Novel imidazopyrazine derivatives

Abstract

The present invention relates to a compound represented by general formula (I) TIFF2023529866000360.tif4248(R x and R 3 ~R 5 is as described herein) or a pharmaceutically acceptable salt thereof. Further provided are pharmaceutical compositions comprising the compounds, methods of making the compounds, and methods of using the compounds as medicines, particularly as antibiotics for the treatment or prevention of bacterial infections and resulting diseases.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to novel imidazopyrazine derivatives that exhibit antibacterial properties. The present invention also relates to methods of using these compounds for the treatment or prevention of bacterial infections and resulting diseases, particularly infections caused by Acinetobacter baumannii and resulting diseases. [Background technology]

[0002] Background of the Invention Acinetobacter baumannii is a Gram-negative, aerobic, non-fermenting bacterium that has been recognized over the past few decades as an emerging pathogen with severely limited treatment options.

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

[0004] A. baumannii occurs most frequently in intensive care units and surgical wards, where widespread antibiotic use allows it to select for resistance to all known antimicrobial agents and can cause infections such as bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections.

[0005] A. baumannii has an extraordinary ability to upregulate and acquire resistance determinants and exhibits environmental persistence that allows it to survive and spread in hospital environments, making this organism a frequent cause of infectious disease outbreaks and a local healthcare-associated pathogen.

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

[0007] According to the Antimicrobial Availability Task Force (AATF) of the Infectious Diseases Society of America (IDSA), Acinetobacter baumannii has been and remains considered "a prime example of the mismatch that exists between unmet medical need and the current antibiotic research and development pipeline." Thus, there is a high demand and need to identify compounds suitable for treating diseases and infections caused by Acinetobacter baumannii.

[0008] The present invention provides novel compounds that exhibit activity against drug-susceptible and drug-resistant strains of Acinetobacter baumannii. Summary of the Invention

[0009] Summary of the Invention In a first aspect, the present invention provides a compound of formula (I) [ka] (R x and R 3 ~R 5 is as defined herein) or a pharmaceutically acceptable salt thereof.

[0010] In one aspect, the present invention provides a method for preparing a compound of formula (I) described herein, comprising: (i) compound (A) to form the compound of formula (I) or a synthetic precursor thereof [ka] (wherein X is halogen or triflate, preferably X is iodo, and the double cross indicates the point of attachment of (A) to the remainder of formula (I), or a synthetic precursor thereof; Boronic acids (R = H) or boronic esters (R = alkyl, or both R's together with the atoms to which they are attached form a heterocyclic ring) (B) [ka] (R 4 is as defined herein), or (ii) compound (C) to form the compound of formula (I) or a synthetic precursor thereof [ka] (The double cross represents the R 4 or its synthetic precursor) and Aryl Halides (D) [ka] (R 3 and R 5 is as defined herein, X is a halogen, and the double cross indicates the point of attachment of (D) to the remainder of formula (I), or a synthetic precursor thereof; (iii) compound (C1) for forming the compound of formula (I) or a synthetic precursor thereof [ka] (X is a halogen and the double cross represents R as defined herein) 4 or its synthetic precursor) and Aniline derivatives (D1) [ka] (R 3 and R 5is as defined herein, where the double cross indicates the point of attachment of (D1) to the remainder of formula (I), or a synthetic precursor thereof; or (iv) Formula (G) [ka] (Ry' is R as defined herein) x Equal to or R x carboxylic acid (E) to form a compound of formula (E), which is a synthetic precursor of [ka] (wherein the double cross indicates the point of attachment of (E) to the remainder of formula (I)) or a synthetic precursor thereof; Primary or secondary amines y and reacting the compound with The present invention provides a method comprising:

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

[0012] In a further aspect, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

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

[0014] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as an antibiotic.

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

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

[0017] In a further aspect, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infection and resulting disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof. DETAILED DESCRIPTION OF THE INVENTION

[0018] definition Detailed Description of the Invention It should be understood that any feature, integer, characteristic, compound, chemical moiety, or group described in connection with a particular aspect, embodiment, or example of the invention is applicable to any other aspect, embodiment, or example described herein, except where inconsistent therewith. All features disclosed herein (including any accompanying claims, abstract, and drawings), and / or all steps of any method or process so disclosed, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel or any novel combination of features disclosed herein (including any accompanying claims, abstract, and drawings), or any novel or any novel combination of steps of any method or process so disclosed.

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

[0020] The term "alkynyl" refers to a monovalent linear or branched hydrocarbon group of 2 to 6 carbon atoms having at least one triple bond ("C2-C6-alkynyl"). In certain embodiments, an alkynyl has 2 to 4 carbon atoms having at least one triple bond. Examples of alkynyl include ethynyl, propynyl, n-butynyl, or isobutynyl. A preferred alkynyl is propynyl.

[0021] The term "alkynyloxy" refers to an alkynyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. Unless otherwise specified, an alkynyloxy group contains 2 to 6 carbon atoms ("C2-C6-alkynyloxy"). In some preferred embodiments, an alkynyloxy group contains 2 to 4 carbon atoms. In still other embodiments, an alkynyloxy group contains 2 to 3 carbon atoms. Some non-limiting examples of alkynyloxy groups include ethynoxy, propynoxy, and butynoxy.

[0022] The term "alkoxy" refers to an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. Unless otherwise specified, an alkoxy group contains 1 to 6 carbon atoms ("C1-C6-alkoxy"). In some preferred embodiments, an alkoxy group contains 1 to 4 carbon atoms. In still other embodiments, an alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. A particularly preferred, but non-limiting example of alkoxy is methoxy.

[0023] The term "halogen" or "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). Preferably, the term "halogen" or "halo" refers to fluoro (F), chloro (Cl), or bromo (Br). Particularly preferred, but non-limiting, examples of "halogen" or "halo" are fluoro (F) and chloro (Cl).

[0024] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms ("C3-C 10 "-cycloalkyl" refers to a saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms, particularly 3 to 7 ring carbon atoms. "Bicyclic cycloalkyl" refers to a cycloalkyl moiety consisting of two saturated carbocyclic rings having two common carbon atoms, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and a spirocyclic moiety, i.e., the two rings are joined through one common ring atom. Preferably, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., 3, 4, 5, or 6 carbon atoms. Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0025] The term "aminoalkynyloxy" refers to an alkynyloxy group in which at least one of the hydrogen atoms of the alkynyloxy group has been replaced with an amino group. Preferably, "aminoalkynyloxy" refers to an alkynyloxy group in which one, two, or three hydrogen atoms of the alkynyloxy group have been replaced with an amino group. A preferred, but non-limiting example, is 4-aminobut-2-ynoxy.

[0026] The term "aminoalkyl" refers to an alkyl group in which at least one of the alkyl group's hydrogen atoms has been replaced with an amino group. Preferably, "aminoalkyl" refers to an alkyl group in which one, two, or three of the alkyl group's hydrogen atoms have been replaced with amino groups. A preferred, but non-limiting example of an aminoalkyl is aminomethyl.

[0027] The terms "heterocycloalkyl" and "heterocyclyl" are used interchangeably and refer to a saturated or partially unsaturated monocyclic or bicyclic, preferably monocyclic, ring system of 3 to 20 ring atoms, preferably 3 to 15 ring atoms, more preferably 3 to 10 ring atoms, and most preferably 3 to 6 ring atoms, in which 1, 2, or 3 of the ring atoms are heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon ("C-C 19-heterocyclyl"). Preferably, one to two of the ring atoms are selected from N and O, with the remaining ring atoms being carbon. "Bicyclic heterocyclyl" refers to a heterocyclic moiety consisting of two rings having two ring atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and a spirocyclic moiety, i.e., the two rings are joined through one common ring atom. Some non-limiting examples of monocyclic heterocyclyl groups include azetidin-3-yl, azetidin-2-yl, oxetan-3-yl, oxetan-2-yl, 2-oxopyrrolidin-1-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, 5-oxopyrrolidin-3-yl, 2-oxo-1-piperidyl, 2-oxo-3-piperidyl, 2-oxo-4-piperidyl, 6-oxo-2-piperidyl, 6-oxo-3-piperidyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, morpholino, morpholin-2-yl, morpholin-3-yl, piperazinyl, and dihydropyridyl.

[0028] The term "aryl" refers to a group having a total of 6 to 14 ring members ("C6-C 14 -aryl"), preferably a monocyclic, bicyclic, or tricyclic carbocyclic ring system having 6 to 12 ring members, more preferably 6 to 10 ring members, wherein at least one ring of the system is aromatic. Some non-limiting examples of aryl include phenyl and 9H-fluorenyl (e.g., 9H-fluoren-9-yl). A particularly preferred, but non-limiting example of aryl is phenyl.

[0029] The term "aryloxy" refers to an aryl group, as defined above, attached to the parent molecular moiety through an oxygen atom. A preferred, but non-limiting example of aryloxy is phenoxy.

[0030] The term "heteroaryl" refers to a monovalent or polyvalent, monocyclic or bicyclic, preferably bicyclic, ring system having a total of 5 to 14 ring members, preferably 5 to 12 ring members, and more preferably 5 to 10 ring members, wherein at least one ring of the system is aromatic and at least one ring of the system contains one or more heteroatoms. Preferably, "heteroaryl" refers to a 5- to 10-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. Most preferably, "heteroaryl" refers to a 5- to 10-membered heteroaryl containing 1 to 2 heteroatoms independently selected from O and N. Some non-limiting examples of heteroaryl include 2-pyridyl, 3-pyridyl, 4-pyridyl, indol-1-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-7-yl, 1,2-benzoxazol-3-yl, 1,2-benzoxazol-4-yl, 1,2-benzoxazol-5-yl, 1,2-benzoxazol-6-yl, 1,2-benzoxazol-7-yl, 1H-indazol-3-yl, 1H- Indazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazolyl, pyrazolyl, pyridazinyl, pyrimidinyl, isoxazolyl and oxadiazolyl. Preferred but non-limiting examples of heteroaryl include pyrazolyl and pyridyl.

[0031] The term "heteroaryloxy" refers to a heteroaryl group, as defined above, attached to the parent molecular moiety through an oxygen atom. A preferred, but non-limiting example of heteroaryloxy is pyridoxy.

[0032] The term "hydroxy" refers to the group --OH.

[0033] The term "amino" refers to the group --NH.sub.2.

[0034] The term "cyano" refers to a -CN (nitrile) group.

[0035] The term "carboxy" refers to the group --COOH.

[0036] The term "carbamoyl" refers to the group -C(O)NH2.

[0037] The term "carbonyl" refers to the group -C(O)-.

[0038] The term "alkoxycarbonyl" refers to a -C(O)-O-alkyl group (ie, an alkyl ester).

[0039] 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 fluoro. 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 fluoro. Particularly preferred, but non-limiting examples of haloalkyl are trifluoromethyl and trifluoroethyl.

[0040] 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 fluoro. 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 fluoro. A particularly preferred, but non-limiting example of a haloalkoxy is trifluoromethoxy (-OCF).

[0041] The term "cyanoalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group has been replaced with a cyano group. Preferably, "cyanoalkoxy" refers to an alkoxy group in which one, two, or three hydrogen atoms of the alkoxy group have been replaced with a cyano group. A particularly preferred, but non-limiting example of a cyanoalkoxy is cyanomethoxy.

[0042] The term "cyanoalkyl" refers to an alkyl group in which at least one of the alkyl group's hydrogen atoms has been replaced with a cyano group. Preferably, "cyanoalkyl" refers to an alkyl group in which one, two, or three of the alkyl group's hydrogen atoms have been replaced with a cyano group. A particularly preferred, but non-limiting, example of a cyanoalkyl is cyanomethyl.

[0043] The term "carboxyalkyl" refers to an alkyl group in which at least one of the alkyl group's hydrogen atoms has been replaced with a carboxy group. Preferably, "carboxyalkyl" refers to an alkyl group in which one, two, or three of the alkyl group's hydrogen atoms have been replaced with a carboxy group. A particularly preferred, but non-limiting, example of a carboxyalkyl is carboxymethyl.

[0044] The term "carbamoylalkyl" refers to an alkyl group in which at least one of the alkyl group's hydrogen atoms is replaced by a carbamoyl group. Preferably, "carbamoylalkyl" refers to an alkyl group in which one, two, or three of the alkyl group's hydrogen atoms are replaced by a carbamoyl group. A particularly preferred, but non-limiting example of a carbamoylalkyl is 2-amino-2-oxo-ethyl.

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

[0046] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the free base or free acid, without being biologically or otherwise undesirable. Salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, especially hydrochloric acid, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, lactic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and N-acetylcysteine. In addition, these salts can be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins, etc. Particular pharmaceutically acceptable salts of compounds of formula (I) are hydrochloride, fumarate, lactate (especially derived from L-(+)-lactic acid), tartrate (especially derived from L-(+)-tartaric acid), and trifluoroacetate.

[0047] The term "protecting group" (PG) refers to a group that selectively blocks a reactive site in a polyfunctional compound so that a chemical reaction can be selectively carried out at an otherwise unprotected reactive site in the relevant conventional sense of synthetic chemistry. The protecting group can be removed at an appropriate time. Exemplary protecting groups are amino-protecting groups, carboxy-protecting groups, or hydroxy-protecting groups. Particular protecting groups are tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), and benzyl (Bn). Further particular protecting groups are tert-butoxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). An even more particular protecting group is tert-butoxycarbonyl (Boc). Exemplary protecting groups and their uses in organic synthesis are described, for example, in Protective Groups in Organic Chemistry, T.W. Greene and P.G.M. Hutts, 5th Edition, 2014, John Wiley & Sons, NY.

[0048] The compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers, e.g. racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0049] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom may be of the "R" or "S" configuration.

[0050] The term "treatment," as used herein, includes: (1) suppressing the symptom, disorder, or condition (e.g., in the case of maintenance treatment, arresting, reducing, or delaying the onset or recurrence of at least one clinical symptom or subclinical disease thereof); and / or (2) alleviating the condition (i.e., causing regression of the symptom, disorder, or condition, or at least one of its clinical symptoms or subclinical symptoms). The benefit to the patient to be treated is either statistically significant or at least discernible to the patient or physician. However, it will be understood that when a patient is administered a medication to treat a disease, the outcome need not necessarily be effective treatment.

[0051] The term "prophylaxis" as used herein includes preventing or delaying the appearance of clinical symptoms of a condition, disorder or condition that develops in a mammal, particularly in a human suffering from or susceptible to the condition, disorder or condition, but who has not yet experienced or exhibited clinical or asymptomatic symptoms of the condition, disorder or condition.

[0052] The term "mammal," as used herein, includes both humans and non-humans, including, but not limited to, humans, non-human primates, canines, felines, murines, bovines, equines, and porcines. In a particularly preferred embodiment, the term "mammal" refers to humans.

[0053] The term "nosocomial infection" refers to a hospital-acquired infection (HAI), which is an infection acquired in a hospital or other health care facility. To emphasize both hospital and non-hospital settings, it may alternatively be called a healthcare-associated infection (HAI or HCAI). Such infections may be acquired in hospitals, nursing homes, rehabilitation facilities, outpatient clinics, or other clinical settings.

[0054] Compounds of the Invention In a first aspect, the present invention provides a compound of formula (I) [ka] (In the formula, R x is the base [ka] base [ka] or base [ka] and R 1 is R 6 -C1-C6-alkyl-, R 6 -C1-C6-alkyl-CH(C1-C6-alkoxycarbonyl)-, R 7 -C1-C6-alkyl-X-C1-C6-alkyl-, group [ka] and groups [ka] is selected from R 2 is selected from hydrogen and C1-C6-alkyl, or R 1 and R 2 together with the nitrogen atom to which they are attached, form R 9 and R 9a forming a 3- to 14-membered heterocycle substituted with R 3 is selected from hydrogen, halogen and C1-C6-alkyl, or R 3 and R 2 together with the atoms to which they are attached form a 3- to 14-membered heterocyclic ring, R 4 is the base [ka] and R 5 is selected from hydrogen, C1-C6-alkyl and halogen, R 6 is the group R 16 -L 2 - and R 7 is the group R 16 -L 3 - and R 8 is the group R 16 -L 4 - and R 8a , R 9a , R 11a , R 12 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 and R 25 are independently selected from hydrogen, halogen, hydroxy, cyano, amino, carbamoyl, carboxy, C-C-alkyl, C-C-alkoxy, halo-C-C-alkyl, cyano-C-C-alkyl, carboxy-C-C-alkyl, hydroxy-C-C-alkyl, halo-C-C-alkoxy, cyano-C-C-alkoxy, C-C-alkynyloxy, amino-C-C-alkynyloxy, aryloxy, (5- to 14-membered heteroaryl)oxy, C-C-alkyl-(5- to 14-membered heteroaryl)oxy) and C-C-alkoxycarbonyl; R 9 is the group R 16 -L 5 -or group [ka] and R 10is C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, C1-C6-alkyl-NH-C1-C6-alkyl, amino-C1-C6-alkyl, carbamoyl, carbamoyl-C1-C6-alkyl, carboxy-C1-C6-alkyl, cyano-C1-C6-alkyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, and groups [ka] is selected from R 11 is selected from C1-C6-alkyl, carbamoyl, carboxy, carboxy-C1-C6-alkyl, and hydroxy-C1-C6-alkyl, R 13 and R 14 are independently C1-C6-alkyl, amino-C1-C6-alkyl, carbamoyl-C1-C6-alkyl, carboxy-C1-C6-alkyl, cyano-C1-C6-alkyl, hydroxy-C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, and groups [ka] Selected from or or R 13 and R 14 together with the nitrogen atom to which they are attached form a 3- to 14-membered heterocycle optionally substituted by 1 to 3 substituents selected from halogen, amino, hydroxy, cyano, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy and halo-C1-C6-alkoxy, R 15 is C1-C6-alkyl, R 16 is the base [ka] base [ka] and groups [ka] is selected from R 17 is the group R 16 -L 7 - and L 1 is selected from a covalent bond, carbonyl, and -C1-C6-alkyl-; L 2 and L 3 is independently selected from a covalent bond, carbonyl, —C-C-alkyl-C(O)—NH—, —C(O)—NH—, —NH—C(O)—, —C(O)—NH—CH(C-C-alkoxycarbonyl)-, —C-C-alkyl-CH(OH)—C-C-alkyl-C(O)—, and —C-C-alkyl-NH—; L 4 , L 5 , L 6 , L 7 , and L 8 is independently selected from a covalent bond, carbonyl, —C-C-alkyl-, —C-C-alkyl-C(O)—, —C-C-alkyl-NH—C(O)—, —C-C-alkyl-C(O)—NH—, —C-C-alkyl-NH—C(O)—C-C-alkyl-, —C-C-alkyl-C(O)—NH—C-C-alkyl-, —C(O)—NH—, —NH—C(O)—, —C(O)—NH—CH(C-C-alkoxycarbonyl)-, —C-C-alkyl-CH(OH)—C-C-alkyl-C(O)—, and —C-C-alkyl-NH—; L 9 is -C1-C6-alkyl- or -C(O)-C1-C6-alkyl-, A, C, D, and E are each independently C6-C 10 -Aryl, C3-C 10 - selected from cycloalkyl, 3- to 14-membered heterocyclyl, and 5- to 14-membered heteroaryl; B is a 3- to 14-membered heterocycle; F is C6-C 10-aryl or 5- to 14-membered heteroaryl, and X is selected from O, S, SO, SO, NH, and N(C-C-alkyl). The present invention provides a compound of the formula:

[0055] In one embodiment, the present invention relates to a compound of formula (I) having formula (II) [ka] (In the formula, R 1 , R 2 , R 3 and R 5 is as defined herein; R 23 is hydrogen or halogen, R 24 is hydrogen or halogen, and R 25 is selected from halogen, C-C-alkoxy, cyano-C-C-alkoxy, halo-C-C-alkoxy, C-C-alkynyloxy, amino-C-C-alkynyloxy, aryloxy, (5- to 14-membered heteroaryl)oxy, and C-C-alkyl-(5- to 14-membered heteroaryl)oxy. or a pharmaceutically acceptable salt thereof.

[0056] In one embodiment, the present invention relates to a compound of formula (I) having formula (III) [ka] (In the formula, R 1 , R 2 , R 3 and R 5 is as defined herein; R 23 is halo-C1-C6-alkyl, and R 24 is selected from hydrogen, C1-C6-alkyl, cyano-C1-C6-alkyl and halo-C1-C6-alkyl. or a pharmaceutically acceptable salt thereof.

[0057] In one embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof: R x is the base [ka] or base [ka] is.

[0058] In a preferred embodiment, the present invention provides R x Based on [ka] or a pharmaceutically acceptable salt thereof.

[0059] In one embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof: R 1 is R 6 -C1-C6-alkyl-, R 6 -C1-C6-alkyl-CH(C1-C6-alkoxycarbonyl)-, R 7 -C1-C6-alkyl-O-C1-C6-alkyl-, group [ka] and groups [ka] is selected from R 2 is selected from hydrogen and C1-C6-alkyl, R 6 is the group R 16 -L2 - and R 7 is the group R 16 -L 3 - and R 8 is the group R 16 -L 4 - and R 8a is hydrogen or C1-C6-alkoxycarbonyl, R 10 is C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, C1-C6-alkyl-NH-C1-C6-alkyl, amino-C1-C6-alkyl, carbamoyl-C1-C6-alkyl, carboxy-C1-C6-alkyl, cyano-C1-C6-alkyl, and the groups [ka] is selected from R 11 is selected from C1-C6-alkyl, carbamoyl, carboxy-C1-C6-alkyl and hydroxy-C1-C6-alkyl, R 11a is hydrogen or carboxy; R 12 is hydrogen or hydroxy, R 13 is C1-C6-alkyl, amino-C1-C6-alkyl, carbamoyl-C1-C6-alkyl, carboxy-C1-C6-alkyl, cyano-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, and the groups [ka] is selected from R 14 is C1-C6-alkyl, carboxy-C1-C6-alkyl, [ka] Selected from or or R13 and R 14 together with the nitrogen atom to which they are attached form a 3- to 14-membered heterocyclic ring, R 15 is C1-C6-alkyl, R 16 is the base [ka] base [ka] and groups [ka] is selected from R 17 is the group R 16 -L 7 - and R 18 is hydrogen, R 19 is selected from hydrogen, amino and C1-C6-alkyl, R 20 is hydrogen or C1-C6 alkyl, R 21 and R 22 are both hydrogen, L 1 is a covalent bond or -C1-C6-alkyl-, L 2 is selected from a covalent bond, carbonyl, —C-C-alkyl-C(O)—NH—, —C(O)—NH—, —C(O)—NH—CH(C-C-alkoxycarbonyl)-, —C-C-alkyl-CH(OH)—C-C-alkyl-C(O)—, and —C-C-alkyl-NH—; L 3 is a covalent bond, L 4is selected from carbonyl, —C-C-alkyl-C(O)—, —C-C-alkyl-C(O)—NH—, —C(O)—NH—, —C-C-alkyl-CH(OH)—C-C-alkyl-C(O)—, and —C-C-alkyl-NH—; L 7 is -C1-C6-alkyl-, L 8 is selected from a covalent bond, —C1-C6-alkyl-, and —C1-C6-alkyl-NH—C(O)—C1-C6-alkyl-; L 9 is -C1-C6-alkyl- or -C(O)-C1-C6-alkyl-, A is C3-C 10 -cycloalkyl or a 3- to 14-membered heterocycle; B is a 3- to 14-membered heterocycle; D is C3-C 10 - selected from cycloalkyl, 3- to 14-membered heterocyclyl, and 5- to 14-membered heteroaryl; E is a 3- to 14-membered heterocyclyl.

[0060] In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, R 1 is R 6 -C1-C6-alkyl-, R 7 -C1-C6-alkyl-O-C1-C6-alkyl-, and groups [ka] is selected from R 2 is selected from hydrogen and C1-C6-alkyl, R 6 is the group R 16 -L 2 - and R 7 is the group R 16 -L 3 - and R 8 is the group R 16-L 4 - and R 8a is hydrogen, R 10 is carbamoyl-C1-C6-alkyl, cyano-C1-C6-alkyl, C1-C6-alkyl, carboxy-C1-C6-alkyl, and the groups [ka] is selected from R 11 is C1-C6-alkyl or carboxy-C1-C6-alkyl, R 11a and R 12 are both hydrogen, R 13 is C1-C6-alkyl, amino-C1-C6-alkyl, carbamoyl-C1-C6-alkyl, and the group [ka] is selected from R 14 is C1-C6-alkyl or carboxy-C1-C6-alkyl, R 15 is C1-C6-alkyl, R 16 is the base [ka] base [ka] and groups [ka] is selected from R 19 and R 20 are both hydrogen, R 21 and R 22 are both hydrogen, L 1 , L 2, and L 3 is a covalent bond, L 4 is —C1-C6-alkyl-C(O)— or —C1-C6-alkyl-C(O)—NH—, L 8 and L 9 is -C1-C6-alkyl-, A is C3-C 10 -cycloalkyl or a 3- to 14-membered heterocycle; B is a 3- to 14-membered heterocycle; D is a 3- to 14-membered heterocyclyl, and E is a 3- to 14-membered heterocyclyl.

[0061] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof: R 1 is R 6 -(CH2) n -, R 7 -(CH2)2-O-(CH2)2-, and the group [ka] is selected from R 2 is selected from hydrogen and methyl; R 6 is the group R 16 -L 2 - and R 7 is the group R 16 -L 3 - and R 8 is the group R 16 -L 4 - and R 8a is hydrogen, R 10 is carbamoyl-CH2-, methyl, carboxy-CH2-, cyano-CH2-, and [ka] is selected from R 11 is methyl or carboxy-CH2-, R 11a and R 12 are both hydrogen, R 13 is methyl, aminopropyl, carbamoyl-CH2-, and the group [ka] is selected from R 14 is methyl or carboxymethyl, R 15 is methyl, R 16 is the base [ka] , base [ka] and groups [ka] is selected from R 19 and R 20 are both hydrogen, R 21 and R 22 are both hydrogen, L 1 , L 2 , and L 3 is a covalent bond, L 4 is —CH—C(O)— or —CH—C(O)—NH—, L 8 and L 9 are both -CH2-, A is cyclohexyl or pyrrolidinyl; B is pyrrolidinyl, piperidyl, or 3-azabicyclo[3.1.0]hexan-6-yl; D is pyrrolidine or azetidine; E is azetidine, and n is 1, 2 or 5.

[0062] In one embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof: R 1 and R 2 together with the nitrogen atom to which they are attached, form R 9 and R 9a forming a 3- to 14-membered heterocycle substituted with R 9 is the group R 16 -L 5 -or group [ka] and R 9a is selected from hydrogen, hydroxy, and C1-C6-alkoxycarbonyl, R 10 is C1-C6-alkyl, C1-C6-alkyl-NH-C1-C6-alkyl, amino-C1-C6-alkyl, carbamoyl-C1-C6-alkyl, and the group [ka] is selected from R 11 is C1-C6-alkyl, R 12 is hydrogen or hydroxy, R 13 is a C1-C6-alkyl or group [ka] and R 14 and R 15 are all C1-C6-alkyl, R 16 is the base [ka] or base [ka] and R 17 is the group R 16 -L 7 - and R 18 is hydrogen, R 19 is hydrogen or amino, R 20 , R 21 and R 22 is hydrogen, B is a 3- to 14-membered heterocycle; C is a 3- to 14-membered heterocycle; D is C3-C 10 -cycloalkyl or 3- to 14-membered heterocyclyl; E is a 3- to 14-membered heterocycle; L 5 is selected from a covalent bond, carbonyl, —C-C-alkyl-, —C-C-alkyl-C(O)—, and —C-C-alkyl-NH—C(O)—; L 6 is a carbonyl, L 7 is -C1-C6-alkyl-, and L 8 and L 9 are all -C1-C6-alkyl-.

[0063] In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, R 1 and R 2 together with the nitrogen atom to which they are attached, form R 9 and R 9a forming a 3- to 14-membered heterocycle substituted with R 9 is the group R 16 -L 5 - and R 9ais hydrogen, R 10 is a carbamoyl-C1-C6-alkyl or group [ka] and R 11 is C1-C6-alkyl, R 13 , R 14 and R 15 is C1-C6-alkyl, R 16 is the base [ka] or base [ka] and R 12 , R 19 , and R 20 is hydrogen, B is a 3- to 14-membered heterocycle; D is a 3- to 14-membered heterocycle; L 5 is selected from carbonyl, —C1-C6-alkyl-, and —C1-C6-alkyl-C(O)—, and L 8 is -C1-C6 alkyl.

[0064] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof: R 1 and R 2 together with the nitrogen atom to which they are attached, form R 9 and R 9a forming a piperazinyl ring substituted with R 9 is the group R 16 -L 5 - and R 9a is hydrogen, R10 is a carbamoylmethyl or [ka] and R 11 is methyl, R 13 , R 14 and R 15 is methyl, R 16 is the base [ka] or base [ka] and R 12 , R 19 , and R 20 is hydrogen, B is piperidyl, D is pyrrolidinyl; L 5 is selected from carbonyl, —(CH)—, and —CH—C(O)—; and L 8 is -CH2-.

[0065] In one embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof: R 3 is selected from fluoro, chloro, methyl, and ethyl; or R 3 and R 2 together with the atoms to which they are attached form a 6-oxo-2,3-dihydropyridinyl ring.

[0066] In one embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof: R 4 is the base [ka] and R 23 is selected from halogen, C-C-alkyl, C-C-alkoxy, halo-C-C-alkyl, cyano-C-C-alkyl, halo-C-C-alkoxy, cyano-C-C-alkoxy, C-C-alkynyloxy, amino-C-C-alkynyloxy, aryloxy, (5- to 14-membered heteroaryl)oxy, and C-C-alkyl-(5- to 14-membered heteroaryl)oxy; R 24 is selected from hydrogen, halogen, and halo-C1-C6-alkyl, R 25 is hydrogen or halogen, and F is C6-C 10 -aryl or 5- to 14-membered heteroaryl.

[0067] In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, R 4 is the base [ka] and R 23 is selected from C1-C6-alkoxy, halo-C1-C6-alkyl, cyano-C1-C6-alkyl, halo-C1-C6-alkoxy, cyano-C1-C6-alkoxy and amino-C2-C6-alkynyloxy, R 24 is selected from hydrogen, halogen, and halo-C1-C6-alkyl, R 25 is hydrogen or halogen, and F is C6-C 10 -aryl or 5- to 14-membered heteroaryl.

[0068] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof: R 4 is the base [ka] and R 23 is selected from methoxy, 2,2-difluoroethyl, cyanomethyl, difluoromethoxy, cyanomethoxy, and 4-aminobut-2-ynoxy; R 24 is selected from hydrogen, fluoro, and CF3; R 25 is hydrogen or fluoro, and F is phenyl or pyrazolyl.

[0069] In a preferred embodiment, the present invention provides R 5 is hydrogen or C1-C6-alkyl; or a pharmaceutically acceptable salt thereof.

[0070] In a particularly preferred embodiment, the present invention provides 5 is hydrogen or methyl; or a pharmaceutically acceptable salt thereof.

[0071] In one embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof: R x is the base [ka] or base [ka] and R 1 is R 6 -C1-C6-alkyl-, R 6-C1-C6-alkyl-CH(C1-C6-alkoxycarbonyl)-, R 7 -C1-C6-alkyl-O-C1-C6-alkyl-, group [ka] and groups [ka] is selected from R 2 is selected from hydrogen and C1-C6-alkyl, or R 1 and R 2 together with the nitrogen atom to which they are attached, form R 9 and R 9a forming a 3- to 14-membered heterocycle substituted with R 3 is selected from hydrogen, halogen and C1-C6-alkyl, or R 3 and R 2 together with the atoms to which they are attached form a 3- to 14-membered heterocyclic ring, R 4 is the base [ka] and R 5 is hydrogen or C1-C6 alkyl, R 6 is the group R 16 -L 2 - and R 7 is the group R 16 -L 3 - and R 8 is the group R 16 -L 4 - and R 8a is hydrogen or C1-C6-alkoxycarbonyl, R 9 is the group R 16 -L 5 -or group [ka] and R 9a is selected from hydrogen, hydroxy, and C1-C6-alkoxycarbonyl, R 10 is C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, C1-C6-alkyl-NH-C1-C6-alkyl, amino-C1-C6-alkyl, carbamoyl-C1-C6-alkyl, carboxy-C1-C6-alkyl, cyano-C1-C6-alkyl, and the groups [ka] is selected from R 11 is selected from C1-C6-alkyl, carbamoyl, carboxy-C1-C6-alkyl and hydroxy-C1-C6-alkyl, R 11a is hydrogen or carboxy; R 12 is hydrogen or hydroxy, R 13 is C1-C6-alkyl, amino-C1-C6-alkyl, carbamoyl-C1-C6-alkyl, carboxy-C1-C6-alkyl, cyano-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, and the groups [ka] is selected from R 14 is C1-C6-alkyl, carboxy-C1-C6-alkyl, [ka] Selected from or or R 13 and R 14 together with the nitrogen atom to which they are attached form a 3- to 14-membered heterocyclic ring, R 15 is C1-C6-alkyl, R 16 is the base [ka] base [ka] and groups [ka] is selected from R 17 is the group R 16 -L 7 - and R 18 is hydrogen, R 19 is selected from hydrogen, amino and C1-C6-alkyl, R 20 is hydrogen or C1-C6 alkyl, R 21 and R 22 are both hydrogen, R 23 is selected from halogen, C-C-alkyl, C-C-alkoxy, halo-C-C-alkyl, cyano-C-C-alkyl, halo-C-C-alkoxy, cyano-C-C-alkoxy, C-C-alkynyloxy, amino-C-C-alkynyloxy, aryloxy, (5- to 14-membered heteroaryl)oxy, and C-C-alkyl-(5- to 14-membered heteroaryl)oxy; R 24 is selected from hydrogen, halogen, and halo-C1-C6-alkyl, R 25 is hydrogen or halogen, L 1 is a covalent bond or -C1-C6-alkyl-, L 2is selected from a covalent bond, carbonyl, —C-C-alkyl-C(O)—NH—, —C(O)—NH—, —C(O)—NH—CH(C-C-alkoxycarbonyl)-, —C-C-alkyl-CH(OH)—C-C-alkyl-C(O)—, and —C-C-alkyl-NH—; L 3 is a covalent bond, L 4 is selected from carbonyl, —C-C-alkyl-C(O)—, —C-C-alkyl-C(O)—NH—, —C(O)—NH—, —C-C-alkyl-CH(OH)—C-C-alkyl-C(O)—, and —C-C-alkyl-NH—; L 5 is selected from a covalent bond, carbonyl, —C-C-alkyl-, —C-C-alkyl-C(O)—, and —C-C-alkyl-NH—C(O)—; L 6 is a carbonyl, L 7 is -C1-C6-alkyl-, L 8 is selected from a covalent bond, —C1-C6-alkyl-, and —C1-C6-alkyl-NH—C(O)—C1-C6-alkyl-; L 9 is -C1-C6-alkyl- or -C(O)-C1-C6-alkyl-, A is C3-C 10 -cycloalkyl or a 3- to 14-membered heterocycle; B is a 3- to 14-membered heterocycle; C is a 3- to 14-membered heterocycle; D is C3-C 10 - selected from cycloalkyl, 3- to 14-membered heterocyclyl, and 5- to 14-membered heteroaryl; E is a 3- to 14-membered heterocyclyl, and F is C6-C 10 -aryl or 5- to 14-membered heteroaryl.

[0072] In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, R x is the base [ka] and R 1 is R 6 -C1-C6-alkyl-, R 7 -C1-C6-alkyl-O-C1-C6-alkyl-, and groups [ka] is selected from R 2 is selected from hydrogen and C1-C6-alkyl, or R 1 and R 2 together with the nitrogen atom to which they are attached, form R 9 and R 9a forming a 3- to 14-membered heterocycle substituted with R 3 is selected from hydrogen, halogen and C1-C6-alkyl, or R 3 and R 2 together with the atoms to which they are attached form a 3- to 14-membered heterocyclic ring, R 4 is the base [ka] and R 5 is hydrogen or C1-C6 alkyl, R 6 is the group R 16 -L 2 - and R 7 is the group R 16 -L 3 - and R 8 is the group R 16 -L 4 - and R 8a is hydrogen, R 9 is the group R 16 -L 5 - and R 9a is hydrogen, R 10 is carbamoyl-C1-C6-alkyl, cyano-C1-C6-alkyl, C1-C6-alkyl, carboxy-C1-C6-alkyl, and the groups [ka] is selected from R 11 is C1-C6-alkyl or carboxy-C1-C6-alkyl, R 11a and R 12 are both hydrogen, R 13 is C1-C6-alkyl, amino-C1-C6-alkyl, carbamoyl-C1-C6-alkyl, and the group [ka] is selected from R 14 is C1-C6-alkyl or carboxy-C1-C6-alkyl, R 15 is C1-C6-alkyl, R 16 is the base [ka] base [ka] and groups [ka] is selected from R 19 and R 20 are both hydrogen, R21 and R 22 are both hydrogen, R 23 is selected from C1-C6-alkoxy, halo-C1-C6-alkyl, cyano-C1-C6-alkyl, halo-C1-C6-alkoxy, cyano-C1-C6-alkoxy and amino-C2-C6-alkynyloxy, R 24 is selected from hydrogen, halogen, and halo-C1-C6-alkyl, R 25 is hydrogen or halogen, L 1 , L 2 , and L 3 is a covalent bond, L 4 is —C1-C6-alkyl-C(O)— or —C1-C6-alkyl-C(O)—NH—, L 5 is selected from carbonyl, —C1-C6-alkyl-, and —C1-C6-alkyl-C(O)—; L 8 and L 9 is -C1-C6-alkyl-, A is C3-C 10 -cycloalkyl or a 3- to 14-membered heterocycle; B is a 3- to 14-membered heterocycle; D is a 3- to 14-membered heterocyclyl; E is a 3- to 14-membered heterocyclyl, and F is C6-C 10 -aryl or 5- to 14-membered heteroaryl.

[0073] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof: R x is the base [ka] and R 1 is R 6-(CH2) n -, R 7 -(CH2)2-O-(CH2)2-, and the group [ka] is selected from R 2 is selected from hydrogen and methyl, or R 1 and R 2 together with the nitrogen atom to which they are attached, form R 9 and R 9a forming a piperazinyl ring substituted with R 3 is selected from fluoro, chloro, methyl, and ethyl; or R 3 and R 2 together with the atoms to which they are attached form a 6-oxo-2,3-dihydropyridinyl ring, R 4 is the base [ka] and R 5 is hydrogen or methyl, R 6 is the group R 16 -L 2 - and R 7 is the group R 16 -L 3 - and R 8 is the group R 16 -L 4 - and R 8a is hydrogen, R 9 is the group R 16 -L 5 - and R 9a is hydrogen, R 10 is carbamoyl-CH2-, methyl, carboxy-CH2-, cyano-CH2-, and [ka] is selected from R 11 is methyl or carboxy-CH2-, R 11a and R 12 are both hydrogen, R 13 is methyl, aminopropyl, carbamoyl-CH2-, and the group [ka] is selected from R 14 is methyl or carboxymethyl, R 15 is methyl, R 16 is the base [ka] base [ka] and groups [ka] is selected from R 19 and R 20 are both hydrogen, R 21 and R 22 are both hydrogen, R 23 is selected from methoxy, 2,2-difluoroethyl, cyanomethyl, difluoromethoxy, cyanomethoxy, and 4-aminobut-2-ynoxy; R 24 is selected from hydrogen, fluoro, and CF3; R 25 is hydrogen or fluoro, L 1 , L 2 , and L 3 is a covalent bond, L 4 is —CH—C(O)— or —CH—C(O)—NH—, L 5 is selected from carbonyl, —(CH)—, and —CH—C(O)—; L 8 and L 9 are both -CH2-, A is cyclohexyl or pyrrolidinyl; B is pyrrolidinyl, piperidyl, or 3-azabicyclo[3.1.0]hexan-6-yl; D is pyrrolidine or azetidine; E is azetidine; F is phenyl or pyrazolyl, and n is 1, 2 or 5.

[0074] In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from the compounds disclosed in Table 1.

[0075] In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from any of the examples disclosed herein.

[0076] In one embodiment, the present invention provides a pharmaceutically acceptable salt of a compound of formula (I) described herein, particularly a pharmaceutically acceptable salt selected from hydrochloride, fumarate, lactate (particularly derived from L-(+)-lactic acid), tartrate (particularly derived from L-(+)-tartaric acid), and trifluoroacetate. In an even more specific embodiment, the present invention provides a compound according to formula (I) described herein (i.e., as the "free base" or "free acid," respectively).

[0077] In some embodiments, compounds of formula (I) are isotopically labeled by having one or more atoms therein replaced by atoms having different atomic masses or mass numbers. Such isotopically labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of the present disclosure. Examples of isotopes that can be incorporated into compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively, e.g., 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 Certain isotopically labeled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e., 3 H and carbon-14, i.e., 14 C are particularly useful for this purpose given their ease of incorporation and ready means of detection. For example, compounds of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99% of a given isotope.

[0078] Heavier isotopes, such as deuterium, i.e. 2 Substitutions such as H may result in greater metabolic stability and may confer certain therapeutic advantages, for example, by increasing in vivo half-life or requiring lower dosages.

[0079] 11 C. 18 F, 15 O and 13Substitution with positron emitting isotopes, such as N, can be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the Examples set forth below, substituting appropriate isotopically labeled reagents for previously employed non-isotopically labeled reagents.

[0080] Manufacturing Process The preparation of the compounds of formula (I) of the present invention can be carried out 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 purification of the resulting products are known to those skilled in the art. The substituents and indices used in the following process descriptions have the meanings previously indicated herein, unless otherwise indicated. More specifically, the compounds of formula (I) can be prepared by the methods shown below, the methods shown in the Examples, or similar methods. Suitable reaction conditions for the individual reaction steps are known to those skilled in the art. For literature-described reaction conditions affecting the reactions described, see, for example, "Comprehensive Organic Transformations: A Guide to Functional Group Preparations," 2nd ed., Richard C. Larock, John Wiley & Sons, New York, NY, 1999." The present inventors have found it convenient to carry out the reactions in the presence or absence of a solvent. There are no particular limitations on the nature of the solvent used, provided it does not adversely affect the reaction or the reagents involved and is capable of dissolving the reagents to at least some extent. The reactions described can occur over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. It is convenient to carry out the reactions described at temperatures ranging from -78°C to reflux. The time required for the reaction can also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents. However, a period of 0.5 hours to several days is usually sufficient to obtain the intermediates and compounds described. The reaction sequence is not limited to the order shown in the scheme, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivities. The starting materials are commercially available or can be prepared by methods similar to those shown below, methods described in the references or examples cited herein, or methods known in the art.

[0081] The following types of organic reactions - or variations thereof - were used throughout this invention: The examples of reagents shown below are options that work in this invention, but can also be substituted with alternatives that are well known in the art and described throughout the literature.

[0082] Amide formation There are numerous ways to form an amide bond. In this invention, several have been used, which can generally be described as follows:

[0083] The corresponding carboxylic acid and a suitable base are combined in a suitable solvent. The coupling reagent is then added, and the mixture is stirred for a short period (usually 5-30 minutes). The corresponding amine is then added, and stirring at a suitable temperature is continued until reaction monitoring reveals the formation of a sufficient amount of product. Alternatively, the carboxylic acid, base, amine, and coupling reagent can be combined a priori. Examples of suitable bases are DIPEA or EtN, examples of coupling reagents are HAUT or 1-propanephosphonic anhydride, and a suitable solvent is DMF. These reactions typically proceed at room temperature, but the temperature may be elevated depending on reactivity.

[0084] Another method is the formation of an activated ester from the corresponding acid using N-hydroxysuccinimide with 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride and subsequent reaction with the corresponding amine to form an amide.

[0085] urea formation There are many methods known in the art for forming ureas that can be applied to synthesize the molecules of the present invention. One option that can be used is to stir two respective amines in a suitable solvent, base, and coupling reagent at a suitable temperature. Alternatively, one of the amines, base, and coupling reagent in a solvent can be first stirred, and then the resulting intermediate is reacted with the second amine. Examples of suitable solvents are DMF, NMP, and DCM. DIPEA is an example of a suitable base, and examples of coupling reagents are N,N'-carbonyldiimidazole or bis(trichloromethyl)carbonate. Depending on the reactivity, the reaction can proceed at various temperatures.

[0086] SNAr The electrophile and nucleophile were combined in a solvent and heated to an appropriate temperature until reaction monitoring indicated the formation of an appropriate amount of product. In some cases, a catalyst additive can accelerate the reaction, and heating in a closed reaction vessel can be beneficial. An example of a suitable solvent is acetonitrile, and an example of a catalyst additive is acetic acid. Depending on the reactivity, the required temperature can vary widely, but temperatures near the boiling point of the mixture were often used. Slightly higher temperatures can be used when working in a closed reaction vessel.

[0087] Suzuki Coupling The aryl halide and boronate were combined with a solvent. A base and a catalyst were added, and the reaction mixture was heated to an appropriate temperature and stirred until reaction monitoring confirmed the formation of a sufficient amount of product. It may be advantageous to carry out the reaction in a sealed reaction vessel with the exclusion of oxygen. The halide and boronate may be used in equimolar amounts or in excess of one. A suitable solvent is, for example, dioxane or a mixture of dioxane and water. An example of a suitable base is sodium carbonate (solid or aqueous solution), and a suitable catalyst may be 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II). The reaction temperature is usually above room temperature, preferably within the boiling point of the mixed solvent, or slightly higher if a sealed reaction vessel is used.

[0088] Reductive amination The reaction of an amine with a ketone or aldehyde in a suitable solvent and a suitable reducing agent, sometimes with the addition of a suitable catalyst. Examples of suitable solvents are THF, methanol, or ethanol. Formation of an imine followed by the addition of a reducing agent may be required. Examples of reducing agents are sodium triacetoxyborohydride or sodium cyanoborohydride. An example of a suitable catalyst is acetic acid. The reaction can proceed at room temperature, but heating may be required.

[0089] Alkylation To a mixture of the corresponding nucleophile in a suitable solvent, an alkylating agent (usually in excess) and a base were added. The mixture was then stirred at a suitable temperature until reaction monitoring showed the formation of a sufficient amount of product. Examples of suitable solvents are dioxane and acetonitrile, and the reaction usually proceeds at room temperature, although higher temperatures may be required depending on reactivity.

[0090] Boc, tBu-ester and Trt deprotection The protected starting material was combined with an appropriate solvent. An appropriate acid was then added, and the mixture was stirred at an appropriate temperature until reaction monitoring indicated the formation of a sufficient amount of product. Examples of suitable solvents are dioxane, methanol, and dichloromethane. Examples of suitable acids are HCl or TFA. The concentrations of these acids can vary from very dilute to very concentrated. For HCl, the preferred concentration range is 0.5-4 M, with TFA ranging from 10-90%. Depending on the sensitivity of other functional groups, such as oxetane or azetidine, TFA may be more suitable than HCl. These reactions usually work well at room temperature, but elevated temperatures may be required depending on stability or if a tBu-ester is present.

[0091] Another method is to combine the protected starting material in a suitable solvent with lithium chloride and a base and heat until reaction monitoring indicates the formation of a sufficient amount of product. An example of a suitable solvent is DMF and a suitable base, triethylamine.

[0092] Phthalimide deprotection The phthalimide protecting group can be removed by stirring the compound with hydrazine hydrate in a suitable solvent such as ethanol at slightly elevated temperatures.

[0093] Cbz deprotection Cbz deprotection can be carried out under standard hydrogenation conditions. One possible method is to dissolve the starting material in a suitable solvent such as methanol or ethanol, add a suitable catalyst such as 10% Pd / C, and hydrogenate under a hydrogen atmosphere with or without pressure at a suitable temperature, usually room temperature.

[0094] Ester hydrolysis The synthetic sequence may require deprotection of the acid moiety in the form of hydrolysis from the corresponding ester. One method is a saponification procedure in which the corresponding ester is stirred with a suitable strong base, such as aqueous sodium hydroxide, in a suitable solvent, such as THF, methanol, water, or a mixture thereof. These reactions usually proceed at room temperature, but may require heating.

[0095] Synthetic Routes for Preparing Compounds of the Invention To construct the molecules of the invention, the following bonds were made in various orders using standard methods known to those skilled in the art. [ka]

[0096] The central imidazo[1,2-a]pyrazine core and R 4 The Suzuki approach can be used to form bonds between R 4 Instead of then R 4 precursor (R z ) can also be used. [ka]

[0097] This formation can be generalized as in Scheme 1, but Suzuki uses R while the boronate is present on the imidazo[1,2-a]pyrazine moiety. 4 / R z The halogen can be oriented in the above direction. Instead of boronic acid, boronic acid esters, trifluoroborates, or other suitable coupling partners can also be used, and other halogens other than iodine can be used. The general procedure for Suzuki coupling described above can be used. For a representative procedure, see Step 2 of Example 1.

[0098] Intermediate type 1, which can be a boronic ester, but also a boronic acid, trifluoroborate or other suitable coupling partner, can be commercially available or may have to be prepared depending on the substitution. [ka]

[0099] Intermediate Type 1 A representative sequence is shown in Scheme 2, where substitution can be modified first by alkylation of the phenol moiety using an alkyl bromide in acetonitrile in the presence of a base (see general procedure for alkylation). This is then followed by boronation using bis(pinacolato)diboron in the presence of a base such as potassium acetate and a palladium catalyst in a suitable solvent such as dioxane at elevated temperature. See steps 1 and 2 of Example 2 for implementation. [ka]

[0100] Modification of the substitution pattern can also be achieved by SNAr using an appropriate activated halo-heteroaromatic system (e.g., 2-chloropyrimidine), which is stirred with the corresponding phenol in a suitable solvent (e.g., DMSO) in the presence of a base (e.g., potassium carbonate) at elevated temperature. Example 3, Step 5 is representative of such a transformation.

[0101] Another way to modify the substitution pattern, for example when consisting of a pyrazole as shown in Scheme 3, is by direct alkylation of the aromatic ring. [ka]

[0102] A representative procedure can be found in the preparation of Example 4.

[0103] It may be necessary to synthesize an appropriate alkylating agent. One possibility is to construct a mesylate, as shown in Scheme 4. This is done by forming a Boc-protected amine from a commercially available diol-monomesylate by reaction with ammonium hydroxide and BocO. The remaining alcohol can then be converted to the corresponding mesylate by reaction with mesyl chloride in the presence of a suitable base, such as triethylamine, in a suitable solvent, such as DCM. This mesylate can then be used to alkylate the aromatic ring. A representative procedure can be found in the preparation of Example 5. [ka]

[0104] Another method for varying the substitution pattern is by performing an Ullman-type coupling, in which a phenol is reacted with an appropriate haloaromatic system at elevated temperatures in the presence of a base, a suitable ligand, and a copper(I) source. An example base is cesium carbonate, and an example ligand / catalyst pair is 2-oxocyclohexanecarboxylate / copper(I) bromide in a suitable solvent such as acetonitrile. Also, the haloaromatic system must be constructed first and may require further modification later. This sequence appears as shown in Scheme 5, where a benzyl azide is reacted with an alkyne in the presence of copper(I) iodide and NBS to form a protected triazole, which is then coupled to the respective phenol as described above. After attachment of the imidazopyrazine moiety and subsequent modifications to this moiety, the protecting group is hydrogenated under standard conditions, followed by another alkylation of the triazole. [ka]

[0105] A representative procedure can be found in the preparation of Example 6.

[0106] Alternatively, modifications such as alkylation can be performed after coupling of the boronate to the imidazo[1,2-a]pyrazine moiety. Sometimes, it may be important to use protecting groups for certain functional groups. An example of this can be found in the synthesis of Example 7.

[0107] When the aromatic ring is a pyrazole, protecting the pyrazole nitrogen can be important for successful synthesis. An example of such a sequence is shown in Scheme 6, where the aromatic ring is iodinated using a suitable reagent such as n-iodosuccinimide. The pyrazole is then first deprotonated using a suitable base such as sodium hydride, and then protected with a trityl group using a reagent such as trityl chloride. Finally, the haloaromatic system is converted to the corresponding boronic acid by halogen-lithium exchange using a suitable reagent such as butyllithium, followed by the addition of a suitable reagent such as boron isopropoxide. [ka]

[0108] The trityl group can be cleaved at a later point using a strong acid such as HCl in dioxane. A representative procedure can be found in the preparation of Example 8.

[0109] The bond between the nitrogen and the imidazo[1,2-a]pyrazine moiety can be formed using the SNAr reaction starting from an 8-halo-imidazo[1,2-a]pyrazine and the corresponding aniline using the general procedure for SNAr described above (Scheme 7). [ka]

[0110] The bond between the 8-amino-imidazo[1,2-a]pyrazine and the adjacent benzene ring can be established by the Buchwald procedure (Scheme 8), in which 8-amino-imidazo[1,2-a]pyrazine is coupled with a halobenzene in the presence of a suitable base and a suitable palladium catalyst in a suitable solvent, usually under an inert atmosphere, at elevated temperatures. Examples include potassium carbonate or sodium tert-butoxide as the base, tert-butanol or THF as the solvent, and Brettphos Pd G3 or 1,1'-bis(diphenylphosphino)ferrocene / tris(dibenzylideneacetone)dipalladium(0) as the catalyst at elevated temperatures. Depending on the substrate, other catalysts or catalyst / ligand combinations may be appropriate. [ka]

[0111] The amide bond present in formula (I) can be constructed by various amide couplings known in the art (Scheme 9). x The amide bond present in the R can also be constructed in this way, as described in the general procedure above.x It may be possible to have an amine consisting of moieties on hand.

[0112] However, this also means that R x must be constructed before or after the fact (R y’ ) and the use of protecting groups such as Boc, tBu or Cbz can be used to provide R such as an amine or acid. x Reactive functional groups in the R can be masked. Subsequent deprotection as described in the general procedure, followed by more amide coupling / urea formation / reductive amination / alkylation / reduction can be used (which may also require subsequent deprotection). A representative sequence can be found in steps 3-7 of Example 9, where R y and then coupling the resulting R y’ Further modifying it to R x was formed (Boc deprotection → amide coupling → Boc deprotection → reductive amination → alkylation to form the quaternary ammonium center). [ka]

[0113] R x Depending on the structure of R y A different sequence of synthetic steps may be required to get there from Example 10 (Boc deprotection to form quaternary ammonium center → Boc deprotection → reductive amination → alkylation).

[0114] R x The alcohol in can be obtained from reduction of the corresponding ester to this alcohol by using a reducing agent (e.g., sodium borohydride) optionally in the presence of an agent such as lithium chloride in a suitable solvent such as THF, ethanol, or a mixture thereof.

[0115] R y You may also need to build parts of R14 = where the aminoalkyl compound can be constructed as shown in Scheme 10. y are coupled by amide coupling and Boc deprotection (a). In parallel, an aldehyde is formed from an alcohol containing a phthalimide-protected amine using tetrabutylammonium chloride, N-chlorosuccinimide, and 2,2,6,6-tetramethyl-1-oxide-piperidine in a buffer solution (NaHCO3 / K2CO3) (b). The two products are then coupled by reductive amination and further modified by reductive amination and alkylation followed by deprotection. Specific procedures can be found in Example 11. [ka]

[0116] R before amide coupling and subsequent further derivatization y Another example of constructing R is shown in Scheme 11. y : Amide coupling of a Cbz-bearing amine with an N-Boc-bearing carboxylic acid, followed by Cbz deprotection. (As shown in Scheme 9) y Amide coupling to attach to the remainder of the molecule, followed by further derivatization to obtain the desired final compound. [ka]

[0117] A representative procedure can be found in the preparation of Example 12.

[0118] R x The methods required to create the above are contained in the steps above, and the sequences that can be used are well illustrated by the specific examples. [ka]

[0119] Intermediate Type 2 I 1Intermediates of type 2, where R3 can be alkyl or H, may be commercially available or may have to be synthesized. A possible use of these intermediates is the SNAr reaction to attach them to an imidazopyrazine moiety (see above). There are multiple ways to prepare them. When R3 = alkyl and R5 = H, a possible sequence is shown in Scheme 12, which shows a Suzuki-type reaction with an alkenyl boronate followed by subsequent hydrogenation. Representative examples are Steps 1 and 2 of Example 13. Alternatively, a direct approach can be used by using the corresponding alkyl borate solution under Suzuki conditions with a base such as potassium carbonate in DMF. An exemplary procedure can be found in Step 1 of Example 4. [ka]

[0120] Alternatively, they may be available from the corresponding nitro compounds by reduction under Bechamp conditions, as shown in Scheme 13. A representative procedure can be found in Step 1 of Example 14. Combination with the modifications in Scheme 12 is possible. [ka]

[0121] Intermediates of type 3 may be commercially available or may have to be synthesized. They are typically used in the same manner as intermediates of type 2. [ka]

[0122] Intermediate Type 3 The synthetic sequence for preparing these compounds is to start from intermediates available via the synthesis of intermediate type 2 (Schemes 11 and 12). The above amide formation can be achieved by reacting R X or its precursor (R y) is installed. In the latter case, the precursor may have to be further modified, for example by hydrogenation in the presence of Pd / C in a suitable solvent such as methanol, before the nitro group is finally reduced to the corresponding aniline. A representative procedure can be found in steps 4-7 of Example 2 or steps 4-7 of Example 15. [ka]

[0123] Intermediates of type 4 are used to attach moieties to imidazo[1,2-a]pyrazine moieties, for example, by Buchwald coupling as described above. [ka]

[0124] Intermediate Type 4 They can be synthesized by methods similar to those described for intermediates of types 2 and 3. Another method for synthesizing them is shown in Scheme 15, in which the alcohol is converted to the corresponding mesylate by reacting it with methanesulfonyl chloride in the presence of a base such as triethylamine in a suitable solvent such as DCM. In the next step, the resulting material is used to alkylate the amide. For this, the amide is first deprotonated with a suitable base such as sodium hydride, followed by the addition of the mesylate and heating. A representative procedure can be found in Example 16. [ka]

[0125] Using a similar approach, R x An alkyl-amine bond can be formed in the reaction mixture. Formation of the corresponding mesylate from the alcohol in Ry, followed by treatment with the corresponding amine in the presence of a suitable base (e.g., DIPEA), which usually need not be as strong as the base described above. A representative example can be found in the preparation of Example 17.

[0126] Another method for synthesizing intermediates of type 4 is shown in Scheme 16. Protection of the acid as the tert.-butyl ester, for example by stirring with N,N-dimethylformamide di-tert-butyl acetal in a suitable solvent such as hot dry toluene, followed by Buchwald coupling to the imidazopyrazine moiety, followed by acid deprotection (for example by stirring in hot HCl in dioxane) to regenerate the acid. [ka]

[0127] As shown in Scheme 8, intermediates of type 5 can be used as reagents. [ka]

[0128] Intermediate Type 5 They can be formed by reacting the corresponding chloride with ammonia, as shown in Scheme 17. Aqueous ammonia can be used and the reaction can be carried out in a suitable solvent, such as isopropanol, in a closed vessel at elevated temperature. A representative procedure can be found in the preparation of Example 18. [ka]

[0129] For practical reasons, it may be advantageous to form the quaternary ammonium center later in the synthesis, which in the present invention is typically done by alkylation as described in the general procedures.

[0130] As noted, there are always many ways to synthesize the molecules of the invention. Scheme 18 provides a non-exhaustive overview of many possible synthetic routes. In this particular scheme, each arrow can consist of multiple steps as described above for the corresponding transformation. [ka]

[0131] In one aspect, the present invention provides a method for preparing a compound of formula (I) described herein, comprising: (i) compound (A) to form the compound of formula (I) or a synthetic precursor thereof [ka] (wherein X is halogen or triflate, preferably X is iodo, and the double cross indicates the point of attachment of (A) to the remainder of formula (I), or a synthetic precursor thereof; Boronic acids (R = H) or boronic esters (R = alkyl, or both R's together with the atoms to which they are attached form a heterocyclic ring) (B) [ka] (R 4 is as defined herein), or (ii) compound (C) to form the compound of formula (I) or a synthetic precursor thereof [ka] (The double cross represents the R 4 or its synthetic precursor) and Aryl Halides (D) [ka] (R 3 and R 5 is as defined herein, X is a halogen, and the double cross indicates the point of attachment of (D) to the remainder of formula (I), or a synthetic precursor thereof; (iii) compound (C1) for forming the compound of formula (I) or a synthetic precursor thereof [ka] (X is a halogen and the double cross represents R as defined herein) 4 or its synthetic precursor) and Aniline derivatives (D1) [ka] (R 3 and R 5 is as defined herein, and the double cross indicates the point of attachment of (D1) to the remainder of formula (I), or a synthetic precursor thereof; (iv) Formula (G) [ka] (Ry' is R as defined herein) x Equal to or R x carboxylic acid (E) to form a compound of formula (E), which is a synthetic precursor of [ka] (wherein the double cross indicates the point of attachment of (E) to the remainder of formula (I)) or a synthetic precursor thereof; Primary or secondary amines y and reacting the compound with The present invention provides a method comprising:

[0132] In one embodiment, the method of the present invention comprises all of steps (i), (ii) and (iv) as outlined above.

[0133] In one embodiment, the method of the present invention comprises all of steps (i), (iii) and (iv) as outlined above.

[0134] In one embodiment, the order of steps (i), (ii), (iii) and (iv) outlined above can be freely changed.

[0135] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, when prepared according to the methods disclosed herein.

[0136] Uses of the Compounds of the Invention As shown in the experimental section, the compounds of formula (I) and their pharmaceutically acceptable salts possess valuable pharmacological properties for the treatment or prevention of infections and resultant diseases caused by pathogens, particularly bacteria, more particularly Acinetobacter species, and most particularly Acinetobacter baumannii, in particular bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections.

[0137] The compounds of formula (I) and their pharmaceutically acceptable salts exhibit activity as antibiotics, particularly as antibiotics against Acinetobacter species, more particularly as antibiotics against Acinetobacter baumannii, and most particularly as pathogen-specific antibiotics against Acinetobacter baumannii.

[0138] The compounds of formula (I) and their pharmaceutically acceptable salts can be used as antibiotics, i.e., as suitable antibacterial pharmaceutical ingredients in the treatment and prevention of bacterial infections, in particular bacterial infections caused by Acinetobacter species, more particularly bacterial infections caused by Acinetobacter baumannii.

[0139] The compounds of the present invention can be used, alone or in combination with other drugs, for the treatment or prevention of infections and resultant diseases caused by pathogens, particularly bacteria, more particularly Acinetobacter species, most particularly Acinetobacter baumannii, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0140] In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

[0141] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as an antibiotic.

[0142] In a further aspect, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of hospital-acquired infections and resulting diseases.

[0143] In certain embodiments, the nosocomial infection and resulting disease is selected from bacteremia, pneumonia, meningitis, urinary tract infections and wound infections, or a combination thereof.

[0144] In a further aspect, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infections and resulting diseases caused by Gram-negative bacteria.

[0145] In certain embodiments, said infections and resulting diseases caused by Gram-negative bacteria are selected from bacteremia, pneumonia, meningitis, urinary tract infections and wound infections, or combinations thereof.

[0146] In a further aspect, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infection and resulting disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof.

[0147] In a further aspect, the present invention provides a method for the treatment or prevention of infection and resulting disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof, comprising administering to a mammal a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0148] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, as an antibiotic.

[0149] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of infection and resulting disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or a combination thereof.

[0150] In a further aspect, the present invention provides the use of a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament useful for the treatment or prevention of infection and resulting disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or a combination thereof.

[0151] In certain embodiments, the infection and resulting disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, or Escherichia coli, or a combination thereof, is selected from bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections, or a combination thereof.

[0152] In a further aspect, the present invention provides a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of infections and resultant diseases caused by pathogens, in particular bacteria, more particularly Acinetobacter species, most particularly Acinetobacter baumannii, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0153] In a further aspect, the present invention provides a method for the treatment or prevention of infections and resultant diseases, particularly bacteremia, pneumonia, meningitis, urinary tract infections and wound infections caused by pathogens, particularly bacteria, more particularly Acinetobacter species, most particularly Acinetobacter baumannii, which method comprises administering to a mammal a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

[0154] In a further aspect, the present invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of infections and resulting diseases caused by pathogens, in particular bacteria, more particularly Acinetobacter species, most particularly Acinetobacter baumannii, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0155] In a further aspect, the present invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of infections and resulting diseases caused by pathogens, particularly bacteria, more particularly Acinetobacter species, most particularly Acinetobacter baumannii, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections. Such a medicament comprises a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[0156] Pharmaceutical Compositions and Administration In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above and one or more pharmaceutically acceptable excipients. Exemplary pharmaceutical compositions are described in Examples 156-159.

[0157] In a further aspect, 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 resulting diseases caused by pathogens, in particular bacteria, more particularly Acinetobacter species, most particularly Acinetobacter baumannii, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0158] The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicines (e.g., in the form of pharmaceutical preparations). Pharmaceutical preparations can be administered to the body orally (e.g., in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, liquids, emulsions, or suspensions), nasally (e.g., in the form of nasal sprays), or rectally (e.g., in the form of suppositories). However, administration can also be carried out parenterally, such as intramuscularly or intravenously (e.g., in the form of injection or infusion solutions).

[0159] The compound of formula (I) and its pharmaceutically acceptable salts can be processed with pharmaceutically inert inorganic or organic excipients for the preparation of tablets, coated tablets, sugar-coated tablets, and hard gelatin capsules. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used as excipients for tablets, sugar-coated tablets, and hard gelatin capsules, for example. Suitable excipients for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc.

[0160] Suitable excipients for the production of solutions and syrups are, by way of example, water, polyols, saccharose, invert sugar, glucose etc.

[0161] Suitable excipients for injection solutions are, by way of example, water, alcohols, polyols, glycerol, vegetable oils etc.

[0162] Suitable excipients for suppositories are, by way of example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols etc.

[0163] In addition, pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying osmotic pressure, buffers, masking agents, or antioxidants. They may also contain other therapeutically valuable substances.

[0164] Dosage can vary widely and will of course be adapted to the individual requirements of each particular 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 (for example, about 300 mg / person) will be appropriate, preferably divided into 1 to 3 individual doses, for example, of the same amount.However, it is clear that the upper limit given herein can be exceeded in indicated cases.

[0165] Co-administration of Compounds of Formula (I) with Other Drugs The compound of Formula (I) or its salt, or the compounds disclosed herein or their pharmaceutically acceptable salts, can be used alone or in combination with other drugs for treatment. For example, the second drug in a combined pharmaceutical formulation or administration regimen may have complementary activity to the compound of Formula (I) so that they do not adversely affect each other. The compounds may be administered together in a single pharmaceutical composition or separately. In one embodiment, the compound or its pharmaceutically acceptable salt can be co-administered with an antibiotic, particularly for the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, or Escherichia coli, or a combination thereof.

[0166] The term "co-administering" refers to simultaneous administration or any manner of separate, consecutive administration of the compound of formula (I) or its salt, or the compound disclosed herein or its pharmaceutically acceptable salt, and one or more additional active pharmaceutical ingredients, including antibiotic preparations.If administration is not simultaneous, the compounds are administered close to each other in time.In addition, it is not important whether the compounds are administered in the same dosage form, for example, one compound may be administered intravenously and another compound may be administered orally.

[0167] Typically, any agent with antibacterial activity can be co-administered. Specific examples of such agents are carbapenems (meropenem), fluoroquinolones (ciprofloxacin), aminoglycosides (amikacin), tetracyclines (tigecycline), colistin, sulbactam, sulbactam plus durrobactam, cefiderocol (fetroja), macrocyclic peptides, and macrolides (erythromycin), as exemplified, for example, in WO2017072062, WO2019185572, and WO2019206853.

[0168] In one aspect, the present invention provides a pharmaceutical composition as described herein, further comprising an additional therapeutic agent.

[0169] In one aspect, the present invention provides a pharmaceutical combination comprising a compound of formula (I) described herein and an additional therapeutic agent.

[0170] In one embodiment, the additional therapeutic agent is an antibiotic agent.

[0171] In one embodiment, the additional therapeutic agent is an antibiotic agent useful for the treatment or prevention of infection and resulting disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, or Escherichia coli, or a combination thereof.

[0172] In one embodiment, the additional therapeutic agent is an antibiotic agent selected from a carbapenem (meropenem), a fluoroquinolone (ciprofloxacin), an aminoglycoside (amikacin), a tetracycline (tigecycline), colistin, sulbactam, sulbactam plus durrobactam, cefiderocol (fetroja), a macrocyclic peptide, and a macrolide (erythromycin), as exemplified in WO2017072062, WO2019185572, and WO2019206853. [Example]

[0173] The present invention will be more fully understood by reference to the following examples, which should not, however, be construed as limiting the scope of the claims to the examples.

[0174] Where preparations are obtained as mixtures 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.

[0175] Unless otherwise stated, all reactions and intermediates were prepared under an argon atmosphere.

[0176] The following abbreviations are used throughout this patent specification: ACN = acetonitrile AcOEt = ethyl acetate AcOH = acetic acid aq=aqueous solution Brettphos Pd G3 = [(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (CAS number 1470372-59-8) CAN = ammonium nitrate DCM = dichloromethane DIEA = diisopropylethylamine DIPEA = diisopropylethylamine DMA = dimethylacetamide DMF = dimethylformamide ESI = Electrospray Ionization EtOAc = ethyl acetate FA = formic acid h=time HATU = 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) Hunig's base = diisopropylethylamine HV=high vacuum LiOH = lithium hydroxide MeCN = acetonitrile MeOH = methanol MgSO4 = Magnesium sulfate MS = mass spectrum NaBH3CN = sodium cyanoborohydride NaBH(OAc)3 = sodium triacetoxyborohydride NaOH = Sodium hydroxide Na2SO4 = sodium sulfate Na2CO3 = Sodium Carbonate NIS = N-iodosuccinimide NMP = N-methylpyrrolidinone Pd(dppf)Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd-118 = [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) [95408-45-0] PdCl2(dtbpf)[1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II)[95408-45-0] PE = petroleum ether Prep HPLC = Preparative HPLC, additives in the eluent can be given by bracketing RT=room temperature TBTU = 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate TEA = Triethylamine THF = tetrahydrofuran TFA = trifluoroacetic acid

[0177] Example 1 2-(2-(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)ethoxy)-N,N,N-trimethylethanaminium iodide [ka]

[0178] Step 1) Intermediate 1 8-chloro-3-iodoimidazo[1,2-a]pyrazine

[0179] 8-Chloroimidaz[1,2-a]pyrazine (5.2 g, 33.9 mmol, 1 equiv.) and NIS (8 g, 35.6 mmol, 1.05 equiv.) were combined with DMF (34 ml). The reaction mixture was stirred at room temperature for 48 hours. Water was added to the suspension, and the solid was filtered, washed with water and MeOH, and dried under high vacuum to give the title compound (7.17 g, 25.6 mmol, 75.8% yield) as an off-white solid. MS (ESI, m / z): 280.0 [M+H] + .

[0180] Process 2) 8-chloro-3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazine

[0181] 8-Chloro-3-iodoimidazo[1,2-a]pyrazine (2 g, 7.16 mmol, 1 equiv.) and 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.32 g, 8.59 mmol, 1.2 equiv.) were combined with dioxane (12 mL) and water (6 mL). Na2CO3 (1.52 g, 14.3 mmol, 2 equiv.) and 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) dichloromethane complex (262 mg, 358 μmol, 0.05 equiv.) were added. The reaction mixture was heated to 80 °C and stirred for 20 h. The reaction mixture was poured into 50 mL of H2O and extracted with EtOAc (3 × 50 mL). The organic layer was dried over MgSO4 and concentrated in vacuo.

[0182] The crude material was purified by flash chromatography (silica gel, 80 g, 0% to 40% EtOAc in heptane) to give the title compound (480 mg, 1.62 mmol, 22.7% yield) as a white solid. MS (ESI, m / z): 296.1 [M+H] + .

[0183] Step 3) Intermediate 2 4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoic acid

[0184] 8-Chloro-3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazine (1.14 g, 3.86 mmol, 1 equiv.), 4-amino-2-methylbenzoic acid (699 mg, 4.63 mmol, 1.2 equiv.) were combined with acetonitrile (15 ml). The reaction mixture was heated to 80° C. and stirred for 2 days. The reaction mixture was filtered through a sintered glass and washed with acetonitrile and methanol. The solid was dried under high vacuum for 30 minutes. Recrystallization from methanol (4 ml) and acetonitrile (8 ml) afforded the title compound (650 mg, 1.58 mmol, 41.1% yield) as a white solid. MS (ESI, m / z): 411.3 [M+H] + .

[0185] Step 4) tert-Butyl (2-(2-(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)ethoxy)ethyl)carbamate

[0186] 4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoic acid (650 mg, 1.58 mmol, 1 equiv.) and tert-butyl (2-(2-aminoethoxy)ethyl)carbamate (485 mg, 2.38 mmol, 1.50 equiv.) were combined with DMF (7 ml). HATU (1.2 g, 3.17 mmol, 2.0 equiv.) and DIPEA (614 mg, 830 μl, 4.75 mmol, 3.0 equiv.) were added, and the reaction mixture was stirred at room temperature for 24 hours. tert-Butyl (2-(2-aminoethoxy)ethyl)carbamate (162 mg, 792 μmol, 0.5 equiv.) and DIPEA (205 mg, 277 μl, 1.58 mmol, 1 equiv.) were added again, and the reaction mixture was stirred for 48 h. The product was concentrated under high vacuum, and the crude material was purified by flash chromatography (silica gel, 40 g, 0% to 10% MeOH in DCM). The product was further purified by another flash chromatography (silica gel, 40 g, 50% to 100% EtOAc in heptane) to give the title compound (810 mg, 1.35 mmol, 85.7% yield) as a light brown solid. MS (ESI, m / z): 597.4 [M+H] + .

[0187] Step 5) N-(2-(2-aminoethoxy)ethyl)-4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamide hydrochloride

[0188] tert-Butyl (2-(2-(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)ethoxy)ethyl)carbamate (650 mg, 1.09 mmol, 1 equiv.) and HCl 3M in MeOH (8.4 g, 7 ml, 21 mmol, 19.3 equiv.) were combined and stirred at room temperature for 7 hours. The product was concentrated under high vacuum to give the title compound (643 mg, 1.2 mmol, 111% yield) as a yellow solid. MS (ESI, m / z): 497.34 [M+H] + .

[0189] Process 6) 2-(2-(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)ethoxy)-N,N,N-trimethylethanaminium iodide

[0190] N-(2-(2-aminoethoxy)ethyl)-4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamide hydrochloride (10 mg, 18.8 μmol, 1 equiv.) was dissolved in 1,4-dioxane (1 ml) and iodomethane (22.8 mg, 10 μl, 161 μmol, 8.56 equiv.) was added. The reaction mixture was stirred at room temperature. Since no reaction was observed, iodomethane (45.6 mg, 20 μl, 321 μmol, 17.1 equiv.) and DIPEA (14.8 mg, 20 μl, 115 μmol, 6.1 equiv.) were added and the reaction mixture was stirred at room temperature for 20 h. The crude material was purified by preparative HPLC to give the title compound (6.6 mg, 9.9 μmol, 52.8% yield) as a colorless oil. MS (ESI, m / z): 539.35 [M] + .

[0191] Example 19 4-(2-(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N,2-dimethylbenzamido)ethyl)-1,1-dimethylpiperidin-1-ium formate [ka]

[0192] Process 1) tert-Butyl 4-(2-(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N,2-dimethylbenzamido)ethyl)piperidine-1-carboxylate

[0193] 4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoic acid (Intermediate 2, 500 mg, 1.22 mmol, 1 equiv.) was combined with DMF (5 ml). tert-Butyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (369 mg, 1.52 mmol, 1.25 equiv.), DIPEA (472 mg, 638 μl, 3.66 mmol, 3.00 equiv.), and HATU (695 mg, 1.83 mmol, 1.50 equiv.) were added and the reaction mixture was stirred at room temperature overnight. tert-Butyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (207 mg, 853 μmol, 0.70 equiv.) was added again and the reaction was stirred at room temperature overnight. DMF was removed and extraction was performed with DCM and saturated ammonium chloride solution. After the organic layer was washed with water and brine and dried over Na2SO4, the solution was evaporated and the crude material was purified by flash chromatography (silica gel, 50 g, 0% to 10% MeOH in DCM) to give the title compound (704.3 mg, 1.11 mmol, 91.1% yield) as a light brown foam. MS (ESI, m / z): 635.6 [M+H] + .

[0194] Step 2) Intermediate 3 4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N,2-dimethyl-N-(2-(piperidin-4-yl)ethyl)benzamide hydrochloride

[0195] tert-Butyl 4-(2-(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N,2-dimethylbenzamido)ethyl)piperidine-1-carboxylate (700 mg, 1.1 mmol, 1 equiv.) was combined with HCl 4M in dioxane (4.14 ml, 16.5 mmol, 15 equiv.) and stirred at room temperature for 1 hour. MeOH was added to dissolve the suspension and the volatiles were removed. The resulting solid was triturated with ether, then filtered and dried under high vacuum to give the title compound (633 mg, 1.11 mmol, 95.6% yield) as a light brown solid. MS (ESI, m / z): 535.4 [M+H] + .

[0196] Process 3) 4-(2-(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N,2-dimethylbenzamido)ethyl)-1,1-dimethylpiperidin-1-ium formate

[0197] 4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N,2-dimethyl-N-(2-(piperidin-4-yl)ethyl)benzamide hydrochloride (30 mg, 52.5 μmol, 1 equiv.) was dissolved in 1,4-dioxane (2 ml) and DIPEA (14.8 mg, 20 μL, 115 μmol, 2.18 equiv.) was added. The reaction mixture was stirred at room temperature for 20 minutes and iodomethane (30 μL) was added. The reaction mixture was stirred at room temperature overnight. The crude material was purified by preparative HPLC to give the title compound (22.4 mg, 36.8 μmol, 70.1% yield). MS (ESI, m / z): 563.3 [M] + .

[0198] Example 20 1-Ethyl-4-(2-(4-((3-(4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)ethyl)-1-methylpiperidin-1-ium formate [ka]

[0199] Process 1) 8-chloro-3-(4-methoxyphenyl)imidazo[1,2-a]pyrazine

[0200] 8-Chloro-3-iodoimidazo[1,2-a]pyrazine (Intermediate 1, 2 g, 7.16 mmol, 1 equiv.) was combined with dioxane (22 ml) and water (11 ml). 2-(4-Methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.01 g, 8.59 mmol, 1.20 equiv.), Na2CO3 (1.52 g, 14.3 mmol, 2.00 equiv.), and 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) dichloromethane complex (262 mg, 358 μmol, 0.05 equiv.) were added, and the reaction mixture was heated to 80 °C and stirred overnight. The reaction mixture was diluted with AcOEt and water (2:1), and the organic layer was separated. The aqueous layer was extracted several times with EtOAc. The combined organic layers were washed with brine, dried over SO4, and concentrated in vacuo. The resulting brown solid was purified by flash chromatography (silica gel, 80 g, 0% to 80% EtOAc in heptane) to give the title compound (1.31 g, 5.04 mmol, 70.5% yield) as a pale yellow solid. MS (ESI, m / z): 260.1 [M+H] + .

[0201] Process 2) 4-((3-(4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoic acid

[0202] 8-Chloro-3-(4-methoxyphenyl)imidazo[1,2-a]pyrazine (1.31 g, 5.04 mmol, 1 equiv.) and 4-amino-2-methylbenzoic acid (915 mg, 6.05 mmol, 1.20 equiv.) were combined with acetonitrile (21 ml). The reaction mixture was stirred at 90 °C for 3 days. After cooling to room temperature, acetonitrile and methanol (1:1) were added to the suspension, and the solid was filtered to obtain the title compound (1.6 g, 4.27 mmol, 84.7% yield) as a pale yellow solid. MS (ESI, m / z): 375.2 [M+H] + .

[0203] Step 3) Intermediate 4 4-((3-(4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methyl-N-(2-(1-methylpiperidin-4-yl)ethyl)benzamide

[0204] 4-((3-(4-Methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoic acid (800 mg, 2.14 mmol, 1 equiv.) was combined with DMF (8 ml). 2-(1-Methylpiperidin-4-yl)ethanamine (456 mg, 3.21 mmol, 1.50 equiv.), DIPEA (828 mg, 1.12 ml, 6.41 mmol, 3.00 equiv.), and HATU (1.22 g, 3.21 mmol, 1.50 equiv.) were added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was directly subjected to preparative HPLC for purification to give the title compound (587.3 mg, 1.18 mmol, 55.1% yield) as a white solid. MS (ESI, m / z): 499.5 [M+H] + .

[0205] Step 4) 1-Ethyl-4-(2-(4-((3-(4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)ethyl)-1-methylpiperidin-1-ium formate

[0206] 4-((3-(4-Methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methyl-N-(2-(1-methylpiperidin-4-yl)ethyl)benzamide (30 mg, 60.2 μmol, 1 equiv.) was dissolved in 1,4-dioxane (4 ml) and DIPEA (29.6 mg, 40 μl, 229 μmol, 3.81 equiv.) was added. The reaction mixture was stirred at room temperature for 20 minutes and iodoethane (37.5 mg, 19.2 μl, 241 μmol, 4 equiv.) was added. The reaction mixture was stirred at room temperature overnight. The crude material was purified by preparative HPLC to give the title compound (27.7 mg, 48.37 μmol, 80.4% yield) as a colorless oil. MS (ESI, m / z): 527.3 [M] + .

[0207] Example 21 2-Chloro-4-[[3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-N-[2-(4,4-dimethylpiperazin-4-ium-1-yl)ethyl]-N-methyl-benzamide 2,2,2-trifluoroacetate [ka]

[0208] Process 1) tert-Butyl 4-(2-(2-chloro-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N-methylbenzamido)ethyl)piperazine-1-carboxylate

[0209] A mixture of 2-chloro-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoic acid (Intermediate 5, 150 mg, 348 μmol, 1 equiv.), tert-butyl 4-(2-(methylamino)ethyl)piperazine-1-carboxylate (84.7 mg, 348 μmol, 1 equiv.), TEA (363 mg, 0.5 mL, 3.59 mmol, 10.3 equiv.), and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (265 mg, 696 μmol, 2 equiv.) in DMF (5 mL) was stirred at room temperature overnight. The mixture was diluted with water and extracted with DCM. The organic layer was dried and concentrated in vacuo to give the title compound (250 mg, 381 μmol, 109% yield), which was used directly in the next step. MS (ESI, m / z): 656.4 [M+H] + .

[0210] Process 2) 2-chloro-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N-methyl-N-(2-(piperazin-1-yl)ethyl)benzamide

[0211] To a solution of tert-butyl 4-(2-(2-chloro-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N-methylbenzamido)ethyl)piperazine-1-carboxylate (250 mg, 381 μmol, 1 equiv.) in CHCl (10 mL) was added TFA (2.96 g, 2 mL, 26 mmol, 68.1 equiv.). The mixture was stirred at room temperature for 3 h and then refluxed overnight. The volatiles were removed and the residue was purified by preparative HPLC to give the title compound (100 mg, 180 μmol, 47.2% yield) as a pale yellow solid. 1H NMR (400MHz, methanol-d4) δ ppm 2.71(s,3 H)3.00(s,3 H)3.69(br s,9 ​​H)3.99(s,3 H)7.13(br t,J=7.83Hz,1 H)7.27-7.42(m,1 H)7.51-7.62(m,2 H)7.68-7.86(m,2 H)7.99(s,1 H)8.12(d,J=1.59Hz,1 H)

[0212] Process 3) 2-Chloro-4-[[3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-N-[2-(4,4-dimethylpiperazin-4-ium-1-yl)ethyl]-N-methyl-benzamide 2,2,2-trifluoroacetate

[0213] A mixture of 2-chloro-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N-methyl-N-(2-(piperazin-1-yl)ethyl)benzamide (60 mg, 108 μmol, 1 equiv.), iodomethane (153 mg, 1.08 mmol, 10 equiv.), and DIPEA (370 mg, 0.5 mL, 2.86 mmol, 26.5 equiv.) in acetonitrile (5 mL) was heated to 50° C. with stirring overnight. The volatiles were concentrated under vacuum, and the residue was purified by preparative HPLC to afford the title compound (50 mg, 70.2 μmol, 65.1% yield) as a pale yellow solid. 1H NMR (400MHz, methanol-d4) δ ppm 3.04(s,2 H)3.29(s,1 H)3.37(s,4 H)3.42(s,5 H)3.52-3.64(m,2 H)3.77-3.89(m,3 H)3.90-3.97(m,4 H)4.02(s,3 H)7.14-7.23(m,1 H)7.41(td,J=8.19,2.20Hz,1 H)7.54(d,J=5.26Hz,1 H)7.65(d,J=8.31Hz,1 H)7.75(dd,J=8.31,2.08Hz,1 H)7.88(dd,J=5.20,2.26Hz,1 H)8.04(s,1 H) 8.09 (d, J = 1.96 Hz, 1 H)

[0214] Example 22 4-[[3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-N-[2-(1,1-dimethylpiperidin-1-ium-4-yl)ethyl]-N,2-dimethyl-benzamide 2,2,2-trifluoroacetate [ka]

[0215] Process 1) tert-Butyl 4-[2-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]-methyl-amino]ethyl]piperidine-1-carboxylate

[0216] To a solution of 4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoic acid (Intermediate 6) (820 mg, 2 mmol, 1.0 equiv.), tert-butyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (582 mg, 2.4 mmol, 1.2 equiv.) in anhydrous DMF (10 mL) was added DIPEA (516 mg, 4 mmol, 2.0 equiv.). The resulting mixture was then stirred at room temperature for 30 minutes, and HATU (1.52 g, 4.0 mmol, 2.0 equiv.) was added to the mixture, followed by stirring for an additional 10 hours. The mixture was poured into water (50 mL), and the aqueous solution was extracted with DCM (50 mL × 2). The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a red oil, which was purified by flash column chromatography to give the title compound (1.0 g, 1.57 mmol, 78.5% yield) as a yellow solid. MS (ESI, m / z): 635.3 [M+H] + .

[0217] Process 2) 4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-N,2-dimethyl-N-[2-(4-piperidyl)ethyl]benzamide

[0218] To a solution of tert-butyl 4-(2-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N,2-dimethylbenzamido)ethyl)piperidine-1-carboxylate (635 mg, 1 mmol) in MeOH (15 ml) was added 1 mol / L hydrochloric acid in EA (5 mL) at room temperature.

[0219] The resulting mixture was stirred for 4.0 hours and then adjusted to pH 7-8 with 2M aqueous sodium carbonate. The mixture was extracted with DCM (50 mL x 2), and the combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to give a red solid, which was purified by preparative HPLC to give the title compound (270 mg, 0.50 mmol, 50.0% yield) as a yellow powder. MS (ESI, m / z): 535.3 [M+H] + .

[0220] Process 3) 4-[[3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-N-[2-(1,1-dimethylpiperidin-1-ium-4-yl)ethyl]-N,2-dimethyl-benzamide 2,2,2-trifluoroacetate

[0221] To a solution of 4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N,2-dimethyl-N-(2-(piperidin-4-yl)ethyl)benzamide (270 mg, 0.5 mmol, 1.0 equiv.) in anhydrous EtOH (10 mL) was added DIPEA (129 mg, 1.0 mmol, 2.0 equiv.). The resulting mixture was then stirred at room temperature for 10 minutes, and iodomethane (710 mg, 5.0 mmol, 10 equiv.) was added to the mixture and stirred for an additional 10 hours. The mixture was poured into water (20 mL), and the aqueous solution was extracted with DCM (50 mL × 2). The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a red oil, which was purified by preparative HPLC to give the title compound (200 mg, 0.30 mmol, 60.0% yield). MS (ESI, m / z): 563.3 [M] + .

[0222] Example 23 1-(Carboxymethyl)-4-(2-(4-((3-(4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)ethyl)-1-methylpiperidin-1-ium formate [ka]

[0223] Step 1) Example 155 1-(2-Methoxy-2-oxoethyl)-4-(2-(4-((3-(4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)ethyl)-1-methylpiperidin-1-ium formate [ka]

[0224] 4-((3-(4-Methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methyl-N-(2-(1-methylpiperidin-4-yl)ethyl)benzamide (Intermediate 4, 30 mg, 60.2 μmol, 1 equiv.) was dissolved in 1,4-dioxane (4 ml) and DIPEA (29.6 mg, 40 μl, 229 μmol, 3.81) was added. The reaction mixture was stirred at room temperature for 20 minutes and methyl 2-bromoacetate (36.8 mg, 22.1 μl, 241 μmol, 4 equiv.) was added. The reaction mixture was stirred at room temperature overnight. The crude material was purified by preparative HPLC to give the title compound (27 mg, 43.8 μmol, 72.8% yield) as a colorless oil. MS (ESI, m / z): 616.2 [M] + .

[0225] Process 2) 1-(Carboxymethyl)-4-(2-(4-((3-(4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)ethyl)-1-methylpiperidin-1-ium formate

[0226] 1-(2-Methoxy-2-oxoethyl)-4-(2-(4-((3-(4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)ethyl)-1-methylpiperidin-1-ium formate (27 mg, 43.8 μmol, 1 equiv.) and LiOH (1 ml, 1 mmol, 22.8 equiv.) were dissolved in THF (1 ml) and MeOH (500 μl). The reaction mixture was heated to 60° C. and stirred for 24 h. The reaction mixture was concentrated in vacuo and acidified with 1 M HCl. The mixture was evaporated to dryness and the crude material was purified by preparative HPLC to give the title compound (15.2 mg, 25.2 μmol, 57.6% yield) as a colorless oil. MS (ESI, m / z): 557.2 [M] + .

[0227] Example 24 4-(2-(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N,2-dimethylbenzamido)ethyl)-1,1-diethylpiperidin-1-ium formate [ka]

[0228] 4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N,2-dimethyl-N-(2-(piperidin-4-yl)ethyl)benzamide hydrochloride (Intermediate 3, 30 mg, 52.5 μmol, 1 equiv.) was dissolved in 1,4-dioxane (4 ml), and DIPEA (29.6 mg, 40 μl, 229 μmol, 4.36 equiv.) was added. The reaction mixture was stirred at room temperature for 20 minutes, and iodoethane (78 mg, 40 μl, 500 μmol, 9.52 equiv.) was added. The reaction mixture was stirred at room temperature overnight. Iodoethane (117 mg, 60 μl, 750 μmol, 14.3 equiv.) was then added again, and the reaction mixture was stirred at room temperature for 2 days. Since the reaction was incomplete due to residual SM, iodoethane (97.5 mg, 50 μL, 625 μmol, 11.9 equiv.) and DIPEA (14.8 mg, 20 μL, 115 μmol, 2.18 equiv.) were added, and the reaction mixture was stirred again at room temperature for 2 days. The crude material was purified by preparative HPLC to give the title compound (20.5 mg, 32.2 μmol, 61.3% yield) as a colorless solid. MS (ESI, m / z): 591.4 [M] + 296.3[M+H] 2+ .

[0229] Example 13 2-(2-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)ethoxy)-N,N,N-trimethylethanaminium formate [ka]

[0230] Process 1) Methyl 4-amino-2-vinylbenzoate

[0231] To a microwave vial was added methyl 4-amino-2-bromobenzoate (1 g, 4.35 mmol, 1 equiv.), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1 g, 1.11 mL, 6.52 mmol, 1.5 equiv.), sodium methoxide (470 mg, 484 μL, 8.69 mmol, 2 equiv.), and tetrakis(triphenylphosphine)palladium(0) (251 mg, 217 μmol, 0.05 equiv.) in THF (8 mL) and water (800 μL). The vial was capped and heated in a microwave at 110 °C for 60 min. The reaction mixture was poured into 20 mL of HO and extracted with EtOAc (3 × 25 mL). The organic layer was dried over MgSO and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 50% EtOAc in heptane) to give the title compound (345 mg, 1.9 mmol, 44.9% yield) as an orange oil. MS (ESI, m / z): 178.2 [M+H] + .

[0232] Step 2) Intermediate 7 Methyl 4-amino-2-ethylbenzoate

[0233] Methyl 4-amino-2-vinylbenzoate (665 mg, 3.75 mmol, 1 equiv.) was dissolved in MeOH (2 ml) and palladium on carbon (39.9 mg, 375 μmol, 0.1 equiv.) was added. The reaction was stirred under hydrogen at room temperature for 4 hours. The reaction mixture was carefully filtered through celite under argon and concentrated in vacuo to give the title compound (601.3 mg, 3.35 mmol, 89.4% yield) as a dark brown oil. MS (ESI, m / z): 180.2 [M+H] + .

[0234] Process 3) Methyl 2-ethyl-4-((3-iodoimidazo[1,2-a]pyrazin-8-yl)amino)benzoate

[0235] 8-Chloro-3-iodoimidazo[1,2-a]pyrazine (Intermediate 1, 1.46 g, 5.23 mmol, 1 equiv.) was combined with acetonitrile (30 ml). Methyl 4-amino-2-ethylbenzoate (937 mg, 5.23 mmol, 1 equiv.) and acetic acid (3 ml) were added. The reaction mixture was stirred at 80° C. for 24 hours. The reaction mixture was filtered and washed with MeOH and acetonitrile. The solid was dried under high vacuum to give the title compound (1.83 g, 4.34 mmol, 83.2% yield) as a white solid. MS (ESI, m / z): 423.1 [M+H] + .

[0236] Step 4) Methyl 4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzoate

[0237] Methyl 2-ethyl-4-((3-iodoimidazo[1,2-a]pyrazin-8-yl)amino)benzoate (450 mg, 1.07 mmol, 1 equiv.), (2,3-difluoro-4-methoxyphenyl)boronic acid (300 mg, 1.6 mmol, 1.5 equiv.), NaCO (226 mg, 2.13 mmol, 2 equiv.), and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (78 mg, 107 μmol, 0.1 equiv.) were mixed in dioxane (4 ml) and water (400 μl). The vial was capped and heated in a microwave at 115 °C for 30 min. The reaction mixture was poured into 20 ml of HO and extracted with EtOAc (3 × 30 ml). The organic layer was dried over MgSO and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 50% EtOAc in heptane) to give the title compound (367 mg, 0.84 mmol, 78.5% yield) as a light brown solid. MS (ESI, m / z): 439.2 [M+H] + .

[0238] Step 5) Intermediate 8 4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzoic acid

[0239] Methyl 4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzoate (365 mg, 833 μmol, 1 equiv.) and LiOH (1 ml, 1 mmol, 1.2 equiv.) were dissolved in THF (2 ml) and MeOH (1 ml). The reaction mixture was heated to 50° C. and stirred for 3 h. The reaction mixture was concentrated in vacuo and acidified with 1 M HCl. The solid was filtered through sintered glass and dried under high vacuum for 2 h to give the title compound (343 mg, 808 μmol, 97.2% yield) as a white solid. MS (ESI, m / z): 425.2 [M+H] + .

[0240] Process 6) tert-Butyl (2-(2-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)ethoxy)ethyl)carbamate

[0241] 4-((3-(2,3-Difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzoic acid (250 mg, 589 μmol, 1 equiv.), DIPEA (305 mg, 412 μl, 2.36 mmol, 4 equiv.), and HATU (336 mg, 884 μmol, 1.5 equiv.) were dissolved in DMF (750 μl). The resulting reaction mixture was stirred at room temperature for 30 minutes. tert-Butyl (2-(2-aminoethoxy)ethyl)carbamate (180 mg, 884 μmol, 1.5 equiv.) was added, and the reaction mixture was stirred at room temperature for 3 hours. Since the reaction was not complete, DIPEA (152 mg, 206 μl, 1.18 mmol, 2 equiv.), HATU (112 mg, 295 μmol, 0.5 equiv.), and tert-butyl (2-(2-aminoethoxy)ethyl)carbamate (84.2 mg, 412 μmol, 0.7 equiv.) were added again, and the reaction mixture was stirred at room temperature for 30 min. tert-butyl (2-(2-aminoethoxy)ethyl)carbamate (180 mg, 884 μmol, 1.5 equiv.) was added, and the reaction mixture was stirred at room temperature for 3 h. The crude material was purified by preparative HPLC to give the title compound (quantitative yield) as a yellow oil. MS (ESI, m / z): 611.3 [M+H] + .

[0242] Step 7) Intermediate 9 N-(2-(2-aminoethoxy)ethyl)-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamide hydrochloride

[0243] tert-Butyl (2-(2-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)ethoxy)ethyl)carbamate (238 mg, 390 μmol, 1 equiv.) and HCl 4M in dioxane (457 mg, 381 μl, 1.52 mmol, 3.91 equiv.) were combined. The reaction mixture was stirred at room temperature for 2 hours. The reaction was concentrated under high vacuum to give the title compound (203.2 mg, 371 μmol, 95.3% yield) as a light brown solid. MS (ESI, m / z): 512.2 [M+H] + .

[0244] Process 8) 2-(2-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)ethoxy)-N,N,N-trimethylethanaminium formate

[0245] N-(2-(2-aminoethoxy)ethyl)-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamide hydrochloride (575 mg, 1.05 mmol, 1 equiv.) was dissolved in 1,4-dioxane (5 mL) and DIPEA (1.11 g, 1.5 mL, 8.59 mmol, 8.17 equiv.) was added. The reaction mixture was stirred at room temperature for 20 minutes, and iodomethane (4.1 g, 1.8 mL, 28.9 mmol, 27.5 equiv.) was added. The reaction mixture was stirred at room temperature overnight.

[0246] The crude material was purified by preparative HPLC and lyophilized to give the title compound (117 mg, 195 μmol, 18.6% yield) as a white solid. MS (ESI, m / z): 553.3 [M] + .

[0247] Example 25 6-(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)-N,N,N-trimethylhexan-1-aminium formate [ka]

[0248] Process 1) tert-Butyl (6-(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)hexyl)carbamate

[0249] 4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoic acid (Intermediate 2, 30 mg, 73.1 μmol, 1 equiv.) was combined with DMF (750 μL). tert-Butyl 6-aminohexyl)carbamate (23.7 mg, 110 μmol, 1.50 equiv.) was added, followed by DIPEA (28.3 mg, 38.3 μL, 219 μmol, 3.00 equiv.) and HATU (41.7 mg, 110 μmol, 1.50 equiv.), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by preparative HPLC to give the title compound (28.6 mg, 46.98 μmol, 64.3% yield) as an off-white solid. MS (ESI, m / z): 609.4 [M+H] + .

[0250] Process 2) N-(6-aminohexyl)-4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamide hydrochloride

[0251] tert-Butyl (6-(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)hexyl)carbamate (28 mg, 46 μmol, 1 equiv.) was combined with HCl 4M in dioxane (173 μl, 690 μmol, 15 equiv.). After stirring for 1 h, the reaction mixture was concentrated to dryness to give the title compound (25.4 mg, 46.6 μmol, 99.3% yield) as an off-white solid. MS (ESI, m / z): 509.2 [M+H] + .

[0252] Process 3) 6-(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)-N,N,N-trimethylhexan-1-aminium formate

[0253] The title compound (12 mg, 20.1 μmol, 41.1% yield) was obtained as a white solid in the same manner as in Example 13, Step 8. MS (ESI, m / z): 551.3 [M] + .

[0254] Example 26 2-[4-[2-chloro-4-[[3-[4-(cyanomethoxy)-2,3-difluorophenyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]piperazin-1-yl]ethyl-trimethylazanium iodide [ka]

[0255] Step 1) Intermediate 10 2-chloro-4-((3-(4-(cyanomethoxy)-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoic acid hydrochloride

[0256] 2-(4-(8-chloroimidazo[1,2-a]pyrazin-3-yl)-2,3-difluorophenoxy)acetonitrile (Intermediate 11, 1.5 g, 4.68 mmol, 1 equiv.) was dissolved in acetonitrile (40 ml) and acetic acid (4 ml). 4-Amino-2-chlorobenzoic acid (883 mg, 5.15 mmol, 1.1 equiv.) was added and the reaction mixture was heated to reflux for 15 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in acetonitrile and filtered. The cake was washed with acetonitrile and heptane and dried under high vacuum for 2 hours to give the title compound (1.44 g, 2.9 mmol, 59.4% yield) as a pale gray solid. MS (ESI, m / z): 456.1 [M+H] + .

[0257] Process 2) 2-(4-(8-((3-chloro-4-(4-(2-(dimethylamino)ethyl)piperazine-1-carbonyl)phenyl)amino)imidazo[1,2-a]pyrazin-3-yl)-2,3-difluorophenoxy)acetonitrile

[0258] 2-Chloro-4-((3-(4-(cyanomethoxy)-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoic acid hydrochloride (700 mg, 1.42 mmol, 1 equiv.) was combined with DMF (9 mL). HATU (811 mg, 2.13 mmol, 1.50 equiv.) and EtN (576 mg, 793 μL, 5.69 mmol, 4.00) were added, followed by N,N-dimethyl-2-(piperazin-1-yl)ethan-1-amine (335 mg, 2.13 mmol, 1.50 equiv.). The reaction mixture was stirred at room temperature. Water was then added to the reaction mixture, and the product was extracted with DCM and dried over NaSO. The crude product was purified by flash chromatography (silica gel, 80 g, 0% to 100% DCM:MeOH:NHOH (100:10:1) in DCM) to give the title compound (642.5 mg, 1.08 mmol, 75.2% yield) as an off-white foam. MS (ESI, m / z): 593.3 [M+H] + .

[0259] Process 3) 2-[4-[2-chloro-4-[[3-[4-(cyanomethoxy)-2,3-difluorophenyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]piperazin-1-yl]ethyl-trimethylazanium iodide

[0260] 2-(4-(8-((3-chloro-4-(4-(2-(dimethylamino)ethyl)piperazine-1-carbonyl)phenyl)amino)imidazo[1,2-a]pyrazin-3-yl)-2,3-difluorophenoxy)acetonitrile (630 mg, 1.06 mmol, 1 equiv) was combined with EtOH (6.4 mL). Iodomethane (180 mg, 79.4 μl, 1.27 mmol, 1.20 equiv) was added and the reaction was stirred at room temperature overnight. Iodomethane (75.1 mg, 33.1 μl, 529 μmol, 0.50 equiv) was added again and stirring was continued at room temperature for 4 h. Ether was added to the formed suspension and the solid was filtered, washed with ether, and dried under high vacuum to give the title compound (629 mg, 853 μmol, 88.7% yield) as a white solid. MS (ESI, m / z): 609.3 [M] + .

[0261] Example 27 2-(1-(4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperidine-4-carboxamide)-N,N,N-trimethylethanaminium formate [ka]

[0262] Process 1) 8-chloro-3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazine

[0263] To a microwave vial was added 8-chloro-3-iodoimidazo[1,2-a]pyrazine (Intermediate 1, 2.5 g, 8.95 mmol, 1 equiv.), (3-fluoro-4-methoxyphenyl)boronic acid (2.28 g, 13.4 mmol, 1.5 equiv.), NaCO (1.9 g, 17.9 mmol, 2 equiv.), and 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) dichloromethane complex (655 mg, 895 μmol, 0.1 equiv.) in dioxane (16 mL) and water (1.6 mL). The vial was capped and heated in a microwave at 120 °C for 60 min. The reaction mixture was poured into 10 mL of HO and extracted with EtOAc (3 × 25 mL). The organic layer was dried over MgSO and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 120 g, 0% to 65% EtOAc in heptane) to give the title compound (1.55 g, 5.58 mmol, 62.7% yield) as a brown solid. MS (ESI, m / z): 278.0 [M+H] + .

[0264] Step 2) Intermediate 12 4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoic acid

[0265] 8-Chloro-3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazine (1 g, 3.6 mmol, 1 equiv.) was combined with acetonitrile (100 ml) and AcOH (1 ml). 4-Amino-2-methylbenzoic acid (680 mg, 4.5 mmol, 1.25 equiv.) was added, and the reaction mixture was stirred at 80 °C overnight. After cooling to room temperature, the solid was filtered, washed with acetonitrile and MeOH, and dried under high vacuum. The mother liquor containing the starting material was reacted again with 0.5 equiv. of 4-amino-2-methylbenzoic acid in 20 ml of acetonitrile (+ 200 μl of AcOH). After stirring for 55 hours, the reaction was cooled, and the solid that formed was filtered, washed with acetonitrile and MeOH, and dried under high vacuum to give the title compound (1.1 g, 2.9 mmol, 79% yield) overall as an off-white solid. MS (ESI, m / z): 393.2 [M + H] + .

[0266] Process 3) Methyl 1-(4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperidine-4-carboxylate

[0267] 4-((3-(3-Fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoic acid (500 mg, 1.27 mmol, 1 equiv.) was combined with DMF (10 ml). DIPEA (494 mg, 668 μl, 3.82 mmol, 3 equiv.) and HATU (969 mg, 2.55 mmol, 2.00 equiv.) were added, and the reaction mixture was stirred at room temperature for 30 minutes. Methyl piperidine-4-carboxylate (274 mg, 1.91 mmol, 1.5 equiv.) was then added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by preparative HPLC to give the title compound (386 mg, 746 μmol, 58.5% yield) as a light brown solid. MS (ESI, m / z): 518.2 [M+H] + .

[0268] Step 4) 1-(4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperidine-4-carboxylic acid

[0269] Methyl 1-(4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperidine-4-carboxylate (386 mg, 746 μmol, 1 equiv.) and 1M LiOH (3.52 ml, 3.52 mmol, 4.71 equiv.) were dissolved in THF (5 ml) and MeOH (2.5 ml). The reaction mixture was heated to 60° C. and stirred overnight. The reaction mixture was concentrated in vacuo and acidified with 1M HCl. The reaction mixture was poured into 1 mL of H2O and extracted with DCM (2 × 2 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give the title compound (340.7 mg, 676 μmol, 86.2% yield) as a light brown solid. MS (ESI, m / z): 504.2 [M+H] + .

[0270] Step 5) tert-Butyl (2-(1-(4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperidine-4-carboxamido)ethyl)(methyl)carbamate

[0271] 1-(4-((3-(3-Fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperidine-4-carboxylic acid (30 mg, 59.6 μmol, 1 equiv.) was combined with DMF (600 μl). DIPEA (23.1 mg, 31.2 μl, 179 μmol, 3.00 equiv.), HATU (34 mg, 89.4 μmol, 1.50 equiv.), and tert-butyl(2-aminoethyl)(methyl)carbamate (15.6 mg, 89.4 μmol, 1.50 equiv.) were added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was directly purified by preparative HPLC to give the title compound (28.2 mg, 42.7 μmol, 71.7% yield) as a white solid. MS (ESI, m / z): 660.4 [M+H] + .

[0272] Process 6) 1-(4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)-N-(2-(methylamino)ethyl)piperidine-4-carboxamide hydrochloride

[0273] tert-Butyl (2-(1-(4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperidine-4-carboxamido)ethyl)(methyl)carbamate (26 mg, 39.4 μmol, 1 equiv.) was combined with HCl 4M in dioxane (98.5 μl, 394 μmol, 10.0 equiv.). After stirring at room temperature for 4 hours, the reaction mixture was concentrated to dryness and dried under high vacuum to give the title compound (24.9 mg, 41.8 μmol, 106% yield) as a pale yellow solid. MS (ESI, m / z): 560.3 [M+H] + .

[0274] Step 7) 2-(1-(4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperidine-4-carboxamide)-N,N,N-trimethylethanaminium formate

[0275] 1-(4-((3-(3-Fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)-N-(2-(methylamino)ethyl)piperidine-4-carboxamide hydrochloride (12 mg, 20.1 μmol, 1 equiv.) was dissolved in 1,4-dioxane (2 ml) and DIPEA (37 mg, 50 μL, 286 μmol, 14.2 equiv.) was added. The reaction mixture was stirred at room temperature for 20 minutes and iodomethane (2.86 mg, 60 μL, 20.1 μmol, 1 equiv.) was added. The reaction mixture was stirred at room temperature overnight. The crude material was purified by preparative HPLC. The product was lyophilized to give the title compound (8.6 mg, 13.6 μmol, 67.4% yield) as a white solid. MS (ESI, m / z): 588.3 [M] + .

[0276] Example 28 3-(4-((3-(4-chloro-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)-N,N,N-trimethylpropan-1-aminium formate [ka]

[0277] Process 1) 8-chloro-3-(4-chloro-2,3-difluorophenyl)imidazo[1,2-a]pyrazine

[0278] To a microwave vial was added 8-chloro-3-iodoimidazo[1,2-a]pyrazine (Intermediate 1, 500 mg, 1.79 mmol, 1 equiv.), (4-chloro-2,3-difluorophenyl)boronic acid (413 mg, 2.15 mmol, 1.2 equiv.), NaCO (379 mg, 3.58 mmol, 2 equiv.), and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (131 mg, 179 μmol, 0.1 equiv.) in dioxane (5 mL) and water (500 μL). The vial was capped and heated in a microwave at 90 °C for 60 min. The reaction mixture was poured into 15 mL of HO and extracted with EtOAc (3 × 15 mL). The organic layer was dried over MgSO and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 45% EtOAc in heptane) to give the title compound (280 mg, 933 μmol, 52.1% yield) as a brown solid. MS (ESI, m / z): 299.9 [M+H] + .

[0279] Process 2) Methyl 4-((3-(4-chloro-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzoate

[0280] 8-Chloro-3-(4-chloro-2,3-difluorophenyl)imidazo[1,2-a]pyrazine (130 mg, 433 μmol, 1 equiv.) and methyl 4-amino-2-ethylbenzoate (Intermediate 7, 93.2 mg, 520 μmol, 1.2 equiv.) were combined with acetonitrile (2 ml) and AcOH (200 μL). The reaction mixture was heated to 80° C. and stirred for 2 days. The reaction mixture was filtered through a sintered glass filter and washed with acetonitrile and methanol. The solid was dried under high vacuum for 30 minutes to give the title compound (83.9 mg, 189 μmol, 43.7% yield) as an off-white solid. MS (ESI, m / z): 443.1 [M+H] + .

[0281] Process 3) 4-((3-(4-chloro-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzoic acid

[0282] Methyl 4-((3-(4-chloro-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzoate (143 mg, 323 μmol, 1 equiv.) and 1 M LiOH (1 ml, 1 mmol, 3.1 equiv.) were dissolved in THF (1 ml) and MeOH (500 μl). The reaction mixture was heated to 60° C. and stirred for 24 h. The reaction mixture was concentrated in vacuo and acidified with 1 M HCl. The solid was filtered through sintered glass and dried under high vacuum to give the title compound (100 mg, 233 μmol, 72.2% yield) as a brown solid. MS (ESI, m / z): 429.1 [M+H] + .

[0283] Step 4) tert-Butyl (3-(4-((3-(4-chloro-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)propyl)carbamate

[0284] Using tert-butyl (3-aminopropyl)carbamate, the title compound (75.9 mg, 129 μmol, 46.4% yield) was obtained as a pale yellow solid in the same manner as in Example 27, Step 5. MS (ESI, m / z): 585.2 [M+H] + .

[0285] Step 5) N-(3-aminopropyl)-4-((3-(4-chloro-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamide hydrochloride

[0286] The title compound (53.2 mg, 102 μmol, 78.6% yield) was obtained as a light brown solid in the same manner as in Example 27, Step 6. MS (ESI, m / z): 485.1 [M+H] + .

[0287] Process 8) 3-(4-((3-(4-chloro-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)-N,N,N-trimethylpropan-1-aminium formate

[0288] The title compound (13.4 mg, 23.4 μmol, 50.8% yield) was obtained as a white solid in the same manner as in Example 27, Step 7. MS (ESI, m / z): 528.2 [M] + .

[0289] Example 29 2-(1-(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperidin-4-yl)-N,N,N-trimethylethanaminium formate [ka]

[0290] Process 1) tert-Butyl (2-(1-(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperidin-4-yl)ethyl)carbamate

[0291] 4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoic acid (Intermediate 2, 30 mg, 73.1 μmol, 1 eq.) was combined with DMF (1 ml). tert-Butyl (2-(piperidin-4-yl)ethyl)carbamate (25 mg, 110 μmol, 1.5 eq.), DIPEA (28.3 mg, 38.3 μl, 219 μmol, 3 eq.) and HATU (55.6 mg, 146 μmol, 2 eq.) were added and stirred at room temperature overnight. The crude material was purified by preparative HPLC to give the title compound (7.6 mg, 12.2 μmol, 16.7% yield) as a white solid. MS (ESI, m / z): 621.4 [M+H]+ .

[0292] Process 2) (4-(2-aminoethyl)piperidin-1-yl)(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylphenyl)methanone hydrochloride

[0293] tert-Butyl (2-(1-(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperidin-4-yl)ethyl)carbamate (7.6 mg, 12.2 μmol, 1 equiv.) and 4M MHCl in dioxane (600 mg, 500 μl, 2 mmol, 163 equiv.) were combined and stirred at room temperature for 30 minutes. The reaction mixture was evaporated and dried under high vacuum to give the title compound (8.1 mg, 14.5 μmol, 119% yield) as a pale yellow solid. MS (ESI, m / z): 521.1 [M+H] + .

[0294] Process 3) 2-(1-(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperidin-4-yl)-N,N,N-trimethylethanaminium formate

[0295] The title compound (12.7 mg, 20.8 μmol, 58.1% yield) was obtained as a white solid in the same manner as in Example 27, Step 7. MS (ESI, m / z): 563.3 [M] + .

[0296] Example 30 [4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-phenyl]-[4-(4,4-dimethylpiperazin-4-ium-1-carbonyl)piperazin-1-yl]methanone formate [ka]

[0297] Process 1) tert-Butyl 4-[4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]piperazine-1-carboxylate

[0298] To a solution of 4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoic acid (Intermediate 2, 1.2 g, 2.92 mmol, 1 equiv.) in DMF (10 mL) was added 1-Boc-piperazine (0.82 g, 4.39 mmol, 1.5 equiv.), N,N-diisopropylethylamine (1.53 mL, 8.77 mmol, 3 equiv.), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.22 g, 5.85 mmol, 2 equiv.). The reaction was stirred at 25 °C for 12 h. 40 mL of water was added, and the mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (40 mL x 3), dried over Na2SO4, filtered, and concentrated. 20 mL of MTBE was added to the residue and stirred for 1 hour. The solid was filtered and dried to give the title compound (1.7 g, 2.94 mmol, 90.43% yield) as a yellow solid. MS (ESI, m / z): 579.3 [M+H] + .

[0299] Step 2) Intermediate 13 [4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-phenyl]-piperazin-1-yl-methanone

[0300] To a solution of tert-butyl 4-[4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]piperazine-1-carboxylate (1.7 g, 2.94 mmol, 1 equiv.) in methanol (10 mL), hydrochloric acid in MeOH (20 mL, 80 mmol, 27.23 equiv.) was added and stirred at 20 °C for 12 h. After concentration, 100 mL of saturated aqueous NaHCO was added and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with DCM:MeOH = 10:1 to give the title compound (800 mg, 1.67 mmol, 56.91% yield) as a yellow solid. MS (ESI, m / z): 479.2 [M + H] + .

[0301] Process 3) [4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-phenyl]-[4-(4-methylpiperazine-1-carbonyl))piperazin-1-yl]methanone

[0302] To a solution of [4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-phenyl]-piperazin-1-yl-methanone (200 mg, 0.420 mmol, 1 equiv) in DMF (5 mL) was added N,N-diisopropylethylamine (0.22 mL, 1.25 mmol, 3 equiv), N,N'-carbonyldiimidazole (74.55 mg, 0.460 mmol, 1.1 equiv) and 1-methylpiperazine (83.73 mg, 0.840 mmol, 2 equiv), and the reaction was then stirred at 60°C for 60 hours. The reaction mixture was purified by preparative HPLC (base) to give the by-product 4-[4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]-N,N-dimethyl-piperazine-1-carboxamide (44.4 mg, 0.080 mmol, 18.13% yield) as a white solid and the title compound (50 mg, 0.080 mmol, 19.78% yield) as a yellow solid. MS (ESI, m / z): 605.0 [M+H] + .

[0303] Step 4) [4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-phenyl]-[4-(4,4-dimethylpiperazin-4-ium-1-carbonyl)piperazin-1-yl]methanone formate

[0304] To a solution of [4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-phenyl]-[4-(4-methylpiperazine-1-carbonyl))piperazin-1-yl]methanone (50 mg, 0.080 mmol, 1 equiv.) in ACN (2 mL) was added iodomethane (35.21 mg, 0.250 mmol, 3 equiv.), which was stirred at 40° C. for 12 h. The reaction mixture was purified by preparative HPLC (FA) to give the title compound (22 mg, 0.030 mmol, 39.18% yield) as a white solid. MS (ESI, m / z): 619.3 [M] + .

[0305] Example 31 [2-[4-[2-chloro-4-[[3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]piperazin-1-yl]-2-oxoethyl]trimethylazanium formate [ka]

[0306] Process 1) 2-(3-fluoro-4-methylsulfanyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0307] A mixture of 4-bromo-2-fluoroanisole (20 g, 97.55 mmol, 1 equiv.), bis(pinacolato)diboron (26.01 g, 102.43 mmol, 1.05 equiv.), potassium acetate (19148 mg, 195.1 mmol, 2 equiv.), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (4776 mg, 5.85 mmol, 0.06 equiv.) in 1,4-dioxane (300 mL) was stirred under N at 80° C. for 4 h. The reaction mixture was concentrated and purified by silica gel chromatography (petroleum ether / ethyl acetate=20 / 1) to give the title compound (18 g, 71.4 mmol, 65.88% yield) as a gray solid.

[0308] Process 2) 8-chloro-3-(3-fluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazine

[0309] A mixture of 8-chloro-3-iodo-imidazo[1,2-a]pyrazine (18 g, 64.41 mmol, 1 equiv.), 2-(3-fluoro-4-methoxy-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (17048 mg, 67.63 mmol, 1.05 equiv.), sodium carbonate (13653 mg, 128.82 mmol, 2 equiv.), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (2628 mg, 3.22 mmol, 0.05 equiv.) in 1,4-dioxane (200 mL) and water (100 mL) was stirred at 80 °C under N for 2 h. Water (200 mL) was added to the mixture, which was then extracted with EtOAc (300 mL × 3). The organic layer was dried over Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (DCM / ethyl acetate = 5 / 1) to give the title compound (21.4 g, 77.07 mmol, 91.77% yield) as a pink solid. MS (ESI, m / z): 278.0 [M+H] + .

[0310] Process 3) 2-chloro-4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoic acid

[0311] A mixture of 8-chloro-3-(3-fluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazine (3 g, 10.8 mmol, 1 equiv.) and 4-amino-2-chlorobenzoic acid (2780.57 mg, 16.21 mmol, 1.5 equiv.) in acetic acid (60 mL) and acetonitrile (6 mL) was stirred at 80° C. for 24 hours. The reaction mixture was filtered. The white solid was triturated with DMF (20 mL) and MeCN (10 mL) at 60° C. for 1 hour. The solid was filtered and washed several times with MeCN to give the title compound (1100 mg, 2.66 mmol, 23.43% yield) as a white solid. MS (ESI, m / z): 413.0 [M+H] + .

[0312] Step 4) tert-Butyl 4-(2-chloro-4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoyl)piperazine-1-carboxylate

[0313] 2-Chloro-4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoic acid (200 mg, 484 μmol, 1 equiv.) was combined with DMF (4 mL). DIPEA (250 mg, 338 μl, 1.94 mmol, 4.00 equiv.) and HATU (276 mg, 727 μmol, 1.50 equiv.) were added and stirred for 15 minutes, after which tert-butyl piperazine-1-carboxylate (135 mg, 727 μmol, 1.50 equiv.) was added. The reaction mixture was stirred overnight at room temperature. Water was added to the reaction, and the product was extracted with AcOEt. The resulting crude product was purified by flash chromatography (silica gel, 25 g, 0% to 10% MeOH in DCM) to give the title compound (377.4 mg, 649 μmol, 130% yield) as an orange viscous oil. MS (ESI, m / z): 581.2 [M+H] + .

[0314] Step 5) (2-chloro-4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)phenyl)(piperazin-1-yl)methanone hydrochloride

[0315] tert-Butyl 4-(2-chloro-4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoyl)piperazine-1-carboxylate (282 mg, 485 μmol, 1 equiv.) was combined with HCl 4M in dioxane (1.21 ml, 4.85 mmol, 10 equiv.). After 50 min, the reaction was evaporated to dryness to give the title compound (300 mg, 579 μmol, 108% yield) as an off-white solid. MS (ESI, m / z): 479.4 [MH] - .

[0316] Process 6) tert-Butyl (2-(4-(2-chloro-4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoyl)piperazin-1-yl)-2-oxoethyl)(methyl)carbamate

[0317] 2-((tert-Butoxycarbonyl)(methyl)amino)acetic acid (110 mg, 580 μmol, 1.20 equiv.) was combined with DMF (2.5 ml). DIPEA (250 mg, 338 μl, 1.93 mmol, 4.00 equiv.) and HATU (276 mg, 725 μmol, 1.50 equiv.) were added and stirred for 15 minutes. After that, (2-chloro-4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)phenyl)(piperazin-1-yl)methanone hydrochloride (250 mg, 483 μmol, 1 equiv.) was added. After stirring for 2 hours, water was added to the reaction mixture, which was then extracted with AcOEt. The crude product obtained after evaporation was purified by flash chromatography (silica gel, 20 g, 0% to 5% MeOH in DCM) to give the title compound (224.6 mg, 344 μmol, 64.2% yield) as an off-white foam. MS (ESI, m / z): 652.2 [M+H] + .

[0318] Step 7) 1-(4-(2-chloro-4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoyl)piperazin-1-yl)-2-(methylamino)ethanone

[0319] tert-Butyl (2-(4-(2-chloro-4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoyl)piperazin-1-yl)-2-oxoethyl)(methyl)carbamate (220 mg, 337 μmol, 1 equiv.) was combined with 4 M HCl in dioxane (843 μl, 3.37 mmol, 10 equiv.). After 1 h, the reaction was evaporated to dryness. The product was taken up in DCM and basified with saturated Na2CO3. After extraction and removal of the solvent, the product was purified by preparative HPLC to give the title compound (48.2 mg, 87.3 μmol, 25.4% yield) as a light brown solid. MS (ESI, m / z): 552.2 [M+H] + .

[0320] Process 8) [2-[4-[2-chloro-4-[[3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]piperazin-1-yl]-2-oxoethyl]trimethylazanium formate

[0321] 1-(4-(2-chloro-4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoyl)piperazin-1-yl)-2-(methylamino)ethanone (41 mg, 74.3 μmol, 1 equiv.) was dissolved in 1,4-dioxane (69.6 μl) and DIPEA (29.6 mg, 40 μl, 229 μmol, 3.08 equiv.) was added. The reaction mixture was stirred at room temperature for 20 minutes, and iodomethane (105 mg, 46.2 μl, 743 μmol, 10 equiv.) was added. The reaction mixture was stirred at room temperature for 24 hours. The crude material was purified by preparative HPLC. The product was lyophilized to afford the title compound (28.7 mg, 45.8 μmol, 61.7% yield) as a white solid. MS (ESI, m / z): 580.4 [M] + .

[0322] Example 32 2-(4-(4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperazin-1-yl)-N,N,N-trimethyl-2-oxoethan-1-aminium iodide [ka]

[0323] Process 1) 2-(Dimethylamino)-1-(4-(4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperazin-1-yl)ethanone

[0324] 4-((3-(3-Fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoic acid (Intermediate 12, 30 mg, 76.5 μmol, 1 equiv.), DIPEA (39.5 mg, 53.4 μl, 306 μmol, 4 equiv.), and HATU (43.6 mg, 115 μmol, 1.5 equiv.) were dissolved in DMF (500 μl). The resulting reaction mixture was stirred at room temperature for 30 minutes. 2-(Dimethylamino)-1-(piperazin-1-yl)ethanone dihydrochloride (28 mg, 115 μmol, 1.5 equiv.) was added, and the reaction mixture was stirred at room temperature for 3 hours. The crude material was purified by preparative HPLC to afford the title compound (23.5 mg, 43 μmol, 56.3% yield) as a pale yellow oil. MS (ESI, m / z): 546.3 [M + H] + .

[0325] Process 2) 2-(4-(4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperazin-1-yl)-N,N,N-trimethyl-2-oxoethan-1-aminium iodide

[0326] 2-(Dimethylamino)-1-(4-(4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperazin-1-yl)ethanone (10 mg, 18.3 μmol, 1 equiv.) was dissolved in 1,4-dioxane (1 ml) and iodomethane (52 mg, 22.8 μl, 367 μmol, 20 equiv.) was added. The reaction mixture was stirred at room temperature for 1 hour. The product was dried under high vacuum and lyophilized to give the title compound (13 mg, 18.9 μmol, 103% yield) as a white solid. MS (ESI, m / z): 560.5 [M] + .

[0327] Example 33 [4-[4-[4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]piperazine-1-carbonyl]morpholin-2-yl]methyltrimethylammonium formate [ka]

[0328] Process 1) [4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-phenyl]-[4-(imidazole-1-carbonyl)piperazin-1-yl]methanone

[0329] To a solution of N,N-diisopropylethylamine (0.11 mL, 0.630 mmol, 0.6 equiv) in ACN (5 mL) was added [4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-phenyl]-piperazin-1-yl-methanone (Intermediate 13, 500 mg, 1.04 mmol, 1 equiv) and N,N'-carbonyldiimidazole (186.38 mg, 1.15 mmol, 1.1 equiv). The reaction was stirred at 30 °C for 24 h. The reaction mixture was concentrated to give the title compound (800 mg, 1.4 mmol, 133.71% yield) as a brown oil. MS (ESI, m / z): 573.2 [M+H] + .

[0330] Process 2) [4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-phenyl]-[4-[2-[(dimethylamino)methyl]morpholine-4-carbonyl]piperazin-1-yl]methanone

[0331] To a solution of [4-[[4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methylphenyl]methyl]piperazin-1-yl]imidazol-1-yl-methanone (320 mg, 0.570 mmol, 1 equiv.) in NMP (5 mL) was added N,N-dimethyl-2-morpholinemethanamine (99.14 mg, 0.690 mmol, 1.2 equiv.) and N,N-diisopropylethylamine (0.2 mL, 1.15 mmol, 2 equiv.). The reaction was stirred at 120 °C for 12 h. The mixture was purified by preparative HPLC (base) and lyophilized to afford the title compound (80.5 mg, 0.120 mmol, 21.66% yield) as a yellow solid. MS (ESI, m / z): 649.3 [M+H] + .

[0332] Process 3) [4-[4-[4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]piperazine-1-carbonyl]morpholin-2-yl]methyltrimethylammonium formate

[0333] To a solution of [4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-phenyl]-[4-[2-[(dimethylamino)methyl]]morpholine-4-carbonyl]piperazin-1-yl]methanone (60 mg, 0.090 mmol, 1 equiv.) in ACN (2 mL) was added iodomethane (39.38 mg, 0.280 mmol, 3 equiv.), which was stirred at 25° C. for 12 h. The reaction mixture was purified by preparative HPLC (FA) to give the title compound (20.1 mg, 0.030 mmol, 30.66% yield) as a white solid. MS (ESI, m / z): 665.3 [M] + .

[0334] Example 34 2-chloro-4-[[3-[4-(cyanomethoxy)-2,3-difluorophenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-N-[2-(4,4-dimethylpiperazin-4-ium-1-yl)ethyl]-N-methyl-benzamide iodide [ka]

[0335] Process 1) tert-Butyl 4-[2-[[2-chloro-4-[[3-[4-(cyanomethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]-methyl-amino]ethyl]piperazine-1-carboxylate

[0336] To a solution of 2-chloro-4-((3-(4-(cyanomethoxy)-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoic acid (Intermediate 10) (456 mg, 1.0 mmol, 1.0 equiv.), tert-butyl 4-(2-(methylamino)ethyl)piperazine-1-carboxylate (300 mg, 1.2 mmol, 1.2 equiv.) in anhydrous DMF (15 mL) was added DIPEA (258 mg, 2.0 mmol, 2.0 equiv.). The resulting mixture was then stirred at room temperature for 30 minutes, and HATU (760 mg, 2.0 mmol, 2.0 equiv.) was added to the mixture, followed by stirring for an additional 10 hours. The mixture was poured into water (50 mL), and the aqueous solution was extracted with DCM (50 mL × 2). The organic layers were combined and washed with water and brine. The mixture was dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the title compound, which was used in the next step without purification (305 mg, 0.45 mmol, 45.0% yield) as a yellow solid. MS (ESI, m / z): 681.2 [M+H] + .

[0337] Process 2) 2-chloro-4-[[3-[4-(cyanomethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-N-methyl-N-(2-piperazin-1-ylethyl)benzamide

[0338] To a solution of tert-butyl 4-(2-(2-chloro-4-((3-(4-(cyanomethoxy)-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N-methylbenzamido)ethyl)piperazine-1-carboxylate (305 mg, 0.45 mmol) in MeOH (10 ml) was added 3 M hydrochloric acid (2.0 mL) at room temperature. The resulting mixture was stirred for 10 h and then adjusted to pH 7-8 with 2 M aqueous sodium carbonate. The mixture was extracted with DCM (50 mL × 2), and the combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to give a red oil, which was purified by preparative HPLC. Preparative HPLC afforded the title compound (100 mg, 0.17 mmol, 37.8% yield) as an off-white powder. MS (ESI, m / z): 581.2 [M+H] + .

[0339] Process 3) 2-Chloro-4-[[3-[4-(cyanomethoxy)-2,3-difluorophenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-N-[2-(4,4-dimethylpiperazin-4-ium-1-yl)ethyl]-N-methyl-benzamide; iodide

[0340] To a solution of 2-chloro-4-((3-(4-(cyanomethoxy)-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N-methyl-N-(2-(piperazin-1-yl)ethyl)benzamide (100 mg, 0.17 mmol, 1.0 equiv.) in anhydrous EtOH (3 mL) was added DIPEA (44 mg, 0.34 mmol, 2.0 equiv.). The resulting mixture was then stirred at room temperature for 10 minutes, and iodomethane (241 mg, 1.7 mmol, 10 equiv.) was added to the mixture, which was then stirred for an additional 10 hours. The mixture was concentrated under reduced pressure to give a red oil, which was purified by preparative HPLC to give the title compound (60 mg, 0.081 mmol, 47.6% yield) as a white powder. MS (ESI, m / z): 609.3 [M] + .

[0341] Example 35 2-(2-(4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N,2-dimethylbenzamido)ethoxy)-N,N,N-trimethylethan-1-aminium chloride [ka]

[0342] Process 1) N-(2-(2-chloroethoxy)ethyl)-4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N,2-dimethylbenzamide

[0343] 4-((3-(3-Fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoic acid (Intermediate 12, 500 mg, 1.27 mmol, 1 equiv.) was combined with DMF (5 ml). HATU (727 mg, 1.91 mmol, 1.50 equiv.), DIPEA (659 mg, 890 μl, 5.1 mmol, 4.00 equiv.), and 2-(2-chloroethoxy)-N-methylethanamine hydrochloride (333 mg, 1.91 mmol, 1.50 equiv.) were added, and the reaction mixture was stirred at room temperature. After 4 hours, water was added to the reaction mixture, and extraction was carried out with AcOEt. The resulting crude product was purified by preparative HPLC to give the title compound (430 mg, 0.84 mmol, 65.9% yield) as a brown foam. MS (ESI, m / z): 512.2 [M + H] + .

[0344] Process 2) 2-(2-(4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N,2-dimethylbenzamido)ethoxy)-N,N,N-trimethylethan-1-aminium chloride

[0345] N-(2-(2-chloroethoxy)ethyl)-4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N,2-dimethylbenzamide (11.5 mg, 22.5 μmol, 1 equiv.) was combined with dioxane (100 μL). TEA (11.4 mg, 15.7 μL, 112 μmol, 5.00 equiv.) and 45% aqueous trimethylamine (6.64 mg, 112 μmol, 5.00 equiv.) were added, and the reaction was heated to 65° C. After stirring for 2 hours, 45% aqueous trimethylamine (6.64 mg, 112 μmol, 5.00 equiv.) was added again, and stirring at 65° C. was continued for 24 hours. The reaction mixture was then transferred to a sealed tube, and 45% aqueous trimethylamine () was added again, and this was stirred at 90° C. overnight. The reaction mixture was evaporated and dried under high vacuum for 1 hour to give the title compound (8.7 mg, 15.2 μmol, 63% yield) as an off-white solid. MS (ESI, m / z): 535.3 [M] + .

[0346] Example 36 2-[[4-[4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]piperazine-1-carbonyl]amino]ethyl-trimethyl-ammonium formate [ka]

[0347] Process 1) 4-[4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]-N-[2-(dimethylamino)ethyl]piperazine-1-carboxamide

[0348] To a solution of [4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-phenyl]-piperazin-1-yl-methanone (Intermediate 13, 200 mg, 0.420 mmol, 1 equiv.) in DCM (5 mL) was added N,N-diisopropylethylamine (0.36 mL, 2.09 mmol, 5 equiv.) and bis(trichloromethyl)carbonate (49.61 mg, 0.170 mmol, 0.4 equiv.) at 0° C. The mixture was stirred at 0° C. for 1 h, and then N,N-dimethylethylenediamine (110.54 mg, 1.25 mmol, 3 equiv.) was added. The reaction mixture was stirred at 25° C. for 12 h. The mixture was concentrated and purified by preparative HPLC (base), then lyophilized to give the title compound (21.1 mg, 0.040 mmol, 8.52% yield) as a yellow solid. MS (ESI, m / z): 593.3 [M+H] + .

[0349] Process 2) 2-[[4-[4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]piperazine-1-carbonyl]amino]ethyl-trimethyl-ammonium formate

[0350] The title compound (61.3 mg, 0.090 mmol, 70.55% yield) was obtained as a yellow solid in the same manner as in Example 33, Step 3. MS (ESI, m / z): 607.2 [M] + .

[0351] Example 37 2-[[(3S,4R)-1-[4-[[3-(3-fluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]-3-hydroxy-piperidine-4-carbonyl]amino]ethyl-trimethyl-ammonium formate [ka]

[0352] Process 1) Ethyl (3S,4R)-1-[4-[[3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]-3-hydroxy-piperidine-4-carboxylate

[0353] To a solution of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.16 g, 3.06 mmol, 2 equiv.) in DMF (20 mL) was added N,N-diisopropylethylamine (0.8 mL, 4.59 mmol, 3 equiv.), 4-[[3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoic acid (Intermediate 12, 600 mg, 1.53 mmol, 1 equiv.), and ethyl (3S,4R)-3-hydroxypiperidine-4-carboxylate (317.83 mg, 1.83 mmol, 1.2 equiv.). The reaction was stirred at 25 °C for 12 h. 50 mL of water was added, and the mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with 1N HCl (50 mL x 2), brine (50 mL), dried over NaSO, filtered, and concentrated to give the title compound (700 mg, 1.28 mmol, 83.6% yield) as a dark green oil. MS (ESI, m / z): 548.2 [M+H] + .

[0354] Process 2) (3S,4R)-1-[4-[[3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]-3-hydroxy-piperidine-4-carboxylic acid

[0355] Ethyl (3S,4R)-1-[4-[[3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]-3-hydroxy-piperidine-4-carboxylate (550 mg, 1 mmol, 1 equiv.) was added to a solution of aqueous sodium hydroxide (10 mL, 20 mmol, 19.91 equiv.) in THF (10 mL) / methanol (10 mL) and stirred at 20 °C for 24 h. The reaction mixture was adjusted to pH 1-2 by adding 3N HCl, extracted with DCM:MeOH 10:1 (60 mL × 3), dried over NaSO, and concentrated to give the title compound (310 mg, 0.600 mmol, 59.41% yield) as a pale yellow solid. MS (ESI, m / z): 520.2 [M+H] + .

[0356] Process 3) (3S,4R)-N-[2-(dimethylamino)ethyl]-1-[4-[[3-(3-fluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]-3-hydroxy-piperidine-4-carboxamide

[0357] To a solution of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (146.38 mg, 0.380 mmol, 2 equiv.) in DMF (10 mL) was added N,N-diisopropylethylamine (0.1 mL, 0.580 mmol, 3 equiv.), N,N-dimethylethylenediamine (20.36 mg, 0.230 mmol, 1.2 equiv.), and (3S,4R)-1-[4-[[3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]-3-hydroxy-piperidine-4-carboxylic acid (100 mg, 0.190 mmol, 1 equiv.). The reaction was stirred at 25 °C for 12 h. 50 mL of water was added, and this was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to give the title compound (100 mg, 0.170 mmol, 88.11% yield) as a dark green oil. MS (ESI, m / z): 590.3 [M+H] + .

[0358] Step 4) 2-[[(3S,4R)-1-[4-[[3-(3-fluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]-3-hydroxy-piperidine-4-carbonyl]amino]ethyl-trimethyl-ammonium formate

[0359] To a solution of (3S,4R)-N-[2-(dimethylamino)ethyl]-1-[4-[[3-(3-fluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]-3-hydroxy-piperidine-4-carboxamide (100 mg, 0.170 mmol, 1 equiv.) in ACN (5 mL) was added methyl iodide (48.14 mg, 0.340 mmol, 2 equiv.) and the reaction mixture was stirred at 40° C. for 12 h. The reaction was concentrated under reduced pressure and purified by preparative HPLC (FA) to give the title compound (21 mg, 0.030 mmol, 18.81% yield) as a white solid. MS (ESI, m / z): 604.3 [M] + .

[0360] Example 38 2-chloro-4-[[3-[4-(cyanomethoxy)-2,3-difluorophenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-N-[2-(1,1-dimethylpiperidin-1-ium-4-yl)ethyl]-N-methyl-benzamide 2,2,2-trifluoroacetate [ka]

[0361] Process 1) tert-Butyl 4-[2-[[2-chloro-4-[[3-[4-(cyanomethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]-methyl-amino]ethyl]piperidine-1-carboxylate

[0362] To a solution of 2-chloro-4-((3-(4-(cyanomethoxy)-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoic acid (Intermediate 10) (456 mg, 1.0 mmol, 1.0 equiv.), tert-butyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (291 mg, 1.2 mmol, 1.2 equiv.) in anhydrous DMF (15 mL) was added DIPEA (258 mg, 2.0 mmol, 2.0 equiv.). The resulting mixture was then stirred at room temperature for 30 minutes, and HATU (760 mg, 2.0 mmol, 2.0 equiv.) was added to the mixture, followed by stirring for an additional 10 hours. The mixture was poured into water (50 mL), and the aqueous solution was extracted with DCM (50 mL × 2). The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound, which was used in the next step without purification (306 mg, 0.45 mmol, 45.0% yield) as a yellow solid. MS (ESI, m / z): 680.2 [M+H] + .

[0363] Process 2) 2-chloro-4-[[3-[4-(cyanomethoxy)-2,3-difluorophenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-N-methyl-N-[2-(4-piperidyl)ethyl]benzamide

[0364] To a solution of tert-butyl 4-(2-(2-chloro-4-((3-(4-(cyanomethoxy)-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N-methylbenzamido)ethyl)piperidine-1-carboxylate (306 mg, 0.45 mmol) in MeOH (10 mL) was added 3.0 M hydrochloric acid (2.0 mL) at room temperature. The resulting mixture was stirred for 10 hours and then adjusted to pH 7-8 with 2 M aqueous sodium carbonate. The mixture was extracted with DCM (50 mL × 2), and the combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to give a red oil, which was purified by preparative HPLC to give the title compound (145 mg, 0.25 mmol, 55.6% yield) as an off-white powder. MS (ESI, m / z): 580.3 [M+H] + .

[0365] Process 3) 2-chloro-4-[[3-[4-(cyanomethoxy)-2,3-difluorophenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-N-[2-(1,1-dimethylpiperidin-1-ium-4-yl)ethyl]-N-methyl-benzamide 2,2,2-trifluoroacetate

[0366] To a solution of 2-chloro-4-((3-(4-(cyanomethoxy)-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N-methyl-N-(2-(piperidin-4-yl)ethyl)benzamide (145 mg, 0.25 mmol, 1.0 equiv.) in anhydrous EtOH (5 mL) was added DIPEA (64 mg, 0.5 mmol, 2.0 equiv.). The resulting mixture was then stirred at room temperature for 10 minutes, and iodomethane (142 mg, 1.0 mmol, 4.0 equiv.) was added to the mixture, which was stirred for an additional 10 hours. The mixture was concentrated under reduced pressure to give a white solid, which was purified by preparative HPLC. The title compound (75 mg, 0.104 mmol, 41.6% yield) was isolated by MS (ESI, m / z): 608.3 [M]. + obtained.

[0367] Example 39 4-(4-(2-(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N,2-dimethylbenzamido)ethyl)piperidin-1-yl)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium formate [ka]

[0368] In a 10 ml round-bottom flask, 4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N,2-dimethyl-N-(2-(piperidin-4-yl)ethyl)benzamide (Intermediate 3, 30 mg, 56.1 μmol, 1 equiv.), 3-carboxy-2-hydroxy-N,N,N-trimethylpropan-1-aminium (13.7 mg, 84.2 μmol, 1.5 equiv.), and DIPEA (29 mg, 39.2 μl, 224 μmol, 4 equiv.) were dissolved in DMF (750 μl) to give a brown solution. The reaction mixture was stirred at room temperature for 1 minute. HATU (32 mg, 84.2 μmol, 1.5 equiv.) was added, and the reaction mixture was stirred at room temperature for 3 hours. The crude material was directly purified by preparative HPLC. The crude material was purified by preparative HPLC to give the title compound (9.8 mg, 13.5 μmol, 24.1% yield) as a colorless oil. MS (ESI, m / z): 678.36 [M] + .

[0369] Example 40 2-(2-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)ethoxy)-N,N,N-triethylethan-1-aminium formate [ka]

[0370] N-(2-(2-aminoethoxy)ethyl)-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamide hydrochloride (Intermediate 9, 30 mg, 54.8 μmol, 1 equiv.) was dissolved in 1,4-dioxane (5 mL) and DIPEA (37 mg, 50 μL, 286 μmol, 5.22 equiv.) was added. The reaction mixture was stirred at room temperature for 20 minutes and iodoethane (117 mg, 60 μL, 750 μmol, 13.7 equiv.) was added. The reaction mixture was stirred at room temperature over the weekend. DIPEA (37 mg, 50 μL, 286 μmol, 5.22 equiv.) and iodoethane (117 mg, 60 μL, 750 μmol, 13.7 equiv.) were added again, and the reaction mixture was stirred at room temperature for 4 hours, then heated and stirred at 55° C. The crude material was purified by preparative HPLC. The product was lyophilized to give the title compound (13 mg, 20.2 μmol, 37% yield) as a white solid. MS (ESI, m / z): 595.6 [M] + .

[0371] Example 41 2-[2-[[4-[[3-[4-(cyanomethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]ethoxy]ethyltrimethylammonium iodide [ka]

[0372] Process 1) 2-[4-(8-chloroimidazo[1,2-a]pyrazin-3-yl)-2,3-difluoro-phenoxy]acetonitrile

[0373] A mixture of 8-chloro-3-iodo-imidazo[1,2-a]pyrazine (2.79 g, 9.98 mmol, 1 equiv.), 2-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetonitrile (4.42 g, 14.97 mmol, 1.5 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.73 g, 1 mmol, 0.100 equiv.), and phosphoric acid, potassium salt (2.48 mL, 29.95 mmol, 3 equiv.) in THF (50 mL) and water (25 mL) was treated under nitrogen at 45 °C for 14 h. Water (5 mL) was added to the mixture, and it was extracted with EA (10 mL × 3). The combined organic layer was concentrated to dryness. The crude product was then purified by flash column chromatography eluting with 20% EtOAc in PE to give the title compound (2.59 g, 8.07 mmol, 80.81% yield) as a brown solid. MS (ESI, m / z): 321.7 [M+H] + .

[0374] Step 2) Intermediate 14 4-[[3-[4-(cyanomethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoic acid

[0375] A mixture of 2-[4-(8-chloroimidazo[1,2-a]pyrazin-3-yl)-2,3-difluoro-phenoxy]acetonitrile (573.0 mg, 1.79 mmol, 1 equiv.) and 4-amino-2-ethyl-benzoic acid (354.2 mg, 2.14 mmol, 1.2 equiv.) in acetonitrile (20 mL) and acetic acid (4 mL) was stirred at 100° C. for 3 h. The mixture was concentrated to dryness. The residue was treated with EA (10 mL). The mixture was stirred at 25° C. for 5 min, filtered, and the solid was dried to give the title compound (556 mg, 1.24 mmol, 69.24% yield) as a brown solid. MS (ESI, m / z): 448.5 [M+H] + .

[0376] Process 3) 4-[[3-[4-(cyanomethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-N-[2-[2-(dimethylamino)ethoxy]ethyl]-2-ethyl-benzamide

[0377] A mixture of 4-[[3-[4-(cyanomethoxy)-2,3-difluorophenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoic acid (220.0 mg, 0.490 mmol, 1 eq. Intermediate 14), 2-[2-(dimethylamino)ethoxy]ethanamine (97.07 mg, 0.730 mmol, 1.5 eq.), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (279.2 mg, 0.730 mmol, 1.5 eq.), and N,N-diisopropylethylamine (0.26 mL, 1.47 mmol, 3 eq.) in DMF (10 mL) was stirred at 25 °C for 3 h. Water (15 mL) was added to the mixture, and it was extracted with EA (10 mL × 3). The combined organic layers were washed with NH4Cl (20 mL), dried over Na2SO4, and concentrated to dryness. The crude product was then purified by flash column chromatography eluting with 10% MeOH in DCM. The desired fractions were concentrated to dryness in vacuo to give the title compound (111.8 mg, 39.71% yield) as a pale gray powder. MS (ESI, m / z): 564.6 [M+H] + .

[0378] Step 4) 2-[2-[[4-[[3-[4-(cyanomethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]ethoxy]ethyltrimethylammonium iodide

[0379] A mixture of 4-[[3-[4-(cyanomethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-N-[2-[2-(dimethylamino)ethoxy]ethyl]-2-ethyl-benzamide (53.0 mg, 0.090 mmol, 1 equiv.), iodomethane (40.04 mg, 0.280 mmol, 3 equiv.), and N,N-diisopropylethylamine (0.03 mL, 0.190 mmol, 2 equiv.) in ethanol (6 mL) was stirred at 80 °C for 14 h. The mixture was concentrated to dryness. The crude product was purified by preparative HPLC. The desired fractions were concentrated to dryness in vacuo to give the title compound (30 mg, 0.040 mmol, 44.94% yield) as a pink gum. MS (ESI, m / z): 578.6 [M] + .

[0380] Example 42 [2-[4-[4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]piperazin-1-yl]-2-oxoethyl]-trimethylammonium chloride [ka]

[0381] To a mixture of [4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-phenyl]-piperazin-1-yl-methanone ((Intermediate 13, 80 mg, 0.170 mmol, 1 equiv.) and carboxymethyl(trimethyl)ammonium chloride (19.75 mg, 0.170 mmol, 1 equiv.) in DMF (1 mL) was added 1-propanephosphonic anhydride (159.59 mg, 0.250 mmol, 1.5 equiv) (50% in DMF solution) and triethylamine (0.07 mL, 0.500 mmol, 3 equiv) were added slowly at 25° C. The mixture was stirred at 25° C. for 48 h. The mixture was then filtered and purified by preparative HPLC (TFA) to give the title compound (15.32 mg, 0.020 mmol, 13.7% yield) as a white solid. MS (ESI, m / z): 578.2 [M] + .

[0382] Example 43 2-[2-[[4-[[3-[2-chloro-4-(cyanomethoxy)-3-fluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]ethoxy]ethyltrimethylammonium iodide [ka]

[0383] Process 1) 2-[2-chloro-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetonitrile

[0384] This compound was prepared similarly to Step 1 of Example 2 using 4-bromo-2-chloro-3-fluoro-phenol. The title compound was obtained as a pink solid. MS (ESI, m / z): 312.1 [M+H] + .

[0385] Process 2) 2-[2-[[4-[[3-[2-chloro-4-(cyanomethoxy)-3-fluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]ethoxy]ethyltrimethylammonium iodide

[0386] This compound was prepared in the same manner as in Example 41 using 2-[3-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetonitrile. The title compound was obtained as a pale yellow solid. MS (ESI, m / z): 594.2 [M] + .

[0387] Example 2 2-[1-[4-[[3-[4-(cyanomethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]-4-piperidyl]ethyl-trimethyl-ammonium formate [ka]

[0388] Process 1) 2-(4-bromo-2,3-difluoro-phenoxy)acetonitrile

[0389] To a mixture of 2-bromoacetonitrile (6.89 g, 57.42 mmol, 1.2 equiv.) in acetonitrile (250 mL), potassium carbonate (9.92 g, 71.77 mmol, 1.5 equiv.) and 4-bromo-2,3-difluoro-phenol (10 g, 47.85 mmol, 1 equiv.) were added at 25° C. The mixture was stirred at 50° C. for 16 hours. The reaction mixture was filtered and concentrated. The residue was purified by chromatography (PE / EA=20 / 1-5 / 1) to give the title compound (11.3 g, 45.56 mmol, 95.22% yield) as a white solid. 1H NMR(400MHz,CHLOROFORM-d)Shift 7.26-7.37(m,1H),6.84(ddd,J=2.14,7.34,9.23Hz,1H),4.86(s,2H).

[0390] Step 2) Intermediate 15 2-[2,3-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetonitrile

[0391] To a mixture of 2-(4-bromo-2,3-difluoro-phenoxy)acetonitrile (11.3 g, 45.56 mmol, 1 equiv.), bis(pinacolato)diboron (13.88 g, 54.67 mmol, 1.2 equiv.), and potassium acetate (13.41 g, 136.68 mmol, 3 equiv.) in 1,4-dioxane (250 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.67 g, 2.28 mmol, 0.05 equiv.) under N at 25 °C. The mixture was stirred at 70 °C for 4 h. The reaction mixture was cooled and filtered. The filtrate was concentrated. The residue was purified by chromatography (PE / EA=100 / 1-10 / 1) and trituration (PE, 50 mL) to give the title compound (7 g, 23.72 mmol, 52.07% yield) as a yellow solid. MS (ESI, m / z): 296.0 [M+H] + .

[0392] Step 3) Intermediate 11 2-[4-(8-chloroimidazo[1,2-a]pyrazin-3-yl)-2,3-difluoro-phenoxy]acetonitrile

[0393] A mixture of 8-chloro-3-iodo-imidazo[1,2-a]pyrazine (Intermediate 1, 3.03 g, 10.84 mmol, 0.8 equiv.), 2-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetonitrile (4 g, 13.56 mmol, 1 equiv.), sodium carbonate (4.31 g, 40.67 mmol, 3 equiv.), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.99 g, 1.36 mmol, 0.1 equiv.) in 1,4-dioxane (60 mL) and water (15 mL) was stirred at 60° C. for 16 hours. The reaction mixture was filtered and concentrated. The residue was extracted with AcOEt (50 mL x 3), and the combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (PE / EA = 1 / 1, Rf = 0.3) to give the title compound (2.8 g, 8.73 mmol, 46.17% yield) as a yellow solid. MS (ESI, m / z): 321.0 [M+H] + .

[0394] Step 4) tert-Butyl N-[2-[1-(2-methyl-4-nitro-benzoyl)-4-piperidyl]ethyl]carbamate

[0395] To a mixture of 2-methyl-4-nitro-benzoic acid (793 mg, 4.38 mmol, 1 equiv.), 4-(2-Boc-aminoethyl)piperidine (1000 mg, 4.38 mmol, 1 equiv.), and triethylamine (1.22 mL, 8.76 mmol, 2 equiv.) in DMF (20 mL) was added 1-propanephosphonic anhydride (2787 mg, 4.38 mmol, 1 equiv.) dropwise at 25° C. under N. The mixture was stirred at 25° C. for 3 h. The reaction mixture was poured into water (100 mL) and extracted with AcOEt (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated. The residue was purified by chemical flash (PE / EA=2 / 1, Rf=0.25) to give the title compound (1700 mg, 4.34 mmol, 99.16% yield) as a colorless oil. MS (ESI, m / z): 292.1 [M+H-Boc] + .

[0396] Step 5) [4-(2-aminoethyl)-1-piperidyl]-(2-methyl-4-nitrophenyl)methanone

[0397] To a mixture of tert-butyl N-[2-[1-(2-methyl-4-nitro-benzoyl)-4-piperidyl]ethyl]carbamate (1.4 g, 3.58 mmol, 1 equiv.) in dichloromethane (30 mL) was added trifluoroacetic acid (3 mL, 38.94 mmol, 10.89 equiv.) dropwise at 25° C. The mixture was stirred at 25° C. for 16 h. The reaction mixture was concentrated to give the title compound (1 g, 3.43 mmol, 95.97% yield) as a colorless oil. MS (ESI, m / z): 292.1 [M+H] + .

[0398] Process 6) Trimethyl-[2-[1-(2-methyl-4-nitro-benzoyl)-4-piperidyl]ethyl]ammonium formate

[0399] To a mixture of [4-(2-aminoethyl)-1-piperidyl]-(2-methyl-4-nitro-phenyl)methanone (1 g, 3.43 mmol, 1 equiv.) and potassium carbonate (3.79 g, 27.46 mmol, 8 equiv.) in acetonitrile (20 mL) was added iodomethane (2.92 g, 20.59 mmol, 6 equiv.) at 25 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was directly purified via preparative HPLC (FA) to afford the title compound (1 g, 2.99 mmol, 87.12% yield) as a yellow gum. MS (ESI, m / z): 334.1 [M] + .

[0400] Step 7) 2-[1-(4-amino-2-methyl-benzoyl)-4-piperidyl]ethyl-trimethyl-ammonium formate / acetate

[0401] A mixture of trimethyl-[2-[1-(2-methyl-4-nitro-benzoyl)-4-piperidyl]ethyl]ammonium formate (400 mg, 1.2 mmol, 1 equiv.) and 10% Pd / C:water 1:1 (0.04 mL, 0.380 mmol, 0.31 equiv.) in methanol (8 mL) was stirred under a hydrogen balloon at 25° C. for 16 h. Two drops of acetic acid were added, and the mixture was stirred with a hydrogen balloon at 25° C. for an additional 16 h. The reaction mixture was filtered and concentrated to give the title compound (360 mg, 1.18 mmol, 98.86% yield) as a yellow oil. MS (ESI, m / z): 305.1 [M] + .

[0402] Process 8) 2-[1-[4-[[3-[4-(cyanomethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]-4-piperidyl]ethyl-trimethyl-ammonium formate

[0403] A mixture of 2-[4-(8-chloroimidazo[1,2-a]pyrazin-3-yl)-2,3-difluoro-phenoxy]acetonitrile (210.66 mg, 0.660 mmol, 1 equiv.) and 2-[1-(4-amino-2-methyl-benzoyl)-4-piperidyl]ethyl-trimethyl-ammonium formate / acetate (200 mg, 0.660 mmol, 1 equiv.) in acetonitrile (2 mL) and acetic acid (0.2 mL) was stirred at 60° C. for 16 hours. The reaction mixture was directly purified by preparative HPLC (FA) and then lyophilized to give the title compound (31 mg, 0.050 mmol, 7.58% yield) as a yellow solid. MS (ESI): m / z=294.7 [M+H] 2+ .

[0404] Example 14 2-[4-[2-bromo-4-[[3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]piperazin-1-yl]ethyl-trimethyl-ammonium 2,2,2-trifluoroacetate [ka]

[0405] Process 1) Methyl 4-amino-2-methyl-benzoate

[0406] A solution of 2-bromo-4-nitro-benzoate (5 g, 19.23 mmol, 1 equiv), iron (6442.66 mg, 115.37 mmol, 6 equiv), and ammonium chloride (1234.19 mg, 23.07 mmol, 1.2 equiv) in 2-propanol (20 mL) / water (80 mL) was stirred at 100° C. for 30 min. The mixture was cooled, filtered, and concentrated under reduced pressure. The residue was partitioned between EtOAc (60 mL) and water (30 mL). The organic layer was washed with brine, dried over NaSO, filtered, and concentrated to give the title compound (4.2 g, 18.26 mmol, 94.95% yield) as a pale yellow solid.

[0407] Step 2) Intermediate 16 Methyl 2-bromo-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzoate

[0408] To a solution of 8-chloro-3-iodo-imidazo[1,2-a]pyrazine (Intermediate 1, 2 g, 7.16 mmol, 1 equiv.) in ACN (18 mL) / acetic acid (2 mL) was added methyl 4-amino-2-bromobenzoate (1646.4 mg, 7.16 mmol, 1 equiv.). The mixture was stirred at 90° C. for 14 hours. The mixture was filtered and the solid was washed with MeCN to give the title compound (2.8 g, 5.92 mmol, 72.78% yield) as a white solid. MS (ESI): m / z = 472.0, 474.0 [M+H] + .

[0409] Process 3) 2-(3-fluoro-4-methylsulfanyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0410] To a solution of 4-bromo-2-fluoroanisole (5 g, 24.39 mmol, 1 equiv.) in 1,4-dioxane (120 mL) / water (10 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1784 mg, 2.44 mmol, 0.1 equiv.), potassium acetate (7180 mg, 73.16 mmol, 3 equiv.), and bis(pinacolato)diboron (6812 mg, 26.83 mmol, 1.1 equiv.). The mixture was degassed with N2 for 5 minutes. The mixture was stirred at 100 °C for 18 hours. The mixture was then filtered and evaporated. The residue was purified by silica column chromatography (petroleum ether / ethyl acetate=1:0 to 20:1) to give the title compound (4.2 g, 16.66 mmol, yield 68.32%) as a pale yellow solid.

[0411] Step 4) Methyl 2-bromo-4-[[3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoate

[0412] To a solution of 2-(3-fluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (245.13 mg, 0.970 mmol, 1.15 equiv.) in 1,4-dioxane (8 mL) / water (2 mL) was added methyl 2-bromo-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzoate (400 mg, 0.850 mmol, 1 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (61.87 mg, 0.080 mmol, 0.1 equiv.), and sodium bicarbonate (213.1 mg, 2.54 mmol, 3 equiv.). The mixture was stirred at 70 °C for 18 h. 20 mL of THF was added to the mixture, which was then stirred for 10 min. The mixture was filtered and the organic layer was concentrated. The residue was purified by column chromatography (petroleum ether: EtOAc = 5:1 to 1:1) to give the title compound (280 mg, 0.590 mmol, 70.26% yield) as an off-white solid. MS (ESI): m / z = 471.0, 473.0 [M+H] + .

[0413] Step 5) 2-Bromo-4-[[3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoic acid

[0414] A solution of methyl 2-bromo-4-[[3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoate (280 mg, 0.590 mmol, 1 equiv.) in methanol (4 mL) was stirred at 80° C. for 10 minutes. When the mixture became clear, sodium hydroxide (4 mL, 16 mmol, 26.93 equiv.) was added. The mixture was stirred at 80° C. for 4 hours. The reaction mixture was concentrated in vacuo, diluted with water, and acidified with 2N HCl. The solid was collected and thoroughly dried to afford the title compound (240 mg, 0.520 mmol, 88.34% yield) as an off-white solid. MS (ESI): m / z = 457.0, 459.0 [M+H] + .

[0415] Process 6) [2-Bromo-4-[[3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]-[4-[2-(dimethylamino)ethyl]piperazin-1-yl]methanone formate

[0416] To a mixture of 1-(2-dimethylaminoethyl)piperazine (82 mg, 0.520 mmol, 1.5 equiv.) and 2-bromo-4-[[3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoic acid (160 mg, 0.350 mmol, 1 equiv.) in DMF (4 mL) was added triethylamine (0.24 mL, 1.75 mmol, 5 equiv.) and 1-propanephosphonic anhydride (1113 mg, 1.75 mmol, 5 equiv.) (50% in EtOAc) at 25 °C. The mixture was then stirred at 40 °C for 16 h. The solvent was removed, and the residue was purified by preparative HPLC (FA) to give the title compound (80 mg, 0.120 mmol, 37.56% yield) as a pale yellow solid. MS(ESI): m / z=596.0, 598.0[M+H] + .

[0417] Step 7) 2-[4-[2-bromo-4-[[3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]piperazin-1-yl]ethyl-trimethyl-ammonium 2,2,2-trifluoroacetate

[0418] To a solution of [2-bromo-4-[[3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]-[4-[2-(dimethylamino)ethyl]piperazin-1-yl]methanone formate (58 mg, 0.100 mmol, 1 equiv.) in acetone (2 mL) was added iodomethane (83 mg, 0.590 mmol, 6 equiv.). The mixture was stirred at 25 °C for 12 h. The solvent was removed, and the residue was purified by preparative HPLC (TFA) to give the title compound (17 mg, 0.020 mmol, 23.47% yield) as a pale yellow solid. MS (ESI, m / z): 610.0, 612.0 [M] + .

[0419] Example 44 2-[2-[[2-Bromo-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]ethoxy]ethyl-trimethyl-ammonium 2,2,2-trifluoroacetate [ka]

[0420] Step 1) Intermediate 17 2-(2,3-Difluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0421] Using 1-bromo-2,3-difluoro-4-methoxy-benzene, the title compound (3 g, 11.11 mmol, 22.52% yield) was obtained as a white solid in a similar manner to Example 14, Step 3.

[0422] Process 2) Methyl 2-bromo-4-[[3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoate

[0423] Using Intermediate 16, the title compound (260 mg, 0.530 mmol, 62.85% yield) was obtained as an off-white solid in a similar manner to Example 14, Step 4. MS (ESI): m / z = 489.0, 491.0 [M+H] + .

[0424] Process 3) 2-Bromo-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoic acid

[0425] The title compound (246 mg, 0.520 mmol, 97.58% yield) was obtained as a pale yellow solid in a similar manner to Example 14, Step 5. MS (ESI): m / z = 475.0, 477.0 [M+H] + .

[0426] Step 4) N-[2-(2-aminoethoxy)ethyl]-2-bromo-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzamide formate

[0427] The title compound (75 mg, 0.120 mmol, 31.11% yield) was obtained as a pale yellow solid in a similar manner to Example 14, Step 6. MS (ESI): m / z = 561.0, 563.0 [M+H] + .

[0428] Step 5) 2-[2-[[2-Bromo-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]ethoxy]ethyl-trimethyl-ammonium 2,2,2-trifluoroacetate

[0429] The title compound (11 mg, 0.020 mmol, 18.57% yield) was obtained as a white solid in the same manner as in Example 14, Step 7. MS (ESI, m / z): 603.0 [M], 605.0 [M] + .

[0430] Example 16 2-[2-[6-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethoxy]ethyl-trimethyl-ammonium formate [ka]

[0431] Process 1) tert-Butyl N-[2-(2-hydroxyethoxy)ethyl]carbamate

[0432] To a mixture of 2-(2-aminoethoxy)ethanol (3000 mg, 28.53 mmol, 1 equiv.) in THF (60 mL) and sodium bicarbonate in water (15 mL, 28.53 mmol, 1 equiv.) was added di-t-butyl dicarbonate (6227 mg, 28.53 mmol, 1 equiv.) at 0° C. The mixture was stirred for 4 h. The mixture was washed with 1 M HCl (5 mL), then brine, dried over NaSO, filtered, and concentrated to give the title compound (5000 mg, 24.36 mmol, 85.38% yield) as a white oil.

[0433] Process 2) 2-[2-(tert-butoxycarbonylamino)ethoxy]ethyl methanesulfonate

[0434] To a mixture of 2-(2-BOC-aminoethoxy)ethanol (3000 mg, 14.62 mmol, 1 equiv.) in DCM (20 mL) and methanesulfonyl chloride (2.03 mL, 26.19 mmol, 1.79 equiv.) at 0 °C, triethylamine (4.07 mL, 29.23 mmol, 2 equiv.) was added at 0 °C. The mixture was stirred for 4 h. The mixture was quenched with aqueous NH4Cl and extracted with AcOEt (10 mL × 2). The organic phase was concentrated and purified by column chromatography (PE:EA = 5:1) to give the title compound (2800 mg, 9.88 mmol, 67.61% yield) as a white oil.

[0435] Process 3) tert-Butyl N-[2-[2-(6-bromo-1-oxo-3,4-dihydroisoquinolin-2-yl)ethoxy]ethyl]carbamate

[0436] To a mixture of 6-bromo-3,4-dihydro-2H-isoquinolin-1-one (399 mg, 1.76 mmol, 1 equiv) in THF (10 mL) was added sodium hydride (105 mg, 2.65 mmol, 1.5 equiv) at 0 °C. The mixture was stirred at 25 °C for 20 min. 2-[2-(tert-butoxycarbonylamino)ethoxy]ethyl methanesulfonate (500 mg, 1.76 mmol, 1 equiv) was added, and the mixture was stirred at 60 °C for 16 h. The reaction mixture was poured into aqueous NH4Cl (saturated, 50 mL). It was extracted with AcOEt (50 mL × 3), and the combined layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (FA) and then lyophilized to give the title compound (350 mg, 0.850 mmol, 47.99% yield) as a yellow solid. MS (ESI): m / z = 413.0, 415.0 [M+H] + .

[0437] Step 4) 2-[2-(2-aminoethoxy)ethyl]-6-bromo-3,4-dihydroisoquinolin-1-one

[0438] To a mixture of tert-butyl N-[2-[2-(6-bromo-1-oxo-3,4-dihydroisoquinolin-2-yl)ethoxy]ethyl]carbamate (120 mg, 0.290 mmol, 1 equiv.) in DCM (1 mL) at 0 °C was added trifluoroacetic acid (0.2 mL, 2.6 mmol, 8.94 equiv.). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated to give the title compound (90 mg, 0.290 mmol, 98.98% yield) as a colorless oil. MS (ESI): m / z = 313.0, 315.0 [M+H] + .

[0439] Step 5) 2-[2-(6-bromo-1-oxo-3,4-dihydroisoquinolin-2-yl)ethoxy]ethyl-trimethyl-ammonium formate

[0440] To a mixture of 2-[2-(2-aminoethoxy)ethyl]-6-bromo-3,4-dihydroisoquinolin-1-one (90 mg, 0.290 mmol, 1 equiv.) and potassium carbonate (317.73 mg, 2.3 mmol, 8 equiv.) in acetonitrile (1 mL) was added methyl iodide (244.73 mg, 1.72 mmol, 6 equiv.) at 25° C. The mixture was stirred at 25° C. for 16 h. Water (2 mL) was added, and the mixture was purified by preparative HPLC (FA) and then lyophilized to give the title compound (80 mg, 0.220 mmol, 78.14% yield) as a white solid. MS (ESI, m / z): 355.0, 357.0 [M] + .

[0441] Step 6) Intermediate 18 8-chloro-3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazine

[0442] To a solution of 8-chloro-3-iodo-imidazo[1,2-a]pyrazine (Intermediate 1, 2000 mg, 7.16 mmol, 1 equiv.) in 1,4-dioxane (50 mL) / water (12 mL) was added 2-(2,3-difluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 17, 2512.64 mg, 9.3 mmol, 1.3 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (523.64 mg, 0.720 mmol, 0.1 equiv.), and sodium carbonate (2275.48 mg, 21.47 mmol, 3 equiv.). The mixture was stirred at 70 °C for 18 h. The mixture was then filtered and concentrated. The residue was purified by silica column chromatography (petroleum ether / ethyl acetate = 10:1 to 1:1) to give the title compound (2 g, 6.76 mmol, 94.52% yield) as a pale gray solid. MS (ESI, m / z): 296.0 [M+H] + .

[0443] Step 7) 3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-amine

[0444] To a solution of 8-chloro-3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazine (500 mg, 1.69 mmol, 1 equiv.) in 1,4-dioxane (5 mL) in a sealed tube was added ammonium hydroxide (10 mL). The mixture was stirred at 100° C. for 20 hours. Removal of the solvent afforded the title compound (495 mg, 1.79 mmol, 105.96% yield) as a crude pale yellow solid. MS (ESI, m / z): 277.0 [M+H] + .

[0445] Process 8) 2-[2-[6-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethoxy]ethyl-trimethyl-ammonium formate

[0446] To a mixture of 2-[2-(6-bromo-1-oxo-3,4-dihydroisoquinolin-2-yl)ethoxy]ethyl-trimethyl-ammonium formate (40 mg, 0.110 mmol, 1 equiv.), 3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-amine (31.01 mg, 0.110 mmol, 1 equiv.), and potassium carbonate (46.55 mg, 0.340 mmol, 3 equiv.) in tert-butanol (1 mL) was added Brettphos Pd G3 (9.26 mg, 0.010 mmol, 0.1 equiv.) under N2 at 25 °C. The mixture was stirred in a microwave at 130 °C for 10 h. The reaction mixture was filtered and concentrated. The residue was purified by preparative HPLC (FA) and then lyophilized to give the title compound (10 mg, 0.020 mmol, 14.41% yield) as a white solid. MS (ESI, m / z): 551.1 [M] + .

[0447] Example 45 2-[2-[[2-chloro-4-[[3-[4-(cyanomethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]ethoxy]ethyl-tripropylammonium iodide [ka]

[0448] Process 1) 2-chloro-4-[[3-[4-(cyanomethoxy)-2,3-difluorophenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-N-[2-[2-(dipropylamino)ethoxy]ethyl]benzamide

[0449] A mixture of N-[2-(2-aminoethoxy)ethyl]-N-propyl-propan-1-amine (0.001 mL, 0.490 mmol, 1.5 equiv.), 2-chloro-4-[[3-[4-(cyanomethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoic acid (150.0 mg, 0.330 mmol, 1 equiv., Intermediate 10), N,N-diisopropylethylamine (0.17 mL, 0.990 mmol, 3 equiv.), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (75.7 mg, 0.390 mmol, 1.2 equiv.) in DMF (3 mL) was stirred at 25 °C for 14 h. Water (10 mL) was added to the mixture, and it was extracted with EA (10 mL × 3). The combined organic layers were concentrated to dryness. The crude product was purified by column chromatography (100% to 10% DCM / MeOH) to give the title compound (123 mg, 0.200 mmol, 59.7% yield) as a brown solid.

[0450] MS(ESI): m / z=626.2, 628.2[M+H] + .

[0451] Process 2) 2-[2-[[2-chloro-4-[[3-[4-(cyanomethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]ethoxy]ethyl-tripropylammonium iodide

[0452] A mixture of 2-chloro-4-[[3-[4-(cyanomethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-N-[2-[2-(dipropylamino)ethoxy]ethyl]benzamide (123.0 mg, 0.200 mmol, 1 equiv.), N,N-diisopropylethylamine (0.07 mL, 0.390 mmol, 2 equiv.), and 1-iodopropane (100.19 mg, 0.590 mmol, 3 equiv.) in ethanol (5 mL) was stirred at 100 °C for 48 h. The mixture was concentrated to dryness. The crude product was purified by preparative HPLC. The desired fractions were dried by lyophilization to give the title compound (60.3 mg, 0.080 mmol, 37.7% yield) as a white solid. MS (ESI, m / z): 668.3, 670.2 [M] + .

[0453] Example 46 2-chloro-4-[[3-[4-(cyanomethoxy)-2,3-difluorophenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-N-[2-[2-(1-methylpyrrolidin-1-ium-1-yl)ethoxy]ethyl]benzamidoformate

[0454] 2-[2-(1-methylpyrrolidin-1-ium-1-yl)ethoxy]ethanamine bromide (0.0 mL, 0.440 mmol, 2 equiv.), 2-chloro-4-[[3-[4-(cyanomethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoic acid (Intermediate 10, 100.0 mg, 0.220 mmol) in DMF (3 mL) A mixture of N,N-diisopropylethylamine (0.11 mL, 0.660 mmol, 3 equiv.), 1-hydroxybenzotriazole (35.58 mg, 0.260 mmol, 1.2 equiv.), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (50.47 mg, 0.260 mmol, 1.2 equiv.) was stirred at 25 °C for 14 h. The mixture was purified by preparative HPLC to give the title compound (47.9 mg, 0.070 mmol, 32.87% yield) as a white solid. MS (ESI, m / z): 610.2, 612.1 [M]+ .

[0455] Example 47 3-[[2-chloro-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]propyltrimethylammonium formate [ka]

[0456] Process 1) 2-chloro-4-[[3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoic acid methyl 2,2,2-trifluoroacetate

[0457] A mixture of methyl 4-amino-2-chlorobenzoate (1883 mg, 10.15 mmol, 1 equiv.), 8-chloro-3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazine (Intermediate 18, 3000 mg, 10.15 mmol, 1 equiv.) in toluene (10 mL) and trifluoroacetic acid (2.35 mL, 30.44 mmol, 3 equiv.) was heated to 100° C. for 16 h. The solvent was removed under reduced pressure, and the solid was triturated with MeCN (30 mL) and filtered to afford the title compound (3.5 g, 7.87 mmol, 48.68% yield) as an off-white solid. MS (ESI): m / z = 445.0, 447.0 [M+H] + .

[0458] Process 2) 2-chloro-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoic acid

[0459] To a solution of methyl 2-chloro-4-[[3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoate (3.5 g, 7.87 mmol, 1 equiv.) in methanol (80 mL) was added sodium hydroxide (20 mL, 80 mmol, 10.17 equiv.). The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated in vacuo, diluted with water, and acidified with 2 N HCl. The solid was collected and thoroughly dried to give the title compound (3.15 g, 7.31 mmol, 92.93% yield) as an off-white solid. MS (ESI): m / z = 431.0, 433.0 [M+H] + .

[0460] Process 3) (2,5-Dioxopyrrolidin-1-yl)2-chloro-4-[[3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoate

[0461] To a solution of 2-chloro-4-[[3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoic acid (500 mg, 1.16 mmol, 1 equiv.) in THF (6 mL) / DMF (2 mL) was added N-hydroxysuccinimide (173.65 mg, 1.51 mmol, 1.3 equiv.) and 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride (244.75 mg, 1.28 mmol, 1.1 equiv.). The mixture was stirred at 25°C for 14 hours. The precipitate was filtered and dried in vacuo to give the title compound (530 mg, 1 mmol, 86.51% yield) as a white solid. MS (ESI): m / z = 528.0, 530.0 [M+H] + .

[0462] Step 4) Intermediate 19 3-[[2-chloro-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]propyltrimethylammonium formate

[0463] To a solution of (2,5-dioxopyrrolidin-1-yl)2-chloro-4-[[3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoate (50 mg, 0.090 mmol, 1 equiv.) in THF (1 mL) was added trimethylamine (5.6 mg, 0.090 mmol, 1 equiv.) and 3-bromopropan-1-amine (19.61 mg, 0.140 mmol, 1.5 equiv.). The mixture was stirred at 25° C. for 2 hours, then warmed to 60° C. and stirred for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (FA) to afford the title compound (23 mg, 0.040 mmol, 45.82% yield) as a white solid. MS (ESI, m / z): 529.0, 531.0 [M] + .

[0464] Example 48 3-[[2-chloro-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]propyltriethylammonium formate [ka]

[0465] To a solution of (2,5-dioxopyrrolidin-1-yl)2-chloro-4-[[3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoate (Intermediate 19, 50 mg, 0.090 mmol, 1 equiv.) in DMF (2 mL) was added 3-bromopropan-1-amine (19.61 mg, 0.140 mmol, 1.5 equiv.) and triethylamine (0.04 mL, 0.280 mmol, 3 equiv.). The mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (FA) to give the title compound (20 mg, 0.030 mmol, 35.03% yield) as a white solid. MS (ESI, m / z): 571.0, 573.0 [M] + .

[0466] Example 49 Tributyl-[3-[[2-chloro-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]propyl]ammonium formate [ka]

[0467] Process 1) 3-(Benzyloxycarbonylamino)propyl-tributyl-ammonium formate

[0468] To a solution of N-(3-bromopropyl)carbamate benzyl (300.0 mg, 1.1 mmol, 1 equiv.) in o-xylene (1 mL) was added tributylamine (0.56 mL, 2.2 mmol, 2 equiv.). The mixture was stirred at 120° C. for 4 h. Water was added to the mixture. The aqueous solution was lyophilized, and the residue was purified by preparative HPLC (FA) to give the title compound (150 mg, 0.400 mmol, 36.04% yield) as a colorless oil, which was used without further purification. MS (ESI, m / z): 377 [M] + .

[0469] Process 2) 3-Aminopropyl(tributyl)ammonium formate

[0470] To a solution of 3-(benzyloxycarbonylamino)propyl-tributyl-ammonium formate (150.0 mg, 0.400 mmol, 1 equiv.) in methanol (4 mL) was added Pd / C (20.0 mg, 0.400 mmol, 1 equiv.). The mixture was stirred under a H balloon at 25 °C for 14 h. The mixture was filtered and the organic layer was concentrated to give 3-aminopropyl(tributyl)ammonium formate (50 mg, 0.210 mmol, 51.7% yield) as a pale yellow oil, which was used in the next step without further purification.

[0471] Process 3) Tributyl-[3-[[2-chloro-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]propyl]ammonium formate

[0472] To a solution of (2,5-dioxopyrrolidin-1-yl)2-chloro-4-[[3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoate (Intermediate 19, 65.05 mg, 0.120 mmol, 0.6 equiv.) in THF (3 mL), 3-aminopropyl(tributyl)ammonium formate (50 mg, 0.210 mmol, 1 equiv.) and N,N-diisopropylethylamine (0.04 mL, 0.210 mmol, 1 equiv.) were added. The mixture was stirred at 60 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (FA) to give the title compound (11 mg, 0.020 mmol, 7.62% yield) as a white solid. MS (ESI, m / z): 655.0 [M] + .

[0473] Example 50 Carboxymethyl-[2-[2-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]ethoxy]ethyl]-dimethyl-ammonium formate [ka]

[0474] Process 1) (2,5-dioxopyrrolidin-1-yl)4-[[3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoate

[0475] Using Intermediate 8, the title compound (1.8 g, 3.45 mmol, 73.25% yield) was obtained as a pale yellow solid in a similar manner to Example 47, Step 3. MS (ESI, m / z): 522.0 [M+H] + .

[0476] Step 2) Intermediate 20 N-[2-(2-aminoethoxy)ethyl]-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethylbenzamide

[0477] To a solution of (2,5-dioxopyrrolidin-1-yl) 4-[[3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoate (1100 mg, 2.11 mmol, 1 equiv.) in THF (20 mL) was added triethylamine (0.44 mL, 3.16 mmol, 1.5 equiv.) and 1,5-diamino-3-oxapentane (329 mg, 3.16 mmol, 1.5 equiv.). The mixture was stirred at 25 °C for 3 h. The solvent was removed. The solid was triturated with water and filtered to give the title compound (912 mg, 1.79 mmol, 84.68% yield) as an off-white solid. MS (ESI, m / z): 511.0 [M+H] + .

[0478] Process 3) 2-[2-[2-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]ethoxy]ethylamino]acetate

[0479] To a solution of N-[2-(2-aminoethoxy)ethyl]-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethylbenzamide (500 mg, 0.980 mmol, 1 equiv.) in DMF (5 mL) was added triethylamine (0.2 mL, 1.47 mmol, 1.5 equiv.) and methyl chloroacetate (138 mg, 1.27 mmol, 1.3 equiv.). The mixture was stirred at 25 °C for 4 h. Water was added to the mixture, and the pH of the mixture was adjusted to approximately 4 with 1 M HCl. The mixture was extracted with EtOAc (5 mL × 3). The pH of the aqueous solution was adjusted to around 8. The resulting suspension was filtered, and the solid was dried to give the title compound (370 mg, 0.640 mmol, 65% yield) as a yellow solid. MS (ESI, m / z): 583.0 [M + H] + .

[0480] Step 4) Intermediate 21 2-[2-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]ethoxy]ethyl-(2-methoxy-2-oxo-ethyl)-dimethylammonium

[0481] To a solution of methyl 2-[2-[2-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]ethoxy]ethylamino]acetate (100 mg, 0.170 mmol, 1 equiv.) in DMF (2 mL) was added iodomethane (146.18 mg, 1.03 mmol, 6 equiv.). The mixture was stirred at 25 °C for 26 h. To improve purification in the next step, BocO was added and stirred for an additional 1 h. Removal of the solvent afforded the title compound (120 mg, 0.200 mmol, quantitative yield) as a yellow gum, which was used without further purification. MS (ESI, m / z): 611.0 [M+H] + .

[0482] Step 5) Carboxymethyl-[2-[2-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]ethoxy]ethyl]-dimethyl-ammonium formate

[0483] To a solution of 2-[2-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]ethoxy]ethyl-(2-methoxy-2-oxo-ethyl)-dimethyl-ammonium (110 mg, 0.180 mmol, 1 equiv.) in methanol (1 mL) was added sodium hydroxide (1 mL, 4 mmol, 22.24 equiv.). The mixture was stirred at 25 °C for 2 h. The pH was adjusted to approximately 6 with 1 M HCl. The solvent was removed, and the residue was purified by preparative HPLC (FA) to give the title compound (20 mg, 0.030 mmol, 17.13% yield) as a white solid. MS (ESI, m / z): 597.0 [M] + .

[0484] Example 51 2-[2-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]ethoxy]ethyl-(2-hydroxyethyl)-dimethyl-ammonium formate [ka]

[0485] To a solution of lithium chloride (19 mg, 0.460 mmol, 4 equiv.) in THF / EtOH (1:1) (2 mL) was added sodium borohydride (17 mg, 0.460 mmol, 4 equiv.). The mixture was stirred for 10 minutes. Then, 2-[2-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]ethoxy]ethyl-(2-methoxy-2-oxo-ethyl)-dimethylammonium (Intermediate 21, 70 mg, 0.110 mmol, 1 equiv.) in THF (0.5 mL) was slowly added. The mixture was stirred for 2 hours. The mixture was quenched with 1N HCl. The mixture was purified by preparative HPLC (FA) to give the title compound (18 mg, 0.030 mmol, 25.02% yield) as a white solid. MS (ESI, m / z): 583.0 [M+H] + .

[0486] Example 15 2-[2-[[4-[[3-(2,3-difluoro-4-prop-2-ynoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]ethoxy]ethyl-trimethyl-ammonium 2,2,2-trifluoroacetate [ka]

[0487] Process 1) 2,3-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

[0488] A mixture of 4-bromo-2,3-difluorophenol (6.5 g, 31.1 mmol, 1 equiv.), bis(pinacolato)diboron (7.9 g, 31.1 mmol, 1 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.28 g, 3.11 mmol, 0.1 equiv.), and potassium acetate (5.83 mL, 93.31 mmol, 3 equiv.) in 1,4-dioxane (500 mL) was stirred under N at 70° C. for 2 h. The mixture was filtered and purified on a silica column eluted with 10% DCM in petroleum ether to give the title compound (3 g, 11.72 mmol, 37.67% yield) as a colorless oil.

[0489] Process 2) 4-(8-chloroimidazo[1,2-a]pyrazin-3-yl)-2,3-difluorophenol

[0490] To a solution of 8-chloro-3-iodo-imidazo[1,2-a]pyrazine (Intermediate 1, 546 mg, 1.95 mmol, 1 equiv.) and 2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (500 mg, 1.95 mmol, 1 equiv.) in 1,4-dioxane (5 mL) and water (0.5 mL) was added 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (71 mg, 0.100 mmol, 0.05 equiv.) and sodium carbonate (621 mg, 5.86 mmol, 3 equiv.) at 20 °C. The mixture was stirred at 60 °C for 16 h. The mixture was filtered and concentrated under reduced pressure to give the title compound (600 mg, 2.13 mmol, 94.37% yield) as a brown solid. MS (ESI, m / z): 282.1 [M + H] + .

[0491] Process 3) 8-chloro-3-(2,3-difluoro-4-prop-2-ynoxy-phenyl)imidazo[1,2-a]pyrazine

[0492] To a solution of 4-(8-chloroimidazo[1,2-a]pyrazin-3-yl)-2,3-difluorophenol (500 mg, 1.78 mmol, 1 equiv.) and propargyl bromide (211 mg, 1.78 mmol, 1 equiv.) in DMF (5 mL) was added potassium carbonate (245 mg, 1.78 mmol, 1 equiv.) at 20° C. The reaction mixture was stirred at 20° C. for 16 hours. The reaction was concentrated and purified by gel silica to give the title compound (200 mg, 0.630 mmol, 35.24% yield) as a white solid. MS (ESI, m / z): 320.0 [M+H] + .

[0493] Step 4) Methyl 4-nitro-2-vinylbenzoate

[0494] A solution of methyl 2-bromo-4-nitrobenzoate (15 g, 57.68 mmol, 1 equiv.), vinylboronic acid pinacol ester (13.33 g, 86.53 mmol, 1.5 equiv.), phosphoric acid, tripotassium salt (36.73 g, 173.05 mmol, 3 equiv.), and 1,1′-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (3.76 g, 5.77 mmol, 0.100 equiv.) in toluene (150 mL) and water (5 mL) was heated to 100° C. under nitrogen for 15 h. The reaction mixture was concentrated, and the residue was purified by conventional silica gel chromatography eluting with petroleum ether / EtOAc (50:1) to give the title compound (6.2 g, 29.93 mmol, 51.88% yield) as a pale yellow solid.

[0495] Step 5) Intermediate 22 4-Nitro-2-vinyl-benzoic acid

[0496] To a solution of methyl 4-nitro-2-vinylbenzoate (2 g, 9.65 mmol, 1 equiv.) in THF (25 mL) and water (5 mL) was added lithium hydroxide. HO (0.81 g, 19.31 mmol, 2 equiv.). The resulting mixture was stirred at 20 °C for 15 h. Most of the solvent was removed, and the mixture was extracted with MTBE (20 mL). The aqueous layer was neutralized with 3 N HCl, extracted with DCM (75 mL × 2), dried over sodium sulfate, and concentrated to give the title compound (1.68 g, 8.7 mmol, 90.1% yield) as a yellow solid.

[0497] Process 6) tert-Butyl N-[2-[2-[(4-nitro-2-vinyl-benzoyl)amino]ethoxy]ethyl]carbamate

[0498] A solution of N-Boc-2-(2-amino-ethoxy)-ethylamine (1.06 g, 5.18 mmol, 1 equiv.), 4-nitro-2-vinyl-benzoic acid (1 g, 5.18 mmol, 1 equiv.), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2362 mg, 6.21 mmol, 1.2 equiv.) in DMF (15 mL) was stirred at 20 °C for 3 h. The solvent was removed, and the residue was treated with water. The mixture was extracted with EtOAc (75 mL × 2). The organic layer was washed with brine (75 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (1.95 g, 5.14 mmol, 99.28% yield) as a yellow oil. MS (ESI, m / z): 402.3 [M+Na] + .

[0499] Step 7) tert-Butyl N-[2-[2-[(4-amino-2-ethyl-benzoyl)amino]ethoxy]ethyl]carbamate

[0500] To a solution of tert-butyl N-[2-[2-[(4-nitro-2-vinyl-benzoyl)amino]ethoxy]ethyl]carbamate (1.95 g, 5.14 mmol, 1 equiv.) in methanol (20 mL) was added 10% Pd / C:water 1:1 (547 mg, 0.510 mmol, 0.1 equiv.), and the mixture was stirred under a hydrogen atmosphere (2280 mmHg) at 30°C for 16 h. The solvent was removed in vacuo to give the title compound (2.38 g, 6.77 mmol, 99.48% yield) as a pale yellow oil. MS (ESI, m / z): 374.1 [M+Na] + .

[0501] Process 8) tert-Butyl N-[2-[2-[[4-[[3-(2,3-difluoro-4-prop-2-ynoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]ethoxy]ethyl]carbamate

[0502] A mixture of 8-chloro-3-(2,3-difluoro-4-prop-2-ynoxyphenyl)imidazo[1,2-a]pyrazine (150 mg, 0.470 mmol, 1 equiv.) and tert-butyl N-[2-[2-[(4-amino-2-ethyl-benzoyl)amino]ethoxy]ethyl]carbamate (198 mg, 0.560 mmol, 1.2 equiv.) in ACN (4.5 mL) and acetic acid (0.5 mL) was heated to 80° C. for 15 hours. The mixture was purified by flash column chromatography to give the title compound (170 mg, 0.270 mmol, 57.09% yield) as a white solid. MS (ESI, m / z): 635.5 [M+H] + .

[0503] Process 9) N-[2-(2-aminoethoxy)ethyl]-4-[[3-(2,3-difluoro-4-prop-2-ynoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide

[0504] To a solution of tert-butyl N-[2-[2-[[4-[[3-(2,3-difluoro-4-prop-2-ynoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]ethoxy]ethyl]carbamate (150 mg, 0.240 mmol, 1 equiv.) in methanol (5 mL) was added hydrogen chloride (6.25 mL, 25 mmol, 105.78 equiv.) in MeOH. The resulting mixture was stirred at 25°C for 4 hours. The residue was purified by preparative HPLC (FA) to give the title compound (92 mg, 0.170 mmol, 72.38% yield) as a white solid. MS (ESI, m / z): 535.5 [M+H] + .

[0505] Step 10) 2-[2-[[4-[[3-(2,3-difluoro-4-prop-2-ynoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]ethoxy]ethyl-trimethyl-ammonium 2,2,2-trifluoroacetate

[0506] To a solution of N-[2-(2-aminoethoxy)ethyl]-4-[[3-(2,3-difluoro-4-prop-2-ynoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide (70 mg, 0.130 mmol, 1 equiv.) in DMF (3 mL) was added iodomethane (372 mg, 2.62 mmol, 20 equiv.). The resulting mixture was stirred at 25° C. for 48 hours. The mixture was concentrated under reduced pressure and purified by preparative HPLC (TFA) to give the title compound (11.9 mg, 0.020 mmol, 12.84% yield) as a colorless oil. MS (ESI, m / z): 577.1 [M+H] + .

[0507] Example 52 (2-amino-2-oxo-ethyl)-[2-[2-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]ethoxy]ethyl]-dimethyl-ammonium formate [ka]

[0508] Process 1) 4-[[3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-N-[2-[2-(dimethylamino)ethoxy]ethyl]-2-ethyl-benzamide

[0509] To a solution of N-[2-(2-aminoethoxy)ethyl]-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethylbenzamide (Intermediate 20, 100 mg, 0.200 mmol, 1 equiv.) in methanol (5 mL) was added aqueous formaldehyde (5 mL, 0.200 mmol, 1 equiv.) and sodium cyanoborohydride (25 mg, 0.390 mmol, 2 equiv.). The resulting mixture was stirred at 15 °C for 15 hours. The mixture was concentrated, and the residue was purified by flash column chromatography to give the title compound (80 mg, 0.150 mmol, 75.83% yield) as a white solid. MS (ESI, m / z): 539.4 [M+H] + .

[0510] Process 2) (2-amino-2-oxo-ethyl)-[2-[2-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-phenyl]methylamino]ethoxy]ethyl]-dimethyl-ammonium formate

[0511] To a solution of 4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-N-[2-[2-(dimethylamino)ethoxy]ethyl]-2-ethylbenzamide (20 mg, 0.040 mmol, 1 equiv.) in DMF (2 mL) was added 2-chloroacetamide (35 mg, 0.370 mmol, 10 equiv.). The resulting mixture was stirred at 20 °C for 15 h. The mixture was concentrated, and the residue was purified by preparative HPLC (FA) to give the title compound (9.9 mg, 0.020 mmol, 41.07% yield) as a white solid. MS (ESI, m / z): 596.4 [M+H] + .

[0512] Example 53 3-Carboxypropyl-[2-[2-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]ethoxy]ethyl]-dimethyl-ammonium formate [ka]

[0513] Process 1) 2-[2-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-phenyl]methylamino]ethoxy]ethyl-(4-methoxy-4-oxo-butyl)-dimethylammonium bromide

[0514] To a solution of 4-[[3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-N-[2-[2-(dimethylamino)ethoxy]ethyl]-2-ethyl-benzamide (Intermediate 23, 60 mg, 0.110 mmol, 1 equiv.) in DMF (2 mL) was added methyl 4-bromobutyrate (101 mg, 0.560 mmol, 5 equiv.). The resulting mixture was stirred at 10°C for 15 hours. The mixture was concentrated, and the residue was purified by preparative HPLC (FA) to give the title compound (30 mg, 0.040 mmol, 38.16% yield) as a white solid. MS (ESI, m / z): 639.4 [M+H] + .

[0515] Process 2) 3-Carboxypropyl-[2-[2-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]ethoxy]ethyl]-dimethyl-ammonium formate

[0516] To a solution of 2-[2-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]ethoxy]ethyl-(4-methoxy-4-oxo-butyl)-dimethylammonium bromide (30 mg, 0.050 mmol, 1 equiv.) in methanol (2 mL) and water (1 mL) was added lithium hydroxide monohydrate (9.85 mg, 0.230 mmol, 5 equiv.). The resulting mixture was stirred at 10°C for 15 hours. The mixture was acidified to pH = 3 with 1N aqueous HCl and then purified by preparative HPLC (FA) to give the title compound (10.3 mg, 0.020 mmol, 31.83% yield) as a white solid. MS (ESI, m / z): 625.4 [M+H] + .

[0517] Example 54 2-(4-(2-chloro-4-((3-(4-(cyanomethoxy)-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoyl)piperazin-1-yl)-N,N,N-trimethyl-2-oxoethan-1-aminium formate [ka]

[0518] Process 1) 2-(4-(8-((3-chloro-4-(4-(dimethylglycyl)piperazine-1-carbonyl)phenyl)amino)imidazo[1,2-a]pyrazin-3-yl)-2,3-difluorophenoxy)acetonitrile

[0519] 2-Chloro-4-((3-(4-(cyanomethoxy)-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoic acid hydrochloride (Intermediate 10, 75 mg, 152 μmol, 1 equiv.) was combined with DMF (1.3 ml). HATU (116 mg, 305 μmol, 2 equiv.) and DIPEA (98.5 mg, 133 μl, 762 μmol, 5.00 equiv.) were added and stirred for 15 minutes. After stirring, 2-(dimethylamino)-1-(piperazin-1-yl)ethan-1-one (39.1 mg, 229 μmol, 1.5 equiv.) was added and the reaction mixture was stirred at room temperature for 1 hour. The crude material was purified by flash chromatography (reverse phase, 12 g, 0% to 100% water:ACN) to give the title compound (43.3 mg, 71 μmol, 46.7% yield) as a light brown solid. MS (ESI, m / z): 610.0 [M+H] + .

[0520] Process 2) 2-(4-(2-chloro-4-((3-(4-(cyanomethoxy)-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoyl)piperazin-1-yl)-N,N,N-trimethyl-2-oxoethan-1-aminium formate

[0521] 2-(4-(8-((3-chloro-4-(4-(dimethylglycyl)piperazine-1-carbonyl)phenyl)amino)imidazo[1,2-a]pyrazin-3-yl)-2,3-difluorophenoxy)acetonitrile (43.3 mg, 71.1 μmol, 1 equiv.) was dissolved in 1,4-dioxane (250 μl) and DIPEA (46.2 mg, 62.5 μl, 358 μmol, 5.03 equiv.) was added. The mixture was stirred at room temperature for 15 minutes, and iodomethane (50.5 mg, 22.1 μl, 355 μmol, 5 equiv.) was added. The reaction mixture was stirred at room temperature overnight. The crude material was purified by preparative HPLC and then lyophilized to afford the title compound (23.5 mg, 35 μmol, 52.3% yield) as a white lyophilized solid. MS (ESI, m / z): 624.5 [M + H] + .

[0522] Example 12 2-(4-(2-chloro-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoyl)piperazin-1-yl)-N,N,N-trimethyl-2-oxoethan-1-aminium iodide [ka]

[0523] Process 1) Benzyl 4-(N-(tert-butoxycarbonyl)-N-methylglycyl)piperazine-1-carboxylate

[0524] In a 25 mL round-bottom flask, N-(tert-butoxycarbonyl)-N-methylglycine (1 g, 5.29 mmol, 1 equiv.) was combined with DMF (10 mL). DIPEA (1.37 g, 1.85 mL, 10.6 mmol, 2.00 equiv.) and HATU (3.01 g, 7.93 mmol, 1.50 equiv.) were added and stirred for 15 min. After that, benzylpiperazine-1-carboxylate (1.75 g, 7.93 mmol, 1.50 equiv.) was added. The reaction mixture was stirred at room temperature for 20 h. HO was added to the reaction mixture, which was then extracted twice with DCM. The crude product was purified by flash chromatography (silica gel, 80 g, 60% to 100% EtOAc in heptane) to give the title compound (1.54 g, 3.93 mmol, 52.1% yield) as a yellow liquid. MS (ESI, m / z): 292.3 [M + H-Boc] + .

[0525] Step 2) Intermediate 24 tert-Butyl methyl (2-oxo-2-(piperazin-1-yl)ethyl)carbamate

[0526] Benzyl 4-(N-(tert-butoxycarbonyl)-N-methylglycyl)piperazine-1-carboxylate (1.54 g, 3.93 mmol, 1 equiv.) was combined with MeOH (15 ml). 10% Pd / C (41.9 mg, 393 μmol, 0.01 equiv.) was added and the reaction mixture was stirred under H for 4 h. The reaction mixture was placed under Ar and filtered through dicalite. After removal of volatiles, the resulting oil was dried under high vacuum to give the title compound (1.42 g, 5.5 mmol, 98.4% yield) as a pale gray viscous oil. MS (ESI, m / z): 258.4 [M+H] + .

[0527] Step 3) Intermediate 5 2-chloro-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoic acid

[0528] 8-Chloro-3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazine (Intermediate 18, 330 mg, 1.12 mmol, 1 equiv.) was combined with acetonitrile (8 ml) and AcOH (800 μl). 4-Amino-2-chlorobenzoic acid (287 mg, 1.67 mmol, 1.5 equiv.) was added, and the reaction mixture was stirred at 90° C. for 1 week. After cooling to room temperature, the ACN and AcOH were removed under vacuum. The product was then precipitated in HCl (1 M). The solid was filtered, washed with HCl, and dried under vacuum to give the title compound (470.5 mg, 1.09 mmol, 93% yield) as a light brown solid. MS (ESI, m / z): 431.1 [M+H] + .

[0529] Step 4) tert-Butyl (2-(4-(2-chloro-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoyl)piperazin-1-yl)-2-oxoethyl)(methyl)carbamate

[0530] 2-Chloro-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoic acid (50 mg, 92.9 μmol, 1 equiv.) was combined with DMF (1.3 ml). HATU (70.6 mg, 186 μmol, 2 equiv.) and DIPEA (36 mg, 48.7 μl, 279 μmol, 3.00 equiv.) were added and stirred for 15 minutes. After that, tert-butyl methyl (2-oxo-2-(piperazin-1-yl)ethyl)carbamate (35.8 mg, 139 μmol, 1.50 equiv.) was added and the reaction mixture was stirred at room temperature for 6 hours. The crude material was purified by preparative HPLC to give the title compound (42.9 mg, 64 μmol, 68.9% yield) as a pale yellow waxy solid. MS (ESI, m / z): 671.3 [M + H] + .

[0531] Step 5) 1-(4-(2-chloro-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoyl)piperazin-1-yl)-2-(methylamino)ethan-1-one hydrochloride

[0532] tert-Butyl (2-(4-(2-chloro-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoyl)piperazin-1-yl)-2-oxoethyl)(methyl)carbamate (42.9 mg, 64 μmol, 1 equiv.) was combined with 4 M HCl in dioxane (160 μl, 640 μmol, 10 equiv.). The reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was dried under high vacuum to give the title compound (36.7 mg, 60.5 μmol, 94.5% yield) as a white solid. MS (ESI, m / z): 571.4 [M+H] + .

[0533] Process 6) 2-(4-(2-chloro-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoyl)piperazin-1-yl)-N,N,N-trimethyl-2-oxoethan-1-aminium iodide

[0534] 1-(4-(2-chloro-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoyl)piperazin-1-yl)-2-(methylamino)ethan-1-one hydrochloride (36.7 mg, 60.5 μmol, 1 equiv.) was dissolved in 1,4-dioxane (386 μl) and DIPEA (39.3 mg, 53.2 μl, 304 μmol, 5.03 equiv.) was added. The reaction mixture was stirred at room temperature for 15 minutes, and iodomethane (85.9 mg, 37.7 μl, 605 μmol, 10 equiv.) was added. The reaction mixture was stirred at room temperature overnight. The crude material was purified by preparative HPLC, and the product was lyophilized to afford the title compound (27.6 mg, 46 μmol, 64.7% yield) as a white solid. MS (ESI, m / z): 600.5 [M + H]+ .

[0535] Example 55 (2S,4R)-2-(4-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperazine-1-carbonyl)-4-hydroxy-1,1-dimethylpyrrolidin-1-ium formate [ka]

[0536] Step 1) Intermediate 25 Methyl 4-((3-iodoimidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoate hydrochloride

[0537] 8-Chloro-3-iodoimidazo[1,2-a]pyrazine (Intermediate 1, 18.18 g, 61.8 mmol, 1 equiv.) was suspended in acetonitrile (90 mL) and acetic acid (9 mL) was added. While stirring, methyl 4-amino-2-methylbenzoate (12.3 g, 74.2 mmol, 1.2 equiv.) was carefully added, and the reaction mixture was heated to 90 °C and stirred overnight. The reaction mixture was cooled to room temperature using an ice bath. The light brown suspension was filtered, washed with 75 mL of cold ACN / MeOH (1:1), and dried under high vacuum overnight to give the title compound (26.23 g, 59 mmol, 95.5% yield) as a white solid. MS (ESI, m / z): 409.1 [M+H] + .

[0538] Process 2) Methyl 4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoate

[0539] Methyl 4-((3-iodoimidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoate hydrochloride (5 g, 11.2 mmol, 1 equiv.) and (2,3-difluoro-4-methoxyphenyl)boronic acid (2.22 g, 11.8 mmol, 1.05 equiv.) were combined with dioxane (75 ml). NaCO (2.62 g, 24.7 mmol, 2.2 equiv.) was dissolved in water (7.5 ml) and added to the reaction mixture with stirring. Argon was sparged through the reaction, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (138 mg, 169 μmol, 0.015 equiv.) was added. The reaction mixture was heated to 110 °C and stirred overnight. The suspension was filtered, the filter cake was washed with EtOAc, and the solvent of the resulting solution was evaporated. The crude material was purified by flash chromatography (silica gel, 330 g, 0% to 50% DCM / MeOH / NH3 (95:5:1)) to give the title compound (4.39 g, 9.72 mmol, 86.5% yield) as an off-white solid. MS (ESI, m / z): 425.2 [M+H] + .

[0540] Step 3) Intermediate 6 4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoic acid

[0541] Methyl 4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoate (4.39 g, 9.72 mmol, 1 equiv.) was combined with EtOH (20 mL) and water (10 mL). LiOH solution (1 M in water) (19.4 ml, 19.4 mmol, 2 equiv.) was added at room temperature. The reaction mixture was heated to 90° C. and stirred for 24 hours. The organic solvent was evaporated and aqueous HCl (25%) was added until pH=0. A precipitate appeared and was isolated by filtration. The filter cake was washed with EtOAc and thoroughly dried under high vacuum to give the title compound (4.12 g, 10 mmol, quantitative yield) as a yellow powder. MS (ESI, m / z): 411.1 [M+H]+ .

[0542] Step 4) tert-Butyl 4-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperazine-1-carboxylate

[0543] 4-((3-(2,3-Difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoic acid (4.12 g, 10 mmol, 1 equiv.) was combined with DMF (40 ml). 1-Boc-piperazine (2.8 g, 15.1 mmol, 1.5 equiv.) and HATU (7.63 g, 20.1 mmol, 2.0 equiv.) were added. The reaction mixture was stirred at room temperature, followed by the addition of DIPEA (6.49 g, 8.77 ml, 50.2 mmol, 5 equiv.). Stirring was continued overnight at room temperature. The reaction mixture was poured into 100 mL of water (basified with 1 M NaOH), which was extracted with 150 mL of EtOAc. The organic layer was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 120 g, 40% heptane / EtOAc (isocratic) followed by 0% to 50% DCM / MeOH / NH3 (95:5:1)) to give the title compound (6.066 g, 10.2 mmol, 101% yield) as a light brown solid. MS (ESI, m / z): 579.3 [M+H] + .

[0544] Step 5) (4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylphenyl)(piperazin-1-yl)methanone hydrochloride

[0545] tert-Butyl 4-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperazine-1-carboxylate (6.066 g, 10.2 mmol, 1 equiv.) was combined with dioxane (80 ml) and MeOH (15 ml). Hydrogen chloride solution (4 M in dioxane) (12.7 ml, 50.8 mmol, 5 equiv.) was added slowly. Stirring at room temperature was continued overnight. Addition of diethyl ether (60 mL) followed by sonication gave a precipitate which was filtered. The filter cake was washed with diethyl ether and dried in vacuo and high vacuum to give the title compound (4.978 g, 9.67 mmol, 95.1% yield) as a white solid. MS (ESI, m / z): 479.2 [M+H] + .

[0546] Process 6) tert-Butyl (2S,4R)-2-(4-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperazine-1-carbonyl)-4-hydroxypyrrolidine-1-carboxylate

[0547] (4-((3-(2,3-Difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylphenyl)(piperazin-1-yl)methanone hydrochloride (2.135 g, 4.02 mmol, 1 equiv.) was combined with DMF (30 ml). (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.39 g, 6.03 mmol, 1.5 equiv.) and HATU (3.06 g, 8.04 mmol, 2.0 equiv.) were added. DIPEA (1.61 g, 2.17 ml, 12.1 mmol, 3.0 equiv.) was added and the reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched with 10 mL of EtOAc, 10 mL of water, and 10 mL of NaOH (1 M). The solution was poured into 250 mL of water and 250 mL of EtOAc and extracted. The organic layer was dried over MgSO, filtered, and evaporated. The crude material was purified by flash chromatography (silica gel, 120 g, 0% to 100% DCM:(DCM / MeOH / NH (95:5:1))) to give the title compound (1.68 g, 2.43 mmol, 60.4% yield) as an off-white foam. MS (ESI, m / z): 692.43 [M+H] + .

[0548] Step 7) (4-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperazin-1-yl)((2S,4R)-4-hydroxypyrrolidin-2-yl)methanone hydrochloride

[0549] tert-Butyl (2S,4R)-2-(4-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperazine-1-carbonyl)-4-hydroxypyrrolidine-1-carboxylate (1.68 g, 2.43 mmol, 1 equiv.) was combined with dioxane. The mixture was stirred at room temperature and hydrogen chloride solution (4 M in dioxane) (3.04 ml, 12.1 mmol, 5 equiv.) was added very slowly. The reaction mixture was stirred at room temperature overnight. Addition of ether and sonication gave a suspension which was filtered. The resulting filter cake was dried under high vacuum at 50° C. to give the title compound (1.606 g, 2.56 mmol, 105% yield) as a pale yellow / off-white solid. MS (ESI, m / z): 590.5 [MH] - .

[0550] Process 8) (2S,4R)-2-(4-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperazine-1-carbonyl)-4-hydroxy-1,1-dimethylpyrrolidin-1-ium formate

[0551] To a white suspension of (4-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperazin-1-yl)((2S,4R)-4-hydroxypyrrolidin-2-yl)methanone hydrochloride (40 mg, 63.7 μmol, 1 equiv.) in DCM (637 μL) was added iodomethane (22.6 mg, 9.96 μL, 159 μmol, 2.5 equiv.) and Hunig's base (8.23 mg, 11.1 μL, 63.7 μmol, 1 equiv.). The reaction mixture was stirred overnight at room temperature and then purified by preparative HPLC to give the title compound (30 mg, 45 μmol, 67.2% yield) as an amorphous white solid. MS (ESI, m / z): 620.3 [M+H] + .

[0552] Example 56 [2-[4-[4-[[3-[4-(cyanomethoxy)-2,3-difluorophenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methylbenzoyl]piperazin-1-yl]-2-oxoethyl]trimethylazanium iodide [ka]

[0553] Process 1) 4-((3-(4-(cyanomethoxy)-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoic acid 2-(4-(8-chloroimidazo[1,2-a]pyrazin-3-yl)-2,3-difluorophenoxy)acetonitrile (intermediate

[0554] 11 (750 mg, 2.34 mmol, 1 equiv.) was combined with acetonitrile (7.5 ml) and AcOH (750 μl). 4-Amino-2-methylbenzoic acid (371 mg, 2.46 mmol, 1.05 equiv.) was added, and the reaction mixture was stirred at 60° C. over the weekend and then at 80° C. for 7 hours. After cooling to room temperature, acetonitrile and a small amount of MeOH were added to the suspension, and the solid was filtered and dried under high vacuum to give the title compound (896.6 mg, 2 mmol, 63.4% yield) as a light brown solid. MS (ESI, m / z): 436.1 [M+H] + .

[0555] Process 2) tert-Butyl (2-(4-(4-((3-(4-(cyanomethoxy)-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperazin-1-yl)-2-oxoethyl)(methyl)carbamate

[0556] 4-((3-(4-(cyanomethoxy)-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoic acid (50 mg, 115 μmol, 1 equiv.) was combined with DMF (1.3 ml). HATU (87.3 mg, 230 μmol, 2 equiv.) and DIPEA (44.5 mg, 60.2 μl, 345 μmol, 3.00 equiv.) were added and stirred for 15 minutes. After that, tert-butylmethyl(2-oxo-2-(piperazin-1-yl)ethyl)carbamate (Intermediate 24, 44.3 mg, 172 μmol, 1.50 equiv.) was added and the reaction mixture was stirred at room temperature overnight. The crude material was purified by preparative HPLC to give the title compound (40.2 mg, 59.5 μmol, 51.9% yield) as a white solid. MS (ESI, m / z): 675.3 [M + H] + .

[0557] Process 3) 2-(2,3-difluoro-4-(8-((3-methyl-4-(4-(methylglycyl)piperazine-1-carbonyl)phenyl)amino)imidazo[1,2-a]pyrazin-3-yl)phenoxy)acetonitrile

[0558] tert-Butyl (2-(4-(4-((3-(4-(cyanomethoxy)-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperazin-1-yl)-2-oxoethyl)(methyl)carbamate (40.2 mg, 59.6 μmol, 1 equiv.) was combined with THF (315 μL). 3.4 M HCl (87.6 μL, 298 μmol, 5 equiv.) was added, and the reaction mixture was stirred at room temperature for 1 h. Additional 3.4 M HCl (87.6 μL, 298 μmol, 5 equiv.) was added, and the reaction mixture was stirred at room temperature overnight. The resulting mixture was poured into water and then adjusted to pH = 10-11 with ammonia solution. The aqueous solution was extracted with DCM and isopropanol (6:1), and after evaporation of the volatiles, the crude material was purified by preparative HPLC to give the title compound (24.6 mg, 42.8 μmol, 71.9% yield) as an off-white solid. MS (ESI, m / z): 575.3 [M+H] + .

[0559] Step 4) [2-[4-[4-[[3-[4-(cyanomethoxy)-2,3-difluorophenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methylbenzoyl]piperazin-1-yl]-2-oxoethyl]trimethylazanium iodide

[0560] 2-(2,3-Difluoro-4-(8-((3-methyl-4-(4-(methylglycyl)piperazine-1-carbonyl)phenyl)amino)imidazo[1,2-a]pyrazin-3-yl)phenoxy)acetonitrile (20 mg, 34.8 μmol, 1 equiv.) was dissolved in 1,4-dioxane (250 μl) and DIPEA (22.6 mg, 30.6 μl, 175 μmol, 5.03 equiv.) was added. The mixture was stirred at room temperature for 15 minutes, and iodomethane (24.7 mg, 10.8 μl, 174 μmol, 5 equiv.) was added. The reaction mixture was stirred at room temperature overnight. The crude material was purified by preparative HPLC, and the product was lyophilized to afford the title compound (11.7 mg, 18 μmol, 51.8% yield) as a white solid. MS (ESI, m / z): 604.2 [M + H] + .

[0561] Example 57 4-[4-[2-[[4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methylbenzoyl]-methylamino]ethyl]-1-methylpiperidin-1-ium-1-yl]butanoic acid hydrochloride [ka]

[0562] Process 1) tert-Butyl 4-(4-(2-(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N,2-dimethylbenzamido)ethyl)piperidin-1-yl)butanoate

[0563] 4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N,2-dimethyl-N-(2-(piperidin-4-yl)ethyl)benzamide hydrochloride (Intermediate 3, 113 mg, 198 μmol, 1 equiv.) was combined with n-BuOH (3 mL). tert-Butyl 4-bromobutanoate (66.2 mg, 297 μmol, 1.5 equiv.), NaCO (83.9 mg, 791 μmol, 4 equiv.), and KI (3.28 mg, 19.8 μmol, 0.1 equiv.) were added, and the reaction mixture was stirred at 105° C. overnight. The reaction mixture was poured into 5 mL of HO and extracted with EtOAc (2×5 mL). The organic layer was concentrated in vacuo. The crude material was purified by preparative HPLC to give the title compound (55.9 mg, 82.5 μmol, 41.7% yield) as a pale yellow solid. MS (ESI, m / z): 677.6 [M+H] + .

[0564] Process 2) 1-(4-(tert-butoxy)-4-oxobutyl)-4-(2-(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N,2-dimethylbenzamido)ethyl)-1-methylpiperidin-1-ium formate

[0565] tert-Butyl 4-(4-(2-(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N,2-dimethylbenzamido)ethyl)piperidin-1-yl)butanoate (55.9 mg, 82.6 μmol, 1 equiv.) was dissolved in 1,4-dioxane (250 μl) and DIPEA (53.7 mg, 72.6 μl, 415 μmol, 5.03 equiv.) was added. The mixture was stirred at room temperature for 15 minutes, and iodomethane (58.6 mg, 25.7 μl, 413 μmol, 5 equiv.) was added. The reaction mixture was stirred at room temperature overnight. The crude material was purified by preparative HPLC to afford the title compound (30.4 mg, 41.2 μmol, 50% yield) as an off-white waxy solid. MS (ESI, m / z): 692.4 [M + H] + .

[0566] Process 3) 4-[4-[2-[[4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methylbenzoyl]-methylamino]ethyl]-1-methylpiperidin-1-ium-1-yl]butanoic acid hydrochloride

[0567] 1-(4-(tert-butoxy)-4-oxobutyl)-4-(2-(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N,2-dimethylbenzamido)ethyl)-1-methylpiperidin-1-ium formate (30.4 mg, 41.3 μmol, 1 equiv.) was dissolved in dioxane (100 μL), and then 4 M HCl in dioxane (206 μL, 826 μmol, 20 equiv.) was added. The reaction mixture was stirred at room temperature over the weekend. The volatiles were removed and the product was lyophilized to give the title compound (21.8 mg, 32.4 μmol, 77% yield) as a yellow solid. MS (ESI, m / z): 635.3 [M+H] + .

[0568] Example 58 [2-[2-[[2-chloro-4-[[3-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]ethylamino]-2-oxoethyl]trimethylammonium formate [ka]

[0569] Step 1) Intermediate 26 Methyl 2-chloro-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzoate

[0570] To a solution of 8-chloro-3-iodo-imidazo[1,2-a]pyrazine (Intermediate 1, 5 g, 17.89 mmol, 1 equiv) in ACN (27.5 mL) / acetic acid (27.5 mL) was added methyl 4-amino-2-chlorobenzoate (3.98 g, 21.47 mmol, 1.2 equiv) and the reaction was stirred at 80° C. for 12 h. After cooling to room temperature, the reaction mixture was filtered, washed with ACN:MeOH=10:1, and dried to give the title compound (6.52 g, 15.2 mmol, 87.83% yield) as an off-white solid.

[0571] Process 2) 2-chloro-4-[[3-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoic acid methyl ester

[0572] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (1.59 g, 6.07 mmol, 1.3 equiv) in water (115 mL) / 1,4-dioxane (115 mL) was added methyl 2-chloro-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzoate (2 g, 4.67 mmol, 1 equiv), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (1.14 g, 1.4 mmol, 0.300 equiv), and sodium carbonate (1.48 g, 14 mmol, 3 equiv) at 25° C. The reaction mixture was stirred at 90° C. under N for 12 h. The reaction mixture was poured into water (100 mL) and extracted with DCM (50 mL x 3). The organic phases were combined and concentrated under reduced pressure. The target compound was purified by silica chromatography column (PE: EtOAc = 50: 1 to 1: 1) to give the title compound (0.400 g, 0.920 mmol, 19.63% yield) as a dark green solid. MS (ESI, m / z): 437.0 [M+H] + .

[0573] Process 3) 2-chloro-4-[[3-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoic acid

[0574] To a solution of methyl 2-chloro-4-[[3-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoate (400 mg, 0.920 mmol, 1 equiv.) in THF (5 mL) was added aqueous sodium hydroxide (5 mL, 10 mmol, 10.92 equiv.). The reaction mixture was stirred at 60 °C for 12 h. The reaction was adjusted to pH 6-7 by adding 1N HCl, and then concentrated under reduced pressure to give the title compound (1 g, 2.37 mmol, quantitative yield) as an off-white solid. MS (ESI, m / z): 423.0 [M+H] + .

[0575] Step 4) tert-Butyl N-[2-[[2-(dimethylamino)acetyl]amino]ethyl]carbamate

[0576] To a solution of N,N-dimethylglycine (1 g, 9.7 mmol, 1 equiv.) in DMF (10 mL) was added 1,1'-carbonyldiimidazole (1.57 g, 9.7 mmol, 1 equiv.). The mixture was stirred at 50 °C for 1 h. N-Boc-ethylenediamine (1.71 g, 10.67 mmol, 1.1 equiv.) was then added to the mixture, which was stirred for 12 h. The reaction mixture was diluted with water (30 mL) and extracted with DCM / MeOH = 10:1 (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to give the title compound (3.5 g, 14.27 mmol, 147.12% yield) as a white solid. MS (ESI, m / z): 246.2 [M+H] + .

[0577] Step 5) [2-[2-(tert-butoxycarbonylamino)ethylamino]-2-oxo-ethyl]-trimethylammonium iodide

[0578] To a solution of tert-butyl N-[2-[[2-(dimethylamino)acetyl]amino]ethyl]carbamate (73 mg, 2.04 mmol, 1 equiv.) in ethyl acetate (10 mL) was added iodomethane (318.1 mg, 2.24 mmol, 1.1 equiv.). The reaction mixture was stirred at 30° C. for 16 hours. It was then filtered, and the filter cake was collected to give the title compound (450 mg, 1.16 mmol, 57.04% yield) as a pale yellow solid. MS (ESI, m / z): 260.3 [M+H] + .

[0579] Process 6) [2-(2-aminoethylamino)-2-oxoethyl]trimethylammonium iodide hydrochloride

[0580] [2-[2-(tert-butoxycarbonylamino)ethylamino]-2-oxo-ethyl]-trimethylammonium iodide (450 mg, 1.16 mmol, 1 equiv.) was added to hydrogen chloride (5 mL, 20 mmol, 17.21 equiv.) in methanol. The reaction mixture was stirred at 30° C. for 1 h. The reaction was concentrated to give the title compound (370 mg, 1.14 mmol, 98.4% yield) as a yellow oil. MS (ESI, m / z): 160.1 [M+H] + .

[0581] Step 7) [2-[2-[[2-chloro-4-[[3-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]ethylamino]-2-oxoethyl]trimethylammonium formate

[0582] To a solution of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (270 mg, 0.710 mmol, 3 equiv.) and N,N-diisopropylethylamine (0.06 mL, 0.350 mmol, 1.5 equiv.) in DMF (4 mL) was added [2-(2-aminoethylamino)-2-oxo-ethyl]-trimethyl-ammonium iodide hydrochloride (92 mg, 0.280 mmol, 1.2 equiv.) and 2-chloro-4-[[3-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoic acid (250 mg, 0.240 mmol, 1 equiv.). The reaction was stirred at 30 °C for 12 h. The mixture product was purified by preparative HPLC (FA) and lyophilized to give the title compound (60 mg, 0.100 mmol, 41.58% yield) as a white solid. MS (ESI, m / z): 564.2 [M+H] + .

[0583] Example 59 [2-[[3-[[2-chloro-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]cyclobutyl]amino]-2-oxoethyl]trimethylammonium formate [ka]

[0584] Process 1) tert-Butyl N-[3-[[2-(dimethylamino)acetyl]amino]cyclobutyl]carbamate

[0585] To a solution of N,N-dimethylglycine (500 mg, 4.85 mmol, 1 equiv.) in DMF (5 mL) was added 1,1'-carbonyldiimidazole (786 mg, 4.85 mmol, 1 equiv.). The reaction mixture was stirred at 50 °C for 1 h. Then, tert-butyl N-(3-aminocyclobutyl)carbamate (903 mg, 4.85 mmol, 1 equiv.) was added to the mixture, which was stirred at 50 °C for 12 h. The reaction mixture was diluted with water (20 mL) and extracted with DCM / MeOH = 10:1 (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to give the title compound (1.31 g, 4.83 mmol, 99.56% yield) as a colorless oil. MS (ESI, m / z): 272.3 [M+H] + .

[0586] Process 2) [2-[[3-(tert-butoxycarbonylamino)cyclobutyl]amino]-2-oxo-ethyl]-trimethylammonium iodide

[0587] To a solution of tert-butyl N-[3-[[2-(dimethylamino)acetyl]amino]cyclobutyl]carbamate (1.31 g, 4.83 mmol, 1 equiv.) in ethyl acetate (15 mL) was added iodomethane (822 mg, 5.79 mmol, 1.2 equiv.). The reaction mixture was stirred at 30° C. for 16 h. The reaction was filtered and the filter cake was collected and dried to give the title compound (1.3 g, 3.15 mmol, 65.16% yield) as a yellow solid. MS (ESI, m / z): 286.3 [M+H] + .

[0588] Step 3) Intermediate 27 [2-[(3-aminocyclobutyl)amino]-2-oxoethyl]-trimethylammonium iodide hydrochloride

[0589] [2-[[3-(tert-butoxycarbonylamino)cyclobutyl]amino]-2-oxo-ethyl]-trimethylammonium iodide (1.3 g, 3.15 mmol, 1 equiv.) was added to 4 M hydrogen chloride in methanol (15 mL, 60 mmol, 19.07 equiv.). The reaction was stirred at 30° C. for 1 h. The reaction mixture was concentrated to give the title compound (1.1 g, 3.15 mmol, quantitative yield) as a yellow oil. MS (ESI, m / z): 186.2 [M+H] + .

[0590] Step 4) [2-[[3-[[2-chloro-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]cyclobutyl]amino]-2-oxoethyl]trimethylammonium formate

[0591] To a solution of 2-chloro-4-[[3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoic acid (Intermediate 5, 100 mg, 0.230 mmol, 1 equiv.) and 2-[(3-aminocyclobutyl)amino]-2-oxo-ethyl]-trimethyl-ammonium iodide hydrochloride salt (97.4 mg, 0.280 mmol, 1.2 equiv.) in DMF (2 mL) was added N,N-diisopropylethylamine (0.12 mL, 0.700 mmol, 3 equiv.) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (132.4 mg, 0.350 mmol, 1.5 equiv.). The reaction was stirred at 30 °C for 16 h. After adjusting the pH to 4-5 with formic acid, the mixture was purified by preparative HPLC (FA) and lyophilized to give the title compound (81.3 mg, 0.130 mmol, 54.38% yield) as a gray solid. MS (ESI, m / z): 598.3 [M+H] + .

[0592] Example 60 2-(4-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)piperidin-1-yl)-N,N,N-trimethyl-2-oxoethan-1-aminium chloride [ka]

[0593] Process 1) tert-Butyl 4-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)piperidine-1-carboxylate

[0594] Under argon, 4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoic acid (Intermediate 6, 200 mg, 487 μmol, 1 equiv.) was suspended in DMF (2 mL). DIPEA (315 mg, 414 μL, 2.44 mmol, 5 equiv.) was added, followed by tert-butyl 4-aminopiperidine-1-carboxylate (117 mg, 584 μmol, 1.2 equiv.) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (HATU) (370 mg, 974 μmol, 2 equiv.). The brown solution was stirred at room temperature for 2 h. The solvent was evaporated and the crude material was purified by flash chromatography (silica gel, 20 g, 0% to 100% DCM / MeOH / NH4OH (95 / 5 / 1) / DCM) to give the title compound (389 mg, 656 μmol, 135% yield) as a light brown solid. MS (ESI, m / z): 593.3 [M+H] + .

[0595] Process 2) 4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methyl-N-(piperidin-4-yl)benzamide

[0596] Under argon, tert-butyl 4-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)piperidine-1-carboxylate (178 mg, 300 μmol, 1 equiv.) was dissolved in DCM (1.5 ml). TFA (1.2 g, 804 μl, 10.5 mmol, 35 equiv.) was added, and the reaction mixture was stirred at room temperature for 1 h. DCM / MeOH / NH4OH was added until the TFA was neutralized and the reaction mixture was evaporated. The crude product was purified by flash chromatography (silica gel, 20 g, 0% to 100% DCM / MeOH / NH4OH (90 / 10 / 1)) to give the title compound (165 mg, 335 μmol, 100% yield) as an off-white solid. MS (ESI, m / z): 493.3 [M+H] + .

[0597] Process 3) 2-(4-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)piperidin-1-yl)-N,N,N-trimethyl-2-oxoethan-1-aminium chloride

[0598] Under argon, 4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methyl-N-(piperidin-4-yl)benzamide (104 mg, 211 μmol, 1 equiv.) was dissolved in DMF (2.08 ml). Betaine hydrochloride (35.7 mg, 232 μmol, 1.1 equiv.) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) HATU (88.3 mg, 232 μmol, 1.1 equiv.) were added, followed by DIPEA (54.6 mg, 73.8 μL, 422 μmol, 2 equiv.). The reaction was stirred at room temperature for 1 hour. The solvent was evaporated and the crude product was then purified by reverse-phase preparative HPLC (FA) to give the title compound (72 mg, 114 μmol, 54.3% yield) as a pale yellow solid. MS (ESI, m / z): 592.4 [M+H] + .

[0599] Example 7 [2-[3-[[2-chloro-4-[[3-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]propylamino]-2-oxoethyl]trimethylammonium formate [ka]

[0600] Step 1) Intermediate 28 2-Chloro-4-[[3-[3-(trifluoromethyl)-1-trityl-pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoic acid

[0601] To a solution of methyl 2-chloro-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzoate (Intermediate 26, 250 mg, 0.580 mmol, 1 equiv.) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1-trityl-pyrazole (441.27 mg, 0.870 mmol, 1.5 equiv.) in 1,4-dioxane (10 mL) / water (1 mL) was added 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (23.8 mg, 0.030 mmol, 0.05 equiv.) and sodium carbonate (123.64 mg, 1.17 mmol, 2 equiv.). The reaction was stirred under N2 at 80°C for 12 hours. Sodium hydroxide (69.99 mg, 1.75 mmol, 3 equiv) and water (3 mL) were then added to the mixture, which was stirred at 80°C for 4 hours. Water (20 mL) was added to the reaction mixture, and the pH was adjusted to 3 with formic acid. The solid was then filtered, and the filter cake was collected and dried to give the title compound (400 mg, 0.600 mmol, 103.11% yield) as a brown solid. MS (ESI, m / z): 665.3 [M+H] + .

[0602] Process 2) tert-Butyl N-[3-[[2-(dimethylamino)acetyl]amino]propyl]carbamate

[0603] To a solution of N,N-dimethylglycine (500 mg, 4.85 mmol, 1 equiv.) in DMF (5 mL) was added 1,1'-carbonyldiimidazole (786 mg, 4.85 mmol, 1 equiv.). The mixture was stirred at 50 °C for 1 h. N-Boc-1,3-diaminopropane (929 mg, 5.33 mmol, 1.1 equiv.) was then added, and the reaction mixture was stirred for 12 h. The reaction mixture was diluted with water (30 mL) and extracted with DCM / MeOH = 10:1 (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to give the title compound (1.05 g, 4.05 mmol, 83.5% yield) as a colorless oil. MS (ESI, m / z): 260.3 [M+H] + .

[0604] Process 3) [2-[3-(tert-butoxycarbonylamino)propylamino]-2-oxo-ethyl]-trimethylammonium iodide

[0605] To a solution of tert-butyl N-[3-[[2-(dimethylamino)acetyl]amino]propyl]carbamate (1.05 g, 4.05 mmol, 1 equiv.) in ethyl acetate (8.33 mL) was added iodomethane (632 mg, 4.45 mmol, 1.1 equiv.). The reaction was stirred at 30° C. for 16 hours. The reaction mixture was filtered, and the filter cake was collected and dried to give the title compound (1.08 g, 2.59 mmol, 63.92% yield) as a white solid. MS (ESI, m / z): 274.2 [M+H] + .

[0606] Step 4) [2-(3-aminopropylamino)-2-oxoethyl]trimethylammonium iodide hydrochloride

[0607] [2-[3-(tert-butoxycarbonylamino)propylamino]-2-oxo-ethyl]-trimethyl-ammonium iodide (1.08 g, 2.69 mmol, 1 equiv.) was added to 4 M hydrogen chloride in methanol (10 mL, 40 mmol, 14.86 equiv.). The reaction was stirred at 30° C. for 1 h. The reaction mixture was concentrated to give the title compound (900 mg, 2.67 mmol, 99.04% yield) as a yellow oil. MS (ESI, m / z): 174.1 [M+H] + .

[0608] Step 5) [2-[3-[[2-chloro-4-[[3-[3-(trifluoromethyl)-1-trityl-pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]propylamino]-2-oxoethyl]trimethylammonium formate

[0609] To a solution of 2-chloro-4-[[3-[3-(trifluoromethyl)-1-trityl-pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoic acid (200 mg, 0.300 mmol, 1 equiv.) and [2-(3-aminopropylamino)-2-oxo-ethyl]-trimethyl-ammonium iodide hydrochloride (122 mg, 0.360 mmol, 1.2 equiv.) in DMF (2 mL) was added N,N-diisopropylethylamine (0.16 mL, 0.900 mmol, 3 equiv.) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (172 mg, 0.450 mmol, 1.5 equiv.). The reaction was stirred at 30 °C for 12 h. The reaction mixture was purified by preparative HPLC (FA) to give the title compound (100 mg, 0.120 mmol, 35.07% yield) as a yellow oil. MS (ESI, m / z): 820.3 [M+H] + .

[0610] Process 6) [2-[3-[[2-chloro-4-[[3-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]propylamino]-2-oxoethyl]trimethylammonium formate

[0611] To a solution of [2-[3-[[2-chloro-4-[[3-[3-(trifluoromethyl)-1-trityl-pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]propylamino]-2-oxoethyl]-trimethylammonium formate (100 mg, 0.120 mmol, 1 equiv.) in DCM (3 mL) was added trifluoroacetic acid (1 mL, 12.98 mmol, 112.45 equiv.). The reaction was stirred at 30 °C for 12 h. The reaction mixture was adjusted to pH = 7 with TEA and purified by preparative HPLC (FA) to give the title compound (14.7 mg, 0.020 mmol, 20.27% yield) as a white solid. MS (ESI, m / z): 578.2 [M+H] + .

[0612] Example 61 [2-[[3-[[2-chloro-4-[[3-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]cyclobutyl]amino]-2-oxoethyl]trimethylammonium formate [ka]

[0613] Process 1) [2-[[3-[[2-chloro-4-[[3-[3-(trifluoromethyl)-1-trityl-pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]cyclobutyl]amino]-2-oxoethyl]trimethylammonium iodide

[0614] Using Intermediate 28 and Intermediate 27, the title compound (105 mg, 0.110 mmol, 42.78% yield) was obtained as a yellow solid in the same manner as in Example 7, Step 5. MS (ESI, m / z): 832.3 [M+H] + .

[0615] Process 2) [2-[[3-[[2-chloro-4-[[3-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]cyclobutyl]amino]-2-oxoethyl]trimethylammonium formate

[0616] The title compound (13.5 mg, 0.020 mmol, 18.64% yield) was obtained as a white solid in a similar manner to Example 7, Step 6. MS (ESI, m / z): 590.2 [M+H] + .

[0617] Example 62 [2-[4-[2-chloro-4-[[3-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]piperazin-1-yl]-2-oxoethyl]trimethylammonium formate [ka]

[0618] Process 1) Methyl 2-chloro-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzoate

[0619] To a solution of 8-chloro-3-iodo-imidazo[1,2-a]pyrazine (Intermediate 1, 5 g, 17.89 mmol, 1 equiv.) in ACN (50 mL) was added acetic acid (5 mL, 17.89 mmol, 1 equiv.) and methyl 4-amino-2-chlorobenzoate (3.98 g, 21.47 mmol, 1.2 equiv.). The reaction was stirred at 80 °C for 48 h. After cooling to room temperature, the reaction mixture was filtered, washed with ACN:MeOH = 10:1, and then dried to give the title compound (6.8 g, 15.87 mmol, 88.68% yield) as an off-white solid. MS (ESI, m / z): 428.9 [M+H] + .

[0620] Process 2) 2-chloro-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzoic acid

[0621] To a solution of methyl 2-chloro-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzoate (6.5 g, 15.17 mmol, 1 equiv.) in THF (40 mL) was added 2 M aqueous sodium hydroxide (40 mL, 80 mmol, 5.28 equiv.) and stirred at 60 °C for 12 h. The reaction mixture was adjusted to pH 1-2 with 3 N HCl and filtered. The filtrate was extracted with DCM (10 mL × 3), dried over NaSO, and concentrated to give the title compound (6 g, 14.47 mmol, 95.43% yield) as a white solid. MS (ESI, m / z): 414.9 [M+H] + .

[0622] Process 3) tert-Butyl 4-[2-chloro-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzoyl]piperazine-1-carboxylate

[0623] To a solution of N,N-diisopropylethylamine (7.56 mL, 43.42 mmol, 3 equiv.), 2-chloro-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzoic acid (6 g, 14.47 mmol, 1 equiv.), and 1-Boc-piperazine (0.08 mL, 15.92 mmol, 1.1 equiv.) in DMF (50 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (11.01 g, 28.94 mmol, 2 equiv.) at 30 °C. The reaction mixture was stirred at 30 °C for 12 h. 100 mL of water was added, and the mixture was filtered to give the title compound (6 g, 10.29 mmol, 71.14% yield) as an off-white solid. MS (ESI, m / z): 583.0 [M + H] + .

[0624] Step 4) tert-Butyl 4-[2-chloro-4-[[3-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]piperazine-1-carboxylate

[0625] To a solution of tert-butyl 4-[2-chloro-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzoyl]piperazine-1-carboxylate (3 g, 5.15 mmol, 1 equiv.) in water (9 mL) / 1,4-dioxane (90 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (1.75 g, 6.69 mmol, 1.3 equiv.), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.42 g, 0.510 mmol, 0.1 equiv.), and sodium carbonate (1637 mg, 15.44 mmol, 3 equiv.) at 25° C. The mixture was stirred under N2 at 90 °C for 12 hours. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (50 ml x 3). The organic phases were combined, concentrated under reduced pressure, and then purified by silica chromatography column (PE: EtOAc = 1:1 to EtOAc) to give the title compound (1.4 g, 2.37 mmol, 36.82% yield) as a light brown solid. MS (ESI, m / z): 591.1 [M+H] + .

[0626] Step 5) [2-chloro-4-[[3-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]-piperazin-1-yl-methanone hydrochloride

[0627] tert-Butyl 4-[2-chloro-4-[[3-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]piperazine-1-carboxylate (1.4 g, 2.37 mmol, 1 equiv.) was added to a solution of hydrochloric acid in dioxane (35.1 mL, 140.43 mmol, 59.28 equiv.), which was then stirred at 20° C. for 2 hours. The mixture was concentrated in vacuo and purified by preparative HPLC (HCl) to give the title compound (900 mg, 1.83 mmol, 77.4% yield) as an off-white solid. MS (ESI, m / z): 491.2 [M+H] + .

[0628] Process 6) [2-[4-[2-chloro-4-[[3-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]piperazin-1-yl]-2-oxoethyl]trimethylammonium formate

[0629] To a solution of N,N-diisopropylethylamine (0.11 mL, 0.610 mmol, 3 equiv.), betaine (33.32 mg, 0.280 mmol, 1.5 equiv.), and [2-chloro-4-[[3-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]-piperazin-1-yl-methanone (100 mg, 0.200 mmol, 1 equiv.) in DMF (1.92 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (154.92 mg, 0.410 mmol, 2 equiv.). The reaction mixture was stirred at 20 °C for 12 h. The mixture was acidified with HCOOH and then purified by preparative HPLC (FA) to give the title compound (28.7 mg, 0.050 mmol, 21.8% yield) as an off-white solid. MS (ESI, m / z): 590.3 [M+H] + .

[0630] Example 63 2-(((1s,4s)-4-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)cyclohexyl)amino)-N,N,N-trimethyl-2-oxoethan-1-aminium chloride [ka]

[0631] Process 1) tert-Butyl ((1s,4s)-4-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)cyclohexyl)carbamate

[0632] Under argon, 4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoic acid (Intermediate 6, 200 mg, 487 μmol, 1 equiv.) was suspended in DMF (2 mL). N-Ethyl-N-isopropylpropan-2-amine (DIPEA) (315 mg, 414 μL, 2.44 mmol, 5 equiv.) was added, followed by tert-butyl (((1s,4s)-4-aminocyclohexyl)carbamate (125 mg, 584 μmol, 1.2 equiv.) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphine. To the resulting solution was added 370 mg of hydroxybenzoate (V) (HATU) (974 μmol, 2 equiv.). The solution was stirred at room temperature for 2 h. The solvent was evaporated, and the crude material was purified by flash chromatography (silica gel, 20 g, 0% to 100% DCM / (DCM / MeOH / NH4OH (95 / 5 / 1))) to give the title compound (366 mg, 603 μmol, 124% yield) as a pale red solid. MS (ESI, m / z): 607.3 [M+H] + .

[0633] Process 2) N-((1s,4s)-4-aminocyclohexyl)-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamide

[0634] Under argon, tert-butyl ((1s,4s)-4-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)cyclohexyl)carbamate (182 mg, 300 μmol, 1 equiv.) was dissolved in DCM (1.5 mL). TFA (1.2 g, 804 μl, 10.5 mmol, 35 equiv.) was added, and the reaction mixture was stirred at room temperature for 1 h. DCM / MeOH / NH4OH was added until the TFA was neutralized and the mixture was evaporated. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 100% DCM / MeOH / NH4OH (90 / 10 / 1)) to give the title compound (131 mg, 259 μmol, 86% yield) as a white solid. MS (ESI, m / z): 507.3 [M + H] + .

[0635] Process 3) 2-(((1s,4s)-4-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)cyclohexyl)amino)-N,N,N-trimethyl-2-oxoethan-1-aminium chloride

[0636] Under argon, 2-(trimethylammonio)acetate (18.6 mg, 159 μmol, 1.15 equiv.) was suspended in DCM (1 mL). 1-Chloro-N,N,2-trimethyl-1-propenylamine (23.1 mg, 22.9 μL, 173 μmol, 1.25 equiv.) was added, and the reaction mixture was stirred at room temperature for 30 min. A suspension containing N-((1s,4s)-4-aminocyclohexyl)-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamide (70 mg, 138 μmol, 1 equiv.) and N-ethyl-N-isopropylpropan-2-amine (44.7 mg, 58.8 μL, 345 μmol, 2.5 equiv.) was added, and the reaction mixture was stirred at room temperature for 1 h. Since the reaction was not complete, 1-carboxy-N,N,N-trimethylmethanaminium chloride (21.2 mg, 138 μmol, 1 equiv.) was dissolved in 1 ml of DMA. 1-Chloro-N,N,2-trimethyl-1-propenylamine (23.1 mg, 22.9 μl, 173 μmol, 1.25 equiv.) was added, and after 30 min at room temperature, this solution was added to the reaction mixture and stirred at room temperature for 1 h. The solvent was evaporated, and the crude material was purified by reverse-phase chromatography under acidic conditions (FA) to give the title compound (5 mg, 7.7 μmol, 5.63% yield) as an off-white solid. MS (ESI, m / z): 606.3 [M+H] + .

[0637] Example 64 [2-[4-[4-[[3-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]piperazin-1-yl]-2-oxoethyl]trimethylammonium formate [ka]

[0638] Process 1) Methyl 4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]-2-methyl-benzoate

[0639] To a solution of 8-chloro-3-iodo-imidazo[1,2-a]pyrazine (Intermediate 1, 5 g, 17.89 mmol, 1 equiv) in ACN (50 mL) / acetic acid (5 mL) was added methyl 4-amino-2-methylbenzoate (3.55 g, 21.47 mmol, 1.2 equiv) and the reaction mixture was stirred at 80° C. for 12 h. After cooling to room temperature, the reaction mixture was filtered, washed with ACN:MeOH=10:1, and dried to give the title compound (6.1 g, 14.94 mmol, 83.53% yield) as an off-white solid.

[0640] Process 2) 4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]-2-methyl-benzoic acid

[0641] To a solution of methyl 4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]-2-methylbenzoate (6.1 g, 14.94 mmol, 1 equiv.) in THF (20 mL) / methanol (20 mL) was added 2 M aqueous sodium hydroxide (20 mL, 40 mmol, 2.68 equiv.) and stirred at 60 °C for 16 h. After cooling to room temperature, the reaction mixture was adjusted to pH 1-2 with 3 N HCl, filtered, and dried to give the title compound (5.8 g, 14.71 mmol, 98.46% yield) as an off-white solid. MS (ESI, m / z): 394.9 [M+H] + .

[0642] Process 3) tert-Butyl 4-[4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]-2-methyl-benzoyl]piperazine-1-carboxylate

[0643] To a solution of 4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]-2-methyl-benzoic acid (3 g, 7.61 mmol, 1 equiv.) in DMF (30 mL) was added 1-Boc-piperazine (1.7 g, 9.13 mmol, 1.2 equiv.), N,N-diisopropylethylamine (3.98 mL, 22.83 mmol, 3 equiv.), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.79 g, 15.22 mmol, 2 equiv.). The reaction mixture was stirred at 30 °C for 16 h. 160 mL of water was added. The mixture was filtered, and the filter cake was dried to give the title compound (3 g, 5.33 mmol, 70.09% yield) as an off-white solid. MS (ESI, m / z): 563.2 [M + H] + .

[0644] Step 4) 2-[4-iodo-3-(trifluoromethyl)pyrazol-1-yl]acetonitrile

[0645] To a mixture of 4-iodo-3-(trifluoromethyl)-1H-pyrazole (10 g, 38.17 mmol, 1 equiv.) in acetone (200 mL) was added potassium carbonate (6.33 g, 45.81 mmol, 1.2 equiv.) and 2-bromoacetonitrile (6.87 g, 57.26 mmol, 1.5 equiv.) at −60° C. The mixture was stirred at 0° C. for 4 hours. The mixture was poured into water (50 mL). The aqueous phase was extracted with EtOAc (50 mL×2). The combined organic phases were washed with brine (100 mL), dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc=20 / 1) to give the title compound (10 g, 33.2 mmol, 87.03% yield) as a colorless oil. 1H NMR(400MHz,CHLOROFORM-d)Shift 7.74(d,J=0.73Hz,1H),5.14(s,2H).

[0646] Step 5) Intermediate 29 2-[4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-3-(trifluoromethyl)pyrazol-1-yl]acetonitrile

[0647] To a solution of 2-[4-iodo-3-(trifluoromethyl)pyrazol-1-yl]acetonitrile (8.45 g, 28.07 mmol, 1 equiv.) in dimethyl sulfoxide (90 mL), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (1.15 g, 1.4 mmol, 0.05 equiv.), potassium acetate (5.26 mL, 84.22 mmol, 3 equiv.), and bis(pinacolato)diboron (10.69 g, 42.11 mmol, 1.5 equiv.) were added under N2. The reaction was stirred at 70 °C for 16 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (60 mL × 2). The combined organic phases were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound (18.8 g, 62.44 mmol, 222.44% yield) as a dark brown oil. MS (ESI, m / z): 299.9 [M+H] + .

[0648] Process 6) tert-Butyl 4-[4-[[3-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]piperazine-1-carboxylate

[0649] To a solution of tert-butyl 4-[4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]-2-methyl-benzoyl]piperazine-1-carboxylate (1.3 g, 2.31 mmol, 1 equiv.) in water (3 mL) / 1,4-dioxane (30 mL) was added 2-[4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-3-(trimethylbenzoyl)piperazine-1-carboxylate] (1.3 g, 2.31 mmol, 1 equiv.). [Fluoromethyl]pyrazol-1-yl]acetonitrile (7.67 g, 22.76 mmol, 9.85 equiv.), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (188.62 mg, 0.230 mmol, 0.10 equiv.), and sodium carbonate (0.73 g, 6.93 mmol, 3 equiv.) were added at 25 °C. The mixture was stirred at 100 °C for 12 hours. The mixture was poured into water (50 mL). The aqueous phase was extracted with EtOAc (50 mL × 2). The combined organic phases were washed with brine (61 mL) and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 90) to give the title compound (900 mg, 1.48 mmol, 63.87% yield) as a brown solid. MS (ESI, m / z): 610.3 [M + H] + .

[0650] Step 7) 2-[4-[8-[3-methyl-4-(piperazine-1-carbonyl)anilino]imidazo[1,2-a]pyrazin-3-yl]-3-(trifluoromethyl)pyrazol-1-yl]acetonitrile

[0651] To a solution of tert-butyl 4-[4-[[3-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]piperazine-1-carboxylate (0.9 g, 1.48 mmol, 1 equiv.) in DCM (45 mL) was added trifluoroacetic acid (9 mL, 116.82 mmol, 79.13 equiv.) and stirred at 20 °C for 2 h. The pH was adjusted to 8-9 by the addition of saturated aqueous Na2CO3. The aqueous phase was extracted with DCM (40 mL × 2). The combined organic phases were dried over Na2SO4, filtered, and concentrated to give the title compound (540 mg, 1.06 mmol, 71.79% yield) as a light brown solid. MS (ESI, m / z): 510.1 [M+H] + .

[0652] Process 8) [2-[4-[4-[[3-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]piperazin-1-yl]-2-oxoethyl]trimethylammonium formate

[0653] To a solution of N,N-diisopropylethylamine (0.11 mL, 0.610 mmol, 3 equiv.), betaine (35.8 mg, 0.310 mmol, 1.5 equiv.), and 2-[4-[8-[3-methyl-4-(piperazine-1-carbonyl)anilino]imidazo[1,2-a]pyrazin-3-yl]-3-(trifluoromethyl)pyrazol-1-yl]acetonitrile (100 mg, 0.200 mmol, 1 equiv.) in DMF (1.85 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (154.92 mg, 0.410 mmol, 2 equiv.), and the reaction mixture was stirred at 20 °C for 12 h. The mixture was acidified with HCOOH and then purified by preparative HPLC (FA) to give the title compound (26.8 mg, 0.040 mmol, 20.1% yield) as an off-white solid. MS (ESI, m / z): 609.3 [M] + .

[0654] Example 65 [2-[4-[2-chloro-4-[[3-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]piperazin-1-yl]-2-oxoethyl]trimethylammonium formate [ka]

[0655] Process 1) 2-chloro-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzoic acid

[0656] To a solution of methyl 2-chloro-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzoate (Intermediate 26, 2 g, 4.67 mmol, 1 equiv.) in THF (7 mL) / methanol (7 mL) was added aqueous sodium hydroxide (7 mL, 14 mmol, 3 equiv.) and stirred at 60 °C for 12 h. After cooling to room temperature, the reaction mixture was adjusted to pH 6-7 with 3N HCl, filtered, and dried to give the title compound (1.5 g, 3.62 mmol, 77.54% yield) as an off-white solid. MS (ESI, m / z): 414.9 [M+H] + .

[0657] Process 2) tert-Butyl 4-[2-chloro-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzoyl]piperazine-1-carboxylate

[0658] The title compound (1 g, 1.72 mmol, 71.14% yield) was obtained as a brown solid in a similar manner to Example 64, Step 3. MS (ESI, m / z): 583.0 [M+H] + .

[0659] Process 3) tert-Butyl 4-[2-chloro-4-[[3-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]piperazine-1-carboxylate

[0660] Using Intermediate 29, the title compound (300 mg, 0.480 mmol, 55.5% yield) was obtained as a brown solid in a similar manner to Example 64, Step 6. MS (ESI, m / z): 630.2 [M+H] + .

[0661] Step 4) 2-[4-[8-[3-chloro-4-(piperazine-1-carbonyl)anilino]imidazo[1,2-a]pyrazin-3-yl]-3-(trifluoromethyl)pyrazol-1-yl]acetonitrile

[0662] To a solution of tert-butyl 4-[2-chloro-4-[[3-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]piperazine-1-carboxylate (300 mg, 0.480 mmol, 1 equiv.) in DCM (5 mL) was added trifluoroacetic acid (1 mL, 12.98 mmol, 27.26 equiv.), and the reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated to give the title compound (177 mg, 0.330 mmol, 70% yield) as a brown solid. MS (ESI, m / z): 530.2 [M+H] + .

[0663] Step 5) [2-[4-[2-chloro-4-[[3-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]piperazin-1-yl]-2-oxoethyl]trimethylammonium formate

[0664] The title compound (38.1 mg, 0.060 mmol, 16.9% yield) was obtained as an off-white solid in a manner similar to that of Example 64, Step 8. MS (ESI, m / z): 629.2 [M] + .

[0665] Example 18 2-(2-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-fluoro-6-methylbenzamido)ethoxy)-N,N,N-trimethylethan-1-aminium hydrogen carbonate [ka]

[0666] Process 1) tert-Butyl 4-bromo-2-fluoro-6-methylbenzoate

[0667] In a pressure tube, 4-bromo-2-fluoro-6-methylbenzoic acid (700 mg, 3 mmol, 1 equiv.) was suspended in dry toluene (1.88 mL) and N,N-dimethylformamide di-tert-butyl acetal (4.41 g, 5.19 mL, 19.5 mmol, 6.5 equiv.) was added. The tube was sealed, and the mixture was heated to 80 °C for 3 h. The reaction mixture was diluted with water, ethyl acetate, and saturated aqueous NaHCO3. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous NaHCO3 and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (40 g column load / gradient: heptane, 0% to 5% ethyl acetate) to afford the title compound (794.9 mg, 2.69 mmol, 89.7% yield) as a colorless oil. MS (ESI, m / z): 290.0 [M + H] + .

[0668] Process 2) 3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-amine

[0669] In a sealed pressure tube, a suspension of 8-chloro-3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazine (Intermediate 18, 1.5 g, 5.07 mmol, 1 equiv.) in isopropanol (20.3 mL) and 25% aqueous ammonia (31.8 g, 35.3 mL, 467 mmol, 92 equiv.) was heated to 100°C for 2 days. The reaction mixture was diluted with water, and the suspension was filtered and washed with water. The solid was collected and dried in vacuo to give the title compound (1.23 g, 4.45 mmol, 87.8% yield) as a brown solid. MS (ESI, m / z): 277.1 [M+H] + .

[0670] Process 3) tert-Butyl 4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-fluoro-6-methylbenzoate

[0671] A suspension of 3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-amine (300 mg, 1.09 mmol, 1 equiv.), tert-butyl 4-bromo-2-fluoro-6-methylbenzoate (628 mg, 2.17 mmol, 2 equiv.), and sodium tert-butoxide (157 mg, 1.63 mmol, 1.5 equiv.) in THF (10.9 mL) was sparged with argon for 5 min while sonicating in an ultrasonic bath in a pressure tube. 1,1'-bis(diphenylphosphino)ferrocene (72.2 mg, 130 μmol, 0.12 equiv.) and tris(dibenzylideneacetone)dipalladium(0) (39.8 mg, 43.4 μmol, 0.04 equiv.) were then added, and degassing was continued for 1 min. The tube was sealed and heated to 130° C. for 3 h.

[0672] The mixture was concentrated in vacuo. The crude material was purified by silica gel chromatography (70 g column load, gradient: heptane, 0% to 60% ethyl acetate) to give the title compound (367 mg, 758 μmol, 69.8% yield) as a yellow solid. MS (ESI, m / z): 485.2 [M+H] + .

[0673] Step 4) 4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-fluoro-6-methylbenzoic acid hydrochloride

[0674] To a solution of tert-butyl 4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-fluoro-6-methylbenzoate (367 mg, 758 μmol, 1 equiv.) in dioxane (1.52 ml) was added 4 M HCl in dioxane (11.4 ml, 45.5 mmol, 60 equiv.) and the reaction was heated to 70° C. for 4 hours. The mixture was diluted with dioxane and concentrated in vacuo to give the title compound (410 mg, 750 μmol, 99% yield) as a light brown solid. MS (ESI, m / z): 429.2 [M+H] + .

[0675] Step 5) 4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N-(2-(2-(dimethylamino)ethoxy)ethyl)-2-fluoro-6-methylbenzamide

[0676] To a solution of 4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-fluoro-6-methylbenzoic acid hydrochloride (90 mg, 194 μmol, 1 equiv.) and DIPEA (125 mg, 169 μl, 968 μmol, 5 equiv.) in dry DMF (861 μl) was added HATU (73.6 mg, 194 μmol, 1 equiv.) and the mixture was stirred at room temperature for 10 minutes. Then, 2-(2-aminoethoxy)-N,N-dimethylethan-1-amine (38.4 mg, 290 μmol, 1.5 equiv.) in dry DMF (430 μl) was added and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo. The crude material was purified by silica gel chromatography (4 g column pre-packed, gradient: heptane, 10% to 80% EtOAc / EtOH / NH4OH 75:25:2) to afford the title compound (83.8 mg, 148 μmol, 76.6% yield) as an off-white solid. MS (ESI, m / z): 543.3 [M+H] + .

[0677] Process 6) 2-(2-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-fluoro-6-methylbenzamido)ethoxy)-N,N,N-trimethylethan-1-aminium hydrogen carbonate

[0678] To a solution of 4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N-(2-(2-(dimethylamino)ethoxy)ethyl)-2-fluoro-6-methylbenzamide (38.2 mg, 70.4 μmol, 1 equiv.) in dioxane (704 μL) was added a solution of iodomethane (12 mg, 5.26 μL, 84.5 μmol, 1.2 equiv.) in dioxane (704 μL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was then dissolved in methanol and dichloromethane and filtered using an Agilent Stratosphere SPE-HCO3- (iodine to hydrogen carbonate exchange) ion exchange column, which was washed with methanol. The filtrate was concentrated in vacuo to give the title compound (43.1 mg, 66.2 μmol, 94% yield) as a yellow solid. MS(ESI,m / z):557.2526[M] + .

[0679] Example 66 2-[[3-[[2-chloro-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]cyclobutyl]amino]ethyl-trimethyl-ammonium formate [ka]

[0680] Process 1) 2-[[3-(tert-butoxycarbonylamino)cyclobutyl]amino]ethyl-trimethyl-ammonium formate

[0681] To a solution of tert-butyl N-(3-aminocyclobutyl)carbamate (500 mg, 2.68 mmol, 1 equiv.) and 2-bromoethyl(trimethyl)ammonium bromide (2.98 g, 12.08 mmol, 4.5 equiv.) in ACN (5 mL) was added sodium iodide (0.12 g, 0.810 mmol, 0.3 equiv.) and diisopropylethylamine (2.11 mL, 12.08 mmol, 4.5 equiv.). The reaction was stirred at 80° C. for 24 h. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (FA) to afford the title compound (500 mg, 1.58 mmol, 68.37% yield) as a dark green oil.

[0682] Step 2) Intermediate 30 2-[(3-aminocyclobutyl)amino]ethyl-trimethyl-ammonium chloride

[0683] To a solution of 2-[[3-(tert-butoxycarbonylamino)cyclobutyl]amino]ethyl-trimethyl-ammonium formate (500 mg, 1.84 mmol, 1 equiv.) was added HCl in MeOH (2.0 mL, 8 mmol, 4.36 equiv.) and the reaction was stirred at 20° C. for 12 h. The reaction mixture was concentrated under reduced pressure to give the title compound (500 mg, 2.41 mmol, 95.48% yield) as a pale yellow oil, which was used without further purification. MS (ESI, m / z): 172.2 [M] + .

[0684] Process 3) 2-[[3-[[2-chloro-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]cyclobutyl]amino]ethyl-trimethyl-ammonium formate

[0685] To a solution of 2-chloro-4-[[3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoic acid (Intermediate 5, 100 mg, 0.230 mmol, 1 equiv.) and 2-[(3-aminocyclobutyl)amino]ethyl-trimethyl-ammonium chloride (57.87 mg, 0.280 mmol, 1.2 equiv.) in DMF (2 mL) was added N,N-diisopropylethylamine (0.12 mL, 0.700 mmol, 3 equiv.) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (132.4 mg, 0.350 mmol, 1.5 equiv.). The reaction was stirred at 30 °C for 16 h. After adjusting the pH to 4-5 with formic acid, the mixture was purified by preparative HPLC (FA) and lyophilized to give the title compound (17.1 mg, 0.030 mmol, 11.38% yield) as an off-white solid. MS (ESI, m / z): 584.3 [M] + .

[0686] Example 67 (S)-2-(3-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)pyrrolidin-1-yl)-N,N,N-trimethyl-2-oxoethan-1-aminium chloride [ka]

[0687] Process 1) tert-Butyl (S)-3-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)pyrrolidine-1-carboxylate

[0688] Using tert-butyl (S)-3-aminopyrrolidine-1-carboxylate and Intermediate 6, the title compound (148 mg, 256 μmol, 52.5% yield) was obtained as a light brown solid in the same manner as in Example 63, Step 1. MS (ESI, m / z): 579.3 [M+H] + .

[0689] Process 2) (S)-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methyl-N-(pyrrolidin-3-yl)benzamide

[0690] The title compound (122 mg, 255 μmol, 85% yield) was obtained as a white solid in a similar manner to Example 63, Step 2. MS (ESI, m / z): 479.3 [M+H] + .

[0691] Process 3) (S)-2-(3-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)pyrrolidin-1-yl)-N,N,N-trimethyl-2-oxoethan-1-aminium chloride

[0692] Under argon, (S)-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methyl-N-(pyrrolidin-3-yl)benzamide (70 mg, 146 μmol, 1 equiv.) was dissolved in DMF (1.43 ml). Betaine hydrochloride (24.7 mg, 161 μmol, 1.1 equiv.) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (61.2 mg, 161 μmol, 1.1 equiv.) were added. DIPEA (37.8 mg, 51.1 μL, 293 μmol, 2 equiv.) was added. The reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the crude product was then purified by reverse phase to give the title compound (17 mg, 27.6 μmol, 18.9% yield) as a light brown solid. MS (ESI, m / z): 578.5 [M] + . Example 68 2-(3-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)piperidin-1-yl)-N,N,N-trimethyl-2-oxoethan-1-aminium chloride [ka]

[0693] Process 1) tert-Butyl 3-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)piperidine-1-carboxylate

[0694] Using tert-butyl 3-aminopiperidine-1-carboxylate and Intermediate 6, the title compound (323 mg, 545 μmol, 112% yield) was obtained as a pale red solid in the same manner as in Example 63, Step 1. MS (ESI, m / z): 593.3 [M+H] + .

[0695] Process 2) 4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methyl-N-(piperidin-3-yl)benzamide

[0696] The title compound (144 mg, 292 μmol, 97% yield) was obtained as a pale yellow solid in a similar manner to Example 63, Step 2. MS (ESI, m / z): 493.3 [M+H] + .

[0697] Process 3) 2-(3-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)piperidin-1-yl)-N,N,N-trimethyl-2-oxoethan-1-aminium chloride

[0698] The title compound (30 mg, 47.8 μmol, 29.4% yield) was obtained as a white solid in the same manner as in Example 67, Step 3. MS (ESI, m / z): 592.5 [M] + .

[0699] Example 69 2-(((1r,4r)-4-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)cyclohexyl)amino)-N,N,N-trimethyl-2-oxoethan-1-aminium chloride [ka]

[0700] Process 1) tert-Butyl ((1r,4r)-4-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)cyclohexyl)carbamate

[0701] Using tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate and Intermediate 6, the title compound (145 mg, 239 μmol, 49% yield) was obtained as a light brown solid in the same manner as in Example 63, Step 1. MS (ESI, m / z): 607.4 [M+H] + .

[0702] Process 2) N-((1r,4r)-4-aminocyclohexyl)-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamide

[0703] The title compound (106 mg, 209 μmol, 69% yield) was obtained as a white solid in a similar manner to Example 63, Step 2. MS (ESI, m / z): 507.3 [M+H] + .

[0704] Process 3) 2-(((1r,4r)-4-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)cyclohexyl)amino)-N,N,N-trimethyl-2-oxoethan-1-aminium chloride

[0705] The title compound (35 mg, 54.5 μmol, 48.4% yield) was obtained as a white solid in the same manner as in Example 67, Step 3. MS (ESI, m / z): 606.5 [M] + . Example 70 (R)-2-(3-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)pyrrolidin-1-yl)-N,N,N-trimethyl-2-oxoethan-1-aminium chloride [ka]

[0706] Process 1) tert-Butyl (R)-3-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)pyrrolidine-1-carboxylate

[0707] Using tert-butyl (R)-3-aminopyrrolidine-1-carboxylate and Intermediate 6, the title compound (146 mg, 252 μmol, 51.8% yield) was obtained as a light brown solid in the same manner as in Example 63, Step 1. MS (ESI, m / z): 579.3 [M+H] + .

[0708] Process 2) (R)-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methyl-N-(pyrrolidin-3-yl)benzamide

[0709] The title compound (108 mg, 226 μmol, 75% yield) was obtained as a white solid in a similar manner to Example 63, Step 2. MS (ESI, m / z): 479.3 [M+H] + .

[0710] Process 3) (R)-2-(3-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)pyrrolidin-1-yl)-N,N,N-trimethyl-2-oxoethan-1-aminium chloride

[0711] The title compound (43 mg, 70 μmol, 55.8% yield) was obtained as a white solid in the same manner as in Example 67, Step 3. MS (ESI, m / z): 578.5 [M] + .

[0712] Example 71 2-Amino-N-(2-(3-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)azetidin-1-yl)-2-oxoethyl)-N,N-dimethyl-2-oxoethan-1-aminium formate [ka]

[0713] Process 1) tert-Butyl 3-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)azetidine-1-carboxylate

[0714] tert-Butyl 3-aminoazetidine-1-carboxylate (89.3 mg, 518 μmol, 1.1 equiv), 4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzoic acid (Intermediate 8, 200 mg, 471 μmol, 1 equiv), and DIPEA (122 mg, 165 μl, 942 μmol, 2 equiv) were combined with DMF (6 mL). HATU (269 mg, 707 μmol, 1.5 equiv) was added. The reaction was stirred at room temperature for 2 hours. The reaction mixture was poured into 50 mL of HO and extracted with EtOAc (3×25 mL). The organic layers were combined, washed with saturated NaCl (25 mL), and evaporated to give the title compound (244 mg, 422 μmol, 89.5% yield) as a white solid. MS (ESI, m / z): 579.8 [M + H] + .

[0715] Process 2) N-(azetidin-3-yl)-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamide

[0716] tert-Butyl 3-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)azetidine-1-carboxylate (244 mg, 422 μmol, 1 equiv.) was combined with THF (5 ml). 4M HCl in water (3.16 ml, 12.7 mmol, 30 equiv.) was added. The reaction was stirred at room temperature for 10 minutes. The crude reaction mixture was concentrated in vacuo to give the title compound (202 mg, 422 μmol, 100% yield) as a white solid. MS (ESI, m / z): 479.5 [M+H] + .

[0717] Process 3) 4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N-(1-(dimethylglycyl)azetidin-3-yl)-2-ethylbenzamide

[0718] N,N-Dimethylglycine (22.4 mg, 217 μmol, 1.3), N-(azetidin-3-yl)-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamide (80 mg, 167 μmol, 1 equiv.), and TEA (84.6 mg, 117 μl, 836 μmol, 5 equiv.) were combined with DMF (5 mL). 1-Propanephosphonic anhydride (160 mg, 251 μmol, 1.5 equiv.) was added. The reaction was stirred at room temperature overnight. The reaction mixture was poured into 50 mL of HO and extracted with EtOAc (3 × 25 mL). The organic layer was dried over NaSO and concentrated in vacuo to give the title compound (61 mg, 108 μmol, 64.7% yield) as a white solid. MS (ESI, m / z): 564.6 [M + H] + .

[0719] Step 4) 2-Amino-N-(2-(3-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)azetidin-1-yl)-2-oxoethyl)-N,N-dimethyl-2-oxoethan-1-aminium formate

[0720] 2-Iodoacetamide (40 mg, 216 μmol, 2 equiv.) and 4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N-(1-(dimethylglycyl)azetidin-3-yl)-2-ethylbenzamide (61 mg, 108 μmol, 1 equiv.) were combined with CHCl (6 ml). The reaction was stirred at room temperature overnight. The crude reaction mixture was concentrated in vacuo and purified by preparative HPLC to give the title compound (25 mg, 36.7 μmol, 34% yield) as a white powder. MS (ESI, m / z): 621.6 [M] + .

[0721] Example 72 2-(((1s,3s)-3-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)cyclobutyl)amino)-N,N,N-trimethyl-2-oxoethan-1-aminium chloride [ka]

[0722] Process 1) tert-Butyl ((1s,3s)-3-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)cyclobutyl)carbamate

[0723] Under argon, 4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoic acid hydrochloride (Intermediate 6, 400 mg, 895 μmol, 1 equiv.) was suspended in DMF (4 ml). N-ethyl-N-isopropylpropan-2-amine (DIPEA) (578 mg, 761 μl, 4.48 mmol, 5 equiv.) was added. tert-Butyl ((1s,3s)-3-aminocyclobutyl)carbamate (200 mg, 1.07 mmol, 1.2 equiv.) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (HATU) (681 mg, 1.79 mmol, 2 equiv.) were added. The reaction mixture was stirred at room temperature for 2 hours. N-ethyl-N-isopropylpropan-2-amine (DIPEA) (144 mg, 190 μl, 1.12 mmol, 1.25 equiv.) and tert-butyl ((1s,3s)-3-aminocyclobutyl)carbamate (50 mg, 268 μmol, 0.3 equiv.) were then added, and the reaction was stirred at room temperature for 30 minutes. The solvent was evaporated and the crude material was purified by flash chromatography (silica gel, 20 g, 0% to 100% DCM / MeOH / NH4OH (95 / 5 / 1)) to give the title compound (416 mg, 719 μmol, 80.3% yield) as a light brown solid. MS (ESI, m / z): 579.4 [M+H] + .

[0724] Process 2) N-((1s,3s)-3-aminocyclobutyl)-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamide

[0725] Under argon, tert-butyl ((1s,3s)-3-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)cyclobutyl)carbamate (416 mg, 719 μmol, 1 equiv.) was suspended in DCM (11 mL). TFA (2.87 g, 1.94 mL, 25.2 mmol, 35 equiv.) was added, and the solution was stirred at room temperature for 1 h. DCM / MeOH / NH was added until the TFA was neutralized and the RM evaporated. The crude product was purified by flash chromatography (silica gel, 20 g, 0% to 100% DCM (DCM / MeOH / NHOH (90 / 10 / 1))) to give the title compound (272 mg, 568 μmol, 79.1% yield) as a pale yellow solid. MS (ESI, m / z): 479.4 [M + H] + .

[0726] Process 3) 2-(((1s,3s)-3-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)cyclobutyl)amino)-N,N,N-trimethyl-2-oxoethan-1-aminium chloride

[0727] Under argon, N-((1s,3s)-3-aminocyclobutyl)-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamide (60 mg, 125 μmol, 1 equiv.) was dissolved in DMF (1.23 ml). Betaine (21.2 mg, 138 μmol, 1.1 equiv.) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (HATU) (52.4 mg, 138 μmol, 1.1 equiv.) were added. DIPEA (32.4 mg, 43.8 μL, 251 μmol, 2 equiv.) was added. The reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the crude product was purified by preparative reverse-phase HPLC under acidic conditions to give the title compound (18 mg, 29.3 μmol, 23.4% yield) as a white solid. MS (ESI, m / z): 578.5 [M] + .

[0728] Example 73 3-(2-chloro-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzamido)-N-(2-hydroxyethyl)-N,N-dimethylpropan-1-aminium formate [ka]

[0729] Process 1) 2-chloro-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N-(3-((2-hydroxyethyl)amino)propyl)benzamide

[0730] 2-Chloro-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoic acid (Intermediate 5, 75 mg, 174 μmol, 1 equiv.) and HATU (79.4 mg, 209 μmol, 1.2 equiv.) were dissolved in DMF (1.74 ml). DIPEA (90 mg, 122 μl, 696 μmol, 4 equiv.) was added and the reaction mixture was stirred for 20 minutes. 2-((3-aminopropyl)amino)ethan-1-ol (24.7 mg, 24.5 μl, 209 μmol, 1.2 equiv.) was added and the reaction mixture was stirred for 1 hour. The mixture was purified by preparative HPLC and the solution was concentrated in vacuo to give the title compound (55 mg, 103 μmol, 56.5% yield) as a white amorphous solid. MS (ESI, m / z): 531.4 [M + H] + .

[0731] Process 2) 3-(2-chloro-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzamido)-N-(2-hydroxyethyl)-N,N-dimethylpropan-1-aminium formate

[0732] 2-Chloro-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N-(3-((2-hydroxyethyl)amino)propyl)benzamide (27 mg, 50.9 μmol, 1 equiv.), MeI (18 mg, 7.95 μl, 127 μmol, 2.5 equiv.), and DIPEA (9.86 mg, 13.3 μl, 76.3 μmol, 1.5 equiv.) were mixed together in DMF (500 μl). The reaction mixture was stirred at room temperature for 16 hours and then purified by preparative separation. HPLC afforded the title compound (18 mg, 29.7 μmol, 55.6% yield) as an off-white amorphous solid. MS (ESI, m / z): 559.4 [M] + .

[0733] Example 74 N-(cyanomethyl)-2-(2-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)ethoxy)-N,N-dimethylethan-1-aminium formate [ka]

[0734] Step 1) Intermediate 23 4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N-(2-(2-(dimethylamino)ethoxy)ethyl)-2-ethylbenzamide

[0735] 4-((3-(2,3-Difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzoic acid (Intermediate 8, 400 mg, 942 μmol, 1 equiv.) was combined with DMF (8 mL). DIPEA (365 mg, 494 μl, 2.83 mmol, 3 equiv.) and HATU (717 mg, 1.88 mmol, 2 equiv.) were added. This was stirred at room temperature for 15 minutes. Then, 2-(2-aminoethoxy)-N,N-dimethylethan-1-amine (187 mg, 1.41 mmol, 1.5 equiv.) was added. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with HO and extracted with DCM (2×100 mL). The organic layer was washed with 50 mL of brine, dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 25 g, 0% to 100% DCM / MeOH / NHOH (100:10:1):DCM) to give the title compound (395.4 mg, 734 μmol, 77.9% yield) as a light brown solid. MS (ESI, m / z): 539.3 [M+H] + .

[0736] Process 2) N-(cyanomethyl)-2-(2-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)ethoxy)-N,N-dimethylethan-1-aminium formate

[0737] 4-((3-(2,3-Difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N-(2-(2-(dimethylamino)ethoxy)ethyl)-2-ethylbenzamide (25 mg, 46.4 μmol, 1 equiv.) and 2-bromoacetonitrile (27.8 mg, 16.2 μl, 232 μmol, 5 equiv.) were mixed together in MeCN (500 μl). The reaction mixture was refluxed for 3 h. The mixture was then diluted with DCM, concentrated in vacuo, and purified by preparative separation. HPLC afforded the title compound (16 mg, 25.6 μmol, 52.5% yield) as a white amorphous solid. MS (ESI, m / z): 578.4 [M] + .

[0738] Example 75 N-(2-(2-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)ethoxy)ethyl)-2-ethoxy-N,N-dimethyl-2-oxoethan-1-aminium formate [ka]

[0739] 4-((3-(2,3-Difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N-(2-(2-(dimethylamino)ethoxy)ethyl)-2-ethylbenzamide (Intermediate 23, 25 mg, 46.4 μmol, 1 equiv.) and ethyl 2-iodoacetate (72.4 mg, 40 μl, 338 μmol, 7.29 equiv.) were mixed together in MeCN (1 ml). The reaction mixture was refluxed for 4 hours. It was then concentrated and purified by preparative separation. HPLC afforded the title compound (14 mg, 20.8 μmol, 42.7% yield) as a white amorphous solid. MS (ESI, m / z): 625.5 [M] + .

[0740] Example 76 Mono(N-(2-amino-2-oxoethyl)-5-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)-N,N-dimethylpentan-1-aminium) monoformate monoiodide [ka]

[0741] Process 1) 4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N-(5-(dimethylamino)pentyl)-2-ethylbenzamide

[0742] 4-((3-(2,3-Difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzoic acid (Intermediate 8, 200 mg, 471 μmol, 1 equiv.) and HATU (215 mg, 565 μmol, 1.2 equiv.) were dissolved in DMF (2 mL). N1,N1-Dimethylpentane-1,5-diamine (73.6 mg, 85.6 μl, 565 μmol, 1.2 equiv.) and DIPEA (128 mg, 173 μl, 990 μmol, 2.1 equiv.) were added sequentially. The reaction mixture was stirred at room temperature for 30 min. Water was added, and the reaction was extracted three times with 20 mL of DCM. The organic layers were combined, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash chromatography (25 g, 0-100% EtOAc / / EtOAc / MeOH / NH3 (75 / 23 / 2)). The solution was concentrated in vacuo to give the title compound (217 mg, 404 μmol, 81.5% yield) as an off-white solid. MS (ESI, m / z): 537.4 [M+H] + .

[0743] Process 2) Mono(N-(2-amino-2-oxoethyl)-5-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)-N,N-dimethylpentan-1-aminium) monoformate monoiodide

[0744] 4-((3-(2,3-Difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N-(5-(dimethylamino)pentyl)-2-ethylbenzamide (66 mg, 123 μmol, 1 equiv.) was dissolved in DCM (1.5 ml). 2-Iodoacetamide (114 mg, 49.5 μl, 615 μmol, 5 equiv.) was added and the reaction mixture was stirred at room temperature for 4 h. The reaction was then concentrated in vacuo and purified by preparative HPLC to give the title compound (45 mg, 66.1 μmol, 51.5% yield) as a white amorphous solid (a 50 / 50 mixture of formate and iodide). MS (ESI, m / z): 594.5 [M] + .

[0745] Example 77 trans-[2-[[4-[[4-[[3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethylbenzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-trimethylazanium formate [ka]

[0746] Process 1) tert-Butyl ((1r,4r)-4-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)cyclohexyl)carbamate

[0747] Under argon, 4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzoic acid hydrochloride (Intermediate 8, 295 mg, 640 μmol, 1 eq) was dissolved in DMF (3.69 ml). N-Ethyl-N-isopropylpropan-2-amine (414 mg, 544 μl, 3.2 mmol, 5 equiv.), trans-tert-butyl((1r,4r)-4-aminocyclohexyl)carbamate (165 mg, 768 μmol, 1.2 equiv.), and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (HATU) (487 mg, 1.28 mmol, 2 equiv.) were added, and the yellow solution was stirred at room temperature for 1 h. The solvent was evaporated and the crude material was purified by flash chromatography (silica gel, 20 g, 0% to 100% DCM:DCM / MeOH / NH4OH (90 / 10 / 1)) to give the title compound (448 mg, 722 μmol, 101% yield) as a yellow solid.

[0748] Process 2) N-((1r,4r)-4-aminocyclohexyl)-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamide

[0749] Under argon, tert-butyl ((1r,4r)-4-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)cyclohexyl)carbamate (397 mg, 640 μmol, 1 equiv.) was suspended in MeOH (4.3 ml). 4 M HCl in dioxane (1.6 ml, 6.4 mmol, 10 equiv.) was added and the reaction mixture was stirred at room temperature for 2 days. 4 M HCl in dioxane (1.6 ml, 6.4 mmol, 10 equiv.) was added again and the mixture was stirred at room temperature over the weekend. DCM / MeOH / NH3 was added until the HCl was neutralized and the reaction mixture was evaporated. The crude product was purified by reverse-phase chromatography under basic conditions to give the title compound (55 mg, 105 μmol, 16.5% yield) as an off-white solid. MS (ESI, m / z): 521.4 [M+H] + .

[0750] Process 3) trans-[2-[[4-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-trimethylammonium formate

[0751] Under argon, betaine hydrochloride (17.9 mg, 116 μmol, 1.1 equivalents) was combined in DMF (1.04 ml). 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (HATU) (44.2 mg, 116 μmol, 1.1 equivalents) and DIPEA (27.3 mg, 36.9 μl, 211 μmol, 2 equivalents) were added. The reaction mixture was stirred at room temperature for 30 minutes. N-((1r,4r)-4-aminocyclohexyl)-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamide (55 mg, 106 μmol, 1 equiv.) was added and the reaction was stirred at room temperature for 1 hour. Betaine hydrochloride (17.9 mg, 116 μmol, 1.1 equiv.), DIPEA (27.3 mg, 36.9 μl, 211 μmol, 2 equiv.), and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (HATU) (44.2 mg, 116 μmol, 1.1 equiv.) were then added again and the reaction mixture was stirred at room temperature for 30 minutes. The solvent was evaporated and the crude product was then purified by preparative reverse-phase HPLC under acidic conditions (formic acid) to give the title compound (27 mg, 40.5 μmol, 38% yield) as an off-white powder. MS (ESI, m / z): 620.5 [M] + .

[0752] Example 4 1-(cyanomethyl)-1-(2-(2-(4-((3-(1-(cyanomethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)ethoxy)ethyl)pyrrolidin-1-ium formate [ka]

[0753] Process 1) Methyl 4-amino-2-ethylbenzoate

[0754] Methyl 4-amino-2-bromobenzoate (20 g, 82.6 mmol, 1 equiv.) was combined with DMF (80 mL). At room temperature, a 1.0 M solution of triethylborane in THF (125 mL, 125 mmol, 1.51 equiv.) was added dropwise over 15 minutes. Potassium carbonate (17.1 g, 124 mmol, 1.5 equiv.) was added. Under an argon atmosphere, Pd(Ph3P)4 (477 mg, 413 μmol, 0.005 equiv.) was added. The yellow suspension was heated to 85°C and stirred for 2 hours. The reaction mixture was poured into 400 mL of ice / water mixture and extracted with 600 mL and 300 mL of EtOAc. The organic layer was washed with 250 mL of brine and dried over Na2SO4. The crude material was purified by flash chromatography (silica gel, 330 g, 0% to 30% EtOAc in heptane) to give the title compound (12.56 g, 70.1 mmol, 84.9% yield) as a white solid. MS (ESI, m / z): 180.1 [M+H] + .

[0755] Step 2) Intermediate 31 Methyl 2-ethyl-4-((3-iodoimidazo[1,2-a]pyrazin-8-yl)amino)benzoate hydrochloride

[0756] 8-Chloro-3-iodoimidazo[1,2-a]pyrazine (Intermediate 1, 16.05 g, 57.4 mmol, 1 equiv.) and methyl 4-amino-2-ethylbenzoate (12.56 g, 70.1 mmol, 1.22 equiv.) were combined with acetonitrile (70 ml) and acetic acid (7 ml). The reaction mixture was heated to 85°C (reflux) and stirred for 15 hours. The reaction was allowed to reach room temperature. The mixture was filtered through a sintered glass filter and washed with 150 ml of ACN / MeOH 1:1. The resulting solid was dried in vacuo to give the title compound (25.76 g, 56.2 mmol, 97.8% yield) as a pale yellow crystalline solid. MS (ESI, m / z): 423.2 [M+H] + .

[0757] Process 3) Methyl 2-ethyl-4-((3-(3-(trifluoromethyl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoate

[0758] To methyl 2-ethyl-4-((3-iodoimidazo[1,2-a]pyrazin-8-yl)amino)benzoate hydrochloride (2 g, 4.36 mmol, 1 equiv.), (3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (1.41 g, 7.85 mmol, 1.8 equiv.), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (534 mg, 654 μmol, 0.15 equiv.), and NaCO (1.06 g, 10 mmol, 2.3 equiv.) was added a degassed solution of dioxane (35 mL) / water (8 mL). The mixture was stirred at 110 °C overnight. The reaction mixture was poured into 75 mL of saturated NaCl and extracted with EtOAc (3 × 75 mL). The organic layers were combined, adsorbed onto Isolute, and purified by flash chromatography (silica gel, SiliCycle 20 g cartridge (40-63 μm), 10% to 100% EtOAc in heptane) to give the title compound (1.534 g, 2.74 mmol, 62.9% yield). MS (ESI, m / z): 431.3 [M+H] + .

[0759] Step 4) Intermediate 32 2-Ethyl-4-((3-(3-(trifluoromethyl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoic acid

[0760] Methyl 2-ethyl-4-((3-(3-(trifluoromethyl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoate (1.534 g, 2.74 mmol, 1 equiv.) was treated with LiOH·HO (576 mg, 13.7 mmol, 5 equiv.) in a mixture of THF (40 mL), MeOH (10 mL), and water (10 mL) at 65 °C overnight. The organic solvent was removed under vacuum. The mixture was dissolved in water and acetic acid (4 mL) was added with stirring. The resulting white suspension was filtered, washed with water, and dried under vacuum to give the title compound (1.168 g, 2.3 mmol, 83.8% yield) as white crystals. MS (ESI, m / z): 417.2 [M+H] + .

[0761] Step 5) 2-Ethyl-N-(2-(2-(pyrrolidin-1-yl)ethoxy)ethyl)-4-((3-(3-(trifluoromethyl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl)amino)benzamide

[0762] To a mixture of 2-ethyl-4-((3-(3-(trifluoromethyl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoic acid (125 mg, 300 μmol, 1 equiv.), TBTU (119 mg, 360 μmol, 1.2 equiv.), and TEA (209 μl, 1.5 mmol, 5 equiv.) in DMF (10 mL) was added 2-(2-(pyrrolidin-1-yl)ethoxy)ethan-1-amine (61.7 mg, 390 μmol, 1.3 equiv.). The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, then diluted with 15 mL of 1 M KHSO4 and extracted with EtOAc (3×10 mL). The solution was concentrated in vacuo, and the resulting material was used without further purification. MS (ESI, m / z): 557.3 [M+H] + .

[0763] Process 6) 1-(cyanomethyl)-1-(2-(2-(4-((3-(1-(cyanomethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)ethoxy)ethyl)pyrrolidin-1-ium formate

[0764] 2-Ethyl-N-(2-(2-(pyrrolidin-1-yl)ethoxy)ethyl)-4-((3-(3-(trifluoromethyl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl)amino)benzamide (22.3 mg, 40 μmol, 1 equiv.) was dissolved in DMF (2 ml). Potassium carbonate (13.8 mg, 100 μmol, 2.5 equiv.) was added, followed by 2-bromoacetonitrile (28.8 mg, 60 μmol, 1.5 equiv.). The mixture was stirred overnight at room temperature. The reaction mixture was purified by preparative HPLC to give the title compound (8.1 mg, 11.9 μmol, 29.7% yield). MS (ESI, m / z): 635.4 [M] + .

[0765] Example 78 4-(cyanomethyl)-4-(2-(2-(4-((3-(1-(cyanomethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)ethoxy)ethyl)morpholin-4-ium formate [ka]

[0766] Process 1) 2-Ethyl-N-(2-(2-morpholinoethoxy)ethyl)-4-((3-(3-(trifluoromethyl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl)amino)benzamide

[0767] The title compound (7 mg, 12 μmol, 1.7% yield) was obtained in the same manner as in Example 4, Step 5, using 2-(2-morpholinoethoxy)ethan-1-amine and Intermediate 32. MS (ESI, m / z): 573.4 [M+H] + .

[0768] Process 2) 4-(cyanomethyl)-4-(2-(2-(4-((3-(1-(cyanomethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)ethoxy)ethyl)morpholin-4-ium formate

[0769] The title compound (4.35 mg, 6 μmol, yield 15.6%) was obtained in the same manner as in Example 4, Step 6. MS (ESI, m / z): 651.4 [M] + .

[0770] Example 9 1-(2-amino-2-oxoethyl)-4-(4-(4-((3-(4-(difluoromethoxy)-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzoyl)piperazine-1-carbonyl)-1-methylpiperidin-1-ium formate [ka]

[0771] Step 1) Intermediate 33 2-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0772] 1-Bromo-4-(difluoromethoxy)-2,3-difluorobenzene (1 g, 3.86 mmol, 1 equiv.), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2 dioxaborolane) (1.18 g, 4.63 mmol, 1.2 equiv.), Pd(dppf)Cl2 (315 mg, 386 μmol, 0.1 equiv.), and potassium acetate (1.14 g, 11.6 mmol, 3 equiv.) were placed in a microwave vial. The vessel was sealed, evacuated, and backfilled with nitrogen five times. DMSO (19.3 ml) was injected. The reaction was heated at 80 °C for 24 h. The mixture was poured into 100 mL of water. The aqueous phase was extracted with EtOAc (50 mL × 3). The organic layers were combined, washed with br...

Claims

1. Formula (I) 【Chemistry 1】 (In the formula, R ｘ is the base 【Chemistry 2】 or base 【Transformation 3】 and R １ is R ６ -C １ -C ６ -alkyl-, R ６ -C １ -C ６ -Alkyl-CH(C １ -C ６ -alkoxycarbonyl)-, R ７ -C １ -C ６ -Alkyl-X-C １ -C ６ -alkyl-, group 【Chemistry 4】 and groups 【Transformation 5】 is selected from R ２ is hydrogen and C １ -C ６ alkyl, or R １ and R ２ together with the nitrogen atom to which they are attached, R ９ and R ９ａ forming a 3- to 14-membered heterocycle substituted with R ３ is hydrogen, halogen and C １ -C ６ - alkyl, or R ３ and R ２ together with the atoms to which they are attached form a 3- to 14-membered heterocyclic ring, R ４ is the base 【Transformation 6】 and R ５ is hydrogen, C １ -C ６ - selected from alkyl, and halogen; R ６ is a group R １６ -L ２ - and R ７ is a group R １６ -L ３ - and R ８ is a group R １６ -L ４ - and R ８ａ , R ９ａ , R １１ａ , R １２ , R １８ , R １９ , R ２０ , R ２１ , R ２２ , R ２３ , R ２４ and R ２５ are independently hydrogen, halogen, hydroxy, cyano, amino, carbamoyl, carboxy, C １ -C ６ -Alkyl, C １ -C ６ -alkoxy, halo-C １ -C ６ -Alkyl, cyano-C １ -C ６ -Alkyl, carboxy-C １ -C ６ -Alkyl, hydroxy-C １ -C ６ -Alkyl, halo-C １ -C ６ -alkoxy, cyano-C １ -C ６ -alkoxy, C ２ -C ６ -alkynyloxy, amino-C ２ -C ６ -alkynyloxy, aryloxy, (5- to 14-membered heteroaryl)oxy, C １ -C ６ -alkyl-(5- to 14-membered heteroaryl)oxy) and C １ -C ６ -alkoxycarbonyl, R ９ is a group R １６ -L ５ - or group 【Transformation 7】 and R １０ is C １ -C ６ -Alkyl, C １ -C ６ -alkoxycarbonyl-C １ -C ６ -Alkyl, C １ -C ６ -Alkyl-NH-C １ -C ６ -Alkyl, amino-C １ -C ６ -Alkyl, carbamoyl, carbamoyl-C １ -C ６ -Alkyl, carboxy-C １ -C ６ -Alkyl, cyano-C １ -C ６ -Alkyl, halo-C １ -C ６ -Alkyl, hydroxy-C １ -C ６ - alkyl and groups 【Transformation 8】 is selected from R １１ is C １ -C ６ -Alkyl, carbamoyl, carboxy, carboxy-C １ -C ６ -Alkyl and hydroxy-C １ -C ６ - alkyl, R １３ and R １４ are independently １ -C ６ -Alkyl, amino-C １ -C ６ -Alkyl, carbamoyl-C １ -C ６ -Alkyl, carboxy-C １ -C ６ -Alkyl, cyano-C １ -C ６ -Alkyl, hydroxy-C １ -C ６ -Alkyl, halo-C １ -C ６ -Alkyl, C １ -C ６ -alkoxycarbonyl-C １ -C ６ - alkyl, and groups 【Chemistry 9】 Selected from or or R １３ and R １４ together with the nitrogen atom to which they are attached, represent halogen, amino, hydroxy, cyano, C １ -C ６ -Alkyl, halo-C １ -C ６ -Alkyl, C １ -C ６ -alkoxy and halo-C １ -C ６ -alkoxy, R １５ is C １ -C ６ - alkyl, R １６ is the base 【Chemistry 10】 base 【Chemistry 11】 and groups 【Chemistry 12】 is selected from R １７ is a group R １６ -L ７ - and L １ represents a covalent bond, a carbonyl, and -C １ -C ６ -alkyl-, L ２ and L ３ are independently a covalent bond, a carbonyl, -C １ -C ６ -Alkyl-C(O)-NH-, -C(O)-NH-, -NH-C(O)-, -C(O)-NH-CH(C １ -C ６ -alkoxycarbonyl)-, -C １ -C ６ -Alkyl-CH(OH)-C １ -C ６ -alkyl-C(O)-, and -C １ -C ６ -alkyl-NH-; L ４ , L ５ , L ６ , L ７ , and L ８ are independently a covalent bond, a carbonyl, -C １ -C ６ -Alkyl-, -C １ -C ６ -Alkyl-C(O)-, -C １ -C ６ -Alkyl-NH-C(O)-, -C １ -C ６ -Alkyl-C(O)-NH-, -C １ -C ６ -Alkyl-NH-C(O)-C １ -C ６ -Alkyl-, -C １ -C ６ -Alkyl-C(O)-NH-C １ -C ６ -Alkyl-, -C(O)-NH-, -NH-C(O)-, -C(O)-NH-CH(C １ -C ６ -alkoxycarbonyl)-, -C １ -C ６ -Alkyl-CH(OH)-C １ -C ６ -alkyl-C(O)-, and -C １ -C ６ -alkyl-NH-; L ９ is -C １ -C ６ -alkyl- or -C(O)-C １ -C ６ -alkyl-, A, C, D, and E are each independently C ６ -C １０ -aryl, C ３ -C １０ - selected from cycloalkyl, 3- to 14-membered heterocyclyl, and 5- to 14-membered heteroaryl; B is a 3- to 14-membered heterocycle; F is C ６ -C １０ -aryl or 5-14 membered heteroaryl, and X is O, S, SO, SO ２ , NH, and N(C １ -C ６ -alkyl) or a pharmaceutically acceptable salt thereof, The compound of formula (I) may be the following compound: 2-(2-(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)ethoxy)-N,N,N-trimethylethanaminium iodide (Compound 1); 2-[1-[4-[[3-[4-(cyanomethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]-4-piperidyl]ethyl-trimethyl-ammonium formate (compound 2); 4-[[3-[4-(4-aminobut-2-ynoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-N-[2-(1,1-dimethylpiperidin-1-ium-4-yl)ethyl]-N,2-dimethyl-benzamidoformate formate (compound 5); 2-(2-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)ethoxy)-N,N,N-trimethylethanaminium formate (compound 13); 2-[4-[2-bromo-4-[[3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]piperazin-1-yl]ethyl-trimethyl-ammonium 2,2,2-trifluoroacetate (compound 14); 2-[2-[[4-[[3-(2,3-difluoro-4-prop-2-ynoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]ethoxy]ethyl-trimethyl-ammonium 2,2,2-trifluoroacetate (compound 15); 2-[2-[6-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethoxy]ethyl-trimethyl-ammonium formate (compound 16); 4-[2-[2-[[2-chloro-4-[[3-[4-(cyanomethoxy)-2,3-difluorophenyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]ethoxy]ethyl]-4-methyl-piperazin-4-ium-2-carboxylic acid formate (compound 17); 4-(2-(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N,2-dimethylbenzamido)ethyl)-1,1-dimethylpiperidin-1-ium formate (compound 19); 1-ethyl-4-(2-(4-((3-(4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)ethyl)-1-methylpiperidin-1-ium formate (compound 20); 2-chloro-4-[[3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-N-[2-(4,4-dimethylpiperazin-4-ium-1-yl)ethyl]-N-methyl-benzamide 2,2,2-trifluoroacetate (compound 21); 4-[[3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-N-[2-(1,1-dimethylpiperidin-1-ium-4-yl)ethyl]-N,2-dimethyl-benzamide 2,2,2-trifluoroacetate (compound 22); 1-(carboxymethyl)-4-(2-(4-((3-(4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)ethyl)-1-methylpiperidin-1-ium formate (compound 23); 4-(2-(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N,2-dimethylbenzamido)ethyl)-1,1-diethylpiperidin-1-ium formate (compound 24); 6-(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)-N,N,N-trimethylhexane-1-aminium formate (compound 25); 2-[4-[2-chloro-4-[[3-[4-(cyanomethoxy)-2,3-difluorophenyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]piperazin-1-yl]ethyl-trimethylazanium iodide (Compound 26); 2-(1-(4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperidine-4-carboxamide)-N,N,N-trimethylethanaminium formate (compound 27); 3-(4-((3-(4-chloro-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)-N,N,N-trimethylpropan-1-aminium formate (compound 28); 2-(1-(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperidin-4-yl)-N,N,N-trimethylethanaminium formate (compound 29); [4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-phenyl]-[4-(4,4-dimethylpiperazin-4-ium-1-carbonyl)piperazin-1-yl]methanone formate (compound 30); [2-[4-[2-chloro-4-[[3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]piperazin-1-yl]-2-oxoethyl]trimethylazanium formate (compound 31); 2-(4-(4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperazin-1-yl)-N,N,N-trimethyl-2-oxoethane-1-aminium iodide (compound 32); [4-[4-[4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]piperazine-1-carbonyl]morpholin-2-yl]methyltrimethylammonium formate (compound 33); 2-chloro-4-[[3-[4-(cyanomethoxy)-2,3-difluorophenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-N-[2-(4,4-dimethylpiperazin-4-ium-1-yl)ethyl]-N-methyl-benzamide iodide (compound 34); 2-(2-(4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N,2-dimethylbenzamido)ethoxy)-N,N,N-trimethylethane-1-aminium chloride (compound 35); 2-[[4-[4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]piperazine-1-carbonyl]amino]ethyl-trimethyl-ammonium formate (compound 36); 2-[[(3S,4R)-1-[4-[[3-(3-fluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]-3-hydroxy-piperidine-4-carbonyl]amino]ethyl-trimethyl-ammonium formate (compound 37); 2-chloro-4-[[3-[4-(cyanomethoxy)-2,3-difluorophenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-N-[2-(1,1-dimethylpiperidin-1-ium-4-yl)ethyl]-N-methyl-benzamide 2,2,2-trifluoroacetate (compound 38); 4-(4-(2-(4-((3-(4-(difluoromethoxy)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-N,2-dimethylbenzamido)ethyl)piperidin-1-yl)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium formate (compound 39); 2-(2-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)ethoxy)-N,N,N-triethylethan-1-aminium formate (compound 40); 2-[2-[[4-[[3-[4-(cyanomethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]ethoxy]ethyltrimethylammonium iodide (compound 41); [2-[4-[4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]piperazin-1-yl]-2-oxoethyl]-trimethylammonium chloride (compound 42); 2-[2-[[4-[[3-[2-chloro-4-(cyanomethoxy)-3-fluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]ethoxy]ethyltrimethylammonium iodide (compound 43); 2-[2-[[2-bromo-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]ethoxy]ethyl-trimethyl-ammonium 2,2,2-trifluoroacetate (compound 44); 2-[2-[[2-chloro-4-[[3-[4-(cyanomethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]ethoxy]ethyl-tripropylammonium iodide (compound 45); 2-chloro-4-[[3-[4-(cyanomethoxy)-2,3-difluorophenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-N-[2-[2-(1-methylpyrrolidin-1-ium-1-yl)ethoxy]ethyl]benzamidoformate (compound 46); 3-[[2-chloro-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]propyltrimethylammonium formate (compound 47); 3-[[2-chloro-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]propyltriethylammonium formate (compound 48); Tributyl-[3-[[2-chloro-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]propyl]ammonium formate (compound 49); Carboxymethyl-[2-[2-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]ethoxy]ethyl]-dimethyl-ammonium formate (compound 50); 2-[2-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]ethoxy]ethyl-(2-hydroxyethyl)-dimethyl-ammonium formate (compound 51); (2-amino-2-oxo-ethyl)-[2-[2-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]ethoxy]ethyl]-dimethyl-ammonium formate (compound 52); 3-carboxypropyl-[2-[2-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]ethoxy]ethyl]-dimethyl-ammonium formate (compound 53); 2-(4-(2-chloro-4-((3-(4-(cyanomethoxy)-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoyl)piperazin-1-yl)-N,N,N-trimethyl-2-oxoethane-1-aminium formate (compound 54); N-[3-[[4-[[3-(2,3-difluoro-4-pyrimidin-2-yloxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]propyl]-1-methyl-1-(pyrrolidin-3-ylmethyl)piperidin-1-ium-4-carboxamide formate (compound 3); 1-(cyanomethyl)-1-(2-(2-(4-((3-(1-(cyanomethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)ethoxy)ethyl)pyrrolidin-1-ium formate (compound 4); [2-[3-[[2-chloro-4-[[3-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]propylamino]-2-oxoethyl]trimethylammonium formate (compound 7); Azetidin-3-ylmethyl-(carboxymethyl)-[5-[[4-[[3-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]pentyl]-methyl-ammonium formate (compound 8); 1-(2-amino-2-oxoethyl)-4-(4-(4-((3-(4-(difluoromethoxy)-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzoyl)piperazine-1-carbonyl)-1-methylpiperidin-1-ium formate (compound 9); N-[2-[1-(Azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]ethyl]-4-[[3-[4-(difluoromethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide diformate (compound 10); 5-aminopentyl-(carboxymethyl)-[5-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]pentyl]-methyl-ammonium 2,2,2-trifluoroacetate (compound 11); 2-(4-(2-chloro-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzoyl)piperazin-1-yl)-N,N,N-trimethyl-2-oxoethane-1-aminium iodide (compound 12); 2-(2-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-fluoro-6-methylbenzamido)ethoxy)-N,N,N-trimethylethane-1-aminium hydrogen carbonate (compound 18); (2S,4R)-2-(4-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzoyl)piperazine-1-carbonyl)-4-hydroxy-1,1-dimethylpyrrolidin-1-ium formate (compound 55); [2-[4-[4-[[3-[4-(cyanomethoxy)-2,3-difluorophenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methylbenzoyl]piperazin-1-yl]-2-oxoethyl]trimethylazanium iodide (compound 56); 4-[4-[2-[[4-[[3-[4-(difluoromethoxy)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methylbenzoyl]-methylamino]ethyl]-1-methylpiperidin-1-ium-1-yl]butanoic acid hydrochloride (compound 57); [2-[2-[[2-chloro-4-[[3-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]ethylamino]-2-oxoethyl]trimethylammonium formate (compound 58); [2-[[3-[[2-chloro-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]cyclobutyl]amino]-2-oxoethyl]trimethylammonium formate (compound 59); 2-(4-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)piperidin-1-yl)-N,N,N-trimethyl-2-oxoethane-1-aminium chloride (compound 60); [2-[[3-[[2-chloro-4-[[3-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]cyclobutyl]amino]-2-oxoethyl]trimethylammonium formate (compound 61); [2-[4-[2-chloro-4-[[3-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]piperazin-1-yl]-2-oxoethyl]trimethylammonium formate (compound 62); 2-(((1s,4s)-4-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)cyclohexyl)amino)-N,N,N-trimethyl-2-oxoethane-1-aminium chloride (compound 63); [2-[4-[4-[[3-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-methyl-benzoyl]piperazin-1-yl]-2-oxoethyl]trimethylammonium formate (compound 64); [2-[4-[2-chloro-4-[[3-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]piperazin-1-yl]-2-oxoethyl]trimethylammonium formate (compound 65); 2-[[3-[[2-chloro-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]cyclobutyl]amino]ethyl-trimethyl-ammonium formate (compound 66); (S)-2-(3-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)pyrrolidin-1-yl)-N,N,N-trimethyl-2-oxoethane-1-aminium chloride (compound 67); 2-(3-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)piperidin-1-yl)-N,N,N-trimethyl-2-oxoethane-1-aminium chloride (compound 68); 2-(((1r,4r)-4-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)cyclohexyl)amino)-N,N,N-trimethyl-2-oxoethane-1-aminium chloride (compound 69); (R)-2-(3-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)pyrrolidin-1-yl)-N,N,N-trimethyl-2-oxoethane-1-aminium chloride (compound 70); 2-amino-N-(2-(3-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)azetidin-1-yl)-2-oxoethyl)-N,N-dimethyl-2-oxoethane-1-aminium formate (compound 71); 2-(((1s,3s)-3-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-methylbenzamido)cyclobutyl)amino)-N,N,N-trimethyl-2-oxoethane-1-aminium chloride (compound 72); 3-(2-chloro-4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)benzamido)-N-(2-hydroxyethyl)-N,N-dimethylpropan-1-aminium formate (compound 73); N-(cyanomethyl)-2-(2-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)ethoxy)-N,N-dimethylethane-1-aminium formate (compound 74); N-(2-(2-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)ethoxy)ethyl)-2-ethoxy-N,N-dimethyl-2-oxoethan-1-aminium formate (compound 75); mono(N-(2-amino-2-oxoethyl)-5-(4-((3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)-N,N-dimethylpentan-1-aminium) monoformate monoiodide (compound 76); trans-[2-[[4-[[4-[[3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethylbenzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-trimethylazanium formate (Compound 77); 4-(cyanomethyl)-4-(2-(2-(4-((3-(1-(cyanomethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)ethoxy)ethyl)morpholin-4-ium formate (compound 78); 5-[[4-[[3-[4-(difluoromethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]pentyl-dimethyl-(2-oxo-2-piperazin-1-yl-ethyl)ammonium bis(2,2,2-trifluoroacetate) (compound 79); N-[[3-(azetidin-3-ylmethyl)-3-methyl-3-azoniabicyclo[3.1.0]hexan-6-yl]methyl]-4-[[3-[4-(difluoromethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide bis(2,2,2-trifluoroacetate) (compound 80); 1-(azetidin-3-ylmethyl)-4-(4-(4-((3-(4-(difluoromethoxy)-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzoyl)piperazine-1-carbonyl)-1-methylpiperidin-1-ium 2,2,2-trifluoroacetate (compound 81); N-[3-[[4-[[3-[4-(difluoromethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]propyl]-1-methyl-1-(pyrrolidin-3-ylmethyl)piperidin-1-ium-4-carboxamide bis(2,2,2-trifluoroacetate) (Compound 82); [4-[1-(2-aminoethyl)-1-methyl-piperidin-1-ium-4-carbonyl]piperazin-1-yl]-[4-[[3-[4-(difluoromethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-phenyl]methanone bis(2,2,2-trifluoroacetate) (compound 83); [4-[[3-[4-(difluoromethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-phenyl]-[4-[1-methyl-1-(pyrrolidin-3-ylmethyl)piperidin-1-ium-4-carbonyl]piperazin-1-yl]methanone bis(2,2,2-trifluoroacetate) (compound 84); [4-[[3-[4-(difluoromethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-phenyl]-[4-[1-methyl-1-[2-(methylamino)ethyl]piperidin-1-ium-4-carbonyl]piperazin-1-yl]methanone bis(2,2,2-trifluoroacetate) (compound 85); [4-[1-[(3-amino-1-bicyclo[1.1.1]pentanyl)methyl]-1-methyl-piperidin-1-ium-4-carbonyl]piperazin-1-yl]-[4-[ [3-[4-(difluoromethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-phenyl]methanone bis(2,2,2-trifluoroacetate) (compound 86); N-[[1-(Azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-4-[[3-[4-(difluoromethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide diformate (compound 87); N-[[1-(Azetidin-3-ylmethyl)-1-methyl-pyrrolidin-1-ium-3-yl]methyl]-4-[[3-[4-(difluoromethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide bis(2,2,2-trifluoroacetate) (compound 88); Bis(azetidin-3-ylmethyl)-[5-[[4-[[3-[4-(difluoromethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]pentyl]-methyl-ammonium bis(2,2,2-trifluoroacetate) (compound 89); N-[2-[1-(Azetidin-3-ylmethyl)-1-methyl-azetidin-1-ium-3-yl]ethyl]-4-[[3-[4-(difluoromethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide diformate (compound 90); N-[2-[1-(Azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]ethyl]-4-[[3-[4-(difluoromethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide diformate (compound 91); N-[3-[4-(azetidin-3-ylmethyl)-4-methyl-piperazin-4-ium-1-yl]-3-oxo-propyl]-4-[[3-[4-(difluoromethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide bis(2,2,2-trifluoroacetate) (compound 92); Methyl 4-[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-carbonyl]-1-[4-[[3-[4-(difluoromethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]piperazine-2-carboxylate bis(2,2,2-trifluoroacetate) (compound 93); Methyl 1-[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-carbonyl]-4-[4-[[3-[4-(difluoromethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]piperazine-2-carboxylate tris(2,2,2-trifluoroacetate) (compound 94); [4-[[3-[4-(difluoromethoxy)-2,3-difluorophenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-phenyl]-[2-[1-methyl-1-(pyrrolidin-3-ylmethyl)piperidin-1-ium-4-carbonyl]-2,6-diazaspiro[3.3]heptan-6-yl]methanone bis(2,2,2-trifluoroacetate) (compound 95); Azetidin-3-ylmethyl-[5-[[4-[[3-[4-(difluoromethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]pentyl]-dimethyl-ammonium bis(2,2,2-trifluoroacetate) (compound 96); [4-[[3-[4-(difluoromethoxy)-2,3-difluorophenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-phenyl]-[4-[4-methyl-4-(pyrrolidin-3-ylmethyl)piperazin-4-ium-1-carbonyl]-1-piperidyl]methanone 2,2,2-trifluoroacetate (compound 97); N-[2-[[4-[[3-[4-(difluoromethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]ethyl]-1-methyl-1-(pyrrolidin-3-ylmethyl)piperidin-1-ium-4-carboxamide bis(2,2,2-trifluoroacetate) (compound 102); [4-[[3-[4-(difluoromethoxy)-2,3-difluorophenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-fluorophenyl]-[4-[1-methyl-1-(pyrrolidin-3-ylmethyl)piperidin-1-ium-4-carbonyl]piperazin-1-yl]methanone 2,2,2-trifluoroacetate (compound 103); 3-aminopropyl-(carboxymethyl)-[5-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]pentyl]-methyl-ammonium formate (compound 104); 4-aminobutyl-(carboxymethyl)-[5-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]pentyl]-methyl-ammonium formate (compound 105); Azetidin-3-ylmethyl-(carboxymethyl)-[5-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]pentyl]-methyl-ammonium formate (compound 106); Azetidin-3-ylmethyl-(3-carboxypropyl)-[5-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]pentyl]-methyl-ammonium 2,2,2-trifluoroacetate (compound 107); 2-[[3-[[2-chloro-4-[[3-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]cyclobutyl]amino]ethyl-trimethyl-ammonium formate (compound 108); Azetidin-3-ylmethyl-(carboxymethyl)-[5-[[4-[[3-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]pentyl]-methyl-ammonium formate (compound 109); Carboxymethyl-[5-[[4-[[3-[1-(cyanomethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]pentyl]-dimethyl-ammonium formate (compound 110); Trimethyl-[2-[4-[2-methyl-4-[[3-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]piperazin-1-yl]-2-oxoethyl]ammonium formate (Compound 111); Bis(carboxymethyl)-[5-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]pentyl]-methyl-ammonium 2,2,2-trifluoroacetate (compound 112); Carboxymethyl-[5-[[4-[[3-[1-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]pentyl]-dimethyl-ammonium formate (compound 113); 2-[4-[[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]-1-methyl-piperidin-1-ium-1-yl]acetic acid 2,2,2-trifluoroacetate (compound 115); [2-chloro-4-[[3-[4-(difluoromethoxy)-2,3-difluorophenyl]imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]-[4-[1-methyl-1-(pyrrolidin-3-ylmethyl)piperidin-1-ium-4-carbonyl]piperazin-1-yl]methanone formate (compound 116); N-[3-[[2-chloro-4-[[3-[4-(difluoromethoxy)-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]propyl]-1-methyl-1-(pyrrolidin-3-ylmethyl)piperidin-1-ium-4-carboxamide formate (compound 117); 4-[[3-(2,3-difluoro-4-pyrimidin-2-yloxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-N-[[1-methyl-1-(pyrrolidin-3-ylmethyl)piperidin-1-ium-4-yl]methyl]benzamidoformate (compound 118); [4-[[3-[4-(difluoromethoxy)-2,3-difluorophenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-phenyl]-[4-methyl-4-(pyrrolidin-3-ylmethyl)piperazin-4-ium-1-yl]methanone formate (compound 119); Methyl (2S)-2-[[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-carbonyl]amino]-3-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]propanoate formate 2,2,2-trifluoroacetate (mixed salts) (Compound 120); Methyl (2S)-2-[[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-carbonyl]amino]-4-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]butanoate formate 2,2,2-trifluoroacetate (mixed salt) (compound 121); Methyl (2S)-3-[[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-carbonyl]amino]-2-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]propanoate formate 2,2,2-trifluoroacetate (mixed salts) (Compound 122); Methyl (2S)-2-[[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-carbonyl]amino]-4-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]butanoate formate 2,2,2-trifluoroacetate (mixed salt) (compound 123); Methyl 1-[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-carbonyl]-4-[[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]piperidine-4-carboxylate formate 2,2,2-trifluoroacetate (mixed salt) (Compound 124); Methyl 2-[1-[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-carbonyl]-4-piperidyl]-2-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]-2-acetate formate 2,2,2-trifluoroacetate (mixed salt) (Compound 125); 1-(Azetidin-3-ylmethyl)-N-[3-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]cyclobutyl]-1-methyl-piperidin-1-ium-4-carboxamidoformate 2,2,2-trifluoroacetate (mixed salt) (Compound 126); 1-(Azetidin-3-ylmethyl)-N-[3-[[[4-[[3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]cyclobutyl]-1-methyl-piperidin-1-ium-4-carboxamidoformate 2,2,2-trifluoroacetate (mixed salt) (Compound 127); 2-[1-(Azetidin-3-ylmethyl)-4-[[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]piperidin-1-ium-1-yl]acetic acid bis(2,2,2-trifluoroacetate) (Compound 128); 1-(Azetidin-3-ylmethyl)-N-[3-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]propyl]-1-methyl-piperidin-1-ium-4-carboxamide bis(trifluoroacetate) (Compound 129); N-[3-[[2-[(3S)-1-(Azetidin-3-ylmethyl)-1-methyl-pyrrolidin-1-ium-3-yl]acetyl]amino]propyl]-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide bis(2,2,2-trifluoroacetate) (compound 130); N-[3-[[2-[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]acetyl]amino]propyl]-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide bis(2,2,2-trifluoroacetate) (compound 131); 4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-N-[[1-methyl-1-[2-oxo-2-(pyrrolidin-3-ylmethylamino)ethyl]piperidin-1-ium-4-yl]methyl]benzamide bis(2,2,2-trifluoroacetate) (compound 132); N-[[[1-[1-(Azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-carbonyl]-4-piperidyl]methyl]-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide bis(2,2,2-trifluoroacetate) (Compound 133); N-[[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethylbenzamide; 2,2,2-trifluoroacetatobis(2,2,2-trifluoroacetate) (compound 134); 4-[[3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-N-[[1-[(1,1-dimethylpyrrolidin-1-ium-3-yl)methyl]-1-methyl-piperidin-1-ium-4-yl]methyl]-2-ethyl-benzamide diformate (compound 135); N-[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide bis(2,2,2-trifluoroacetate) (compound 136); 4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-N-[rac-(1S,5R)-3-(azetidin-3-ylmethyl)-3-methyl-3-azoniabicyclo[3.1.0]hexan-6-yl]benzamide bis(2,2,2-trifluoroacetate) (compound 137); N-[[1-(Azetidin-3-ylmethyl)-1-methyl-pyrrolidin-1-ium-3-yl]methyl]-2-ethyl-4-[[3-[3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrazin-8-yl]amino]benzamide bis(2,2,2-trifluoroacetate) (Compound 138); Bis(azetidin-3-ylmethyl)-[3-[[4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]propyl]-methyl-ammonium bis(2,2,2-trifluoroacetate) (compound 139); 4-[[3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-N-[[1-methyl-1-(3-pyridylmethyl)piperidin-1-ium-4-yl]methyl]benzamide; 2,2,2-trifluoroacetate (Compound 140); N-[[1-(azetidin-3-ylmethyl)-1-(2-hydroxyethyl)piperidin-1-ium-4-yl]methyl]-4-[[3-(2,3-difluoro-4-methoxy)-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide 2,2,2-trifluoroacetate (compound 141); 4-[[3-(2,3-difluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-N-[[1-methyl-1-(pyrrolidin-2-ylmethyl)piperidin-1-ium-4-yl]methyl]benzamide 2,2,2-trifluoroacetate (compound 142); N-[[1-(azetidin-3-ylmethyl)-1-ethyl-piperidin-1-ium-4-yl]methyl]-4-[[3-(2,3-difluoro-4-methoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamidoformate (compound 143); and 4-[[3-(2,3-difluoro-4-phenoxy-phenyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-N-[[1-methyl-1-(pyrrolidin-3-ylmethyl)piperidin-1-ium-4-yl]methyl]benzamidoformate (Compound 145) or a pharmaceutically acceptable salt thereof.

2. A method for preparing a compound of formula (I) according to claim 1, comprising: (i) compound (A) to form the compound of formula (I) or a synthetic precursor thereof 【Chemistry 13】 (wherein X is a halogen or triflate, preferably X is iodo, and the double cross indicates the point of attachment of (A) to the remainder of formula (I)), or a synthetic precursor thereof; Boronic acids (R = H) or boronic esters (R = alkyl, or both R's together with the atoms to which they are attached form a heterocyclic ring) (B) 【Chemistry 14】 (R ４ is as defined in claim 1), or (ii) compound (C) to form the compound of formula (I) or a synthetic precursor thereof 【Chemistry 15】 (The double cross is R as defined in claim 1. ４ or R ４ (showing the point of attachment of (C) to the synthetic precursor of Aryl halide (D) 【Chemistry 16】 (R ３ and R ５ is as defined in claim 1, wherein X is a halogen and the double cross indicates the point of attachment of (D) to the remainder of formula (I), or a synthetic precursor thereof; (iii) compound (C1) for forming the compound of formula (I) or a synthetic precursor thereof 【Chemistry 17】 (X is a halogen and the double cross is R as defined in claim 1) ４ or R ４ (showing the point of attachment of (C1) to the synthetic precursor of Aniline derivative (D1) [Chemistry 18] (R ３ and R ５ is as defined in claim 1, where the double cross indicates the point of attachment of (D1) to the remainder of formula (I), or a synthetic precursor thereof; (iv) Formula (G) 【Chemistry 19】 (R ｙ’ is R according to claim 1 ｘ or R ｘ to form a compound of formula (E), which is a synthetic precursor of 【Chemistry 20】 (where the double cross indicates the point of attachment of (E) to the remainder of formula (I)) or a synthetic precursor thereof; Primary or secondary amine R ｙ and reacting the compound with A method comprising:

3. 10. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof for use as a therapeutically active substance.

4. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier.

5. 10. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 for use as an antibiotic.

6. 10. A compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of nosocomial infections and resulting diseases.

7. 10. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of infections and resulting diseases caused by Gram-negative bacteria.

8. 8. The compound for use according to claim 7, wherein the Gram-negative bacteria is selected from Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, and Escherichia coli.

9. 9. The compound for use according to claim 8, wherein the Gram-negative bacterium is Acinetobacter baumannii.

10. 10. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof.

11. 10. A pharmaceutical composition for use in a method for the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or combinations thereof, comprising a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

12. 10. Use of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof for the preparation of an antibiotic.

13. 10. Use of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament useful for the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or a combination thereof.

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