embodiment, the present invention provides the use of compounds of formula (I) defined above, or pharmaceutically acceptable salts thereof, for the preparation of pharmaceuticals for the treatment or prevention of infections and diseases caused by pathogens, particularly bacteria, more specifically Acinetobacter species, most specifically Acinetobacter baumanni, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections. Such pharmaceuticals comprise compounds of formula (I) defined above or pharmaceutically acceptable salts thereof.

[0202] Pharmaceutical composition and administration In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable additives. Exemplary pharmaceutical compositions are described in Examples 1 to 4.

[0203] In a further embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, for the treatment or prevention of infections and diseases caused by pathogens, particularly bacteria, more specifically Acinetobacter species, most specifically Acinetobacter baumanni, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0204] Compounds of formula (I) and their pharmaceutically acceptable salts may be used as pharmaceuticals (e.g., in the form of pharmaceutical formulations). Pharmaceutical formulations may be administered into the body orally (e.g., in the form of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g., in the form of nasal sprays), or rectally (e.g., in the form of suppositories). However, administration may be carried out parenterally, for example, intramuscularly or intravenously (e.g., in the form of injections or infusions).

[0205] Compounds of formula (I) and their pharmaceutically acceptable salts may be treated with pharmaceutically inert inorganic or organic additives for the manufacture of tablets, coated tablets, dragees, and hard gelatin capsules. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc., may be used as such additives for tablets, dragees, and hard gelatin capsules, for example.

[0206] Suitable additives for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid substances, and liquid polyols.

[0207] Suitable additives for the production of solutions and syrups include, for example, water, polyols, sucrose, invert sugar, and glucose.

[0208] Suitable additives for injection solutions include, for example, water, alcohol, polyols, glycerol, and vegetable oils.

[0209] Suitable additives for suppositories include, for example, natural oils or hydrogenated oils, waxes, fats, and semi-solid or liquid polyols.

[0210] Furthermore, pharmaceutical preparations may contain preservatives, solubilizers, viscosity enhancers, stabilizers, humectants, emulsifiers, sweeteners, colorants, flavorings, salts to alter osmotic pressure, buffers, masking agents, or antioxidants. They may also contain other therapeutically useful substances.

[0211] Dosages can vary widely and, of course, to suit the individual requirements of each specific case. Generally, for oral administration, a daily dose of about 0.1 mg to 20 mg / kg body weight, preferably about 0.5 mg to 4 mg / kg body weight (e.g., about 300 mg / person), may be appropriately divided into 1 to 3 individual doses, each consisting of, for example, the same amount. However, it is clear that the upper limits given herein may be exceeded where indicated.

[0212] Co-administration of the compound of formula (I) with other drugs The compound of formula (I) or a salt thereof, or any compound disclosed herein or a pharmaceutically acceptable salt thereof, may be used alone or in combination with other agents for treatment. For example, the second agent in a combination pharmaceutical formulation or administration regimen may have complementary activity to the compound of formula (I) so as not to adversely affect each other. The compounds may be administered together or separately in a single pharmaceutical composition. In one embodiment, the compound or a pharmaceutically acceptable salt may be co-administered with an antibiotic, in particular an antibiotic for the treatment or prevention of infections and diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof.

[0213] The term "co-administration" refers to the simultaneous administration, or any separate, sequential administration, of one or more further active pharmaceutical ingredients, including the compound of formula (I) or a salt thereof, or the compounds disclosed herein or pharmaceutically acceptable salts thereof, as well as antibiotic preparations. If the administrations are not simultaneous, the compounds are administered at close intervals. Furthermore, it is not important whether the compounds are administered in the same dosage form; for example, one compound may be administered intravenously and another orally.

[0214] Typically, antimicrobial agents can be co-administered. Specific examples of such agents are carbapenems (meropenem), fluoroquinolones (ciprofloxacin), aminoglycosides (amikacin), tetracyclines (tigecycline), colistin, sulbactam, sulbactam + durlobactam, cefiderocol (fetroja), macrocyclic peptides, and macrolides (erythromycin), as illustrated in International Publication Nos. 2017072062, 2019185572, and 2019206853, respectively.

[0215] In one embodiment, the present invention provides a pharmaceutical composition according to this specification, further comprising a further therapeutic agent.

[0216] In one embodiment, the present invention provides a pharmaceutically acceptable combination comprising a compound of formula (I) described herein and an additional therapeutic agent.

[0217] In one embodiment, the additional therapeutic agent is an antibiotic preparation.

[0218] In one embodiment, the additional therapeutic agent is an antibiotic preparation useful for treating or preventing infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof.

[0219] In one embodiment, the additional therapeutic agent is an antibiotic preparation selected from carbapenems (meropenem), fluoroquinolones (ciprofloxacin), aminoglycosides (amikacin), tetracyclines (tigecycline), colistin, sulbactam, sulbactam + durlobactam, cefiderocol (fetroja), macrocyclic peptides, and macrolides (erythromycin), as exemplified in International Publication Nos. 2017072062, 2019185572, and 2019206853.

[0220] Examples The present invention will be better understood by referring to the following embodiments. However, the claims should not be construed as being limited to the scope of these embodiments.

[0221] If the preparation is obtained as a mixture of enantiomers, the pure enantiomers can be separated by the methods described herein or by methods known to those skilled in the art, such as chiral chromatography (e.g., chiral SFC) or crystallization.

[0222] Unless otherwise specified, all reaction examples and intermediates were prepared under an argon atmosphere.

[0223] Intermediate A1 tert-butyl(2-chloropyrimidine-5-yl)carbamate 25 mL of microwave vial was mixed with 2-chloropyrimidine-5-amine (250 mg, 1.93 mmol) in THF (10 mL), Boc2O (1.26 g, 1.34 mL, 5.79 mmol), DIPEA (748 mg, 1.01 mL, 5.79 mmol), and DMAP (23.6 mg, 193 μmol) in THF (10 mL). The vial was capped and heated under microwave at 50°C for 2 hours. The unpurified reaction mixture was concentrated under reduced pressure. The unpurified substance was purified by flash chromatography to obtain tert-butyl(2-chloropyrimidine-5-yl)carbamate (440 mg). MS [M+H] + :230.0.

[0224] Intermediate A2.1 2-Chloro-5-(2-methoxyethoxy)pyrimidine In a 50 mL round-bottom flask, 2-chloropyrimidine-5-ol (200 mg, 1.53 mmol), 1-bromo-2-methoxyethane (319 mg, 2.3 mmol), and K2CO3 (318 mg, 2.3 mmol) were mixed with DMF (5 mL) to obtain a light brown solution. The reaction mixture was heated to 50 °C and stirred for 3 hours. The reaction mixture was poured into 20 mL of H2O and extracted with Depositphotos (25 mL x 3). The organic layers were combined, washed with saturated NaCl (25 mL x 3), dried over Na2SO4, and concentrated under reduced pressure to obtain 2-chloro-5-(2-methoxyethoxy)pyrimidine (280 mg). MS [M+H] + :189.4.

[0225] The following intermediates were prepared in the same manner as intermediate B4.1. [Table 1]

[0226] Intermediate A3 6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-pyrazolo[3,4-d]pyrimidine 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (200 mg, 1.29 mmol), DHP (142 mg, 154 μl, 1.68 mmol), and p-TsOH (24.6 mg, 129 μmol) in THF (10 mL) were added to a 25 mL microwave vial. The vial was capped and heated at 60°C for 1 hour. The unpurified reaction mixture was concentrated under reduced pressure. The unpurified substance was purified by flash chromatography (silica gel, 12 g, 0%~5% MeOH in DCM) to obtain 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-pyrazolo[3,4-d]pyrimidine (200 mg). MS [M+H] + :238.8.

[0227] Intermediate A4.1 4-Iodo-1-(2-methoxyethyl)pyrazole 4-iodo-1H-pyrazole (500 mg, 2.58 mmol), 1-bromo-2-methoxyethane (537 mg, 3.87 mmol), and K2CO3 (712 mg, 5.16 mmol) in MeCN (10 mL) were added to a 25 mL microwave vial. The vial was capped and heated at 100°C for 2 hours. The reaction mixture was passed through fiberglass paper and filtered. The filtrate was concentrated under reduced pressure. The unpurified material was purified by flash chromatography to obtain 4-iodo-1-(2-methoxyethyl)-pyrazole (459 mg). MS [M+H] + :252.9.

[0228] The following intermediates were prepared in the same manner as intermediate A4.1. [Table 2]

[0229] Intermediate A5 2-(2-chloropyrimidine-4-yl)oxyethanol To a solution of 2,4-dichloropyrimidine (1 g, 6.7 mmol) in MeCN (33.6 mL), tert-butyl(2-hydroxyethyl) carbamate (1.1 g, 6.7 mmol) and cesium carbonate (3.3 g, 10.1 mmol) were added, and the reaction mixture was stirred at 80°C for 48 hours. After cooling to room temperature, saturated NaHCO3 was added, and the product was extracted with phenylethylamine. The organic extract was dried, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to obtain the labeled product as a pale yellow oily substance of 283 mg. MS [M+H] + :274.1.

[0230] Intermediate A6.1 tert-butyl N-tert-butoxycarbonyl-N-(2-chloropyrimidine-4-yl)carbamate 2-Chloropyrimidine-4-amine (500 mg, 3.9 mmol), di-tert-butyl dicarbonate (1.0 g, 1.1 mL, 4.6 mmol), and N,N-dimethylpyridine-4-amine (47.2 mg, 386 μmol) were stirred in acetonitrile (15.4 mL) at room temperature for 3 hours. After completion, silica gel (100-200 mesh) was added to absorb the substances, and the sample was purified by flash chromatography to obtain the marked compound as a colorless oily substance of 505 mg. MS [M-Boc- t [AD+H] + :179.3.

[0231] The following intermediates were prepared in the same manner as intermediate A6. [Table 3]

[0232] Intermediate A7 9H-Fluoren-9-ylmethyl N-(3-amino-3-oxopropyl)-N-(6-bromo-3-pyridyl)carbamate Step 1: 6-Bromo-N-[3-[tert-butyl(dimethyl)silyl]oxypropyl]pyridine-3-amine (6-bromo-3-pyridyl)amine (2.4 g, 14.2 mmol), 3-[tert-butyl(dimethyl)silyl]oxypropionaldehyde (2.7 g, 14.2 mol), and acetic acid (170.1 mg, 162.1 uL, 2.8 mmol) were dissolved in dichloromethane (50 mL). Sodium triacetoxyborohydride (3.6 g, 17.0 mmol) was added in fractions to this solution. After addition, the mixture was stirred at room temperature for 1 hour. The mixture was poured into 100 mL of water and extracted with DCM (50 mL x 2). The extracts were combined, washed with saline solution, and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography to obtain the marked compound as 3.0 g of pale yellow solid. MS [M+H] + :345.6.

[0233] Step 2: 9H-Fluoren-9-ylmethyl N-(6-bromo-3-pyridyl)-N-(3-hydroxypropyl)carbamate (6-bromo-3-pyridyl)-[3-[tert-butyl(dimethyl)silyl]oxypropyl]amine (3.0 g, 8.7 mmol) was dissolved in 5 mL of toluene, and this solution was added dropwise at 0°C to a solution of 9H-fluoren-9-ylmethyl chlorocarboxylic acid (2.2 g, 8.7 mmol) in ultra-dried anhydrous toluene (20 mL). After addition, the mixture was stirred at 0°C for 1 hour, then at room temperature for another 1 hour. A yellow precipitate was formed. The mixture was stirred overnight. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography to obtain the marked compound as 2.0 g of a pale yellow oil. MS [M+H] + :453.1.

[0234] Step 3: 3-[(6-bromo-3-pyridyl)-(9H-fluoren-9-ylmethoxycarbonyl)amino]propanoic acid Iodobenzene diacetate (703.4 mg, 2.2 mmol), TEMPO (62.4 mg, 0.4 mmol), and N-(6-bromo-3-pyridyl)-N-(3-hydroxypropyl)carbamate 9H-fluoren-9-yl methyl ester (900 mg, 2.0 mmol) were mixed in a reaction vessel, and acetonitrile (11 mL) and water (6 mL) were added. After stirring the reaction mixture for 3 hours, another batch of iodobenzene diacetate (703.4 mg, 2.2 mmol) was added. Stirring was continued overnight (approximately 18 hours). The solvent was removed under reduced pressure, and the residue was purified by flash chromatography to obtain the marked compound as a pale yellow foam, 778 mg. MS [M+H] + :467.1.

[0235] Step 4: 9H-Fluoren-9-ylmethyl N-(3-amino-3-oxo-propyl)-N-(6-bromo-3-pyridyl)carbamate 3-[(6-bromo-3-pyridyl)-(9H-fluoren-9-ylmethoxycarbonyl)amino]propionic acid (142 mg, 0.3 mmol), ammonium chloride (32.5 mg, 0.6 mmol), and DIEA (196.4 mg, 265.4 μL, 1.5 mmol) were stirred in N,N-dimethylacetamide (5 mL) for 1 minute. HATU (138.6 mg, 0.4 mmol) was added to the mixture, and the resulting solution was stirred at 25°C for 1 hour. The mixture was poured into 100 mL of water and extracted with ELISA (50 mL x 3). The extracts were combined, washed with 50 mL of saline solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography to obtain the marked compound as a pale yellow oily substance of 114 mg. MS [M+H] + :466.1.

[0236] Intermediate A8 Benzyl 2-[3-oxo-4-(4-piperidylmethyl)piperazine-1-yl]acetate Step 1: tert-butyl 4-[[4-(2-benzyloxy-2-oxo-ethyl)-2-oxo-piperazine-1-yl]methyl]piperidine-1-carboxylate 3-Ketopiperazine-1-carboxylate benzyl ester (1.0 g, 4.3 mmol) was dissolved in super-dried N,N-dimethylformamide (28.5 mL). The solution was cooled to 0°C. NaH (204.9 mg, 5.1 mmol) was added gradually to this solution. After addition, the mixture was stirred at the same temperature for 1 hour. Then, the ice bath was removed and stirring was continued at room temperature for 1 hour. Next, 4-(iodomethyl)piperidine-1-carboxylate tert-butyl ester (1.7 g, 5.1 mmol) was added all at once. Stirring was continued at room temperature for 18 hours. The mixture was poured into 100 mL of water and extracted with ELISA (50 mL x 3). The extracts were combined, washed with 50 mL of saline solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography to obtain the marked compound as 854 mg of a pale yellow oil. MS [M+H] + :454.2.

[0237] Step 2: Benzyl 2-[3-oxo-4-(4-piperidylmethyl)piperazine-1-yl]acetate 4-[(1-tert-butoxycarbonyl-4-piperidyl)methyl]-3-ketopiperazine-1-carboxylate benzyl ester (850 mg, 2.0 mmol) was dissolved in dichloromethane (4 mL) and 1 mL of TFA. The solvent was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and the residue was used in the next step without further purification. A pale yellow oily substance, 600 mg. MS [M+H] + :332.4.

[0238] Intermediate A9.1 4-Methoxy-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyrazole-1-yl]pyrimidine Step 1: 2-[4-bromo-3-(trifluoromethyl)pyrazole-1-yl]-4-methoxypyrimidine To a solution of 2-chloro-4-methoxypyrimidine (134 mg, 930 μmol) and 4-bromo-3-(trifluoromethyl)-1H-pyrazole (200 mg, 930 μmol) in MeCN (4.7 mL), N-ethyl-N-isopropylpropan-2-amine (180 mg, 243 μL, 1.4 mmol) and cesium carbonate (455 mg, 1.4 mmol) were added. After heating at 100 °C for 3 hours, the mixture was cooled to room temperature. Silica gel with a mesh size of 100-200 was added to absorb the substance, and the sample was purified by flash chromatography to obtain 300 mg of white powder. MS [M+H] + :322.9.

[0239] Step 2: 4-Methoxy-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyrazole-1-yl]pyrimidine 2-(4-bromo-3-(trifluoromethyl)pyrazole-1-yl)-4-methoxypyrimidine (300 mg, 929 μmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (283 mg, 1.11 mmol), a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (37.9 mg, 46.4 μmol), potassium acetate (273 mg, 2.8 mmol), and anhydrous DMSO (4.6 mL) were placed in a microwave tube. The container was sealed, evacuated, and filled with nitrogen five times. The mixture was heated at 80°C for 18 hours. Then the temperature was raised to 100°C and stirring was continued for 18 hours. The reaction mixture was cooled to room temperature and poured into 100 mL of water. The aqueous phase was extracted with toluene (60 mL x 4). The organic layers were combined, washed with saline solution (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography to obtain 58 mg of the labeled compound as a white powder. MS [M+H] + :370.5.

[0240] The following intermediates were prepared in the same manner as intermediate A9.1. [Table 4]

[0241] Intermediate A9.3 6-[3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-yl]pyridine-3-amine Step 1: 2-[4-bromo-3-(difluoromethyl)pyrazole-1-yl]-5-nitropyridine Sodium hydride (243.7 mg, 6.09 mmol) was added at 0°C to a solution of 4-bromo-3-(difluoromethyl)-1H-pyrazole (800.0 mg, 4.06 mmol) in DMF (20.0 mL). The mixture was stirred at 0°C for 30 minutes. Then, 2-chloro-5-nitropyridine (772.7 mg, 4.87 mmol) was added, and the mixture was stirred at 0°C for 1 hour. The mixture was poured into water (50.0 mL), filtered, and the filter cake was washed with water (20.0 mL x 3) and dried under reduced pressure to obtain 2-[4-bromo-3-(difluoromethyl)pyrazole-1-yl]-5-nitropyridine (1.0 g, 3.13 mmol, yield 77%) as a brown solid. MS[M+2+H] + :320.9.

[0242] Step 2: 6-[4-bromo-3-(difluoromethyl)pyrazole-1-yl]pyridine-3-amine Iron (1.7 g, 31.34 mmol) was added to a solution of 2-[4-bromo-3-(difluoromethyl)pyrazole-1-yl]-5-nitropyridine (1.0 g, 3.13 mmol) in acetic acid (50.0 mL). The mixture was stirred at 20°C for 3 hours. The reaction mixture was filtered, and the filtration cake was washed with DCM (20.0 mL). The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography to obtain 6-[4-bromo-3-(difluoromethyl)pyrazole-1-yl]pyridine-3-amine (700.0 mg, 2.42 mmol) as a brown solid. MS[M+2+H] + :290.9.

[0243] Step 3: 6-[3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-yl]pyridine-3-amine To a solution of 6-[4-bromo-3-(difluoromethyl)pyrazole-1-yl]pyridine-3-amine (300.0 mg, 1.04 mmol) and bis(pinacorato)diborone (289.9 mg, 1.14 mmol) in 1,4-dioxane (10.0 mL), potassium acetate (203.7 mg, 2.08 mmol) and Pd(dppf)Cl2 (113.8 mg, 0.17 mmol) were added under argon in a glove box. The mixture was stirred at 100°C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by flash column (with 0.1% FA as an additive) and dried by freeze-drying to obtain 6-[3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-yl]pyridine-3-amine (150.0 mg, 0.45 mmol) as a yellow solid. MS[M+H] + :337.1.

[0244] Intermediate A9.4 tert-butyl N-[6-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-yl]-3-pyridyl]carbamate Step 1: 2-(3-methoxypyrazole-1-yl)-5-nitropyridine Sodium hydride (550.5 mg, 13.76 mmol) was added at 0°C to a solution of 3-methoxy-1H-pyrazole (0.9 g, 9.17 mmol) in DMF (20.0 mL). The mixture was stirred at 0°C for 30 minutes. 2-chloro-5-nitropyridine (1.7 g, 11.01 mmol) was added, and the mixture was stirred at 0°C for 1 hour. The reaction mixture was poured into water (50.0 mL), filtered, the filter cake was washed with water (20.0 mL), and then dried under reduced pressure to obtain 2-(3-methoxypyrazole-1-yl)-5-nitropyridine (1.8 g, 8.18 mmol) as a yellow solid. MS[M+H]+ :220.9.

[0245] Step 2: 2-(4-bromo-3-methoxypyrazole-1-yl)-5-nitropyridine N-bromosuccinimide (0.8 g, 4.49 mmol) was added to a solution of 2-(3-methoxypyrazole-1-yl)-5-nitropyridine (0.8 g, 3.63 mmol) in DCM (1.0 mL). The mixture was stirred at 20°C for 12 hours. The reaction mixture was poured into an aqueous solution of Na2S2O3 (10.0 mL) and extracted with EA (100.0 mL × 3). The organic matter was washed with water (50.0 mL × 2), followed by saturated salt solution (50.0 mL). The organic matter was then separated, dried, concentrated and dried to obtain 2-(4-bromo-3-methoxypyrazole-1-yl)-5-nitropyridine (1.0 g, 3.34 mmol) as a yellow solid. MS[M+2+H] + :300.9.

[0246] Step 3: 6-(4-bromo-3-methoxypyrazole-1-yl)pyridine-3-amine Iron (1.9 g, 33.44 mmol) was added to a solution of 2-(4-bromo-3-methoxypyrazole-1-yl)-5-nitropyridine (1.0 g, 3.34 mmol) in acetic acid (30.0 mL). The mixture was stirred at 20°C for 12 hours. The reaction mixture was filtered, the filter cake was washed with DCM (20.0 mL x 3), and the filtrate was concentrated under reduced pressure and purified with silica gel to obtain 6-(4-bromo-3-methoxypyrazole-1-yl)pyridine-3-amine (800.0 mg, 2.97 mmol) as a brown solid. MS[M+H] + :268.9.

[0247] Step 4: tert-butyl N-[6-(4-bromo-3-methoxypyrazole-1-yl)-3-pyridyl]carbamate Di-t-butyl dicarbonate (567.7 mg, 2.60 mmol) was added to the solution of the obtained 6-(4-bromo-3-methoxypyrazole-1-yl)pyridin-3-amine (350.0 mg, 1.30 mmol) in methanol (30.0 mL). The mixture was stirred at 20°C for 12 hours. The reaction mixture was subjected to a filter, the filter cake was washed with DCM (20.0 mL x 3), and the filtrate was concentrated under reduced pressure and purified by silica gel column to obtain tert-butyl N-[6-(4-bromo-3-methoxypyrazole-1-yl)-3-pyridyl]carbamate (450.0 mg, 1.22 mmol) as a brown solid. MS[M+H] + :369.2.

[0248] Step 5: tert-butyl N-[6-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-yl]-3-pyridyl]carbamate To a solution of tert-butyl N-[6-(4-bromo-3-methoxypyrazole-1-yl)-3-pyridyl]carbamate (450.0 mg, 1.22 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (340.4 mg, 1.34 mmol) in 1,4-dioxane (10.0 mL), potassium acetate (239.2 mg, 2.44 mmol) and Pd(dppf)Cl2 (133.6 mg, 0.18 mmol) were added under argon in a glove box. The mixture was stirred at 100°C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Purification by flash column (with 0.1% FA as an additive) yielded tert-butyl N-[6-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-yl]-3-pyridyl]carbamate (150.0 mg, 0.36 mmol) as a yellow solid. MS[M+H] + :417.3.

[0249] Intermediate A9.5 tert-butyl N-[6-[3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-yl]-3-pyridyl]carbamate Step 1: 4-bromo-1-(5-nitro-2-pyridyl)pyrazole-3-carbonitrile To a solution of compound 4-bromo-1H-pyrazole-3-carbonitrile (1.0 g, 5.81 mmol) in DMF (8.0 mL), N,N-diisopropylethylamine (2.0 mL, 11.63 mmol) and 2-chloro-5-nitropyridine (0.7 mL, 6.40 mmol) were added. The mixture was stirred under N2 at 80°C for 12 hours. The reaction was stopped with water (10 mL), the residue was filtered, and concentrated under reduced pressure to obtain 4-bromo-1-(5-nitro-2-pyridyl)pyrazole-3-carbonitrile (1.2 g, 4.08 mmol) as a brown solid.

[0250] Step 2: 1-(5-amino-2-pyridyl)-4-bromopyrazole-3-carbonitrile To a solution of 4-bromo-1-(5-nitro-2-pyridyl)pyrazole-3-carbonitrile (1.5 g, 5.10 mmol) in acetic acid (20.0 mL), Fe (1.4 g, 25.50 mmol) was added. The mixture was stirred under N2 at 25°C for 6 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The unpurified product was purified by chromatographic column flushing and concentrated to obtain 1-(5-amino-2-pyridyl)-4-bromo-pyrazole-3-carbonitrile (0.5 g, 1.89 mmol) as a white solid. MS[M+H] + :263.9.

[0251] Step 3: tert-butyl N-[6-(4-bromo-3-cyanopyrazole-1-yl)-3-pyridyl]carbamate Di-t-butyl dicarbonate (619.8 mg, 2.80 mmol) was added to a solution of 1-(5-amino-2-pyridyl)-4-bromo-pyrazole-3-carbonitrile (0.5 g, 1.89 mmol) in DMF (5.0 mL). The mixture was stirred under N2 at 25°C for 12 hours, and water (25 mL) was added to the reaction mixture. Extraction was performed with RINKAN (20 mL x 3) ethyl acetate. The combined organic layer was washed with saline (10 mL), dried over Na2SO4, and concentrated under reduced pressure to remove the solvent. The unpurified product was then purified by chromatographic column flushing and concentrated to obtain tert-butyl N-[6-(4-bromo-3-cyanopyrazole-1-yl)-3-pyridyl]carbamate (0.5 g, 1.37 mmol) as a yellow oil. MS[M+H] + :366.

[0252] Step 4: [1-[5-(tert-butoxycarbonylamino)-2-pyridyl]-3-cyanopyrazole-4-yl]boronic acid A mixture of the compounds tert-butyl N-[6-(4-bromo-3-cyanopyrazole-1-yl)-3-pyridyl]carbamate (0.5 g, 1.37 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (418.4 mg, 1.65 mmol), potassium acetate (0.2 mL, 2.75 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (112.0 mg, 0.14 mmol) was prepared in a flask. 1,4-dioxane (5.0 mL) was added to the mixture by syringe. The mixture was stirred under N2 at 90°C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The product was purified by reverse-phase chromatography (with 0.1% FA as an additive) and dried to obtain [1-[5-(tert-butoxycarbonylamino)-2-pyridyl]-3-cyanopyrazole-4-yl]boronic acid (268.0 mg, 0.81 mmol) as a white solid. MS[M+H] + :330.1.

[0253] Intermediate A9.6 tert-butyl N-[6-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-yl]-3-pyridyl]carbamate Step 1: 2-(4-bromo-3-methylpyrazole-1-yl)-5-nitropyridine To a solution of 4-bromo-3-methyl-1H-pyrazole (1.0 g, 6.21 mmol) in DMF (8.0 mL), NaH (871.3 mg, 9.32 mmol) and 2-chloro-5-nitropyridine (0.7 mL, 6.83 mmol) were added at 0°C. The mixture was stirred under N2 at 25°C for 3 hours. The reaction was stopped with water (10 mL), filtered through Celite, washed with water, and concentrated to obtain the unpurified product 2-(3-bromopyrazole-1-yl)-5-nitropyridine (1.5 g, 5.58 mmol) as a yellow solid. MS[M+H] + :282.9.

[0254] Step 2: 6-(4-bromo-3-methylpyrazole-1-yl)pyridine-3-amine To a solution of 2-(3-bromopyrazole-1-yl)-5-nitropyridine (1.6 g, 5.83 mmol) in acetic acid (20.0 mL), Fe (2.6 g, 46.63 mmol) was added. The mixture was stirred under N2 at 25°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The unpurified product was purified by chromatographic column flushing and concentrated to obtain 6-(4-bromo-3-methylpyrazole-1-yl)pyridine-3-amine (0.6 g, 2.37 mmol) as a yellow solid. MS[M+H] + :254.9.

[0255] Step 3: tert-butyl N-[6-(4-bromo-3-methylpyrazole-1-yl)-3-pyridyl]carbamate To the solution of the obtained 6-(4-bromo-3-methylpyrazole-1-yl)pyridine-3-amine (250.0 mg, 0.99 mmol) in methanol (0.5 mL), di-t-butyl dicarbonate (0.3 mL, 1.48 mmol) was added. The mixture was stirred under N2 at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent and obtain the unpurified product tert-butyl N-[6-(4-bromo-3-methylpyrazole-1-yl)-3-pyridyl]carbamate (280.0 mg, 0.79 mmol). MS[M+H] + :353.0.

[0256] Step 4: tert-butyl N-[6-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-yl]-3-pyridyl]carbamate A mixture of tert-butyl N-[6-(4-bromo-3-methylpyrazole-1-yl)-3-pyridyl]carbamate (250.0 mg, 0.71 mmol), bis(pinacolato)diborone (179.7 mg, 0.71 mmol), potassium acetate (0.09 mL, 1.42 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (57.8 mg, 0.07 mmol) was placed in a flask. 1,4-dioxane (5.0 mL) was added to the mixture by syringe. The flask was degassed and purged four times with N2 gas. The mixture was stirred under N2 at 90°C for 2 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the product was then purified by reverse-phase chromatography (with 0.1% FA as an additive). After drying, tert-butyl N-[6-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-yl]-3-pyridyl]carbamate (120.0 mg, 0.30 mmol) was obtained as a white solid. MS[M+H] + :317.1.

[0257] Intermediate A9.7 tert-butyl N-[6-[3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-yl]-3-pyridyl]carbamate Step 1: 2-(3-bromopyrazole-1-yl)-5-nitropyridine To a solution of 3-bromo-1H-pyrazole (1.0 g, 6.8 mmol) in THF (20.0 mL), 60% sodium hydride (299.3 mg, 7.48 mmol) in oil was slowly added at 0°C. After the addition, the reaction mixture was stirred at 0°C for 0.5 hours. 2-chloro-5-nitropyridine (1.2 g, 7.48 mmol) was added to this mixture at 0°C. The reaction mixture was stirred at 25°C for 2.5 hours. The reaction was stopped with saturated aqueous NH4Cl solution (50.0 mL) and extracted with ₹ (30.0 mL × 3). The combined organic layer was dried over Na2SO4 and concentrated to obtain the unpurified product. This unpurified product was purified by silica gel chromatography (PE:siRNA=20:1) to obtain 2-(3-bromopyrazole-1-yl)-5-nitropyridine (1.5 g, 5.58 mmol) as a yellow solid. MS[M+H] + :268.8.

[0258] Step 2: 5-Nitro-2-(3-vinylpyrazole-1-yl)pyridine To a solution of 2-(3-bromopyrazole-1-yl)-5-nitropyridine (900.0 mg, 3.35 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (772.7 mg, 5.02 mmol), and potassium carbonate (924.6 mg, 6.69 mmol) in 1,4-dioxane (25.0 mL) and water (2.5 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (244.7 mg, 0.33 mmol) was added all at once under N2. The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the residue. This residue was diluted with siRNA (100.0 mL) and washed with saline solution (20.0 mL x 2). The organic layer was dried over Na2SO4 and concentrated to obtain the unpurified product. This unpurified product was purified by silica gel chromatography to obtain 5-nitro-2-(3-vinylpyrazole-1-yl)pyridine (1.1 g, 5.09 mmol) as a yellow solid. MS[M+H] + :217.1.

[0259] Step 3: 6-(3-ethylpyrazole-1-yl)pyridine-3-amine To a solution of 5-nitro-2-(3-vinylpyrazole-1-yl)pyridine (900.0 mg, 4.16 mmol) in methanol (5.0 mL), palladium carbon (10%) (443.0 mg, 0.42 mmol) was added in one step under N2 conditions. H2 was introduced into the system. The reaction mixture was stirred at 25°C for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain 6-(3-ethylpyrazole-1-yl)pyridine-3-amine (740.0 mg, 3.93 mmol) as a colorless oil, which was used directly in the next step without further purification. MS[M+H] + :189.2.

[0260] Step 4: tert-butyl N-[6-(3-ethylpyrazole-1-yl)-3-pyridyl]carbamate Di-t-butyl dicarbonate (1.32 mL, 5.74 mmol) was added in a single dose to a solution of 6-(3-ethylpyrazole-1-yl)pyridine-3-amine (900.0 mg, 4.78 mmol) and triethylamine (1.33 mL, 9.56 mmol) in ACN (20.0 mL). The reaction mixture was stirred at 60°C for 2 hours. The reaction mixture was concentrated to obtain the unpurified product. This unpurified product was purified by silica gel chromatography to obtain tert-butyl N-[6-(3-ethylpyrazole-1-yl)-3-pyridyl]carbamate (800.0 mg, 2.77 mmol) as a yellow oily substance. MS[M+H] + :289.2.

[0261] Step 5: tert-butyl N-[6-(4-bromo-3-ethyl-pyrazole-1-yl)-3-pyridyl]carbamate 700.0 mg, 2.43 mmol of tert-butyl N-[6-(3-ethylpyrazole-1-yl)-3-pyridyl]carbamate was added in one step to a solution of 20.0 mL of ACN (432.0 mg, 2.43 mmol). The reaction mixture was stirred at 25°C for 2 hours. The reaction was stopped with 20.0 mL of saturated aqueous Na₂SO₃ solution and extracted with ELISA (30.0 mL x 2). The combined organic layer was dried over Na₂SO₄ and concentrated to obtain the unpurified product. This unpurified product was purified by preparative HPLC (neutral) to obtain 220.0 mg, 0.6 mmol of tert-butyl N-[6-(4-bromo-3-ethylpyrazole-1-yl)-3-pyridyl]carbamate as a red solid. MS[M+H] + :367.2.

[0262] Step 6: tert-butyl N-[6-[3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-yl]-3-pyridyl]carbamate [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (19.9 mg, 0.03 mmol) was added in a single dose under N2 to a solution of bis(pinacolato)diborone (138.3 mg, 0.54 mmol), tert-butyl N-[6-(4-bromo-3-ethyl-pyrazole-1-yl)-3-pyridyl]carbamate (100.0 mg, 0.27 mmol), and potassium acetate (66.8 mg, 0.68 mmol) in 1,4-dioxane (2.0 mL). The reaction mixture was stirred at 100 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the unpurified product. This unpurified product was purified by Prep-TLC (PE:siRNA=1:1) to obtain tert-butyl N-[6-[3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-yl]-3-pyridyl]carbamate (120.0 mg, 0.29 mmol, yield 38%) as a yellow oil. MS[M+H] + :289.2.

[0263] Intermediate A9.8 tert-butyl N-[6-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyrazole-1-yl]pyridazine-3-yl]carbamate Step 1: tert-butyl N-(6-chloropyridazine-3-yl)carbamate Di-t-butyl dicarbonate (15.1 g, 69.47 mmol) was added in a single dose to a solution of 6-chloropyridazine-3-amine (6.0 g, 46.31 mmol), triethylamine (9.68 mL, 69.47 mmol), and 4-dimethylaminopyridine (2.8 g, 23.16 mmol) in ACN (20.0 mL). The reaction mixture was stirred at 80°C for 16 hours. The reaction was stopped with saturated Na₂CO₃ aqueous solution (50.0 mL) and extracted with siRNA (100.0 mL × 2). The combined organic layer was dried over Na₂SO₄ and concentrated to obtain the unpurified product. This unpurified product was purified by silica gel chromatography to obtain tert-butyl N-(6-chloropyridazine-3-yl)carbamate (5.6 g, 24.38 mmol) as a pale yellow solid. [MS [M+H-C4H8]] + :174.1.

[0264] Step 2: 6-[4-bromo-3-(trifluoromethyl)pyrazole-1-yl]pyridazine-3-amine To a solution of tert-butyl N-(6-chloropyridazin-3-yl)carbamate (2.2 g, 9.3 mmol) and potassium carbonate (1.9 g, 13.96 mmol) in DMF (40.0 mL), tert-butyl N-(6-chloropyridazin-3-yl)carbamate (2.0 g, 9.3 mmol) and cesium fluoride (141.3 mg, 0.930 mmol) were added in one step. The reaction mixture was stirred at 120 °C for 48 hours. The reaction mixture was diluted with ELISA (200.0 mL) and washed with saline solution (50.0 mL x 3). The organic layer was dried over Na₂SO₄ and concentrated to obtain the unpurified product. This unpurified product was purified by preparative HPLC (TFA) to obtain 6-[4-bromo-3-(trifluoromethyl)pyrazole-1-yl]pyridazine-3-amine (350.0 mg, 1.14 mmol) as a yellow solid. MS([M+H] + :308.0.

[0265] Step 3: tert-butyl N-[6-[4-bromo-3-(trifluoromethyl)pyrazole-1-yl]pyridazine-3-yl]carbamate Di-t-butyl dicarbonate (297.5 mg, 1.36 mmol) was added in a single dose to a solution of 6-[4-bromo-3-(trifluoromethyl)pyrazole-1-yl]pyridazine-3-amine (350.0 mg, 1.14 mmol), triethylamine (0.48 mL, 3.41 mmol), and 4-dimethylaminopyridine (138.8 mg, 1.14 mmol) in DMF (10.0 mL). The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was diluted with saline solution (20.0 mL) and extracted with ethyl acetate (10.0 mL x 3). The combined organic layer was dried over Na2SO4 and concentrated to obtain the unpurified product. This unpurified product was purified by preparative HPLC (FA) to obtain tert-butyl N-[6-[4-bromo-3-(trifluoromethyl)pyrazole-1-yl]pyridazin-3-yl]carbamate (90.0 mg, 0.22 mmol) as a yellow solid. MS [M+2+H] + :410.0.

[0266] Step 4: tert-butyl N-[6-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyrazole-1-yl]pyridazine-3-yl]carbamate To a solution of tert-butyl N-[6-[4-bromo-3-(trifluoromethyl)pyrazole-1-yl]pyridazin-3-yl]carbamate (90.0 mg, 0.220 mmol), bis(pinacolato)diborone (83.9 mg, 0.33 mmol), and potassium acetate (43.2 mg, 0.44 mmol) in 1,4-dioxane (2.0 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (16.1 mg, 0.02 mmol) was added all at once under N2 conditions. The reaction mixture was stirred at 100°C for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the unpurified product. This unpurified product was purified by Prep-TLC (PE:siRNA=4:1) to obtain tert-butyl N-[6-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyrazole-1-yl]pyridazine-3-yl]carbamate (100.0 mg, 0.22 mmol, yield 42%) as a yellow solid. MS [M+H] + :456.2.

[0267] Intermediate A9.9 Trimethyl-[2-[[4-methyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyrazole-1-yl]pyrazole-1-yl]methoxy]ethyl]silane Step 1: Trimethyl-[2-[(4-methylpyrazole-1-yl)methoxyethyl]silane A solution of 4-methyl-1H-pyrazole (5.0 g, 60.9 mmol) in THF (50.0 mL) was degassed and purged three times with N2. Then, sodium hydride (60%) (3.65 g, 91.35 mmol) was added to the mixture at 0°C. The mixture was stirred at 0°C for 0.5 hours. Then, 2-(trimethylsilyl)ethoxymethyl chloride (12.9 mL, 73.08 mmol) was added to the mixture at 0°C. The reaction mixture was stirred under an N2 atmosphere at 20°C for 2 hours. The reaction was stopped with saturated NH4Cl aqueous solution (100 mL) and extracted with Depositphotos (100.0 mL × 3). The combined organic layers were washed with saline solution (100 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain the unpurified product trimethyl-[2-[(4-methylpyrazole-1-yl)methoxyethyl]silane (15.0 g, 70.63 mmol) as a yellow solid, which was used directly in the next step. MS [M+H] + :213.3.

[0268] Step 2: 2-[(3-bromo-4-methylpyrazole-1-yl)methoxy]ethyl-trimethyl-silane A solution of trimethyl-[2-[(4-methylpyrazole-1-yl)methoxy]ethyl]silane (5.0 g, 23.54 mmol) in ACN (50 mL) was degassed and purged three times with N2. Then, N-bromosuccinimide (5.0 g, 28.25 mmol) was added to the mixture. The reaction mixture was stirred under an N2 atmosphere at 20°C for 16 hours. The mixture was extracted with siRNA (100.0 mL × 3). The combined organic layers were washed with saline (100 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain the unpurified product. The unpurified product was purified by silica gel chromatography (PE: siRNA = 50 / 1 to 20 / 1) to obtain 2-[(3-bromo-4-methylpyrazole-1-yl)methoxy]ethyl-trimethyl-silane (4.4 g, 15.11 mmol) as a yellow oil. MS([M+H] + :293.0.

[0269] Step 3: [4-Methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-yl]boronic acid A mixture of 2-[(3-bromo-4-methylpyrazole-1-yl)methoxy]ethyl-trimethyl-silane (2.5 g, 8.58 mmol), bis(pinacolato)diborone (5.4 g, 21.46 mmol), potassium acetate (1.61 mL, 25.75 mmol), and X-PHOS (409.1 mg, 0.86 mmol) in 1,4-dioxane (40.0 mL) was degassed and purged three times with N2. Then, tris(dibenzylideneacetone)dipalladium(0) (393.0 mg, 0.43 mmol) was added to the mixture. The reaction mixture was stirred at 100°C for 16 hours under an N2 atmosphere. The mixture was filtered and concentrated under reduced pressure to obtain the unpurified product. The unpurified product was purified by preparative HPLC (TFA) to obtain [4-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-yl]boronic acid (970.0 mg, 3.79 mmol) as a yellow solid. MS [M+H] + :257.2.

[0270] Step 4: 2-[[3-[4-bromo-3-(trifluoromethyl)pyrazole-1-yl]-4-methylpyrazole-1-yl]methoxy]ethyl-trimethyl-silane To a solution of 4-bromo-3-(trifluoromethyl)-1H-pyrazole (400.0 mg, 1.86 mmol), [4-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-yl]boronic acid (572.0 mg, 2.23 mmol), molecular sieve 4A (400.0 mg), and pyridine (0.3 mL, 3.72 mmol) in 1,2-dichloroethane (20.0 mL), copper(II) acetate monohydrate (74.3 mg, 0.37 mmol) was added in one step. Then, O2 (15 psi) was introduced into the system. The reaction mixture was stirred at 60°C for 6 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the unpurified product. This unpurified product was purified by silica gel chromatography (PE:siRNA = 100:1 to 50:1) to obtain 2-[[3-[4-bromo-3-(trifluoromethyl)pyrazole-1-yl]-4-methylpyrazole-1-yl]methoxy]ethyl-trimethyl-silane (360.0 mg, 0.85 mmol, yield 39%) as a yellow oil. MS [M+H] + :425.0.

[0271] Step 5: Trimethyl-[2-[[4-methyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyrazole-1-yl]pyrazole-1-yl]methoxy]ethyl]silane To a solution of bis(pinacolato)diborone (322.4 mg, 1.27 mmol), 2-[[3-[4-bromo-3-(trifluoromethyl)pyrazole-1-yl]-4-methylpyrazole-1-yl]methoxy]ethyl-trimethyl-silane (360.0 mg, 0.85 mmol), and potassium acetate (166.1 mg, 1.69 mmol) in 1,4-dioxane (10.0 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (61.9 mg, 0.08 mmol) was added all at once under N2 conditions. The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the unpurified product. This unpurified product was purified by Prep-TLC (PE:siRNA=20:1) to obtain trimethyl-[2-[[4-methyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyrazole-1-yl]pyrazole-1-yl]methoxy]ethyl]silane (300.0 mg, 0.64 mmol, yield 40%) as a yellow oil. MS([M+H] + :473.0.

[0272] Intermediate A10 9H-Fluoren-9-ylmethyl N-(6-bromo-3-pyridyl)-N-(2-methoxyethyl)carbamate Step 1: 6-Bromo-N-(2-methoxyethyl)pyridine-3-amine 6-bromopyridine-3-amine (500 mg, 2.89 mmol), sodium iodide (216.6 mg, 1.45 mmol), and 1-bromo-2-methoxyethane (482.02 mg, 325.91 μL) were dissolved in anhydrous tetrahydrofuran (28.9 mL). The solution was cooled to 0°C. NaH (138.72 mg, 3.47 mmol) was added to this solution in fractional amounts. The mixture was stirred at 0°C for 4 hours. Then, a further amount of NaH (138.72 mg, 3.47 mmol) was added, and the mixture was refluxed at 70°C for 2 hours. The mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography to obtain 6-bromo-N-(2-methoxyethyl)pyridine-3-amine (373 mg). MS [M+H] + :231.1.

[0273] Step 2: 9H-Fluoren-9-ylmethyl N-(6-bromo-3-pyridyl)-N-(2-methoxyethyl)carbamate A mixture of 6-bromo-N-(2-methoxyethyl)pyridine-3-amine (3.7 g, 16.01 mmol), 9H-fluoren-9-ylmethylcarbonochloride (4.56 g, 17.61 mmol), and NaHCO3 (2.02 g, 24.02 mmol) was stirred in 1,4-dioxane (80.06 mL) at 0°C for 18 hours. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography to obtain 9H-fluoren-9-ylmethyl N-(6-bromo-3-pyridyl)-N-(2-methoxyethyl)carbamate (6.2 g) as a yellow oil. MS [M+H] + :453.2.

[0274] Intermediate A11.1 2-[(5-iodo-4-methylpyrazole-1-yl)methoxy]ethyl-trimethyl-silane At room temperature, a mixture of 5-iodo-4-methyl-1H-pyrazole (2 g, 9.62 mmol), 2-(chloromethoxy)ethyl-trimethyl-silane (1.92 g, 2.04 mL, 11.5 mmol), and DIPEA (1.86 g, 2.51 mL, 14.4 mmol) was stirred in DCM (45 mL) for 2 hours. The solution was then poured into water and acidified to pH = 5-6 with 1N HCl aqueous solution. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated to obtain a mixture of 2-[(5-iodo-4-methylpyrazole-1-yl)methoxy]ethyl-trimethyl-silane and 2-[(3-iodo-4-methylpyrazole-1-yl)methoxy]ethyl-trimethyl-silane (1.9 g) as an oil.

[0275] The following intermediates were prepared in the same manner as intermediate A11.1. [Table 5]

[0276] Intermediate A12 5-Nitro-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyrazole-1-yl]pyridine 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (7.8 g, 30 mmol) was dissolved in dimethyl sulfoxide (100 mL) and triethylamine (3.0 mL), to which 2-chloro-5-nitropyridine (4.8 g, 30 mmol) was added. The mixture was then stirred at 130 °C for 3 hours. The mixture was poured into water, and the aqueous solution was extracted by DCM. The combined organic layer was washed with water and brine and dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure, and the residue was purified by flash column to obtain 5-nitro-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyrazole-1-yl]pyridine (10 g) as a yellow solid. MS [M+H] + :385.1.

[0277] Intermediate B1.1 tert-butyl 4-[(5-bromo-1-methylimidazole-2-carbonyl)amino]-2-chlorobenzoate Step 1: tert-butyl 2-chloro-4-nitro-benzoate A mixture of 2-chloro-4-nitrobenzoic acid (15.0 g, 74.42 mmol), N,N-dimethylpyridine-4-amine (2.73 g, 22.33 mmol), and N,N-diethylethaneamine (31.12 mL, 223.26 mmol) in THF (80 mL) was mixed with a solution of tert-butoxycarbonyl tert-butyl carbonate (24.36 g, 111.63 mmol) in THF (20 mL) at -10°C. The resulting mixture was heated to 25°C and stirred for a further 14 hours. The mixture was concentrated. The residue was treated with EA (50 mL) and H2O (50 mL). The mixture was extracted with EA. The combined organic layer was concentrated. Next, the unpurified product was purified by flash column chromatography to obtain tert-butyl 2-chloro-4-nitro-benzoate (18.8 g) as a colorless solid.

[0278] Step 2: tert-butyl 4-amino-2-chlorobenzoate Iron (20.37 g, 364.81 mmol) was added to a mixture of tert-butyl 2-chloro-4-nitro-benzoate (18.8 g, 72.96 mmol) and ammonium chloride (19.51 g, 364.81 mmol) in ethanol (200 mL) and water (200 mL). The mixture was stirred at 25°C for 14 hours. The mixture was filtered through Celite. The filtrate was concentrated to remove ethanol. The mixture was extracted with EA. The combined organic layer was dried over anhydrous Na2SO4 and concentrated to obtain tert-butyl 4-amino-2-chloro-benzoate (16.31 g) as a pale yellow solid. MS [M+H] + :228.1.

[0279] Step 3: tert-butyl 4-[(5-bromo-1-methylimidazole-2-carbonyl)amino]-2-chlorobenzoate A mixture of 5-bromo-1-methylimidazole-2-carboxylate hydrochloride (7.0 g, 28.99 mmol), tert-butyl 4-amino-2-chlorobenzoate (6.0 g, 26.35 mmol), HATU (13.23 g, 34.79 mmol), and DIPEA (16.16 mL, 92.77 mmol) in DMF (15 mL) was stirred at 25°C for 3 hours. Water (10 mL) was added to the mixture and extracted with EA. The combined organic layer was concentrated. The unpurified product was purified by FCC to obtain tert-butyl 4-[(5-bromo-1-methylimidazole-2-carbonyl)amino]-2-chlorobenzoate (8 g, 19.29 mmol) as a white solid. MS [M+H] + :414.0

[0280] The following intermediates were prepared in the same manner as intermediate B1.1. [Table 6]

[0281] Intermediate B2.1 5-Bromo-N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-1-methylimidazole-2-carboxamide Step 1: 4-(5-bromo-1-methylimidazole-2-carboxamide)-2-chlorobenzoic acid In a 250 mL round-bottom flask, tert-butyl 4-(5-bromo-1-methylimidazole-2-carboxamide)-2-chlorobenzoate (5 g, 12.1 mmol) was mixed with CH2Cl2 (30 mL) to obtain a pale brown solution. TFA (41.2 g, 27.9 mL, 362 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The unpurified reaction mixture was concentrated under reduced pressure. The unpurified product was used directly in the next step to obtain 4-(5-bromo-1-methylimidazole-2-carboxamide)-2-chlorobenzoic acid (4.32 g). MS [M+H] + :359.8.

[0282] Step 2: tert-butyl 4-(4-(5-bromo-1-methylimidazole-2-carboxamide)-2-chlorobenzoyl)piperazine-1-carboxylate In a 100 mL round-bottom flask, 4-(5-bromo-1-methylimidazole-2-carboxamide)-2-chlorobenzoic acid (2 g, 5.58 mmol), tert-butylpiperazine-1-carboxylate (1.19 g, 6.41 mmol), and DIEA (2.16 g, 2.92 mL, 16.7 mmol) were mixed with DMF (15 mL) to obtain a colorless solution. HATU (2.76 g, 7.25 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 150 mL of H2O and extracted with ELISA (75 mL x 3). The organic layers were combined, washed with saturated NaCl (75 mL x 1), dried over Na2SO4, and concentrated under reduced pressure to obtain tert-butyl 4-(4-(5-bromo-1-methylimidazole-2-carboxamide)-2-chlorobenzoyl)piperazine-1-carboxylate (2.94 g). MS [M+H] + :527.9.

[0283] The following intermediates were prepared in the same manner as intermediate B2.1. [Table 7]

[0284] Intermediate B3.1 5-Bromo-N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-1-methylimidazole-2-carboxamide In a 100 mL round-bottom flask, tert-butyl 4-(4-(5-bromo-1-methylimidazole-2-carboxamide)-2-chlorobenzoyl)piperazine-1-carboxylate (2.94 g, 5.58 mmol) was mixed with THF (20 mL) to obtain a pale brown solution. HCl (in water) (11.6 mL, 140 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The unpurified product was used directly in the next step to obtain 5-bromo-N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-1-methylimidazole-2-carboxamide (2.38 g). MS [M+H] + :427.8.

[0285] The following intermediates were prepared in the same manner as intermediate B3.1. [Table 8]

[0286] Intermediate B4.1 tert-butyl 4-(4-(4-(5-bromo-1-methylimidazole-2-carboxamide)-2-chlorobenzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate In a 100 mL round-bottom flask, 5-bromo-N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-1-methylimidazole-2-carboxamide (2.38 g, 5.58 mmol), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2.05 g, 8.92 mmol), and DIEA (2.16 g, 2.92 mL, 16.7 mmol) were mixed with DMF (15 mL) to obtain a pale brown solution. HATU (3.39 g, 8.92 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 150 mL of H2O and extracted with ELISA (50 mL x 3). The organic layers were combined, washed with saturated NaCl (75 mL x 1), dried over Na2SO4, and concentrated under reduced pressure. tert-butyl 4-(4-(4-(5-bromo-1-methylimidazole-2-carboxamide)-2-chlorobenzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (3.56g). MS [M+H] + :638.9.

[0287] The following intermediates were prepared in the same manner as intermediate B4.1. [Table 9-1] [Table 9-2]

[0288] Intermediate C1 tert-butyl 2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazole-4-yl]imidazole-2-carbonyl]amino]benzoate In a 100 mL round-bottom flask, tert-butyl 4-(5-bromo-1-methylimidazole-2-carboxamide)-2-chlorobenzoate (2 g, 4.82 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (1.64 g, 6.27 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (314 mg, 482 μmol), and Na2CO3 (1.53 g, 14.5 mmol) were mixed with 1,4-dioxane (30 mL) and water (3 mL), and stirred under N2 for 15 hours. The filtrate was concentrated under reduced pressure. The unpurified substance was purified by flash chromatography (silica gel, 20 g, 0%~10% MeOH in DCM) to obtain tert-butyl 2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-imidazole-2-carboxamide)benzoate (2 g). MS [M+H] + :470.7.

[0289] The following intermediates were prepared in the same manner as intermediate C1. [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5]

[0290] Intermediate D1 tert-butyl 4-(2-chloro-4-(1-methyl-5-(1-(5-nitropyridine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-imidazole-2-carboxamide)benzoyl)piperazine-1-carboxylate Step 1: tert-butyl 4-(2-chloro-4-(1-methyl-5-(1-(5-nitropyridine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-imidazole-2-carboxamide)benzoyl)piperazine-1-carboxylate In a 25 mL microwave vial, tert-butyl 4-(2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-imidazole-2-carboxamide)benzoyl)piperazine-1-carboxylate (1.5 g, 2.58 mmol), 2-chloro-5-nitropyridine (531 mg, 3.35 mmol), and K2CO3 (712 mg, 5.15 mmol) were added in MeCN (18 mL). The vial was capped and heated at 100°C for 2 hours. The unpurified reaction mixture was concentrated under reduced pressure. The reaction mixture was passed through fiberglass paper and filtered. The filtrate was concentrated under reduced pressure. The unpurified substance was purified by flash chromatography (silica gel, 40 g, 0%~10% MeOH in DCM) to obtain tert-butyl 4-(2-chloro-4-(1-methyl-5-(1-(5-nitropyridine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-imidazole-2-carboxamide)benzoyl)piperazine-1-carboxylate (1.4 g). MS [M+H] + :704.2.

[0291] The following intermediates were prepared in the same manner as intermediate D1. [Table 11-1] [Table 11-2] [Table 11-3]

[0292] Intermediate E1 N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-1-methyl-5-(1-(5-nitropyridine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-imidazole-2-carboxamide Step 1: N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-1-methyl-5-(1-(5-nitropyridine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-imidazole-2-carboxamide In a 100 mL round-bottom flask, tert-butyl 4-(2-chloro-4-(1-methyl-5-(1-(5-nitropyridine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-imidazole-2-carboxamide)benzoyl)piperazine-1-carboxylate (1.4 g, 1.99 mmol) was mixed with THF (8 mL) to obtain a pale brown solution. HCl aqueous solution (6.63 mL, 79.5 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The unpurified reaction mixture was concentrated under reduced pressure. The unpurified product was used directly in the next step to obtain N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-1-methyl-5-(1-(5-nitropyridine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-imidazole-2-carboxamide (1.2 g). MS [M+H] + :604.2.

[0293] The following intermediates were prepared in the same manner as intermediate E1. [Table 12-1] [Table 12-2]

[0294] Intermediate F1 N-[3-chloro-4-[4-[2-(3-hydroxypyrrolidine-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide Step 1: N-[3-chloro-4-[4-(2-chloroacetyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide To a solution of N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide and 2,2,2-trifluoroacetic acid (300 mg, 0.42 mmol) in acetonitrile (5 mL), sodium carbonate (132.9 mg, 1.3 mmol) was added, followed by the dropwise addition of chloroacetyl chloride (47.2 mg, 0.42 mmol) at 0°C. The reaction mixture was stirred for 2 hours and then warmed to room temperature. The reaction mixture was washed with saline solution and extracted in DCM. The organic layer was dried over anhydrous sodium 2SO4 and concentrated under reduced pressure. The residue was used directly in the next step without further purification. MS [M+H] + :680.2.

[0295] Step 2: N-[3-chloro-4-[4-[2-(3-hydroxypyrrolidine-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide To a solution of N-[3-chloro-4-[4-(2-chloroacetyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide (230 mg, 0.34 mmol) in acetonitrile (3 mL), 3-pyrrolidinol (29.5 mg, 0.34 mmol) and TEA (68.4 mg, 0.68 mmol) were added, and the reaction mixture was stirred at 70°C for 30 minutes. The reaction mixture was cooled to room temperature. The reaction mixture was washed with saline solution and extracted in DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was used directly in the next step without further purification. MS [M+H] + :731.2. Intermediate G1 tert-butyl4-(4-(4-(5-(1-(5-aminopyridine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl)-1-methylimidazole-2-carboxamide)-2-chlorobenzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate Step 1: tert-butyl 4-(4-(4-(5-(1-(5-aminopyridine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl)-1-methylimidazole-2-carboxamide)-2-chlorobenzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate In a 100 mL round-bottom flask, tert-butyl 4-(4-(2-chloro-4-(1-methyl-5-(1-(5-nitropyridine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-imidazole-2-carboxamide)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (47 mg, 57.7 μmol) was mixed with EtOH (6 mL) / water (6 mL) to form a pale yellow solution. Zinc (75.4 mg, 1.15 mmol) and NH4Cl (61.7 mg, 1.15 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was passed through glass fiber paper and filtered. The filtrate was poured into 20 mL of H2O and extracted with ELISA (25 mL x 3). The organic layers were combined, washed with saturated NaCl (25 mL x 1), dried over Na2SO4, and concentrated under reduced pressure to obtain tert-butyl 4-(4-(4-(5-(1-(5-aminopyridine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-1-methyl-imidazole-2-carboxamide)-2-chlorobenzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (45.3 mg). MS [M+H] + :785.0.

[0296] The following intermediates and compounds were prepared in the same manner as intermediate G1. [Table 13-1] [Table 13-2]

[0297] Intermediate H1 N-[4-[[(1S,5R)-3-azabicyclo[3.1.0]hexane-6-yl]carbamoyl]-3-chlorophenyl]-1-methyl-5-[1-pyrimidine-2-yl-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide Step 1: tert-butyl(1R,5S,6S)-6-(2-chloro-4-(1-methyl-5-(1-(pyrimidine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-imidazole-2-carboxamide)benzamide)-3-azabicyclo[3.1.0]hexane-3-carboxylate In a 50 mL round-bottom flask, 2-chloro-4-(1-methyl-5-(1-(pyrimidine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-imidazole-2-carboxamide)benzoic acid (340 mg, 691 μmol), tert-butyl(1R,5S,6S)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (206 mg, 1.04 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridine-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (394 mg, 1.04 mmol), and DIPEA (179 mg, 1.38 mmol) were mixed with DMF (5 mL) to obtain a pale brown solution. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 25 mL of H2O and extracted with ELISA (25 mL x 3). The organic layers were combined, washed with saturated NaCl (25 mL x 1), dried over Na2SO4, and concentrated under reduced pressure to obtain tert-butyl(1R,5S,6S)-6-(2-chloro-4-(1-methyl-5-(1-(pyrimidine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-imidazole-2-carboxamide)benzamide)-3-azabicyclo[3.1.0]hexane-3-carboxylate (240 mg). MS [M+H] + :672.2.

[0298] Step 2: N-(4-(((1R,5S,6S)-3-azabicyclo[3.1.0]hexane-6-yl)carbamoyl)-3-chlorophenyl)-1-methyl-5-(1-(pyrimidine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-imidazole-2-carboxamide In a 50 mL round-bottom flask, tert-butyl(1R,5S,6S)-6-(2-chloro-4-(1-methyl-5-(1-(pyrimidine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-imidazole-2-carboxamide)benzamide)-3-azabicyclo[3.1.0]hexane-3-carboxylate (240 mg, 357 μmol) was mixed with THF (2 mL) to obtain a pale brown solution. 1.19 mL, 14.3 mmol, aqueous HCl was added. The reaction mixture was stirred at room temperature for 1 hour. The unpurified reaction mixture was concentrated under reduced pressure. The unpurified product was used directly in the next step to obtain N-(4-(((1R,5S,6S)-3-azabicyclo[3.1.0]hexane-6-yl)carbamoyl)-3-chlorophenyl)-1-methyl-5-(1-(pyrimidine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-imidazole-2-carboxamide (204 mg). MS [M+H] + :572.7.

[0299] Intermediate I1 tert-butyl4-[2-chloro-4-[[5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylate Under N2 protection, a mixture of tert-butyl 4-[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazole-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylate (600 mg, 1.03 mmol), 2-bromo-5-methoxypyridine (581.54 mg, 3.09 mmol), CuI (196.35 mg, 1.03 mmol), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (219.97 mg, 1.55 mmol) in DMF (10 mL) was heated at 100 °C for 16 hours. The mixture was concentrated, and the residue was purified by flash column to obtain tert-butyl 4-[2-chloro-4-[[5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxylate (500 mg). MS [M+H] + :689.4.

[0300] The following intermediates were prepared in the same manner as intermediate I1. [Table 14]

[0301] Example A1 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pyrimidine-2-yl-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid [ka] Step 1: tert-butyl 4-(4-(2-chloro-4-(1-methyl-5-(1-(pyrimidine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)imidazole-2-carboxamide)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate In a 5 mL microwave vial, tert-butyl 4-(4-(2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-imidazole-2-carboxamide)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (60 mg, 86.6 μmol), 2-chloropyrimidine (14.9 mg, 130 μmol), and K2CO3 (23.9 mg, 173 μmol) were added in DMF (2 mL). The vial was capped and heated under microwave at 100 °C for 1 hour. The reaction mixture was poured into 25 mL of H2O and extracted with ELISA (25 mL x 3). The organic layers were combined, washed with saturated NaCl (25 mL x 3), dried over Na2SO4, and concentrated under reduced pressure to obtain tert-butyl 4-(4-(2-chloro-4-(1-methyl-5-(1-(pyrimidine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-imidazole-2-carboxamide)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (66.8 mg). MS [M+H] + :771.8.

[0302] Step 2: N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pyrimidine-2-yl-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid In a 25 mL round-bottom flask, tert-butyl 4-(4-(2-chloro-4-(1-methyl-5-(1-(pyrimidine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-imidazole-2-carboxamide)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (66 mg, 85.6 μmol) was mixed with THF (3 mL) to obtain a light brown solution. HCl aqueous solution (1.43 mL, 17.1 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The unpurified reaction mixture was concentrated under reduced pressure. The unpurified substance was purified by preparative HPLC to obtain N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pyrimidine-2-yl-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide (37 mg). MS [M+H] + :671.4.

[0303] The following compounds were prepared in the same manner as in Example A1. [Table 15-1] [Table 15-2] [Table 15-3] [Table 15-4] [Table 15-5]

[0304] Example B1 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(dimethylamino)pyrimidine-2-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid [ka] Step 1: tert-butyl 4-(4-(2-chloro-4-(5-(1-(5-(dimethylaminopyrimidine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl)-1-methylimidazole-2-carboxamide)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate In a 5 mL microwave vial, tert-butyl 4-(4-(2-chloro-4-(5-(1-(5-fluoropyrimidine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl)-1-methylimidazole-2-carboxamide)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (50 mg, 63.4 μmol) and dimethylamine (317 μl, 634 μmol) were added in MeOH (2 mL). The vial was capped and heated under microwave at 100 °C for 2 hours. The unpurified reaction mixture was concentrated under reduced pressure. The unpurified product was used directly in the next step to obtain tert-butyl 4-(4-(2-chloro-4-(5-(1-(5-(dimethylamino)pyrimidine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl)-1-methylimidazole-2-carboxamide)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (51 mg). MS [M+H] + :814.8.

[0305] Step 2: N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(dimethylamino)pyrimidine-2-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid In a 50 mL round-bottom flask, tert-butyl 4-(4-(2-chloro-4-(5-(1-(5-(dimethylamino)pyrimidine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-1-methylimidazole-2-carboxamide)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (51 mg, 62.6 μmol) was mixed with THF (2 mL) to obtain a pale brown solution. HCl (522 μl, 6.26 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. The unpurified reaction mixture was concentrated under reduced pressure. The unpurified substance was purified by preparative HPLC to obtain N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(dimethylamino)pyrimidine-2-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid (8.3 mg). MS [M+H] + :714.3.

[0306] The following compounds were prepared in the same manner as in Example B1. [Table 16]

[0307] Example C1 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid [ka] Process 1: 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid In a 50 mL round-bottom flask, tert-butyl 4-(4-(4-(5-(1-(5-aminopyridine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-1-methyl-imidazole-2-carboxamide)-2-chlorobenzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (45 mg, 57.3 μmol) was mixed with THF (2 mL) to obtain a light brown solution. HCl (478 μl, 5.73 mmol) was added. The reaction mixture was stirred at room temperature for 20 minutes. The unpurified reaction mixture was concentrated under reduced pressure. The unpurified substance was purified by preparative HPLC to obtain 5-(1-(5-aminopyridine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-N-(3-chloro-4-(4-(piperidine-4-carbonyl)piperazine-1-carbonyl)phenyl)-1-methyl-imidazole-2-carboxamide diformate (14.8 mg). MS [M+H] + :713.0.

[0308] The following compounds were prepared in the same manner as in Example C1: [Table 17-1] [Table 17-2] [Table 17-3] [Table 17-4]

[0309] Example D1 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid [ka] Step 1: tert-butyl 4-[4-[2-chloro-4-[[1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate In a 25 mL microwave vial, tert-butyl 4-(4-(4-(5-(1-(5-aminopyridine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl)-1-methylimidazole-2-carboxamide)-2-chlorobenzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (240 mg, 306 μmol), formaldehyde (275 mg, 253 μl, 9.17 mmol), and sodium methoxide (495 mg, 9.17 mmol) were added in MeOH (10 mL). The vial was capped and heated under microwave at 50°C for 15 hours. The reaction mixture was cooled to room temperature and NaBH4 (405 mg, 10.7 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The unpurified reaction mixture was concentrated under reduced pressure. The reaction mixture was poured into 25 mL of saturated NH4Cl and extracted with ELISA (25 mL x 3). The organic layers were combined and washed with saturated NaCl (25 mL x 1). The organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain tert-butyl 4-(4-(2-chloro-4-(1-methyl-5-(1-(5-(methylamino)pyridine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-imidazole-2-carboxamide)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (169 mg). MS [M+H] + :799.7.

[0310] Step 2: N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid In a 50 mL round-bottom flask, tert-butyl 4-(4-(2-chloro-4-(1-methyl-5-(1-(5-(methylamino)pyridine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-imidazole-2-carboxamide)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (24 mg, 30 μmol) was mixed with THF (2 mL) to obtain a pale brown solution. HCl (500 μl, 6.01 mmol) was added. The reaction mixture was stirred at room temperature for 20 minutes. The unpurified reaction mixture was concentrated under reduced pressure. The unpurified substance was purified by preparative HPLC to obtain N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid (2 mg). MS [M+H] + :699.2.

[0311] The following compounds were prepared in the same manner as in Example D1. [Table 18-1] [Table 18-2]

[0312] Example E1 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[1-(2-methoxyethyl)pyrazole-4-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid [ka] Step 1: tert-butyl 4-(4-(2-chloro-4-(5-(1'-(2-methoxyethyl)-3-(trifluoromethyl)-1'H-[1,4'-bipyrazole]-4-yl)-1-methylimidazole-2-carboxamide)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate To a 5 mL microwave vial, tert-butyl 4-(4-(2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-imidazole-2-carboxamide)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (60 mg, 86.6 μmol), 4-iodo-1-(2-methoxyethyl)-pyrazole (21.8 mg, 86.6 μmol), copper(I) iodide (1.65 mg, 8.66 μmol), cesium carbonate (56.4 mg, 173 μmol), and trans-(1R,2R)N,N'-dimethylcyclohexane-1,2-diamine (2.46 mg, 17.3 μmol) were added in DMF (2 mL). The vial was capped and heated under microwave at 150°C for 1 hour. The reaction mixture was poured into 25 mL of H2O and extracted with ELISA (25 mL x 3). The organic layers were combined and washed with ELISA (25 mL x 3), dried over Na2SO4, and concentrated under reduced pressure. The unpurified material was purified by flash chromatography to obtain tert-butyl4-(4-(2-chloro-4-(5-(1'-(2-methoxyethyl)-3-(trifluoromethyl)-1'H-[1,4'-bipyrazole]-4-yl)-1-methylimidazole-2-carboxamide)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (40 mg). MS [M+H] + :817.8.

[0313] Step 2: N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[1-(2-methoxyethyl)pyrazole-4-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid In a 100 mL round-bottom flask, tert-butyl 4-(4-(2-chloro-4-(5-(1'-(2-methoxyethyl)-3-(trifluoromethyl)-1'H-[1,4'-bipyrazole]-4-yl)-1-methylimidazole-2-carboxamide)benzoyl)piperazine-1-carbonyl)piperidine-1-carboxylate (40 mg, 48.9 μmol) was mixed with THF (2 mL) to obtain a pale brown solution. HCl (408 μl, 4.89 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The unpurified reaction mixture was concentrated under reduced pressure. The unpurified substance was purified by preparative HPLC to obtain N-(3-chloro-4-(4-(piperidine-4-carbonyl)piperazine-1-carbonyl)phenyl)-5-(1'-(2-methoxyethyl)-3-(trifluoromethyl)-1'H-[1,4'-bipirazole]-4-yl)-1-methylimidazole-2-carboxamide formate (6.7 mg). MS [M+H] + :717.1.

[0314] The following compounds were prepared in the same manner as in Example E1. [Table 19-1] [Table 19-2]

[0315] Example F1 N-[4-[4-[(1R,5S)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]-3-chlorophenyl]-1-methyl-5-[1-pyrimidine-2-yl-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid [ka] Step 1: tert-butyl(1R,5S,6R)-6-(4-(2-chloro-4-(1-methyl-5-(1-(pyrimidine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-imidazole-2-carboxamide)benzoyl)piperazine-1-carbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate In a 50 mL round-bottom flask, N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-1-methyl-5-(1-(pyrimidine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl)-imidazole-2-carboxamide (55 mg, 98.2 μmol), (1R,5S,6R)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0] Hexane-6-carboxylic acid (29 mg, 128 μmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridine-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (48.6 mg, 128 μmol), and DIPEA (25.4 mg, 34.3 μl, 196 μmol) were mixed with DMF (3 mL) to obtain a pale brown solution. The reaction mixture was poured into 25 mL of H2O and extracted with ELISA (3 × 25 mL). The organic layers were combined, washed with saturated NaCl (1 × 25 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain tert-butyl(1R,5S,6R)-6-(4-(2-chloro-4-(1-methyl-5-(1-(pyrimidine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-imidazole-2-carboxamide)benzoyl)piperazine-1-carbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (75.6 mg). MS [M+H] + :769.4.

[0316] Step 2: N-[4-[4-[(1R,5S)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]-3-chlorophenyl]-1-methyl-5-[1-pyrimidine-2-yl-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid In a 50 mL round-bottom flask, tert-butyl(1R,5S,6R)-6-(4-(2-chloro-4-(1-methyl-5-(1-(pyrimidine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-imidazole-2-carboxamide)benzoyl)piperazine-1-carbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (75 mg, 97.5 μmol) was mixed with THF (2 mL) to obtain a pale brown solution. HCl (813 μl, 9.75 mmol) was added. The reaction mixture was stirred at room temperature for 20 minutes. The unpurified reaction mixture was concentrated under reduced pressure. The unpurified substance was purified by preparative HPLC to obtain N-(4-(4-((1R,5S,6R)-3-azabicyclo[3.1.0]hexane-6-carbonyl)piperazine-1-carbonyl)-3-chlorophenyl)-1-methyl-5-(1-(pyrimidine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-imidazole-2-carboxamide formate (21.7 mg). MS [M+H] + :669.7.

[0317] The following compounds were prepared in the same manner as in Example F1. [Table 20]

[0318] Example G1 N-[4-[4-[1-(azetidine-3-ylmethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chlorophenyl]-1-methyl-5-[1-pyrimidine-2-yl-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid [ka] Step 1: tert-butyl 3-((4-(4-(2-chloro-4-(1-methyl-5-(1-(pyrimidine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-imidazole-2-carboxamide)benzoyl)piperazine-1-carbonyl)piperidine-1-yl)methyl)azetidine-1-carboxylate In a 50 mL round-bottom flask, N-(3-chloro-4-(4-(piperidine-4-carbonyl)piperazine-1-carbonyl)phenyl)-1-methyl-5-(1-(pyrimidine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-imidazole-2-carboxamide (143 mg, 213 μmol), tert-butyl 3-formylazetidine-1-carboxylate (59.2 mg, 320 μmol), and NaBH3CN (26.8 mg, 426 μmol) were mixed with MeOH (5 mL) to obtain a pale brown solution. The reaction mixture was heated to 45 °C and stirred for 15 hours. The unpurified reaction mixture was concentrated under reduced pressure. The reaction mixture was poured into 25 mL of H2O and extracted with ELISA (25 mL x 3). The organic layers were combined and washed with saturated NaCl (25 mL x 1). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain tert-butyl 3-((4-(4-(2-chloro-4-(1-methyl-5-(1-(pyrimidine-2-yl)-3-(trifluoromethyl)-pyrazole-4-yl)-imidazole-2-carboxamide)benzoyl)piperazine-1-carbonyl)piperidine-1-yl)methyl)azetidine-1-carboxylate (179 mg). MS [M+H] + :840.5.

[0319] Step 2: N-[4-[4-[1-(azetidine-3-ylmethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chlorophenyl]-1-methyl-5-[1-pyrimidine-2-yl-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid In a 50 mL round-bottom flask, tert-butyl 3-((4-(4-(2-chloro-4-(1-methyl-5-(1-(pyrimidine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl)-imidazole-2-carboxamide)benzoyl)piperazine-1-carbonyl)piperidine-1-yl)methyl)azetidine-1-carboxylate (80 mg, 95.2 μmol) was mixed with THF (2 mL) to obtain a pale brown solution. HCl (635 μl, 7.62 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The unpurified reaction mixture was concentrated under reduced pressure. The unpurified substance was purified by preparative HPLC to obtain N-[4-[4-[1-(azetidine-3-ylmethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chlorophenyl]-1-methyl-5-[1-pyrimidine-2-yl-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid (15.3 mg). MS [M+H] + :740.1.

[0320] Example H1 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperazine-1-carbonyl)piperidine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid [ka] Step 1: tert-butyl 4-[1-[2-chloro-4-[[1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carbonyl]piperazine-1-carboxylate 1-[2-chloro-4-[[1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxylic acid (135 mg, 0.2 mmol), tert-butylpiperazine-1-carboxylate (51.8 mg, 0.3 mmol), HATU (97.0 mg, 0.2 mmol), and DIEA (149.8 mg, 202.4 μL, 1.2 mmol) were stirred in acetonitrile (2.3 mL) at 25°C for 0.5 hours. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography to obtain the marked compound as a pale yellow oil. MS [M+H] + :815.4.

[0321] Step 2: 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperazine-1-carbonyl)piperidine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid; 4-[1-[2-chloro-4-[1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carbonyl]amino]benzoyl]isonipecotoyl]piperazine-1-carboxylate tert-butyl ester (300 mg, 0.4 mmol) was dissolved in 3 mL of 1 M HCl / MeOH solution and stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and the residue was dissolved in ethanol (3.7 mL). Zinc (481.2 mg, 7.4 mmol) and ammonium chloride (98.4 mg, 1.8 mmol) were added to this solution. The mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was purified by preparative HPLC to obtain the labeled product as a pale yellow powder of 50 mg. [M+H] + :685.2.

[0322] The following compounds were prepared in the same manner as in Example H1. [Table 21]

[0323] Example I1 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-[(2-oxopiperazine-1-yl)methyl]piperidine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid [ka] Step 1: Benzyl 4-[[1-[2-chloro-4-[[1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carbonyl]amino]benzoyl]-4-piperidyl]methyl]-3-oxopiperazine-1-carboxylate 2-Chloro-4-[[1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carbonyl]amino]benzoic acid (165 mg, 0.3 mmol), benzyl 2-[3-oxo-4-(4-piperidylmethyl)piperazin-1-yl]acetate (144.7 mg, 0.4 mmol), DIEA (217.1 mg, 293.4 μL, 1.7 mmol), and HATU (153.3 mg, 0.4 mmol) were stirred in acetonitrile (5 mL) at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography to obtain the marked compound as a pale yellow oily substance of 250 mg. MS[M+H] + :849.6.

[0324] Step 2: N-[3-chloro-4-[4-[(2-oxopiperazine-1-yl)methyl]piperidine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide Benzyl 4-[[1-[2-chloro-4-[[1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carbonyl]amino]benzoyl]-4-piperidyl]methyl]-3-oxopiperazine-1-carboxylate (250 mg, 0.3 mmol) was heated in TFA (5 mL) under microwave at 100°C for 1 hour. The solvent was removed under reduced pressure, and the residue was used in the next step without purification. MS [M+H] + :715.4.

[0325] Step 3: 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-[(2-oxopiperazine-1-yl)methyl]piperidine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid N-[3-chloro-4-[4-[(2-oxopiperazine-1-yl)methyl]piperidine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide (100 mg, 0.1 mmol) was dissolved in ethanol (4 mL) and 1 mL of water (1 mL). Ammonium chloride (74.8 mg, 1.4 mmol) and zinc (182.9 mg, 2.8 mmol) were added to this solution. The mixture was stirred at room temperature for 3 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure, the residue was dissolved in DMF, and the compound was purified by preparative HPLC to obtain the marked compound as a pale yellow powder of 50 mg. MS[M+H] + :685.6

[0326] The following compounds were prepared in the same manner as in Example I1. [Table 22]

[0327] Example J1 N-[3-chloro-4-[4-[(2S)-4-hydroxypiperidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid; [ka] Step 1: tert-butyl(2S)-2-[4-[2-chloro-4-[[1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-4-oxo-piperidine-1-carboxylate Intermediate E1 (300 mg, 0.5 mmol), 1-(tert-butoxycarbonyl)-4-oxopiperidine-2-carboxylic acid (135.2 mg, 0.6 mmol), HATU (193.6 mg, 0.5 mmol), and DIEA (299.2 mg, 404.3 μL, 2.3 mmol) were stirred in acetonitrile (4.6 mL) at 25°C for 0.5 hours. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography to obtain the marked compound as a pale yellow oily substance of 380 mg. MS[M+H] + :829.9.

[0328] Step 2: N-[3-chloro-4-[4-[(2S)-4-hydroxypiperidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide (2S)-2-[4-[2-chloro-4-[[1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-4-keto-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 0.6 mmol) was dissolved in methanol (6.0 mL), and NaBH4 (22.8 mg, 0.6 mmol) was added all at once. The mixture was stirred at room temperature for 30 minutes. Then, 5 mL of 1 M HCl / MeOH solution was added, and stirring was continued for 3 hours. The solvent was removed under reduced pressure, the residue was neutralized with TEA, and the mixture was purified by flash chromatography to obtain the marked compound as 350 mg of a pale yellow oil. MS[M+H] + :731.4.

[0329] Step 3: N-[3-chloro-4-[4-[(2S)-4-hydroxypiperidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid; N-[3-chloro-4-[4-[(2S)-4-hydroxypiperidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide (350 mg, 0.5 mmol) was dissolved in ethanol (5.5 mL) and 1 mL of water. Ammonium chloride (129 mg, 2.4 mmol) and zinc (629 mg, 9.6 mmol) were added to this solution. The mixture was stirred at room temperature for 3 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure, the residue was dissolved in DMF, and purified by preparative HPLC to obtain the marked compound as a pale yellow powder of 50 mg. MS[M+H] + :701.2.

[0330] Example K1 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(ethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid; [ka] Step 1: tert-butyl 4-[4-[2-chloro-4-[[5-[1-[5-(ethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate At 0°C, tert-butyl 4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (460 mg, 0.586 mmol) was dissolved in methanol (30 mL) and 5M acetaldehyde (228.47 mg, 292.91 μL, 1.46 mmol) and acetic acid (211.07 mg, 201.21 μL, 3.51 mmol) were added. The solution was then stirred at 0°C for 30 minutes. Next, NaBH3CN (184.07 mg, 2.93 mmol) was added and the mixture was stirred at 0°C for 2 hours. The excess water was gradually added, and the solution was neutralized by adding a 3N sodium hydroxide aqueous solution (pH = approximately 8). The mixture was stirred for 1 hour. The aqueous layer was extracted by DCM. The combined organic layers were concentrated, and the residue was purified by flash column to obtain tert-butyl 4-[4-[2-chloro-4-[[5-[1-[5-(ethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (410 mg) as a yellow solid. MS [M+H] + :813.6.

[0331] Step 2: N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(ethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formic acid; At room temperature, a mixture of tert-butyl 4-[4-[2-chloro-4-[[5-[1-[5-(ethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (100 mg, 0.123 mmol) and 4M 1,4-dioxane hydrochloride solution (89.7 mg, 0.62 mL, 20 equivalents) was stirred for 4 hours. The mixture was then concentrated and basicized to pH 8-9 with NH3.H2O. The aqueous layer was extracted with DCM. The organic layer was concentrated, and the residue was purified by preparative HPLC to obtain N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(ethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide:formic acid (19 mg) as a pale yellow powder. MS [M+H] + :713.4

[0332] Intermediate Y1 4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]-2-chlorobenzoic acid [ka] Step 1: 2-Chloro-4-[[1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carbonyl]amino]methyl benzoate In a 250 mL round-bottom flask, 2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazole-4-yl]imidazole-2-carbonyl]amino]methyl benzoate [2489205-78-7] (1.88 g, 4.4 mmol, 1 equivalent), 2-bromo-5-nitropyridine (1.25 g, 6.16 mmol, 1.4 equivalents), and K2CO3 (1.83 g, 13.21 mmol, 3 equivalents) were mixed in acetonitrile (70 mL). The mixture was heated under reflux (80°C) for 1 hour. The reaction mixture was filtered, and the filtrate was purified by silica gel chromatography (10% to 100% siRNA in heptane) to obtain the marked compound (2.76 g, 83.2%) as a light brown solid with a purity of 73% by UV chromatography. The substance was used without further purification. MS:550.1[M+H] + ,ESI pos

[0333] Step 2: 4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chlorobenzoate methyl ester 2-chloro-4-[[1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carbonyl]amino]methyl benzoate (2730 mg, 3.62 mmol, 1 equivalent) and ammonium chloride (2.91 g, 54.37 mmol, 15 equivalents) were mixed with ethanol (10 mL) and water (5 mL) to obtain a grayish-white solution. Zinc powder (3.55 g, 54.37 mmol, 15 equivalents) was added, and the reaction mixture was stirred under nitrogen at room temperature for 48 hours. 200 ml of 1 M Na2CO3 was added to the mixture, and the suspension was filtered. Ethanol was evaporated from the filtrate. The filter cake was washed with ethyl acetate and mixed with the remaining filtrate. The resulting mixture was extracted twice with ethyl acetate, and the combined organic layers were dried over Na2SO4 and evaporated to dryness. Next, the unpurified substance was purified as a dry pack on Isolute HM-N by silica gel chromatography using DCM / MeOH as the eluent, yielding the marked compound (1699 mg, 67.6%) as a yellow solid with 75% purity by UV elution. MS: 520.1[M+H] + ,ESI pos

[0334] Step 3: 4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]-2-chlorobenzoic acid 4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chlorobenzoate methyl ester (1699 mg, 2.45 mmol, 1 equivalent) was dissolved in THF (5 mL) and MeOH (5 mL). Lithium hydroxide monohydrate (1.03 g, 24.51 mmol, 10 equivalents) was added, and the reaction mixture was stirred at 22°C for 24 hours. The clear solution was acidified with 4 M HCl solution (pH approximately 1). The organic solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate and water, and the mixture was extracted twice with RINKAN. The combined organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to obtain the marked compound (1518 mg, quantitative) as an orange solid, which was used without further purification. MS 504.1 [MH] - ,ESI neg

[0335] Intermediate Y2 2-[[4-(methoxymethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyrazole-1-yl]pyrazole-1-yl]methoxy]ethyl-trimethyl-silane [ka] Step 1: 2-[[4-(methoxymethyl)pyrazole-1-yl]methoxy]ethyl-trimethyl-silane To a solution of [1-(2-trimethylsilylethoxymethyl)pyrazole-4-yl]methanol [1382867-01-7] (5.5 g, 24.08 mmol, 1 equivalent) in THF (100 mL), 60% sodium hydride (1.44 g, 36.13 mmol, 1.5 equivalents) in oil was slowly added at 0°C. After the addition, the reaction mixture was stirred at 0°C for 1 hour. Next, iodomethane (1.8 mL, 28.9 mmol, 1.2 equivalents) was added to the mixture at 0°C. The reaction mixture was stirred at 25°C for 12 hours. The reaction was stopped with NH4Cl (100.0 mL) and extracted with SiO2 (100.0 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated. This unpurified product was purified by silica gel chromatography using PE / siRNA as the eluent to obtain the marked compound (5 g, 20.63 mmol, yield 78.54%) as a yellow oily substance. MS:243.3,[M+H] + ,ESI pos

[0336] Step 2: 2-[[3-bromo-4-(methoxymethyl)pyrazole-1-yl]methoxy]ethyl-trimethyl-silane To a solution of 2-[[4-(methoxymethyl)pyrazole-1-yl]methoxy]ethyl-trimethyl-silane (4.0 g, 16.5 mmol, 1 equivalent) in THF (60 mL), 2 M LDA (16.5 mL, 33 mmol, 2 equivalents) was added under nitrogen at -78°C. The mixture was stirred at -78°C for 1 hour. Next, 1,2-dibromotetrachloroethane (8.0 g, 24.57 mmol, 1.49 equivalents) in THF (40 mL) was added at -78°C. The mixture was stirred at -78°C for 2 hours. The reaction mixture was poured into an aqueous HCl solution (0.5 M, 100 mL) and extracted with EA (100 mL x 3). The organic layer was washed with saline solution, dried over Na2SO4, and concentrated to dryness. Next, the unpurified product was purified by flash column (with 0.1% FA as an additive), dried by freeze-drying, and the marked compound (3.5 g, 10.89 mmol, yield 66.01%) was obtained as a pale yellow oily substance. MS:219.0[M-OCH2CH2SiMe3] ESI pos

[0337] Step 3: [4-(methoxymethyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-3-yl]boronic acid A mixture of bis(pinacolato)diborone (2.61 g, 10.27 mmol, 1.1 equivalent), 2-[[3-bromo-4-(methoxymethyl)pyrazole-1-yl]methoxy]ethyl-trimethyl-silane (3.0 g, 9.34 mmol, 1 equivalent), potassium acetate (0.88 mL, 14.01 mmol, 1.5 equivalents), and X-PHOS (890.27 mg, 1.87 mmol, 0.200 equivalents) in 1,4-dioxane (20 mL) was degassed and purged three times with N2. Then, tris(dibenzylideneacetone)dipalladium(0) (855.04 mg, 0.930 mmol, 0.100 equivalents) was added to the mixture. The reaction mixture was stirred at 100°C for 16 hours under an N2 atmosphere. The mixture was filtered and concentrated under reduced pressure. The unpurified substance was purified by preparative HPLC (with 0.1% FA as an additive), and the labeled compound (1.7 g, 63.6%) was obtained as a yellow oily substance. MS: 287.1[M+H] + ,ESI pos

[0338] Step 4: 2-[[3-[4-bromo-3-(trifluoromethyl)pyrazole-1-yl]-4-(methoxymethyl)pyrazole-1-yl]methoxy]ethyl-trimethyl-silane A mixture of [4-(methoxymethyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-3-yl]boronic acid (1.2 g, 4.19 mmol, 1 equivalent), 4-bromo-3-(trifluoromethyl)-1H-pyrazole (1.2 g, 5.58 mmol, 1.33 equivalents), copper(II) acetate monohydrate (0.84 g, 4.19 mmol, 1 equivalent), and a 4 Å molecular sieve (1.0 g) was degassed and purged four times with N2 gas. DMF (14 mL) and pyridine (1.7 mL, 20.96 mmol, 5 equivalents) were added to the mixture by syringe. The mixture was stirred under oxygen at 80°C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The unpurified substance was purified by flash column (with 0.1% FA as an additive), dried by freeze-drying, and the marked compound (1 g, 2.2 mmol, yield 52.38%) was obtained as a green oily substance. MS 425.2[M-30+H]ESI pos

[0339] Step 5: 2-[[4-(methoxymethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyrazole-1-yl]pyrazole-1-yl]methoxy]ethyl-trimethyl-silane To a mixture of 2-[[3-[4-bromo-3-(trifluoromethyl)pyrazole-1-yl]-4-(methoxymethyl)pyrazole-1-yl]methoxy]ethyl-trimethyl-silane (900.0 mg, 1.98 mmol, 1 equivalent) in THF (9 mL), 1.3 Mi-Pr-MgCl·LiCl (3.6 mL, 4.68 mmol, 2.37 equivalents) was added under nitrogen at 0°C. The mixture was stirred at 20°C for 2 hours. Then, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (489.6 mg, 2.63 mmol, 1.33 equivalents) was added to the mixture at 0°C. The mixture was stirred at 20°C for 2 hours. The reaction mixture was poured into 0.5 M HCl (50 mL) and extracted with toluene (50 mL x 2). The organic matter was washed with water (50 mL x 2), followed by saturated sodium chloride solution (50 mL x 1). The organic layer was then separated, dried (MgSO4), concentrated, and dried to obtain the marked compound (1500 mg, 2.99 mmol, 99.7% yield) as a yellow oily substance, which was used without further purification. MS:471.4 [M-30+H] ESI pos

[0340] Intermediate Y3 tert-butyl4-[4-[4-[[5-[1-(4-amino-5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]-2-chlorobenzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate [ka] Step 1: N-(2-fluoro-5-nitro-4-pyridyl)-1,1-diphenyl-methanymine Diphenylmethaneimine (0.6 mL, 3.6 mmol, 1.2 equivalents) was added to a solution of 2,4-difluoro-5-nitropyridine (480.0 mg, 3 mmol, 1 equivalent) and triethylamine (0.84 mL, 6 mmol, 2 equivalents) in ACN (10 mL). The mixture was stirred at 20°C for 4 hours. The mixture was diluted with EA (40 mL) and then washed with saline solution (20 mL x 2). The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the marked compound (1.2 g, 3.73 mmol, quantitative yield) as a red, rubbery substance, which was used without further purification. MS:322.1,[M+H] + ,ESI pos

[0341] Step 2: tert-butyl4-[4-[4-[[5-[1-[4-(benzhydrideneamino)-5-nitro-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate To a solution of tert-butyl 4-[4-[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazole-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate[2489205-74-3] (400.0 mg, 0.580 mmol, 1 equivalent) and triethylamine (0.24 mL, 1.73 mmol, 3 equivalents) in DMSO (6 mL), N-(2-fluoro-5-nitro-4-pyridyl)-1,1-diphenyl-methanymine (463.57 mg, 0.870 mmol, 1.5 equivalents) was added. The mixture was stirred at 80°C for 16 hours. The mixture was diluted with EA (100 mL) and then washed with saline solution (30 mL x 3). The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the marked compound (800 mg, 0.800 mmol, quantitative yield) as a pale yellow solid, which was used without further purification. MS:894.4,[M-Boc+H] + ,ESI pos

[0342] Step 3: tert-butyl4-[4-[4-[[5-[1-(4-amino-5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate To a solution of tert-butyl 4-[4-[4-[[5-[1-[4-(benzhydrideneamino)-5-nitro-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (800.0 mg, 0.560 mmol, 1 equivalent) and sodium acetate (462 mg, 5.63 mmol, 10 equivalents) in methanol (10 mL), hydroxylamine hydrochloride (313 mg, 4.51 mmol, 8 equivalents) was added. The mixture was stirred at 20°C for 5 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions) to obtain the marked compound (440 mg, 0.530 mmol, yield 94.11%) as a pale yellow solid. MS 730.4,[M-Boc+H] + ,ESI pos

[0343] Example Z14 [ka] Step 1: N-[4-[4-(aminomethyl)piperidine-1-carbonyl]-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 1:1 formic acid To a solution of 4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]-2-chlorobenzoic acid (15.7 mg, 0.031 mmol, 1 equivalent) in N,N-dimethylformamide (1 mL), HATU (14.1 mg, 0.037 mmol, 1.2 equivalents) and Et3N (21.6 μL, 0.155 mmol, 5 equivalents) were added. The mixture was stirred at room temperature for 10 minutes and then added to N-(4-piperidylmethyl)carbamate tert-butyl ester (10.6 mg, 0.050 mmol, 1.6 equivalents). The reaction mixture was stirred at room temperature overnight. Next, the mixture was evaporated to dryness, dissolved in dichloromethane (1 mL), and treated overnight at room temperature with 4 M HCl (77.5 μL, 0.310 mmol, 10 equivalents). The mixture was concentrated to dryness, dissolved in 1.5 mL of MeOH, and purified by preparative HPLC using a Gemini 5 μm C18 75x30 column and water (+0.05% formic acid) / acetonitrile as the eluent to obtain the marked compound (12.4 mg, 65.9%). MS: 602.3[M+H] + ,ESI pos

[0344] The following compounds were prepared in the same manner as in Example Z14. [Table 23-1] [Table 23-2] [Table 23-3] [Table 23-4] [Table 23-5] [Table 23-6] [Table 23-7] [Table 23-8] [Table 23-9] [Table 23-10] [Table 23-11]

[0345] Example Z22 [ka] Step 1: 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[2-[(2S,4R)-4-hydroxyprolyl]-2,8-diazaspiro[4.5]decane-8-carbonyl]phenyl]-1-methylimidazole-2-carboxamide, 1:1 formic acid (2S, 4R)-1-tert-butoxycarbonyl-4-hydroxyproline (6.24 mg, 0.027 mmol, 1.5 equivalents) dissolved in DMF was mixed with HATU (10.27 mg, 0.027 mmol, 1.5 equivalents) and Et3N (7.53 uL, 0.054 mmol, 3 equivalents). The mixture was stirred at room temperature for 10 minutes, and then 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(2,8-diazaspiro[4.5]decane-8-carbonyl)phenyl]-1-methylimidazole-2-carboxamide, 1:1 formic acid (11.3 mg, 0.018 mmol, 1 equivalent) was added. The mixture was stirred at room temperature overnight, and then evaporated to dryness. Next, the residue was dissolved in 1 ml of DCM and treated overnight at room temperature with 4 M HCl (180 uL, 0.720 mmol, 40 equivalents). The mixture was then evaporated to dryness, dissolved in 1 ml of MeOH, and directly purified by preparative HPLC using a Gemini 5um C1875 x 30 column and water (+0.05% formic acid) / acetonitrile as the eluent, yielding the marked compound (4.2 mg, 29.3%). MS: 739.5 [MH] - ,ESI neg

[0346] The following compounds were prepared in the same manner as in Example Z22. If the preparation of the reagent is not yet described, it can be prepared in the same manner as in Example Z14. [Table 24-1] [Table 24-2] [Table 24-3] [Table 24-4] [Table 24-5] [Table 24-6] [Table 24-7]

[0347] Example Z31 N-[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]-5-[1-(6-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide [ka] Step 1: 4-[4-[2-chloro-4-[[5-[1-(6-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate tert-butyl ester A mixture of 4-[4-[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazole-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylic acid tert-butyl ester [2489205-74-3] (50 mg, 0.072 mmol, 1 equivalent) in ultra-dried N,N-dimethylformamide (1.6 mL) was treated with K2CO3 (19.94 mg, 0.144 mmol, 2 equivalents) and stirred at room temperature for 5 minutes. Then, 2-fluoro-6-methoxypyridine (28.6 mg, 26 μL, 0.225 mmol, 3.12 equivalents) was added. The mixture was stirred at 125 °C for 30 minutes under microwave irradiation. Next, K2CO3 (19.94 mg, 0.144 mmol, 2 equivalents) and 2-fluoro-6-methoxypyridine (28.6 mg, 26 μL, 0.225 mmol, 3.12 equivalents) were added again, and heating under microwave irradiation was repeated at 125°C for 30 minutes. The reaction mixture was diluted with a semi-saturated NH4Cl aqueous solution (40 mL) and extracted with ₹ (3 × 20 mL). The combined organic layer was washed with saline solution (15 mL), dried over sodium sulfate, filtered, and concentrated. The unpurified substance was purified by silica gel chromatography using DCM / MeOH as the eluent to obtain the marked compound (22 mg, 38.11%) as a grayish-white solid. MS:798.5,[MH] - ,ESI neg

[0348] Step 2: N-[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]-5-[1-(6-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide A mixture of 4-[4-[2-chloro-4-[[5-[1-(6-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate tert-butyl ester (22 mg, 0.027 mmol, 1 equivalent) in dichloromethane (5 mL) and TFA (1 mL, 12.98 mmol, 472.14 equivalents) was stirred at room temperature for 5 hours and then concentrated under reduced pressure. The unpurified substance was purified by reverse-phase HPLC to obtain the marked compound (7 mg, 36.37%) as a white lyophilized powder. MS:698.3,[MH] - ,ESI neg

[0349] The following compounds were prepared in the same manner as in Example Z31. [Table 25]

[0350] Example Z10 5-[1-(6-amino-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]-1-methylimidazole-2-carboxamide, 1:1 formic acid [ka] Step 1: 4-[4-[2-chloro-4-[[1-methyl-5-[1-(6-nitro-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate tert-butyl ester In a 5 ml microwave vial, 1.5 ml of N-methyl-2-pyrrolidinone was mixed with 4-[4-[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazole-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate tert-butyl ester [2489205-74-3] (100 mg, 0.144 mmol, 1 equivalent), potassium carbonate (59.82 mg, 0.433 mmol, 3 equivalents), and 5-chloro-2-nitropyridine (34.31 mg, 0.216 mmol, 1.5 equivalents). The vial was capped and heated in a microwave at 120°C for 60 minutes. Water was added to the reaction mixture, and the product was extracted with AcOEt. The unpurified substance was purified by silica gel column chromatography using MeOH / DCM as the eluent to obtain the indicated compound (98.3 mg, 48.48%) as a brown solid, which was used without further purification. MS: 815.3 [M+H] + ,ESI pos

[0351] Step 2: 5-[1-(6-amino-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]-1-methylimidazole-2-carboxamide. 1:1 formic acid To a mixture of 4-[4-[2-chloro-4-[[1-methyl-5-[1-(6-nitro-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylic acid tert-butyl ester (98.3 mg, 0.070 mmol, 1 equivalent) in ethanol (900 μL) and water (300 μL), ammonium chloride (187.06 mg, 3.5 mmol, 50 equivalents) and zinc (91.49 mg, 1.4 mmol, 20 equivalents) were added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then filtered, the solvent was evaporated, and the residue was dried under high vacuum. The residue was dissolved in dichloromethane (1 ml), and 4M HCl (87.42 μL, 0.350 mmol, 5 equivalents) in dioxane was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness and then purified by preparative HPLC to obtain the marked compound (9.2 mg, 17.27%) as a pale yellow lyophilized solid. MS: 685.2[M+H] + ,ESI pos

[0352] Example Z29 5-[1-(5-aminopyrazine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]-1-methylimidazole-2-carboxamide, 1:1 formic acid [ka] This example, similar to Example Z10, was prepared in the first step using 2-bromo-5-nitropyrazine in acetonitrile at 80°C. The marked compound was obtained as a white solid (4.2 mg). MS: 686.2[M+H] + ,ESI pos

[0353] Example Z28 N-[4-(5-aminopentylcarbamoyl)-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide, 1:1 hydrogen chloride [ka] Step 1: N-[5-[[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazole-4-yl]imidazole-2-carbonyl]amino]benzoyl]amino]pentyl]carbamate tert-butyl ester 2-Chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazole-4-yl]imidazole-2-carbonyl]amino]benzoic acid [2489205-74-3] (200 mg, 0.483 mmol, 1 equivalent) was mixed with N,N-dimethylformamide (4 mL) to obtain a pale yellow suspension. DIPEAγ (187 mg, 253.29 μL, 1.45 mmol, 3 equivalents) and N-(5-aminopentyl)carbamate tert-butyl ester (147 mg, 150.9 μL, 0.725 mmol, 1.5 equivalents) were added, followed by HATU (275.7 mg, 0.725 mmol, 1.5 equivalents). The reaction mixture was stirred overnight at room temperature, water was added, and the mixture was extracted with AcOEt. The organic layer was washed with 5% LiCl solution and saline solution, and then dried over Na2SO4. After filtering and evaporating the solvent, the residue was purified by silica gel column chromatography using DCM / MeOH as the eluent to obtain the marked compound (212 mg, 68.94%) as a brown foam. MS: 596[MH] - ,ESI neg

[0354] Steps 2+3: N-[4-(5-aminopentylcarbamoyl)-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide, 1:1 hydrogen chloride The indicated compound was prepared in the same manner as in Example Z10, using 2-bromo-5-nitropyridine in acetonitrile at 80°C in the first step, and obtained as a yellow solid (177 mg, UV purity 77%). MS: 590.2[M+H] + ,ESI pos

[0355] Example Z75 N-[3-Chloro-4-(4-Isonipecotoylpiperazine-1-carbonyl)phenyl]-5-[1-(6-Methoxy-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide [ka] Step 1: 4-[4-[2-chloro-4-[[5-[1-(6-methoxy-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate tert-butyl ester A mixture of 4-[4-[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazole-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylic acid tert-butyl ester [2489205-74-3] (56 mg, 0.081 mmol, 1 equivalent) and (6-methoxy-3-pyridyl)boronic acid (22.24 mg, 0.145 mmol, 1.8 equivalents) in ultra-dried N,N-dimethylformamide (1.25 mL) was treated with cupric acetate (30.82 mg, 0.170 mmol, 2.1 equivalents) and pyridine (12.78 mg, 13.07 μL, 0.162 mmol, 2 equivalents), and the mixture was stirred at 50°C under air for 20.5 hours. The reaction mixture was suspended in 15 mL of NaHCO3 aqueous solution and 5 mL of 5% EDTA aqueous solution, and extracted with toluene (3 × 10 mL). The combined organic layer was washed with saline solution (10 mL), dried over Na₂SO₄, filtered, and concentrated. Purification by MPLC using heptane / toluene / EtOH as the eluent yielded the marked compound (21 mg, 29.88%) as a grayish-white solid. MS 798.5, [MH] - ,ESI neg

[0356] Step 2: N-[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]-5-[1-(6-methoxy-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamyl A mixture of 4-[4-[2-chloro-4-[[5-[1-(6-methoxy-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylic acid tert-butyl ester (31 mg, 0.036 mmol, 1 equivalent) in dichloromethane (4 mL) and TFA (1.18 g, 0.800 mL, 10.38 mmol, 291.36 equivalents) was stirred at room temperature for 3 hours and concentrated. Purification by reverse-phase HPLC yielded the marked compound (3.1 mg, 11.8%) as a white lyophilized solid. MS:744.4,[M+HCOO]- ,ESI neg

[0357] Example Z30 N-[3-chloro-4-[4-[(2S,4R)-4-hydroxyprolyl]piperazine-1-carbonyl]phenyl]-5-[1-(6-chloro-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide, 1:1 hydrogen chloride [ka] Step 1: Methyl 2-chloro-4-(1-methyl-5-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-1H-imidazole-2-carboxamide)benzoate Methyl 4-(5-bromo-1-methyl-1H-imidazole-2-carboxamide)-2-chlorobenzoate [2489205-77-6] (3.3 g, 8.86 mmol, 1 equivalent), (3-(trifluoromethyl)-1H-pyrazole-4-yl)boronic acid (1.59 g, 8.86 mmol, 1 equivalent), and Na2CO3 (2.16 g, 20.4 mmol, 2.30 equivalents) were passed through dioxane (20 ml) and water (2 ml) with argon for 2 minutes. Then, 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (dtbpf) (577 mg, 886 μmol, 0.1 equivalent) was added. The mixture was divided into three pressure tubes, sealed, and then heated to 100°C for 60 minutes under microwave irradiation. (3-(trifluoromethyl)-1H-pyrazole-4-yl)boronic acid (797 mg, 4.43 mmol, 0.5 equivalents) and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (dtbpf) (289 mg, 443 μmol, 0.05 equivalents) were added again, and the reaction mixture was heated to 100°C for 30 minutes under microwave irradiation. The reaction mixture was filtered through dikalyte and washed with MeOH. The resulting solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using MeOH in DCM as the eluent to obtain the marked compound (2.85 g, 6.33 mmol, yield 71.5%) as a brown solid. MS: 428.2[M+H]+

[0358] Step 2: 2-Chloro-4-[[1-methyl-5-[1-(6-nitro-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carbonyl]amino]methyl benzoate / 2-Chloro-4-[[5-[1-(6-chloro-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methyl-imidazole-2-carbonyl]amino]methyl benzoate The indicated compound was prepared using 5-chloro-2-nitropyridine, starting from 2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazole-4-yl]imidazole-2-carbonyl]amino]methyl benzoate (800 mg), in the same manner as in Example Z10. A mixture of 2-chloro-4-[[5-[1-(6-chloro-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methyl-imidazole-2-carbonyl]amino]methyl benzoate in an approximately 2:1 ratio was obtained as a pale yellow solid (215.5 mg, 11.02%). The unpurified substance was used without further purification. MS: 550.1[M+H] + ,ESI pos

[0359] Step 3: 2-Chloro-4-[[5-[1-(6-chloro-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]benzoic acid A mixture of 2-chloro-4-[[5-[1-(6-chloro-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]methyl benzoate and 2-chloro-4-[[1-methyl-5-[1-(6-nitro-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carbonyl]amino]methyl benzoate (215 mg, 0.197 mmol, 1 equivalent) was mixed with methanol (0.500 mL) and tetrahydrofuran (1 mL) to obtain a yellow solution. 1 M LiOH (493.51 μL, 0.494 mmol, 2.5 equivalents) was added, and the reaction mixture was stirred overnight at room temperature, then at 40°C for a further 24 hours. After cooling to room temperature, volatile substances were removed. The residue was diluted with water and acidified with 1 M HCl solution. The resulting suspension was filtered and washed with water. The resulting pale brown solid was purified by preparative reverse-phase HPLC to obtain 2-chloro-4-[[5-[1-(6-chloro-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]benzoic acid (23.4 mg, 18.05%) as a pale yellow solid. MS: 525.0[M+H] + ,ESI pos

[0360] Step 4: (2S,4R)-2-[4-[2-chloro-4-[[5-[1-(6-chloro-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-4-hydroxypyrrolidine-1-carboxylate tert-butyl ester 2-chloro-4-[[5-[1-(6-chloro-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]benzoic acid (23 mg, 0.035 mmol, 1 equivalent) was mixed with N,N-dimethylformamide (400 μL) to obtain a pale yellow solution. (2S, 4R)-4-hydroxy-2-(piperazine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (15.7 mg, 0.053 mmol, 1.5 equivalents), DIPEA (13.6 mg, 18.3 μL, 0.105 mmol, 3 equivalents), and HATU (19.98 mg, 0.053 mmol, 1.5 equivalents) were added, and the reaction mixture was stirred at room temperature for 1 hour. Water was then added to the reaction mixture, and the product was extracted with AcOEt. The organic layer was washed with 5% LiCl solution and saline solution, and dried over Na2SO4. After filtration and evaporation to dryness, the unpurified material was purified by silica gel chromatography using DCM:MeOH as the eluate, and the marked compound (29 mg, 99.56%) was obtained as a grayish-white foam. MS:806.2[M+H] + ,ESI pos.

[0361] Step 5: N-[3-chloro-4-[4-[(2S,4R)-4-hydroxyprolyl]piperazine-1-carbonyl]phenyl]-5-[1-(6-chloro-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide, 1:1 hydrogen chloride In a 5 ml round-bottom flask, (2S,4R)-2-[4-[2-chloro-4-[[5-[1-(6-chloro-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (5 mg, 0.006 mmol, 1 equivalent) was mixed with dichloromethane (100 μL) to obtain a colorless solution. 4 M HCl (7.52 μL, 0.030 mmol, 5 equivalents) was added to the dioxane, and the reaction mixture was stirred at room temperature for 1 hour. After removing volatile substances, the residue was freeze-dried to obtain the marked compound (3.4 mg, 68.5%) as a white freeze-dried solid. MS:706.2 [M+H] + ,ESI pos.

[0362] Example Z89 5-[1-[5-(2-aminoethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]-1-methylimidazole-2-carboxamide, 1:2 2,2,2-trifluoroacetic acid [ka] Step 1: 4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylic acid 9H-fluoren-9-yl methyl ester A mixture of 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-1-methylimidazole-2-carboxamide, 1:1 formic acid (100 mg, 0.162 mmol, 1 equivalent), and 1-[(9h-fluoren-9-ylmethoxy)carbonyl]piperidine-4-carboxylic acid (59.8 mg, 0.170 mmol, 1.05 equivalents) in N,N-dimethylformamide (2 mL) was treated with N-ethyldiisopropylamine (83.8 mg, 113 μL, 0.649 mmol, 4 equivalents), followed by PyAOP (101.5 mg, 0.195 mmol, 1.2 equivalents), and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was transferred to hemisaturated NaHCO3 (50 mL) and extracted with ethyl acetate (3 × 22 mL). The combined organic layer was washed with saline solution (20 mL), dried over Na2SO4, filtered, and concentrated. Purification by MPLC using heptane / ethyl acetate / etOH as the eluent yielded the marked compound (137 mg, 85.65%) as a pale yellow solid. MS: 454.6, [M + 2H] 2+ ,ESI pos

[0363] Step 2: 4-[4-[4-[[5-[1-[5-[2-(tert-butoxycarbonylamino)ethylamino]-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylic acid 9H-fluoren-9-yl methyl ester A mixture of 4-[4-[4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylic acid 9H-fluoren-9-yl methyl ester (137 mg, 0.139 mmol, 1 equivalent) in dichloromethane (2 mL) was treated with molecular sieves, 3 Å, N-(2-ketoethyl)carbamate tert-butyl ester (33.2 mg, 0.208 mmol, 1.5 equivalents) and acetic acid (15.9 μL, 0.278 mmol, 2 equivalents), cooled to 0°C, and stirred for 10 minutes. Subsequently, sodium triacetoxyborohydride (51.5 mg, 0.243 mmol, 1.75 equivalents) was gradually added over 30 minutes, followed by stirring at room temperature for 2 hours. The mixture was diluted with toluene and semi-saturated NaHCO3 aqueous solution (50 mL) and extracted with toluene (3 × 20 mL). The combined organic layer was washed with saline solution (20 mL), dried over Na2SO4, filtered, and concentrated. Purification by MPLC using heptane / toluene / EtOH as the eluent yielded the marked compound (128 mg, 78.94%) as a grayish-white solid, which was used without further purification. MS:1094.9,[M+HCOO] - ,ESI neg

[0364] Step 3: N-[2-[[6-[4-[2-[[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]carbamoyl]-3-methyl-imidazole-4-yl]-3-(trifluoromethyl)pyrazole-1-yl]-3-pyridyl]amino]ethyl]carbamate tert-butyl ester A mixture of 4-[4-[4-[[5-[1-[5-[2-(tert-butoxycarbonylamino)ethylamino]-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylic acid 9H-fluoren-9-yl methyl ester (128 mg, 0.110 mmol, 1 equivalent) in acetonitrile (2.5 mL) was treated with 2 M dimethylamine in THF (548.3 μL, 1.1 mmol, 10 equivalents), and the mixture was stirred at room temperature for 3 hours and evaporated. The residue was obtained by purification by MPLC using DCM / MeOH / Et3N as the eluent, dissolved in 0.1 M NaOH (25 mL), and extracted with siRNA (3 × 12 mL). The combined organic matter was washed with saline solution (12 ml), dried (Na2SO4), filtered, and evaporated to obtain the marked compound (60 mg, 60.77%) as a white solid. MS:872.6,[M+HCOO] - ,ESI neg

[0365] Step 4: 5-[1-[5-(2-aminoethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]-1-methylimidazole-2-carboxamide, 1:2 2,2,2-trifluoroacetic acid A mixture of N-[2-[[6-[4-[2-[[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]carbamoyl]-3-methylimidazole-4-yl]-3-(trifluoromethyl)pyrazole-1-yl]-3-pyridyl]amino]ethyl]carbamate tert-butyl ester (23 mg, 0.026 mmol, 1 equivalent) in dichloromethane (0.958 mL) and 4M HCl (613.13 mg, 510.94 μL, 2.04 mmol, 80 equivalents) was stirred at room temperature for 4.5 hours and evaporated. Purification by reverse-phase HPLC yielded the marked compound (12 mg, 49.12%) as a white lyophilized solid. 772.7,[M+HCOO] - ,ESI neg

[0366] Example Z76 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(diethylcarbamoyl)phenyl]-1-methylimidazole-2-carboxamide [ka] 4-[[5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]-2-chlorobenzoic acid (18 mg, 0.029 mmol, 1 equivalent) in N,N-dimethylformamide (2 mL) and Et3N (14.58 mg, 20.09 μL, 0.144 mmol, 5 equivalents) was mixed with TBTU (12.03 mg, 0.037 mmol, 1.3 equivalents) and DSPE-PEG-2K-amine [47922-26-4] (104.48 mg, 0.037 mmol, 1.3 equivalents). The reaction mixture was stirred at room temperature. The mixture was purified by preparative HPLC to obtain the marked compound (5.6 mg, 33.94%) as a pale yellow powder and an unexpected byproduct. MS: 559.3 [MH] - ,ESI neg

[0367] Example Z88 N-[6-[4-[2-[[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]carbamoyl]-3-methylimidazole-4-yl]-3-(trifluoromethyl)pyrazole-1-yl]-3-pyridyl]isonipecotamide, 1:2 hydrogen chloride [ka] Step 1: 4-[[6-[4-[2-[[4-[4-(1-tert-butoxycarbonylisopicotoyl)piperazine-1-carbonyl]-3-chlorophenyl]carbamoyl]-3-methylimidazole-4-yl]-3-(trifluoromethyl)pyrazole-1-yl]-3-pyridyl]carbamoyl]piperidine-1-carboxylate tert-butyl ester 1-tert-butoxycarbonylisopicotinic acid (264.2 mg, 1.15 mmol, 1.05 equivalents) and 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-1-methylimidazole-2-carboxamide (630 mg, 1.1 mmol, 1 equivalent) were dissolved in super-dried N,N-dimethylformamide (5.49 mL). DIEA (425.6 mg, 575.1 uL, 3.29 mmol, 3 equivalents) was added, and the mixture was cooled to 0°C. HATU (500.8 mg, 1.32 mmol, 1.2 equivalents) was added, and the mixture was stirred overnight at room temperature. The mixture was diluted with DCM and washed with 2 × 30 mL of water and saline solution. The aqueous layer was extracted with 2 × 30 mL of DCM. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The unpurified material was purified by silica gel chromatography to obtain the marked compound (110 mg, 9.35%) as a pink, waxy solid. MS: 896.4[M+H-BOC] + ,ESI pos

[0368] Step 2: N-[6-[4-[2-[[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]carbamoyl]-3-methylimidazole-4-yl]-3-(trifluoromethyl)pyrazole-1-yl]-3-pyridyl]isonipecotamide, 1:2 hydrogen chloride 4-[[6-[4-[2-[[4-[4-(1-tert-butoxycarbonylisopicotoyl)piperazine-1-carbonyl]-3-chlorophenyl]carbamoyl]-3-methylimidazole-4-yl]-3-(trifluoromethyl)pyrazole-1-yl]-3-pyridyl]carbamoyl]piperidine-1-carboxylic acid tert-butyl ester (110 mg, 0.103 mmol, 1 equivalent) was dissolved in 1,4-dioxane in 4M hydrochloric acid (769.97 uL, 3.08 mmol, 30 equivalents), and the mixture was stirred overnight at room temperature. The mixture was smeared with diethyl ether (6 × 50 mL), the solid was recovered, and concentrated under reduced pressure to obtain the marked compound (79 mg, 81.45%) as a light brown crystalline solid. MS: 794.5 [MH]- ,ESI neg

[0369] Example Z9 N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[4-(methoxymethyl)-1H-pyrazole-3-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide, formic acid [ka] Step 1: 5-bromo-N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide To a solution of 1-methylpiperidine-4-carboxylic acid (3301.83 mg, 23.06 mmol, 1.2 equivalents) in DMF (80 mL), N,N-diisopropylethylamine (10.04 mL, 57.65 mmol, 3 equivalents), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (8768.37 mg, 23.06 mmol, 1.2 equivalents), and 5-bromo-N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-1-methylimidazole-2-carboxamide [2489205-92-5] (8.2 g, 19.2 mmol, 1 equivalent) were added at 0°C. The mixture was stirred under N2 at 0°C for 2 hours. The mixture was directly purified by reverse-phase chromatography (with FA as an additive) and dried by freeze-drying to obtain the marked compound (7 g, 12.68 mmol, yield 66.01%) as a white solid. MS: 553.1 [M+H] + ,ESI pos

[0370] Step 2: N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[4-(methoxymethyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-3-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide 5-Bromo-N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide (144.99 mg, 0.260 mmol, 1 equivalent) and 2-[[4-(methoxymethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyrazole-1-yl]pyrazole-1-yl]methoxy]ethyl-trimethyl-silane (200.0 mg, 0.260 mmol, 1 equivalent) were dissolved in 1,4-dioxane (5 mL) and water (0.500 mL) under argon in a glove box, with sodium carbonate (55.69 mg, 0.530 mmol, 2 equivalents) and CyJohnPhos Pd(clotyl)Cl(Pd-188[692782-19-7]) (25.69 mg, 0.040 mmol, 0.150 equivalents) was added. The mixture was stirred at 90 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by flash column (with 0.1% FA as an additive) and dried by freeze-drying to obtain the marked compound (100 mg, 0.120 mmol, yield 44.92%) as a yellow solid. MS:847.6,[M+H],ESI pos

[0371] Step 3: N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[4-(methoxymethyl)-1H-pyrazole-3-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide, formic acid To a solution of N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[4-(methoxymethyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-3-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide (100.0 mg, 0.120 mmol, 1 equivalent) in DCM (2.5 mL), TFA (0.3 mL) was added. The mixture was stirred at 20°C for 1 hour. The mixture was then concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (2.5 mL), and then NH3·H2O (0.5 mL) was added. The mixture was stirred at 20°C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (with 0.1% FA as an additive) and dried by lyophilization to obtain the marked compound (50 mg, 0.070 mmol, yield 52.82%) as a white solid. MS:717.2,[M+H],ESI pos

[0372] Example Z77 5-[1-(6-amino-5-methyl-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid [ka] Step 1: tert-butyl4-[4-[4-[[5-[1-(6-amino-5-methyl-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate tert-butyl 4-[4-[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazole-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate[2489205-74-3](50.0mg, 0.070mmol, 1 equivalent), 2-amino-5-iodo-3-methyl To a solution of tylpyridine (25.32 mg, 0.110 mmol, 1.5 equivalents), 2-(2,6-dimethylanilino)-2-oxoacetic acid (6.97 mg, 0.040 mmol, 0.500 equivalents), phosphoric acid, and potassium salt (45.9 mg, 0.220 mmol, 3 equivalents) in DMSO (2 mL), copper(I) iodide (13.7 mg, 0.070 mmol, 1 equivalent) was added under N2. The mixture was degassed and then stirred under N2 at 120°C for 16 hours. The reaction mixture was cooled to room temperature. Ether (5 mL) and water (10 mL) were added, and the layers were separated. The aqueous phase was extracted with Ether (10 mL x 2). The combined extract was washed with saline solution (30 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (FA conditions) to obtain the marked compound (50 mg, yield 86.7%) as a yellow solid. MS: 799.5[M+H] + ,ESI pos

[0373] Step 2: 5-[1-(6-amino-5-methyl-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid Trifluoroacetic acid (2.0 mL, 25.96 mmol, 414.96 equivalents) was added to a solution of tert-butyl 4-[4-[4-[[5-[1-(6-amino-5-methyl-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (50.0 mg, 0.060 mmol, 1 equivalent) in DCM (2 mL). The mixture was stirred at 10°C for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions) to obtain the marked compound (22.2 mg, 0.030 mmol, yield 47.62%) as a white solid. MS:699.3[M+H] + ,ESI pos

[0374] The following compounds were prepared in the same manner as in Example Z77. [Table 26]

[0375] Example Z74 5-[1-(6-amino-5-fluoro-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide [ka] Step 1: tert-butyl4-[4-[4-[[5-[1-(6-amino-5-fluoro-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate tert-butyl 4-[4-[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazole-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate[2489205-74-3](200.0mg, 0.290 mmol, 1 equivalent), trans-(1r,2r)-N,N'-bis To a solution of methyl-1,2-cyclohexanediamine (16.42 mg, 0.120 mmol, 0.400 equivalents), 5-bromo-3-fluoropyridine-2-amine (66.14 mg, 0.350 mmol, 1.2 equivalents), phosphoric acid, and potassium salt (0.07 mL, 0.870 mmol, 3 equivalents) in DMSO (5 mL), copper(I) iodide (0.01 mL, 0.290 mmol, 1 equivalent) was added. The mixture was degassed and then stirred under N2 at 120°C for 16 hours. Water (20 mL) and EA (20 mL) were then added, and the mixture was filtered through a Celite pad. The solid was washed with EA (10 mL x 2). The organic layer was separated from the filtrate. The aqueous layer was extracted with EA (20 mL x 2). The combined organic layers were washed with saline solution (20 mL x 2), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions) to obtain the labeled compound (40 mg, 0.050 mmol, yield 17.26%) as a pale yellow solid. MS: 803.0[M+H] + ,ESI pos

[0376] Step 2: 5-[1-(6-amino-5-fluoro-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide Trifluoroacetic acid (1.0 mL, 12.98 mmol, 260.64 equivalents) was added to a solution of tert-butyl 4-[4-[4-[[5-[1-(6-amino-5-fluoro-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (40.0 mg, 0.050 mmol, 1 equivalent) in DCM (2 mL). The mixture was stirred at 15°C for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions) to obtain the marked compound (14.8 mg, 0.020 mmol, yield 40.42%) as a white solid. MS 703.2,[M+H] + ,ESI pos

[0377] Example Z79 5-[1-(6-amino-2-methyl-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid [ka] This example was prepared using 5-iodo-6-methylpyridine-2-amine in the same manner as in Example Z74, and obtained as a white solid (20.4 mg). MS: 699.4[M+H] + ,ESIpos

[0378] Example Z81 5-[1-(5-amino-3-methyl-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide [ka] Step 1: tert-butyl 4-[4-[2-chloro-4-[[1-methyl-5-[1-(3-methyl-5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-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-pyrazole-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate[2489205-74-3] (100.0 mg, 0.140 mmol, 1 equivalent) and N,N-diisopropylethylamine (0.1 mL, 0.580 mmol, 4 equivalents) were dissolved in DMF (2 mL), to which 2-chloro-3-methyl-5-nitropyridine (37.35 mg, 0.220 mmol, 1.5 equivalents) was added. The mixture was stirred at 120 °C for 16 hours. The mixture was purified by preparative HPLC (FA conditions) to obtain the marked compound (92 mg, 0.110 mmol, yield 76.9%) as a light brown solid. MS:829.4,[M+H] + ,ESI pos

[0379] Step 2: tert-butyl4-[4-[4-[[5-[1-(5-amino-3-methyl-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]-2-chlorobenzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate Iron powder (96.98 mg, 1.74 mmol, 20 equivalents) was added to a solution of tert-butyl 4-[4-[2-chloro-4-[[1-methyl-5-[1-(3-methyl-5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (72.0 mg, 0.090 mmol, 1 equivalent) and saturated NH4Cl water (2.0 mL) and methanol (2 mL). The mixture was stirred at 30°C for 16 hours. The mixture was diluted with water (20 mL) and EA (20 mL) and then filtered. The filtrate was extracted with EA (30 mL x 2). The combined organic layers were washed with saline solution (30 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the marked compound (80 mg, 0.100 mmol, yield 115.28%) as a pale yellow solid. MS:799.4,[M+H] + ,ESI pos

[0380] Step 3: 5-[1-(5-amino-3-methyl-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide Trifluoroacetic acid (1.0 mL, 12.98 mmol, 129.68 equivalents) was added to a solution of tert-butyl 4-[4-[4-[[5-[1-(5-amino-3-methyl-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (80.0 mg, 0.100 mmol, 1 equivalent) in DCM (2 mL). The mixture was stirred at 15°C for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions) to obtain the marked compound (40.7 mg, 0.060 mmol, yield 56.88%) as a grayish-white solid. MS:699.2,[M+H] + ,ESI pos

[0381] Example Z86 5-[1-(5-amino-6-methylpyridine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl]-#N!-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid [ka] This compound was prepared in the same manner as Z81 using 6-chloro-2-methyl-3-nitropyridine in the first step. The marked compound was obtained as a grayish-white solid (42.7 mg). MS:699.4,[M+H] + ,ESI pos

[0382] Example Z82 5-[1-(5-amino-4-methyl-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide [ka] This compound was prepared in the same manner as Z81, using 2-chloro-4-methyl-5-nitropyridine and DMSO as the solvent in the first step. The marked compound was obtained as a pale yellow solid (33.7 mg). MS:699.2,[M+H] + ,ESI pos

[0383] Example Z83 5-[1-(5-amino-2-fluoro-4-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid [ka] This compound was prepared in the same manner as Z81 in the first step, using 2,4-difluoro-5-nitropyridine and trimethylamine as bases at 15°C. The marked compound was obtained as a gray solid (15.5 mg). MS:703.2,[M+H] + ,ESI pos

[0384] Example Z80 5-[1-(5-amino-4-chloro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid [ka] Step 1: tert-butyl4-[4-[4-[[5-[1-(5-amino-4-chloro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate To a solution of tert-butyl 4-[4-[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazole-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate[2489205-74-3] (100.0 mg, 0.140 mmol, 1 equivalent) and tert-butyl N-(4-chloro-6-fluoro-3-pyridyl)carbamate (49.82 mg, 0.200 mmol, 1.4 equivalents) in DMF (1 mL), cesium carbonate (70.51 mg, 0.220 mmol, 1.5 equivalents) was added. The mixture was stirred at 80°C for 16 hours. The mixture was filtered, concentrated, and purified by reverse-phase HPLC (FA) to obtain the marked compound (60 mg, 0.070 mmol, yield 45.21%) as a yellow oil. MS:919.4,[M+H] + ,ESI pos

[0385] Step 2: 5-[1-(5-amino-4-chloro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid To a solution of tert-butyl 4-[4-[4-[[5-[1-(5-amino-4-chloro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (20.0 mg, 0.020 mmol, 1 equivalent) in DCM (0.500 mL), trifluoroacetic acid (0.5 mL, 6.49 mmol, 265.98 equivalents) was added. The mixture was stirred at 15 °C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (FA conditions) to obtain the marked compound (13.6 mg, 0.020 mmol, yield 72.52%) as a white solid. MS:719.2,[M+H] + ,ESI pos

[0386] Example Z84 5-[1-(6-amino-2-fluoro-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid [ka] Step 1: 6-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-amine To a solution of 6-fluoro-5-iodopyridine-2-amine (670.0 mg, 2.82 mmol, 1 equivalent), bis(pinacolato)diborone (1072 mg, 4.22 mmol, 1.5 equivalents), and potassium acetate (829 mg, 8.45 mmol, 3 equivalents) in 1,4-dioxane (6 mL), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (229.71 mg, 0.280 mmol, 0.100 equivalents) was added under N2. The mixture was degassed and then stirred under N2 at 90°C for 18 hours. The mixture was cooled and then filtered through a Celite pad. The solid was washed with EA (10 mL x 3). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 1:0-2:1) to obtain the marked compound (620 mg, 2.6 mmol, yield 46.26%) as a light brown solid, which was used without further purification. MS:239.2,[M+H] + ,ESI pos

[0387] Step 2: tert-butyl4-[4-[4-[[5-[1-(6-amino-2-fluoro-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate To a solution of tert-butyl 4-[4-[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazole-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate[2489205-74-3] (120.0 mg, 0.170 mmol, 1 equivalent), 6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-amine (82.43 mg, 0.350 mmol, 2 equivalents), and 4-dimethylaminopyridine (42.3 mg, 0.350 mmol, 2 equivalents) in ACN (1.5 mL) and methanol (1.5 mL), cupric acetate (62.89 mg, 0.350 mmol, 2 equivalents) was added. The mixture was stirred under O2 at 50°C for 16 hours. Again, tert-butyl 4-[4-[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazole-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (120.0 mg, 0.170 mmol, 1 equivalent) was added to the mixture. The mixture was stirred for a further 24 hours at 50°C. Again, tert-butyl 4-[4-[2-chloro-4-[[1-methyl-5-[3-(trifluoromethyl)-1H-pyrazole-4-yl]imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (120.0 mg, 0.170 mmol, 1 equivalent) was added to the mixture. The mixture was stirred at 50°C for a further 24 hours. The mixture was then diluted with EA (20 mL). The mixture was filtered through a Celite pad. The cake was washed with EA (5 mL x 4). The combined filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions) to obtain the marked compound (20 mg, 0.020 mmol, yield 14.38%) as a light brown solid. MS:703.1,[M-Boc+H] + ,ESI pos

[0388] Step 3: 5-[1-(6-amino-2-fluoro-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid Trifluoroacetic acid (0.6 mL, 7.79 mmol, 417.02 equivalents) was added to a solution of tert-butyl 4-[4-[4-[[5-[1-(6-amino-2-fluoro-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (15.0 mg, 0.020 mmol, 1 equivalent) in DCM (0.400 mL). The mixture was stirred at 15 °C for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions) to obtain the marked compound (11.2 mg, 0.010 mmol, yield 78.42%) as a white solid. MS:703.1,[M+H] + ,ESI pos

[0389] Example Z85 5-[1-(4-amino-5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formic acid [ka] Trifluoroacetic acid (0.06 mL, 0.060 mmol, 1 equivalent) was added to a solution of tert-butyl 4-[4-[4-[[5-[1-(4-amino-5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (50.0 mg, 0.060 mmol, 1 equivalent) in DCM (1 mL). The mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions) to obtain the marked compound (28.1 mg, 0.040 mmol, yield 59.88%) as a white solid. MS:730.1,[M+H] + ,ESI pos

[0390] Example Z87 N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(4,5-diamino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide [ka] Step 1: tert-butyl 4-[4-[2-chloro-4-[[5-[1-(4,5-diamino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate Iron powder (33.63 mg, 0.600 mmol, 10 equivalents) was added to a solution of tert-butyl 4-[4-[4-[[5-[1-(4-amino-5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methyl-imidazole-2-carbonyl]amino]-2-chloro-benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (50.0 mg, 0.060 mmol, 1 equivalent) in methanol (1 mL) and saturated ammonium chloride water (0.06 mL, 0.060 mmol, 1 equivalent). The mixture was stirred at 25°C for 16 hours. The mixture was diluted with water (20 mL) and EA (10 mL). The mixture was filtered through a Celite pad, and the solid was washed with EA (5 mL x 3). The combined filtrate was extracted with EA (20 mL x 3). The combined organic layers were washed with saline solution (30 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the marked compound (40 mg, 0.050 mmol, yield 83%) as a pale yellow solid. MS:800.2,[M+H] + ,ESI pos

[0391] Step 2: N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(4,5-diamino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide Trifluoroacetic acid (0.5 mL, 6.49 mmol, 129.84 equivalents) was added to a solution of tert-butyl 4-[4-[2-chloro-4-[[5-[1-(4,5-diamino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]piperidine-1-carboxylate (40.0 mg, 0.050 mmol, 1 equivalent) in DCM (1 mL). The mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure. The residue was dissolved in EtOH (3 mL) and water (1 mL). NaOH (30 mg) was added to the mixture. The mixture was stirred at 20 °C for 16 hours. The mixture was adjusted to pH=6 with 4 M HCl (in MeOH) and then concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions) to obtain the marked compound (10.4 mg, 0.010 mmol, yield 29.07%) as a white solid. MS: 700.1, [M+H] + ,ESI pos

[0392] Assay procedure Antimicrobial susceptibility testing: Determination of the 90% growth inhibitory concentration (IC90) The in vitro antimicrobial activity of the compound was determined according to the following procedure:

[0393] This assay used 10-point Iso-Sensitest broth medium to quantitatively measure the in vitro activity of compounds against Acinetobacter baumanni ATCC17961.

[0394] Stock DMSO compounds were serially diluted 2-fold in a 384-well microtiter plate (e.g., in the range of final concentrations from 50 to 0.097 μM), 49 μl of bacterial suspension was seeded into Iso-Sensitest medium, and the final cell concentration was ~5x10⁶ at a final volume of 50 μl / well. (5) The concentration was set to CFU / ml. Microtiter plates were incubated at 35±2°C.

[0395] Bacterial cell growth was determined by measuring optical density at λ=600nm every 20 minutes over a 16-hour time course. Growth inhibition was calculated during the logarithmic growth of bacterial cells, and the concentrations that inhibited growth by 50% (IC50) and 90% (IC90) were determined.

[0396] Table 1 shows the 90% growth inhibitory concentration (IC90) of the compound of the present invention obtained in micromoles per liter against the Acinetobacter baumanni ATCC17961 strain.

[0397] The specific compounds of the present invention exhibit an IC90 (Acinetobacter baumannii ATCC17961) ≤ 25 μmol / L.

[0398] More specific compounds of the present invention exhibit an IC90 (Acinetobacter baumannii ATCC17961) ≤ 5 μmol / L.

[0399] Most of the specific compounds of the present invention exhibit an IC90 (Acinetobacter baumannii ATCC17961) ≤ 1 μmol / L. [Table 27-1] [Table 27-2] [Table 27-3]

[0400] Minimum Inhibitory Concentration Protocol (MIC) Assay Table 2 shows the in vitro efficacy of the compounds of the present invention against the Acinetobacter baumanni strain ATCC17978, as evaluated by the MIC (minimum inhibitory concentration) assay as follows.

[0401] The test compound was prepared from a 10 mM DMSO stock solution. The highest dose was diluted from 10 mM to 2.5 mM with DMSO, followed by 11 consecutive 2-fold dilutions with DMSO in a master plate (Greiner, catalog number: 651201). 2 μL of the compound was transferred from the master plate to a new 96-well assay plate (Costar, 3599).

[0402] 22g of powder (BD,212322) was added to 1L of purified water, autoclaved, and sterile CaCl2 (20mg / liter) and MgCl were obtained. 2( Cation-modified Mueller-Hinton broth (CAMHB), a growth medium, was prepared by supplementing with 10 mg / liter.

[0403] Each vial of the test microorganism was kept frozen in the gas phase of a liquid nitrogen freezer. The bacterial strain ATCC17978 was removed from the liquid nitrogen freezer, thawed at room temperature, and the bacteria were diluted with CAMHB medium to a final inoculum of 2 × 10⁶. 5 The solution was diluted to a concentration of CFU / mL. 98 μL of the prepared bacterial suspension was dispensed into an assay plate and pipetted five times.

[0404] Next, the assay plates were incubated in humid ambient air at 35±2°C for 20 hours. After incubation, the minimum MIC (μg / mL) value of the drug that inhibits visible microbial growth was recorded by visually assessing bacterial growth through a magnifying mirror of an MIC reader, and the assay plates were imaged as raw data using a Qcount system. Meanwhile, the OD600 of the assay plates was recorded as raw OD data using SpectraMaxPlus384. [Table 28]

[0405] Example 1 The compound of formula (I) can be used in a manner known to itself as an active ingredient to manufacture tablets of the following composition. per tablet Active ingredient 200mg Microcrystalline cellulose 155mg Corn starch 25mg Talc 25mg Hydroxypropyl methylcellulose 20 mg 425mg

[0406] Example 2 The compound of formula (I) can be used as an active ingredient in a manner known to itself to produce capsules of the following composition: per capsule Active ingredient: 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5mg Magnesium stearate 0.5 mg 220.0 mg

[0407] Example 3 The compound of formula (I) can be used in known ways as an active ingredient for the preparation of injection solutions of the following compositions. Active ingredient 100mg Lactic acid 90% 100mg Add an appropriate amount of NaOH or HCl to adjust the pH to 4.0. To adjust the osmotic pressure to 290 mOsm / kg, add an appropriate amount of sodium chloride or glucose. Add 100ml of water for injection (WFI)

[0408] Example 4 The compound of formula (I) can be used in known ways as an active ingredient for the preparation of injection solutions of the following compositions. Active ingredient 100mg Hydroxypropyl-β-cyclodextrin 10g Add an appropriate amount of NaOH or HCl to adjust the pH to 7.4. To adjust the osmotic pressure to 290 mOsm / kg, add an appropriate amount of sodium chloride or glucose. Add 100ml of water for injection (WFI)

Claims

1. Equation (I) 【Chemistry 1】 (In the formula, R １ and R ２ Together with the nitrogen atom to which they are bonded, they form the base of formula (II), (III), or (IV) 【Chemistry 2】 Forming; or R １ is C １ -C ６ -alkyl, amino-C １ -C ６ -alkyl, amino-C １ -C ６ -alkoxy-C １ -C ６ -alkyl, and the group 【Transformation 3】 Selected from; R ２ is hydrogen and C １ -C ６ - Selected from alkyl groups; R ３ is hydrogen, halogen, C １ -C ６ - Alkyl and C １ -C ６ - Selected from alkoxy; R ４ and R ６ These are, independently, hydrogen and C １ -C ６ - Alkyl, C １ -C ６ - Alkoxy, cyano, halo-C １ -C ６ -Alkyl and halo-C １ -C ６ - Selected from alkoxy; R ５ａ , R ５ｂ and R ５ｃ These are, independently, hydrogen, halogen, hydroxyl, and C. １ -C ６ - Alkyl, C １ -C ６ -alkoxy, amino-C １ -C ６ -alkoxy, hydroxy-C １ -C ６ -Alkyl, Halo-C １ -C ６ - Alkyl, C １ -C ６ -Alkoxy-C １ -C ６ -Alkyl-, C １ -C ６ -Alkoxy-C １ -C ６ -alkoxy-, amino, C １ -C ６ -Alkyl-NH-, (C １ -C ６ -Alkyl) ２ N-, C １ -C ６ -Alkyl-NH-C(O)-,amino-C １ -C ６ -Alkyl-NH-, C １ -C ６ -Alkoxy-C １ -C ６ -Alkyl-NH-,Carbamoyl-C １ -C ６ Selected from alkyl-NH-, (3-14 member heterocyclyl)-C(O)-NH-, carbamoyl, and nitro; R ７ is hydrogen, C １ -C ６ -Alkyl and halo-C １ -C ６ - Selected from alkyl groups; R ８ａ is hydrogen, C １ -C ６ -Alkyl,Carbamoyl-C １ -C ６ - Alkyl, and group 【Chemistry 4】 Selected from; R ８ｂ Hydrogen, hydroxy, oxo, hydroxy-C １ -C ６ - Alkyl, group 【Transformation 5】 Selected from; R ８ｃ is hydrogen, C １ -C ６ -Alkyl, amino-C １ -C ６ - Alkyl, amino, C １ -C ６ -Alkyl-NH- and C １ -C ６ -Alkoxy-C １ -C ６ - Selected from alkyl groups; R ８ｄ is hydrogen or C １ -C ６ -alkyl; R ９ａ 、R ９ｂ 、R １０ａ 、R １０ｂ 、R １２ａ and R １２ｂ are each independently selected from hydrogen, halogen, C １ -C ６ -alkyl, C １ -C ６ -alkoxy, halo-C １ -C ６ -alkyl, halo-C １ -C ６ -alkoxy, amino, nitro and hydroxy; R １１ａ and R １１ｂ These are, independently, hydrogen, halogen, and C. １ -C ６ - Alkyl, C １ -C ６ - Alkoxy, Halo-C １ -C ６ -Alkyl, amino-C １ -C ６ -Alkyl, hydroxy-C １ -C ６ -Alkyl, Halo-C １ -C ６ - Alkoxy, amino, nitro, hydroxy and group 【Transformation 6】 Selected from; Y is a carbonyl group, and X is a covalent bond, NH, N(C) １ -C ６ -Alkyl), NH-C １ -C ６ - Alkyldiyl, and C １ -C ６ - Selected from alkyldiyl; or X is a carbonyl group, Y is a covalent bond, NH, N(C) １ -C ６ -Alkyl), NH-C １ -C ６ - Alkyldiyl, and C １ -C ６ - Selected from alkyldiyl; X is C １ -C ６ -It is an alkyldiyl, and Y is a covalent bond; L １ and L ３ Each of these is independently bonded by a covalent bond, -C(O)-NH-C １ -C ６ -Alkyldiyl-, -C １ -C ６ -alkyldiyl-NH-C(O)-, -C(O)-NH-C １ -C ６ -Alkoxy-C １ -C ６ -Alkyldiyl-, -C １ -C ６ -Alkoxy-C １ -C ６ -Alkyldiyl-NH-C(O)-, carbonyl and C １ -C ６ - Selected from alkyldiyl; L ２ and L ４ These are, independently, covalent bonds, carbonyl, -O-, -NH-C(O)-, -C(O)-NH-, and -C(O)-NH-C １ -C ６ -Alkyldiyl-, -C １ -C ６ -Alkyldiyl-NH-C(O)-, and C １ -C ６ - Selected from alkyldiyl; A is a 5- to 14-membered heteroaryl; B, C, D, E, and G are each independently selected from 3- to 14-membered heterocyclyls and 5- to 14-membered heteroaryls; F is a 3-14 member heterocyclyl and C ３ -C １０ - Selected from cycloalkyl groups) Compounds of or pharmaceutically acceptable salts thereof.

2. The compound of formula (I) is given by formula (I-I) 【Transformation 7】 (In the formula, R １３ However, 【Transformation 8】 or base 【Chemistry 9】 And; A, C, R ３ , R ４ , R ５ａ , R ５ｂ , R ５ｃ , R ６ , R ７ , R ８ａ and R ８ｂ However, as described in claim 1.) A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

3. The compound of formula (I) is the compound of formula (I-II) 【Chemistry 10】 (In the formula, R １３ is, 【Chemistry 11】 or base 【Chemistry 12】 And; A, C, R ３ , R ５ａ , R ５ｂ , R ５ｃ , R ８ａ and R ８ｂ However, as described in claim 1.) A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

4. R １ and R ２ However, together with the nitrogen atom to which they are bonded, they form the base of formula (II), (III), or (IV) 【Chemistry 13】 Forming; or R １ However, C １ -C ６ -Alkyl, amino-C １ -C ６ -Alkyl, amino-C １ -C ６ -Alkoxy-C １ -C ６ - Alkyl, and group 【Chemistry 14】 Selected from; R ２ However, hydrogen and C １ -C ６ - Selected from alkyl groups; R ９ａ However, it is hydrogen or hydroxyl; R ９ｂ , R １０ｂ , and R １２ｂ However, each of them is hydrogen; R ８ａ However, hydrogen, C １ -C ６ -Alkyl,Carbamoyl-C １ -C ６ - Alkyl, and group 【Chemistry 15】 Selected from; R ８ｂ However, hydrogen, hydroxy, oxo, hydroxy-C １ -C ６ - Alkyl and group 【Chemistry 16】 Selected from; R ８ｃ However, hydrogen, C １ -C ６ -Alkyl, amino-C １ -C ６ - Alkyl, amino, C １ -C ６ -Alkyl-NH- and C １ -C ６ -Alkoxy-C １ -C ６ - Selected from alkyl groups; R ８ｄ However, hydrogen or C １ -C ６ - Alkyl; R １０ａ However, they are selected from amino and nitro; R １１ａ However, hydrogen, amino-C １ -C ６ -Alkyl, hydroxy-C １ -C ６ - Alkyl, amino, hydroxy and group 【Chemistry 17】 Selected from; R １１ｂ However, hydrogen, halo-C １ -C ６ -Alkyl and hydroxy-C １ -C ６ - Selected from alkyl groups; R １２ａ However, it is selected from hydrogen and hydroxyl; X is a carbonyl group, and Y is a covalent bond or C １ -C ６ - Is it alkyldiyl? or X is NH, N(C) １ -C ６ -alkyl) and NH-C １ -C ６ - Selected from alkyldiyl groups; whether Y is a carbonyl group; or X is C １ -C ６ -It is an alkyldiyl, and Y is a covalent bond; L １ C １ -C ６ -It is alkyldiyl; L ２ is -O-; L ３ is a covalent bond, C(O)-NH-C １ -C ６ -Alkyldiyl-, -C(O)-NH-C １ -C ６ -Alkoxy-C １ -C ６ -Alkyldiyl-, and C １ -C ６ - Selected from alkyldiyl; L ４ However, carbonyl, -C(O)-NH-, and -C(O)-NH-C １ -C ６ Selected from -alkyldiyl-; B, C, D, and G are each independently 3- to 14-membered heterocyclines; E is a 5- to 14-membered heteroaryl; F is a 5-14 member heteroaryl, C ３ -C １０ - A compound of formula (I) according to claim 1, selected from cycloalkyls and 3- to 14-membered heterocyclines, or a pharmaceutically acceptable salt thereof.

5. R １ and R ２ However, together with the nitrogen atom to which they are bonded, they form the base of formula (II), (III), or (IV) [Chemistry 18] Forming; or R １ is the basis 【Chemistry 19】 And; R ２ C １ -C ６ - Alkyl; R ８ａ However, hydrogen and C １ -C ６ - Selected from alkyl groups; R ８ｂ However, it is selected from hydrogen and hydroxyl; R ８ｃ However, hydrogen or C １ -C ６ It is alkyl-NH-; R ８ｄ is hydrogen; R １１ａ is the basis 【Chemistry 20】 And; R １１ｂ is hydrogen; R １２ａ is hydroxyl; R １２ｂ is hydrogen; X is a carbonyl group; Y is covalent or C １ -C ６ -It is alkyldiyl; L ３ The bond is covalent; L ４ is a carbonyl group; A compound of formula (I) according to claim 4 or a pharmaceutically acceptable salt thereof, wherein B, C, F, and G are each independently a 3- to 14-membered heterocycline.

6. R １ and R ２ However, together with the nitrogen atom to which they are bonded, they form the base of formula (II), (III), or (IV) 【Chemistry 21】 Forming; or R １ is the basis 【Chemistry 22】 And; R ２ is methyl; R ８ａ However, hydrogen and methyl are selected; R ８ｂ However, it is selected from hydrogen and hydroxyl; R ８ｃ However, it is hydrogen or methyl-NH-; R ８ｄ is hydrogen; R １１ａ is the basis 【Chemistry 23】 And; R １１ｂ is hydrogen; R １２ａ is hydroxyl; R １２ｂ is hydrogen; X is a carbonyl group; Y is covalent or -CH ２ - and; L ３ The bond is covalent; L ４ is a carbonyl group; B is selected from piperazinil, piperidyl, and 2,8-diazaspiro[4.5]decane-8-yl; C is selected from piperidil and pyrrolidinil; F is piperidil; A compound of formula (I) according to claim 5 or a pharmaceutically acceptable salt thereof, wherein G is pyrrolidinyl.

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

8. R ３ A compound of formula (I) according to claim 7 or a pharmaceutically acceptable salt thereof, wherein is a halogen.

9. R ３ A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 8, wherein is chloro.

10. R ４ However, C １ -C ６ - Alkyl, C １ -C ６ - Alkoxy, cyano and halo-C １ -C ６ - Selected from alkyl groups; R ６ However, hydrogen and halo-C １ -C ６ - A compound of formula (I) according to any one of claims 1, 2, and 4-9, selected from alkyl groups, or a pharmaceutically acceptable salt thereof.

11. R ４ Hello C １ -C ６ - Alkyl; R ６ A compound of formula (I) according to claim 10 or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

12. R ４ ga CF ３ And; R ６ A compound of formula (I) according to claim 11 or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

13. A is a 5- to 14-membered heteroaryl; R ５ａ However, hydrogen, halogen, C １ -C ６ - Alkyl, C １ -C ６ -alkoxy, amino-C １ -C ６ -alkoxy, hydroxy-C １ -C ６ -Alkyl, Halo-C １ -C ６ - Alkyl, C １ -C ６ -Alkoxy-C １ -C ６ -Alkyl-, C １ -C ６ -Alkoxy-C １ -C ６ -alkoxy-, amino, C １ -C ６ -Alkyl-NH-, (C １ -C ６ -Alkyl) ２ N-, C １ -C ６ -Alkyl-NH-C(O)-,amino-C １ -C ６ -Alkyl-NH-, C １ -C ６ -Alkoxy-C １ -C ６ -Alkyl-NH-,Carbamoyl-C １ -C ６ Selected from alkyl-NH-, (3-14 member heterocyclyl)-C(O)-NH-, carbamoyl, and nitro; R ５ｂ However, these are selected from hydrogen, halogens, and aminos; R ５ｃ A compound of formula (I) according to any one of claims 1 to 12, wherein is hydrogen, or a pharmaceutically acceptable salt thereof.

14. A is a 5- to 14-membered heteroaryl; R ５ａ However, halogen, C １ -C ６ - Alkyl, C １ -C ６ -alkoxy, hydroxy-C １ -C ６ -Alkyl, amino-C １ -C ６ - Alkyl, C １ -C ６ -alkyl-NH-,amino-C １ -C ６ Selected from alkyl, NH, and amino; R ５ｂ However, it is hydrogen or amino; R ５ｃ A compound of formula (I) according to claim 13 or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

15. A is pyridyl; R ５ａ However, these are selected from fluoro, methyl, methoxy, hydroxymethyl, methylamino, 2-aminoethyl-NH-, and amino; R ５ｂ However, it is hydrogen or amino; R ５ｃ A compound of formula (I) according to claim 14 or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

16. R ７ C １ -C ６ - A compound of formula (I) according to any one of claims 1, 2, and 4 to 15, which is alkyl, or a pharmaceutically acceptable salt thereof.

17. R ７ A compound of formula (I) according to claim 16 or a pharmaceutically acceptable salt thereof, wherein is methyl.

18. R １ and R ２ However, together with the nitrogen atom to which they are bonded, they form the base of formula (II), (III), or (IV) 【Chemistry 24】 Forming; or R １ However, C １ -C ６ -Alkyl, amino-C １ -C ６ -Alkyl, amino-C １ -C ６ -Alkoxy-C １ -C ６ - Alkyl, and group 【Chemistry 25】 Selected from; R ２ However, hydrogen and C １ -C ６ - Selected from alkyl groups; R ３ However, halogen or C １ -C ６ It is alkyl; R ４ However, C １ -C ６ - Alkyl, C １ -C ６ - Alkoxy, cyano and halo-C １ -C ６ - Selected from alkyl groups; R ５ａ However, hydrogen, halogen, C １ -C ６ - Alkyl, C １ -C ６ -alkoxy, amino-C １ -C ６ -alkoxy, hydroxy-C １ -C ６ -Alkyl, Halo-C １ -C ６ - Alkyl, C １ -C ６ -Alkoxy-C １ -C ６ -Alkyl-, C １ -C ６ -Alkoxy-C １ -C ６ -alkoxy-, amino, C １ -C ６ -Alkyl-NH-, (C １ -C ６ -Alkyl) ２ N-, C １ -C ６ -Alkyl-NH-C(O)-,amino-C １ -C ６ -Alkyl-NH-, C １ -C ６ -Alkoxy-C １ -C ６ -Alkyl-NH-,Carbamoyl-C １ -C ６ Selected from alkyl-NH-, (3-14 member heterocyclyl)-C(O)-NH-, carbamoyl, and nitro; R ５ｂ However, these are selected from hydrogen, halogens, and aminos; R ５ｃ is hydrogen; R ６ However, hydrogen and halo-C １ -C ６ - Selected from alkyl groups; R ７ C １ -C ６ - Alkyl; R ８ａ However, hydrogen, C １ -C ６ -Alkyl,Carbamoyl-C １ -C ６ - Alkyl, and group 【Chemistry 26】 Selected from; R ８ｂ However, hydrogen, hydroxy, oxo, hydroxy-C １ -C ６ - Alkyl and group 【Chemistry 27】 Selected from; R ８ｃ However, hydrogen, C １ -C ６ -Alkyl, amino-C １ -C ６ - Alkyl, amino, C １ -C ６ -Alkyl-NH- and C １ -C ６ -Alkoxy-C １ -C ６ - Selected from alkyl groups; R ８ｄ However, hydrogen or C １ -C ６ - Alkyl; R ９ａ However, it is hydrogen or hydroxyl; R ９ｂ , R １０ｂ , and R １２ｂ However, each of them is hydrogen; R １０ａ However, they are selected from amino and nitro; R １１ａ However, hydrogen, amino-C １ -C ６ -Alkyl, hydroxy-C １ -C ６ - Alkyl, amino, hydroxy and group 【Chemistry 28】 Selected from; R １１ｂ However, hydrogen, halo-C １ -C ６ -Alkyl and hydroxy-C １ -C ６ - Selected from alkyl groups; R １２ａ However, it is selected from hydrogen and hydroxyl; X is a carbonyl group, and Y is a covalent bond or C １ -C ６ - Is it alkyldiyl? or X is NH, N(C) １ -C ６ -alkyl) and NH-C １ -C ６ - Selected from alkyldiyl groups; whether Y is a carbonyl group; or X is C １ -C ６ -It is an alkyldiyl, and Y is a covalent bond; L １ C １ -C ６ -It is alkyldiyl; L ２ is -O-; L ３ is a covalent bond, C(O)-NH-C １ -C ６ -Alkyldiyl-, -C(O)-NH-C １ -C ６ -Alkoxy-C １ -C ６ -Alkyldiyl-, and C １ -C ６ - Selected from alkyldiyl; L ４ However, carbonyl, -C(O)-NH-, and -C(O)-NH-C １ -C ６ Selected from -alkyldiyl-; A is a 5- to 14-membered heteroaryl; B, C, D, and G are each independently 3- to 14-membered heterocyclines; E is a 5- to 14-membered heteroaryl; F is a 5-14 member heteroaryl, C ３ -C １０ - A compound of formula (I) according to claim 1, selected from cycloalkyls and 3- to 14-membered heterocyclines, or a pharmaceutically acceptable salt thereof.

19. R １ and R ２ However, together with the nitrogen atom to which they are bonded, they form the base of formula (II), (III), or (IV) 【Chemistry 29】 Forming; or R １ is the basis 【Transformation 30】 And; R ２ C １ -C ６ - Alkyl; R ３ is a halogen; R ４ Hello C １ -C ６ - Alkyl; R ５ａ However, halogen, C １ -C ６ - Alkyl, C １ -C ６ -alkoxy, hydroxy-C １ -C ６ -Alkyl, amino-C １ -C ６ - Alkyl, C １ -C ６ -alkyl-NH-,amino-C １ -C ６ Selected from alkyl, NH, and amino; R ５ｂ However, it is hydrogen or amino; R ５ｃ and R ６ is hydrogen; R ７ C １ -C ６ - Alkyl; R ８ａ However, hydrogen and C １ -C ６ - Selected from alkyl groups; R ８ｂ However, it is selected from hydrogen and hydroxyl; R ８ｃ However, hydrogen or C １ -C ６ It is alkyl-NH-; R ８ｄ is hydrogen; R １１ａ is the basis 【Chemistry 31】 And; R １１ｂ is hydrogen; R １２ａ is hydroxyl; R １２ｂ is hydrogen; X is a carbonyl group; Y is covalent or C １ -C ６ -It is alkyldiyl; L ３ The bond is covalent; L ４ is a carbonyl group; A is a 5- to 14-membered heteroaryl; A compound of formula (I) according to claim 18 or a pharmaceutically acceptable salt thereof, wherein B, C, F, and G are each independently a 3- to 14-membered heterocycline.

20. R １ and R ２ However, together with the nitrogen atom to which they are bonded, they form the base of formula (II), (III), or (IV) 【Chemistry 32】 Forming; or R １ is the basis 【Transformation 33】 And; R ２ is methyl; R ３ That is Chlorophyll; R ４ ga CF ３ And; R ５ａ However, these are selected from fluoro, methyl, methoxy, hydroxymethyl, methylamino, 2-aminoethyl-NH-, and amino; R ５ｂ However, it is hydrogen or amino; R ５ｃ and R ６ is hydrogen; R ７ is methyl; R ８ａ However, hydrogen and methyl are selected; R ８ｂ However, it is selected from hydrogen and hydroxyl; R ８ｃ However, it is hydrogen or methyl-NH-; R ８ｄ is hydrogen; R １１ａ is the basis 【Transformation 34】 And; R １１ｂ is hydrogen; R １２ａ is hydroxyl; R １２ｂ is hydrogen; X is a carbonyl group; Y is covalent or -CH ２ - and; L ３ The bond is covalent; L ４ is a carbonyl group; A is pyridyl; B is selected from piperazinil, piperidyl, and 2,8-diazaspiro[4.5]decane-8-yl; C is selected from piperidil and pyrrolidinil; F is piperidil; A compound of formula (I) according to claim 19 or a pharmaceutically acceptable salt thereof, wherein G is pyrrolidinyl.

21. The compound of formula (I) above, N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pyrimidine-2-yl-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formate; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(4-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formate; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(5-chloro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formate; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxypyrimidine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formate; 5-[1-(5-aminopyrimidine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formate; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(2-methoxyethoxy)pyrimidine-2-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formate; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(2-methoxyethoxy)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formate; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(5-fluoropyrimidine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formate; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(1h-pyrazolo[3,4-d]pyrimidine-6-yl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formate; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[3-(trifluoromethyl)-1-[3-(trifluoromethyl)-2-pyridyl]pyrazole-4-yl]imidazole-2-carboxamide; formate; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formate; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(4-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formate; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formate; 5-[1-[4-(2-aminoethoxy)pyrimidine-2-yl]-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formate; 5-[1-(4-aminopyrimidine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 2,2,2-trifluoroacetate; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[4-(methylamino)pyrimidine-2-yl]-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; 2,2,2-trifluoroacetate; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[4-(dimethylamino)pyrimidine-2-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 2,2,2-trifluoroacetate; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[4-(dimethylamino)pyrimidine-2-yl]-5-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 2,2,2-trifluoroacetate; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[4-(2-methoxyethylamino)pyrimidine-2-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 2,2,2-trifluoroacetate; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-pyrazine-2-yl-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; 2,2,2-trifluoroacetate; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(dimethylamino)pyrimidine-2-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formate; 5-[1-[5-(2-aminoethylamino)pyrimidine-2-yl]-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formate; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[6-(dimethylamino)pyridazin-3-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formate; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formate; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(2-methoxyethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formate; 5-[1-[5-[(3-amino-3-oxopropyl)amino]-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formate; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formate; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(4-methoxypyrimidine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formate; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(2-methoxypyrimidine-4-yl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formate; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[[1-(piperidine-4-carbonyl)-4-piperidyl]methylcarbamoyl]phenyl]-1-methylimidazole-2-carboxamide; formate; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-[(3S)-morpholine-3-carbonyl]piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formate; 5-[1-(5-amino-2-pyridyl)-3-(difluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-methoxypyrazole-4-yl]-N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-cyanopyrazole-4-yl]-N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-methylpyrazole-4-yl]-N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-ethyl-pyrazole-4-yl]-N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 2,2,2-trifluoroacetate; 5-[1-(6-aminopyridazine-3-yl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 2,2,2-trifluoroacetate; N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(4-methyl-1H-pyrazole-3-yl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; 2,2,2-trifluoroacetate; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-[2-(3-hydroxypyrrolidine-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formate; N-[3-chloro-4-[4-[(2S,3S)-3-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formate; N-[3-chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formate; N-[3-chloro-4-[4-[(2S,3S)-3-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formate; N-[3-chloro-4-[4-[2-(3-hydroxypyrrolidine-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formate; 1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-methyl-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]imidazole-2-carboxamide; formate; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-[5-(methylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formic acid butylamino (formic acidarbthylamino)-2-py; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[1-(2-methoxyethyl)pyrazole-4-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formate; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[1-(2-methoxyethyl)-5-methylpyrazole-4-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formate; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[1-(2-methoxyethyl)imidazole-4-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formate; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(1-methylimidazole-4-yl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formate; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-methyl-1H-pyrazole-4-yl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formate; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-methyl-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formate; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(4-methyl-1H-pyrazole-5-yl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; 2,2,2-trifluoroacetate; N-[4-[4-[(1R,5S)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]-3-chlorophenyl]-1-methyl-5-[1-pyrimidine-2-yl-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formate; N-[3-chloro-4-[[(1R,5S)-3-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]-3-azabicyclo[3.1.0]hexane-6-yl]carbamoyl]phenyl]-1-methyl-5-[1-pyrimidine-2-yl-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formate; N-[3-chloro-4-[[(1S,5R)-3-(piperidine-4-carbonyl)-3-azabicyclo[3.1.0]hexane-6-yl]carbamoyl]phenyl]-1-methyl-5-[1-pyrimidine-2-yl-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formate; N-[3-chloro-4-[4-[(3S,4R)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[1-(5-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formate; N-[4-[4-[1-(azetidine-3-ylmethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chlorophenyl]-1-methyl-5-[1-pyrimidine-2-yl-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formate; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperazine-1-carbonyl)piperidine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formate; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-[3-(hydroxymethyl)piperazine-1-carbonyl]piperidine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formate; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-[(2-oxopiperazine-1-yl)methyl]piperidine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; formate; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(1H-pyrazole-3-ylmethylcarbamoyl)phenyl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S)-4-hydroxypiperidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-5-[1-(5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]imidazole-2-carboxamide; formate; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[5-(ethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; formate; N-[4-[(3R)-3-(aminomethyl)pyrroridine-1-carbonyl]-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; N-[4-(3-aminopropylcarbamoyl)-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(4-piperidylmethylcarbamoyl)phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(methylamino)piperidine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[(3-methylolpyrrolidine-3-yl)carbamoyl]phenyl]-1-methylimidazole-2-carboxamide; N-[4-[[1-(aminomethyl)cyclopropyl]carbamoyl]-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; N-[4-[(3S)-3-(aminomethyl)pyrroridine-1-carbonyl]-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(2,8-diazaspiro[4.5]decane-8-carbonyl)phenyl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[4-(1-methylpiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-[4-(methoxymethyl)-1H-pyrazole-3-yl]-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 5-[1-(6-amino-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]-1-methylimidazole-2-carboxamide; N-[4-[cis-(3-aminocyclobutyl)carbamoyl]-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; N-[4-(2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carbonyl)-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[methyl(4-piperidyl)carbamoyl]phenyl]-1-methylimidazole-2-carboxamide; N-[4-[4-(aminomethyl)piperidine-1-carbonyl]-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; N-[4-[[3-(aminomethyl)-3-(chloromethyl)cyclobutyl]carbamoyl]-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; N-[4-[[trans-3-aminocyclopentyl]carbamoyl]-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; N-[4-(2-aminoethylcarbamoyl)-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; N-[4-[(2-aminocyclopropyl)methylcarbamoyl]-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; N-[4-[trans-(3-aminocyclobutyl)carbamoyl]-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; N-[4-(4-aminopiperidine-1-carbonyl)-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; N-[4-[2-(2-aminoethoxy)ethylcarbamoyl]-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[2-[(2S,4R)-4-hydroxyprolyl]-2,8-diazaspiro[4.5]decane-8-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[[(1R,3R)-3-[[(2S,4R)-4-hydroxyprolyl]amino]cyclopentyl]carbamoyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-[[(2S,4R)-4-hydroxyprolyl]amino]piperidine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[6-[[(2S,4R)-4-hydroxyprolyl]amino]-2-azaspiro[3.3]heptan-2-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[3-[[(2S,4R)-4-hydroxyprolyl]amino]propylcarbamoyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-aminopyridine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl]-#N!-[3-chloro-4-[[4-(hydroxymethyl)-1-[#rac!-(2#R!,4#S!)-4-hydroxypyrrolidine-2-carbonyl]pyrrolidine-3-yl]carbamoyl]phenyl]-1-methylimidazole-2-carboxamide; N-[4-(5-aminopentylcarbamoyl)-3-chlorophenyl]-5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 5-[1-(5-aminopyrazine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxyprolyl]piperazine-1-carbonyl]phenyl]-5-[1-(6-chloro-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]-5-[1-(6-methoxy-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[2-[[(2S,4R)-4-hydroxyprolyl]amino]ethylcarbamoyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[[1-[(2S,4R)-4-hydroxyprolyl]-4-piperidyl]methylcarbamoyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[[1-[(2S,4R)-4-hydroxyprolyl]-4-piperidyl]-methyl-carbamoyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[[2-[[(2S,4R)-4-hydroxyprolyl]amino]cyclopropyl]methylcarbamoyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[5-[(2S,4R)-4-hydroxyprolyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-2-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[trans-[3-[[(2S,4R)-4-hydroxyprolyl]amino]cyclobutyl]carbamoyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[(3S)-3-[[[(2S,4R)-4-hydroxyprolyl]amino]methyl]pyrrolidine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[2-[2-[[(2S,4R)-4-hydroxyprolyl]amino]ethoxy]ethylcarbamoyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[[(7S)-2-[(2S,4R)-4-hydroxyprolyl]-5-oxa-2-azaspiro[3.4]octan-7-yl]carbamoyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[cis-[3-[[(2S,4R)-4-hydroxyprolyl]amino]cyclobutyl]carbamoyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[[1-[[(2S,4R)-4-hydroxyprolyl]amino]cyclopropyl]methylcarbamoyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[(3R)-3-[[[(2S,4R)-4-hydroxyprolyl]amino]methyl]pyrrolidine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-[[[(2S,4R)-4-hydroxyprolyl]amino]methyl]piperidine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-[[(2S,4R)-4-hydroxyprolyl]-methyl-amino]piperidine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[[3-[[(2S,4R)-4-hydroxyprolyl]amino]-1-bicyclo[1.1.1]pentanyl]carbamoyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[[(1S,3S)-3-[[(2S,4R)-4-hydroxyprolyl]amino]cyclopentyl]carbamoyl]phenyl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]-5-[1-(6-methoxypyrimidine-4-yl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(2-chloropyridine-4-yl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(4,7-diazaspiro[2.5]octane-7-carbonyl)phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[(3R)-3-methyl-1,4-diazepan-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(3,9-diazabicyclo[3.3.1]nonane-3-carbonyl)phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[(2S,6R)-2,6-dimethylpiperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(3,6-diazabicyclo[3.1.1]heptan-6-carbonyl)phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[(2S)-2-methylpiperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(3,3-dimethylpiperazine-1-carbonyl)phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[(3S)-3-isopropylpiperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(3,6-diazabicyclo[3.2.0]heptan-3-carbonyl)phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(1,4-diazepan-1-carbonyl)phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[(3S)-3-methylpiperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(3,8-diazabicyclo[3.2.1]octane-8-carbonyl)phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[(2R)-2-ethylpiperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[(2S)-2-ethylpiperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(2-piperazinoethylcarbamoyl)phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[(1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(4,7-diazaspiro[2.5]octane-4-carbonyl)phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[(2S,3R)-2,3-dimethylpiperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[3-(methoxymethyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[(1R,5R)-3,6-diazabicyclo[3.2.0]heptan-3-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-3-fluoro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-6-fluoro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]-5-[1-(2-methoxy-4-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 5-[1-(6-amino-5-fluoro-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]-5-[1-(6-methoxy-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(diethylcarbamoyl)phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(6-amino-5-methyl-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(6-amino-4-methyl-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(6-amino-2-methyl-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-4-chloro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-3-methyl-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-4-methyl-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-2-fluoro-4-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(6-amino-2-fluoro-3-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(4-amino-5-nitro-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; 5-[1-(5-amino-6-methylpyridine-2-yl)-3-(trifluoromethyl)pyrazole-4-yl]-#N!-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methylimidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[1-(4,5-diamino-2-pyridyl)-3-(trifluoromethyl)pyrazole-4-yl]-1-methylimidazole-2-carboxamide; N-[6-[4-[2-[[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]carbamoyl]-3-methylimidazole-4-yl]-3-(trifluoromethyl)pyrazole-1-yl]-3-pyridyl]isonipecotamide; and 5-[1-[5-(2-aminoethylamino)-2-pyridyl]-3-(trifluoromethyl)pyrazole-4-yl]-N-[3-chloro-4-(4-isonipecotoylpiperazine-1-carbonyl)phenyl]-1-methylimidazole-2-carboxamide A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

22. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, and a therapeutically inactive carrier.

23. The pharmaceutical composition according to claim 22 for use as an antibiotic.

24. The pharmaceutical composition according to claim 22 for use in the treatment or prevention of hospital-acquired infections and diseases resulting therefrom.

25. The pharmaceutical composition according to claim 22, for use in the treatment or prevention of infections caused by Gram-negative bacteria and diseases resulting therefrom.

26. The pharmaceutical composition according to claim 25, wherein the Gram-negative bacteria are selected from Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, Enterobacter species, and Escherichia coli.

27. The pharmaceutical composition according to claim 26, wherein the Gram-negative bacterium is Acinetobacter baumanni.

28. The pharmaceutical composition according to claim 22 for use in the treatment or prevention of infections and diseases caused by Enterococcus faecium, Staphylococcus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli or combinations thereof.

29. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 21 for the preparation of a medicament useful for the treatment or prevention of infections and diseases caused by Enterococcus faecium, Staphylococcus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli or combinations thereof.

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