Imidazopyridine derivatives and use thereof

Abstract

Imidazopyridine derivatives and the use thereof. Specifically, the present invention relates to imidazopyridine derivatives represented by general formula (I) and pharmaceutically acceptable salts thereof. The present invention also relates to the use of the compounds in the treatment or prevention of bacterial infections and diseases caused thereby, in particular in the treatment or prevention of Acinetobacter baumannii infection diseases.

Description

Imidazopyridine derivatives and uses thereof TECHNICAL FIELD

[0001] The present invention relates to novel imidazopyridine derivatives and uses of the compounds for the treatment of diseases, in particular for the treatment or prevention of Acinetobacter baumannii infections and resulting diseases. BACKGROUND

[0002] Acinetobacter baumannii, a gram-negative bacterium, is a strict aerobic, non-lactose fermenting opportunistic pathogen, without flagella, low mobility, and strong vitality, widely exists in nature.

[0003] Acinetobacter baumannii infection occurs mostly in hospitalized patients, and its most notable feature is multi-drug resistance. According to statistics, the probability of multi-drug resistance is 4 times that of other gram-negative bacteria such as Klebsiella pneumoniae and Pseudomonas aeruginosa. At the same time, it has the characteristics of high mortality and great difficulty in treatment. Acinetobacter baumannii infection accounts for more than 10% of all hospital-acquired infections in the United States, and the mortality rate in patients with sepsis and pneumonia is more than 50%. It is resistant to most first-line antibiotics, and the World Health Organization calls it one of the most threatening strains to humans.

[0004] Acinetobacter baumannii infection occurs mostly in intensive care units and surgical wards, and mainly manifests as bacteremia, pneumonia, meningitis, urinary tract infection and wound infection.

[0005] The genome of Acinetobacter baumannii can rapidly mutate when it faces adversity and stress, so it has strong environmental adaptability, which is the basis for its ability to adapt to harsh environments that other pathogens cannot adapt to, strong drug resistance and infectivity. The main manifestations are the ability to resist dry environments, the ability to move and transfer, and the ability to form biofilms. Acinetobacter baumannii is defined by the Infectious Diseases Society of America (IDSA) Antimicrobial Availability Workgroup as a "major example of the mismatch between unmet medical need and the current antimicrobial drug development pipeline". Therefore, the development of drugs against Acinetobacter baumannii is imminent in the clinic. The present invention provides novel compounds that exhibit activity against Acinetobacter baumannii. SUMMARY

[0006] The technical problem solved by the present invention is to provide imidazopyridine derivatives, a method for preparing the same, and uses thereof in the treatment of bacterial infections.

[0007] To solve the technical problem of the present invention, the present invention provides the following technical solutions:

[0008] In a first aspect, the present application provides an imidazopyridine compound having the structure of Formula (I),

[0009] wherein R1is selected from methylamino, ethylamino, propylamino, butylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, N-(2-(2-aminoethoxy)ethylamino, N,N-dimethylamino, N,N-diethylamino, N-methyl-N-ethylamino, N-methylformamido, N-morpholino, N-thiomorpholino, N-oxothiomorpholino, N-piperazino, N-methylpiperidin-4-formamide, N,N-dimethylpiperidin-4-formamide;

[0010] R2is selected from hydrogen, halogen, C1-C6alkyl;

[0011] R3, R4, and R5are each independently selected from hydrogen;

[0012] R6and R7are each independently selected from hydrogen, halogen, cyano, C1-C3alkyl, C1-C3alkoxy;

[0013] R8is halogen, cyano, C1-C3alkoxy, C1-C3alkyl, phenyl;

[0014] R3, R4, R5, R9, and R 10 are hydrogen;

[0015] In preferred embodiments, the present application provides a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1is methylamino, N-morpholino, N-methylpiperidin-4-formamide, and N,N-dimethylpiperidin-4-formamide.

[0016] In preferred embodiments, the present application provides a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2is methyl.

[0017] In preferred embodiments, the present application provides a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen.

[0018] In preferred embodiments, the present application provides a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen.

[0019] In preferred embodiments, the present application provides a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R5is hydrogen.

[0020] In preferred embodiments, the present application provides a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R6is hydrogen.

[0021] In preferred embodiments, the present application provides a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R7is hydrogen.

[0022] In a preferred embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R8is C1-C6-alkoxy, C1-C6-alkyl, trifluoromethoxy, cyclopropoxy, cyclopropylmethoxy and phenyl.

[0023] In a particularly preferred embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R8is methoxy.

[0024] In a preferred embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R9is hydrogen, halogen, trifluoromethyl and cyano.

[0025] In a preferred embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 10 is hydrogen and cyano.

[0026] In a preferred embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R9is hydrogen, halogen, trifluoromethyl and cyano.

[0027] In a second aspect, the present application provides a pharmaceutical composition comprising the imidazopyridine compound of the first aspect and pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier or excipient, further comprising one or more other active ingredients.

[0028] The compound of the present application or a pharmaceutical composition containing it can be administered in unit dosage form, and the route of administration can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, buccal, ocular, pulmonary and respiratory, dermal, vaginal, rectal, etc.

[0029] The administration dosage form can be a liquid dosage form, a solid dosage form or a semi-solid dosage form. The liquid dosage form can be a solution (including true solution and colloidal solution), an emulsion (including o / w type, w / o type and multiple emulsion), a suspension, an injection (including water injection, powder injection and infusion), eye drops, nose drops, lotion and liniment, etc.; the solid dosage form can be a tablet (including ordinary tablet, enteric-coated tablet, chewing tablet, dispersible tablet, effervescent tablet, oral disintegrating tablet), a capsule (including hard capsule, soft capsule, enteric-coated capsule), a granule, a powder, a pellet, a drop, a suppository, a film, a patch, an aerosol (powder) mist, a spray, etc.; the semi-solid dosage form can be an ointment, a gel, a paste, etc.

[0030] The compound of the present application can be prepared into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

[0031] To prepare tablets of the compound of the present application, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, solubilizers. The diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agents can be water, ethanol, isopropyl alcohol, etc.; the binders can be starch paste, dextrin, sugar syrup, honey, glucose solution, microcrystalline cellulose, acacia paste, gelatin paste, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecylsulfate, etc.; the lubricants and solubilizers can be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0032] The tablets can also be further prepared into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

[0033] To prepare capsules of the drug delivery unit, the effective ingredient, the compound of the present application, can be mixed with diluents and solubilizers, and the mixture can be directly placed in hard or soft capsules. The effective ingredient, the compound of the present application, can also be first mixed with diluents, binders and disintegrants to prepare granules or pellets, and then placed in hard or soft capsules. The various diluents, binders, wetting agents, disintegrants and solubilizers used for preparing tablets of the compound of the present application can also be used for preparing capsules of the compound of the present application.

[0034] To prepare injections of the compound of the present application, water, ethanol, isopropyl alcohol, propylene glycol or their mixtures can be used as solvents, and appropriate amounts of solubilizers, solubilizers, pH adjustors and osmotic pressure adjustors commonly used in the art can be added. The solubilizers or solubilizers can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; the pH adjustors can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure adjustors can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. If lyophilized powder injections are prepared, mannitol, glucose, etc. can also be added as supporting agents.

[0035] In addition, if necessary, coloring agents, preservatives, flavors, flavoring agents or other additives can also be added to the pharmaceutical preparations.

[0036] For the purpose of administration and enhancement of therapeutic effect, the pharmaceutical or pharmaceutical composition of the present application can be administered by any known administration method.

[0037] The dosage of the pharmaceutical composition of the compound of the present application can vary greatly depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the administration route and dosage form, etc. Generally, the suitable dosage of the compound of the present application per day ranges from 0.1 to 50 mg / Kg of body weight. The above dosage can be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the administration schedule selected from other therapeutic means. The compound or composition of the present application can be administered alone or in combination with other therapeutic drugs or symptomatic drugs. When the compound of the present application has synergistic effect with other therapeutic drugs, the dosage thereof should be adjusted according to the actual situation.

[0038] In a third aspect, the present application provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of an infection and a disease caused thereby by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or a combination thereof. In particular, the present application provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of an infection and a disease caused thereby by Gram-negative bacteria. Most particularly, the present application provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of an infection and a disease caused thereby by Acinetobacter baumannii. In particular, sepsis, pneumonia, meningitis, urinary tract infection and wound infection.

[0039] In a fourth aspect, the present application provides a method for preparing the imidazopyridine compound of the first aspect.

[0040] The compounds of formula (I) of the present application can be prepared according to sequential or convergent synthetic routes. The synthesis of the compounds of the present application is illustrated in the following schemes. The skills required to carry out the reactions and purify the resulting compounds are known to those skilled in the art. The substituents used in the following description of the processes have the meanings provided herein unless expressly stated otherwise. In more detail, the compounds of formula (I) can be prepared by the methods described below, the methods provided in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. The reaction sequence is not limited to the one displayed in the schemes, but the order of the reaction steps can be freely varied depending on the starting materials and their respective reactivity. Starting materials are commercially available or can be prepared by methods analogous to those described below, by the methods described in the present specification or by methods known in the art.

[0041] The synthesis of the compounds of formula (I) can be accomplished according to the general synthetic routes outlined in Scheme I and Scheme II below.

[0042] Scheme 1

[0043] a) The boronic acid II is reacted with the imidazopyridine derivative III in the presence of a coupling agent (such as DAPCy) and a base (K3P04) to form compound IV.

[0044] b) IV is conveniently reacted in the presence of a transition metal catalyst (such as Pd(OAc)2) and a base (such as NaOtBu), a ligand (BINAP) to give the imidazopyridine derivative (I). These imidazopyridines (I) can be the final desired compounds or can be further derivatized to give the final imidazopyridine derivative (I).

[0045] Scheme II

[0046] b) The tert-butyl 4-amino-2-methylbenzoate can be obtained commercially or by methods known in the art and can be conveniently reacted with intermediate IV under metal catalyzed reaction conditions to give intermediate VI.

[0047] c) Acid derivative VII can be obtained in the presence of an acid. Examples of acids include trifluoroacetic acid. Acid derivative VII is conveniently reacted with piperidine-4-carboxylic acid tert-butyl ester under varying coupling reaction conditions (coupling reaction conditions include: HATU, HBTU, and the like, in the presence of a base such as DIPEA, NEt3, and the like) to provide amide VIII. Piperidine-4-carboxylic acid tert-butyl ester is commercially available, known in the art, or prepared according to methods known in the art. Similarly, acid derivative IX is obtained in the presence of trifluoroacetic acid, and acid derivative IX is reacted with diethylamine or methylamine, and the like, under coupling conditions (coupling reaction conditions include: HATU, HBTU, and the like, in the presence of a base such as DIPEA, NEt3, and the like) to provide a compound of Formula (I).

[0048] The term

[0049] The term "alkyl" means a monovalent or polyvalent (e.g., monovalent or divalent) straight-chain or branched-chain saturated hydrocarbon group (a "Ci-C6-alkyl") containing one to six carbon atoms (e.g., one, two, three, four, five, or six carbon atoms). In some examples, the alkyl group contains one to three carbon atoms, e.g., one, two, or three carbon atoms. Some non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, and 2,2-dimethylpropyl. One particularly preferred, but non-limiting, example of an alkyl group is methyl.

[0050] The term "alkoxy" means an alkyl group as previously defined attached to the parent molecular moiety through an oxygen atom. Unless otherwise indicated, an alkoxy group contains one to six carbon atoms ("Ci-C6-alkoxy"). In some preferred examples, the alkoxy group contains one to four carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and t-butoxy. One particularly preferred, but non-limiting, example of an alkoxy group is methoxy.

[0051] The term "halogen" or "halo" means fluorine (F), chlorine (CI), bromine (Br), or iodine (I). Preferably, the term "halogen" or "halo" means fluorine (F), chlorine (CI), or bromine (Br). Particularly preferred, but non-limiting, examples of "halogen" or "halo" are fluorine (F) and chlorine (CI). The term "cycloalkyl" means a saturated or unsaturated, mono- or bicyclic hydrocarbon group having from 3 to 12 ring carbon atoms ("C3-C12-cycloalkyl"). In some examples, the cycloalkyl group contains 3 to 8 ring carbon atoms. Some non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. One particularly preferred, but non-limiting, example of a cycloalkyl group is cyclopropyl. 12"Cycloalkyl" refers to a saturated carbocyclic radical of 3-10 ring atoms, preferably 3-8 ring atoms. In some preferred embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon group having 3 to 10 ring carbon atoms, particularly 3 to 8 ring carbon atoms. "Bicyclic cycloalkyl" refers to a cycloalkyl moiety consisting of two saturated carbocyclic rings having two common carbon atoms, i.e., a bridge separating the two rings is a single bond or a chain of one or two ring atoms, as well as a spiro moiety, i.e., two rings connected by a common ring atom. Preferably, the cycloalkyl group is a saturated monocyclic hydrocarbon group having 3 to 6 ring carbon atoms (e.g., 3, 4, 5, or 6 carbon atoms). Some non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The terms "heterocycloalkyl" and "heterocyclyl" are used interchangeably to refer to a saturated or partially unsaturated monocyclic or bicyclic, preferably monocyclic, ring system of 3 to 10 ring atoms, preferably 3 to 8 ring atoms, wherein 1, 2, or 3 of the ring atoms are heteroatoms selected from N, O, and S, with the remainder of the ring atoms being carbon. Preferably, 1-2 of the ring atoms are selected from N and O, with the remainder of the ring atoms being carbon. "Bicyclic heterocyclyl" refers to a heterocyclic moiety consisting of two rings having two common ring atoms, i.e., a bridge separating the two rings is a single bond or a chain of one or two ring atoms, as well as a spiro moiety, i.e., two rings connected by a common ring atom. Some non-limiting examples of monocyclic heterocyclyl groups include morpholine, thiomorpholine, piperazine, methylpiperazinyl, and 2-oxa-6-azaspiro[3.3]heptane.

[0052] The term "aminoalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group has been replaced by an amino group. A preferred, but non-limiting example of an aminoalkyl group is aminomethyl, aminoethyl, and N,N-dimethylamino.

[0053] The term "cyano" refers to a -CN (nitrile) group.

[0054] The term "oxo" refers to an oxygen atom (=0) bonded to the parent molecular moiety by a double bond.

[0055] The term "amino" refers to an -NH2 group.

[0056] The term "carboxyl" refers to a -COOH group.

[0057] The term "carbamoyl" refers to a -C(O)NH2 group.

[0058] The term "carbonyl" denotes a -C(O)- group.

[0059] The term "prevent" includes preventing or delaying the appearance of clinical symptoms of the relevant state, disease, or condition in a mammal, and especially in a human that can be afflicted with or predisposed to the state, disease, or condition, but has not yet been diagnosed with a clinical or subclinical symptom of the state, disease, or condition.

[0060] The term "mammal" includes both human and non-human, and includes, but is not limited to, humans, non-human primates, canids, felines, murines, bovids, equids, and porcines. In a particularly preferred example, the term "mammal" refers to a human.

[0061] Beneficial technical effects

[0062] The imidazopyridine derivatives in the present application are novel in structure, show obvious inhibitory effect on Acinetobacter baumannii in vitro and in mice, and have good safety, and are expected to become a new type of anti-Acinetobacter baumannii therapeutic drug. BRIEF DESCRIPTION OF DRAWINGS

[0063] Figure 1 Survival curve of Example 7 and Example 27 in mice with Acinetobacter baumannii infection model

[0064] Figure 2 Survival curve of acute toxicity in mice DETAILED DESCRIPTION

[0065] The present application can be further described by the following examples, however, the scope of the present application is not limited to the following examples. Those skilled in the art can understand that various changes and modifications can be made to the present application without departing from the spirit and scope of the present application.

[0066] Unless otherwise indicated, all metal- involved coupling reaction examples and intermediates were prepared under a nitrogen atmosphere.

[0067] The following abbreviations are used herein:

[0068] (R)-BINAP = (R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, ACN = acetonitrile, aq. = aqueous, Boc = tert-butoxycarbonyl, CAS = Chemical Abstracts Service Registry Number, DCM = dichloromethane, DMF = N,N-dimethylformamide, DMSO = dimethyl sulfoxide, DMSO-d6 = deuterated dimethyl sulfoxide, HATU = N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate DIPEA = N,N-diisopropylethylamine, MeOD = deuterated methanol, EA = ethyl acetate, CDI = N,N'-carbonyldiimidazole, EI = electron impact, ESI = electrospray ionization, ESI += electrospray ionization positive ion mode, ESP = electrospray ionization negative ion mode, H2= hydrogen, h = hour, H2O = water, K3PO4= potassium phosphate tribasic, LC-MS = liquid chromatography coupled with mass spectrometry, MeOH = methanol, min = minute, mL = milliliter, MS = mass spectrometry, N2= nitrogen, Na2SO4= sodium sulfate, Pd / C = palladium on carbon, Pd(DAPCy) = trans-bis(dicyclohexylamine) palladium(II) acetate, Pd(OAc)2= palladium acetate, PE = petroleum ether, R f = retention factor, RM = reaction mixture, RT = room temperature, prep-TLC = preparative thin layer chromatography, UV = ultraviolet.

[0069] Intermediate 13: 5-(8-bromoimidazo[l,2-a]pyridin-3-yl)-2-methoxybenzonitrile

[0070] 8-bromo-3-iodoimidazo[l,2-a]pyridine (300 mg, 928.99 mmol) and 3-cyano-4- methoxyphenylboronic acid (180.84 mg, 1.02 mmol) were dissolved in ethanol (8 mL) and stirred at 75 °C for 2 h. The mixture was allowed to cool to room temperature, diluted with 20 mL of dichloromethane and filtered over celite. The filtrate was poured into water (20 mL) and the aqueous solution was extracted with dichloromethane (20 mL x 2). The organic layers were combined, washed with water and brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. Purification by column chromatography afforded the title compound (201 mg, 66% yield) as a light yellow solid. MS (ESI, m / z): 328.17 [M+H] + .

[0071] The following intermediates were prepared analogously:

[0072] Intermediate A: 4-amino-2-methylphenyl(morpholinyl)methanone

[0073] Step 1: 4-nitro-2-methylphenyl(morpholinyl)methanone

[0074] Dissolve 2-methyl-4-nitrobenzoic acid (500 mg, 2.76 mmol) and CDI (537 mg, 3.31 mmol) in 5 mL of anhydrous DMF, stir at 75 °C for 10 min, and then stir at room temperature for 1.5 h. Add morpholine (480.35 mg, 5.52 mmol) to the mixture, and stir at room temperature for 12 h. Dilute the mixture with water and extract with EA (20 mL x 2). Dry the combined organic phase over anhydrous Na2SO4, and concentrate under reduced pressure. Purify by column chromatography to obtain 4-nitro-2-methylphenyl(morpholinyl)methanone (655.73 mg, 95% yield) as a light pink solid. MS (ESI, m / z): 251.10 [M+H] + .

[0075] Step 2: 4-Amino-2-methylphenyl(morpholinyl)methanone

[0076] Dissolve 4-nitro-2-methylphenyl(morpholinyl)methanone (500 mg) in 10 mL of methanol, add 10% Pd / C (50 mg), and then place in a hydrogenation apparatus to react for 8 h. Filter the mixture over celite, and concentrate under reduced pressure to obtain 4-amino-2-methylphenyl(morpholinyl)methanone (426.80 mg, 97% yield) as a light pink solid. MS (ESI, m / z): 221.12 [M+H] + .

[0077] The following intermediates are prepared similarly:

[0078] Example 7: 2-Methoxy-5-(8-((3-methyl-4-(morpholine-4-carbonyl)phenyl)amino)imidazo[1,2- a]pyridin-3-yl)benzonitrile

[0079] Dissolve 4-amino-2-methylphenyl(morpholinyl)methanone (302.05 mg, 1.37 mmol) and intermediate 13 (300 mg, 0.91 mmol) in toluene (6 mL), and add NaOtBu (351.42 mg, 3.66 mmol), BINAP (71.15 mg, 0.11 mmol), and Pd(OAc)2 (20.52 mg, 0.091 mmol) to the mixture. Purge the mixture with N2 for 5 min, stir the reaction mixture, and heat to stir at 100 °C for 12 h under N2 atmosphere. When the reaction is completed, pour the mixture into water (20 mL), and extract the aqueous solution with dichloromethane (20 mL x 2). Dry the combined organic layer over anhydrous Na2SO4, concentrate under reduced pressure, and separate by column chromatography to obtain the title compound as a light pink solid (160 mg, 37.5% yield).

[0080] MS (ESI, m / z): 468.20 [M+H] + . 1 H NMR (400 MHz, DMSO-D6) δ 8.43 (s, 1H), 7.99 (dd, J = 11.59, 4.50 Hz, 2H), 7.91 (dd, J = 8.77, 2.36 Hz, 1H), 7.70 (s, 1H), 7.37 (d, J = 8.87 Hz, 1H), 7.34 - 7.26 (m, 1H), 7.26 - 7.15 (m, 2H), 7.08 (d, J = 8.22 Hz, 1H), 6.97 (d, J = 7.49 Hz, 1H), 6.81 (t, J = 7.16 Hz, 1H), 3.95 (s, 3H), 3.54 (d, J = 46.89 Hz, 6H), 3.18 (s, 2H), 2.18 (s, 3H).

[0081] The following examples were prepared in analogy to example 7

[0082] Example 1 : 4-((3-(4-methoxyphenyl)imidazo[l,2-a]pyridin-8-yl)amino)-N,2- dimethylbenzamide

[0083] Example 1 was obtained from Intermediate 1 and Intermediate B by the synthetic procedure as in example 7.

[0084] MS (ESI, m / z): 387.18 [M+H] + . 1 H NMR (500 MHz, DMSO-D6) δ 8.45 (s, 1H), 8.03 (q, J = 4.53 Hz, 1H), 7.96 (dd, J = 6.85, 0.90 Hz, 1H), 7.62 (s, 1H), 7.59 (d, J = 2.13 Hz, 1H), 7.57 (d, J = 2.13 Hz, 1H), 7.31 (d, J = 8.23 Hz, 1H), 7.22 (d, J = 2.21 Hz, 1H), 7.19 (dd, J = 8.24, 2.28 Hz, 1H), 7.13 (d, J = 2.15 Hz, 1H), 7.12 (d, J = 2.10 Hz, 1H), 6.98 (dd, J = 7.48, 0.89 Hz, 1H), 6.84 (t, J = 7.13 Hz, 1H), 5.28 (s, 1H), 3.84 (s, 3H), 2.74 (d, J = 4.50 Hz, 3H), 2.35 (s, 3H).

[0085] Example 2: 4-((3-(3-chloro-4-(trifluoromethoxy)phenyl)imidazo[l,2- a]pyridin-8-yl)amino)-N,2-dimethylbenzamide

[0086] Example 2 was obtained from Intermediate 2 and Intermediate B by the synthetic method as in Example 7.

[0087] MS (ESI, m / z): 475.11 [M+H]+. + . 1 H NMR (500 MHz, DMSO-D6) δ 8.45 (s, 1H), 7.99 (q, J = 4.49 Hz, 1H), 7.94 (dd, J = 6.83, 0.88 Hz, 1H), 7.90 (dd, J = 8.67, 2.33 Hz, 1H), 7.79 (d, J = 2.25 Hz, 1H), 7.70 (s, 1H), 7.42 (d, J = 8.77 Hz, 1H), 7.28 (d, J = 8.25 Hz, 1H), 7.18 (d, J = 2.26 Hz, 1H), 7.16 (dd, J = 8.23, 2.29 Hz, 1H), 6.97 (dd, J = 7.48, 0.89 Hz, 1H), 6.85 - 6.81 (m, 1H), 2.70 (d, J = 4.55 Hz, 3H), 2.31 (s, 3H).

[0088] Example 3: 4-((3-(3-chloro-4-(cyclopropylmethoxy)phenyl)imidazo[l,2- a]pyridin-8-yl)amino)-N,2-dimethylbenzamide

[0089] Example 3 was obtained from Intermediate 3 and Intermediate B by the synthetic method as in Example 7.

[0090] MS (ESI, m / z): 461.17 [M+H]+. 1H NMR (500 MHz, DMSO-D6) δ 8.43 (s, 1H), 7.99 (q, J = 4.54 Hz, 1H), 7.94 (dd, J = 6.83, 0.88 Hz, 1H), 7.67 (d, J = 2.21 Hz, 1H), 7.65 (s, 1H), 7.53 (dd, J = 8.52, 2.23 Hz, 1H), 7.26 (dd, J = 9.78, 8.44 Hz, 2H), 7.18 (d, J = 2.27 Hz, 1H), 7.15 (dd, J = 8.26, 2.29 Hz, 1H), 6.96 (dd, J = 7.54, 0.90 Hz, 1H), 6.82 (t, J = 7.15 Hz, 1H), 3.97 (s, 2H), 2.70 (s, 3H), 2.31 (s, 3H), 1.28 - 1.23 (m, 1H), 0.60 - 0.56 (m, 2H), 0.38 - 0.33 (m, 2H).

[0091] Example 4: N-ethyl-4-(3-(4-methoxyphenyl)imidazo[l,2-a]pyridin-8- ylamino)-2-methylbenzamide

[0092] Example 4 was obtained from Intermediate 1 and Intermediate C by the synthetic method as in Example 7.

[0093] MS (ESI, m / z): 401.19 [M+H]+. 1 H NMR (500 MHz, DMSO-D6) δ 8.44 (s, 1H), 8.09 (t, J = 5.59 Hz, 1H), 7.96 (dd, J = 6.79, 0.91 Hz, 1H), 7.62 (s, 1H), 7.60 - 7.55 (m, 2H), 7.30 (d, J = 8.19 Hz, 1H), 7.24 - 7.18 (m, 2H), 7.15 - 7.11 (m, 2H), 6.97 (dd, J = 7.53, 0.92 Hz, 1H), 6.84 (t, J = 7.14 Hz, 1H), 3.84 (s, 3H), 3.23 (qd, J = 7.20, 5.56 Hz, 2H), 2.35 (s, 3H), 1.11 (t, J = 7.19 Hz, 3H).

[0094] Example 5: 4-(3-(4-methoxyphenyl)imidazo[l,2-a]pyridin-8-ylamino)-N,N,2- trimethylbenzamide

[0095] Example 5 was obtained from Intermediate 1 and commercially purchased 4-amino-N,N,2-trimethylbenzamide by the synthetic method as in Example 7.

[0096] MS (ESI, m / z): 401.19 [M+H]+. 1 H NMR (400 MHz, DMSO) δ 8.31 (s, 1H), 8.10 (d, J = 6.68 Hz, 1H), 7.64 (d, J = 8.42 Hz, 2H), 7.51 (d, J = 7.86 Hz, 1H), 7.30 - 7.11 (m, 7H), 3.86 (s, 3H), 3.00 (s, 3H), 2.82 (s, 3H), 2.21 (s, 3H).

[0097] Example 6: (4-(3-(4-methoxyphenyl)imidazo[l,2-a]pyridin-8-yl)amino)-2- methylphenyl)(morpholinyl)methanone

[0098] Example 6 was obtained from Intermediate 1 and Intermediate A by the synthetic method as in Example 7.

[0099] MS (ESI, m / z): 443.20 [M+H]+. 1 H NMR (500 MHz, DMSO-D6) δ 8.41 (s, 1H), 7.91 (dd, J = 6.79, 0.88 Hz, 1H), 7.58 (s, 1H), 7.56 - 7.52 (m, 2H), 7.25 - 7.16 (m, 2H), 7.11 - 7.06 (m, 3H), 6.94 (dd, J = 7.51, 0.91 Hz, 1H), 6.79 (t, J = 7.12 Hz, 1H), 3.80 (s, 3H), 3.54 (d, J = 59.24 Hz, 6H), 3.20 (d, J = 18.41 Hz, 2H), 2.18 (s, 3H).

[0100] Example 8: (4-(3-(4-methoxyphenyl)imidazo[l,2-a]pyridin-8-yl)amino)-2- methylphenyl)(thiomorpholinyl)methanone

[0101] Example 8 was obtained from Intermediate 1 and Intermediate D by the synthetic method as in Example 7.

[0102] MS (ESI, m / z): 459.18 [M+H]+. 1H NMR (500 MHz, DMSO-D6) δ 8.44 (s, 1H), 7.62 (s, 1H), 7.59 (d, J = 2.09 Hz, 1H), 7.57 (d, J = 2.15 Hz, 1H), 7.27 (d, J = 2.19 Hz, 1H), 7.23 (dd, J = 8.19, 2.25 Hz, 1H), 7.14 - 7.11 (m, 3H), 6.99 (dd, J = 7.48, 0.89 Hz, 1H), 6.83 (t, J = 7.14 Hz, 1H), 3.84 (s, 3H), 3.58 (d, 4H), 2.68 (d, J = 6.77 Hz, 4H), 2.20 (s, 3H).

[0103] Example 9: (4-(3-(4-methoxyphenyl)imidazo[l,2-a]pyridin-8-yl)amino)-2- methylphenyl)(piperazin-l-yl)methanone

[0104] Example 9 was obtained from Intermediate 1 and Intermediate H by the synthetic method as in Example 7. 200 mg of Intermediate I was dissolved in 2 mL of dichloromethane, 0.925 mL of 4 mol / L HC1, 1,4-dioxane solution was added, and a precipitated solid was separated out as the reaction proceeded. The precipitate was filtered out after 4 h of reaction to obtain 150 mg of a light yellow solid, which was Example 9.

[0105] MS (ESI, m / z): 442.22 [M+H]+. 1 H NMR (500 MHz, DMSO-D6) δ 8.44 (s, 1H), 7.62 (s, 1H), 7.59 (d, J = 2.09 Hz, 1H), 7.57 (d, J = 2.15 Hz, 1H), 7.27 (d, J = 2.19 Hz, 1H), 7.23 (dd, J = 8.19, 2.25 Hz, 1H), 7.14 - 7.11 (m, 3H), 6.99 (dd, J = 7.48, 0.89 Hz, 1H), 6.83 (t, J = 7.14 Hz, 1H), 3.84 (s, 3H), 3.58 (d, 4H), 2.68 (d, J = 6.77 Hz, 4H), 2.20 (s, 3H).

[0106] Example 10: (4-(3-(4-ethoxyphenyl)imidazo[l,2-a]pyridin-8-ylamino)-2- methylphenyl)(morpholinyl)methanone

[0107] Example 10 was obtained from Intermediate 4 and Intermediate A by the synthetic method as in Example 7.

[0108] MS (ESI, m / z): 457.22 [M+H]+.1 H NMR (500 MHz, DMSO-D6) δ 8.40 (s, 1H), 7.91 (dd, J = 6.86, 0.90 Hz, 1H), 7.58 (s, 1H), 7.53 (d, J = 2.12 Hz, 1H), 7.52 (d, J = 2.12 Hz, 1H), 7.23 (d, J = 2.20 Hz, 1H), 7.19 (dd, J = 8.21, 2.23 Hz, 1H), 7.10 - 7.04 (m, 3H), 6.95 (dd, J = 7.48, 0.90 Hz, 1H), 6.79 (t, J = 7.12 Hz, 1H), 4.07 (q, J = 6.97 Hz, 2H), 3.54 (d, J = 59.61 Hz, 7H), 3.18 (s, 2H), 2.18 (s, 3H), 1.33 (t, J = 6.96 Hz, 3H).

[0109] Example 11: (4-(3-chloro-4-cyclopropoxyphenyl)imidazo[l,2-a]pyridin-8-yl)amino)-2- methylphenyl)(morpholinyl)methanone

[0110] Example 11 was obtained from Intermediate 5 and Intermediate A by the synthetic method as in Example 7.

[0111] MS (ESI, m / z): 503.18 [M+H]+. 1 H NMR (500 MHz, DMSO-D6) δ 8.51 (s, 1H), 8.12 (dd, J = 6.80, 0.90 Hz, 1H), 8.03 (q, J = 4.54 Hz, 1H), 7.78 (s, 1H), 7.65 (d, J = 2.00 Hz, 1H), 7.58 (d, J = 8.18 Hz, 1H), 7.28 (dd, J = 8.17, 2.00 Hz, 1H), 7.23 (d, J = 2.27 Hz, 1H), 7.20 (dd, J = 8.28, 2.27 Hz, 1H), 7.02 (dd, J = 7.52, 0.89 Hz, 1H), 6.89 (t, J = 7.16 Hz, 1H), 4.12 (dq, J = 5.96, 3.03 Hz, 1H), 3.58 (d, J = 61.79 Hz, 6H), 3.22 (s, 2H), 2.35 (s, 3H), 0.89 - 0.82 (m, 2H), 0.82 - 0.75 (m, 2H).

[0112] Example 12: (4-(3-chloro-4-methoxyphenyl)imidazo[l,2-a]pyridin-8-yl)amino)-2- methylphenyl)(morpholinyl)methanone

[0113] Example 12: (4-(3-(2-chloro-[l,l'-biphenyl]-4-yl)imidazo[l,2- a]pyridin-8-yl)amino)-2-methylphenyl)(morpholinomethyl)ketone was obtained from Intermediate 6 and Intermediate A by the synthetic method as in Example 7.

[0114] MS (ESI, m / z): 477.16 [M+H]+. 1 H NMR (500 MHz, DMSO-D6) δ 8.46 (s, 1H), 7.99 - 7.97 (m, 1H), 7.91 (d, J = 8.42 Hz, 1H), 7.72 (d, J = 2.21 Hz, 1H), 7.70 (s, 1H), 7.61 (dd, J = 8.50, 2.22 Hz, 1H), 7.26 (d, J = 2.19 Hz, 1H), 7.23 (dd, J = 8.26, 2.23 Hz, 1H), 7.00 (d, J = 7.34 Hz, 1H), 6.85 (t, J = 7.16 Hz, 1H), 6.77 (ddd, J = 8.38, 6.81, 1.27 Hz, 1H), 3.94 (s, 3H), 3.58 (d, J = 58.96 Hz, 7H), 3.23 (d, J = 7.69 Hz, 1H), 2.22 (s, 3H).

[0115] Example 13: (4-(3-(2-chloro-[l,l'-biphenyl]-4-yl)imidazo[l,2- a]pyridin-8-yl)amino)-2-methylphenyl)(morpholinomethyl)ketone

[0116] Example 13: (4-(3-(2-chloro-[l,l'-biphenyl]-4-yl)imidazo[l,2- a]pyridin-8-yl)amino)-2-methylphenyl)(morpholinomethyl)ketone was obtained from Intermediate 6 and Intermediate A by the synthetic method as in Example 7.

[0117] MS (ESI, m / z): 523.18 [M+H]+. 1 H NMR (500 MHz, DMSO-D6) δ 8.50 (s, 1H), 8.13 (dd, J = 6.80, 0.88 Hz, 1H), 7.88 (s, 1H), 7.86 (s, 1H), 7.82 - 7.77 (m, 5H), 7.57 (d, J = 2.03 Hz, 1H), 7.56 (d, J = 2.01 Hz, 1H), 7.28 (d, J = 2.20 Hz, 1H), 7.23 (d, J = 2.25 Hz, 1H), 7.13 (d, J = 8.21 Hz, 1H), 7.03 (dd, J = 7.49, 0.89 Hz, 1H), 6.89 (t, J = 7.16 Hz, 1H), 3.53 (s, 6H), 3.23 (s, 2H), 2.22 (s, 3H).

[0118] Example 14: (4-(3-chloro-4-methylphenyl)imidazo[l,2-a]pyridin-8- yl)amino)-2-methylphenyl)(morpholinomethyl)ketone

[0119] Example 14 was obtained from Intermediate 8 and Intermediate A by the synthetic method as in Example 7.

[0120] MS (ESI, m / z): 461.16 [M+H]+. 1 H NMR (500 MHz, DMSO-D6) δ 8.44 (s, 1H), 8.00 (dd, J = 6.80, 0.87 Hz, 1H), 7.72 (s, 1H), 7.67 (d, J = 1.74 Hz, 1H), 7.52 (dd, J = 7.83, 1.78 Hz, 1H), 7.49 (d, J = 7.82 Hz, 1H), 7.23 (d, J = 2.17 Hz, 1H), 7.19 (dd, J = 8.23, 2.24 Hz, 1H), 7.08 (d, J = 8.16 Hz, 1H), 6.98 (d, J = 7.47 Hz, 1H), 6.83 (t, J = 7.17 Hz, 1H), 3.60 (s, 4H), 3.18 (s, 4H), 2.37 (s, 3H), 2.18 (s, 3H).

[0121] Example 15: (4-(3-(3,4-dichlorophenyl)imidazo[l,2-a]pyridin-8-yl)amino)-2- methylphenyl)(morpholinyl)methanone

[0122] Example 15 was obtained from Intermediate 9 and Intermediate A by the synthetic method as in Example 7.

[0123] MS (ESI, m / z): 481.11 [M+H]+. 1 H NMR (500 MHz, DMSO-D6) δ 8.47 (s, 1H), 8.05 (dd, J = 6.85, 0.88 Hz, 1H), 7.92 (d, J = 2.09 Hz, 1H), 7.81 (s, 1H), 7.78 - 7.74 (m, 1H), 7.66 (dd, J = 8.35, 2.11 Hz, 1H), 7.23 (d, J = 2.19 Hz, 1H), 7.19 (dd, J = 8.25, 2.21 Hz, 1H), 7.08 (d, J = 8.18 Hz, 1H), 7.00 (dd, J = 7.54, 0.89 Hz, 1H), 6.85 (t, J = 7.17 Hz, 1H), 3.62 (d, J = 16.91 Hz, 6H), 3.16 (d, J = 23.37 Hz, 2H), 2.18 (s, 3H).

[0124] Example 16: (4-(4-methoxy-3-trifluoromethylphenyl)imidazo[l,2-a]pyridin-8- amino)-2-methylphenyl)(morpholinyl)methanone

[0125] Example 16 was obtained from Intermediate 10 and Intermediate A by the synthetic method as in Example 7.

[0126] MS (ESI, m / z): 511.19 [M+H]+. 1 H NMR (500 MHz, DMSO-D6) δ 8.52 (s, 1H), 8.14 (dd, J = 6.79, 0.87 Hz, 1H), 8.03 (d, J = 4.61 Hz, 1H), 8.02 (d, J = 2.17 Hz, 1H), 7.87 (s, 1H), 7.53 - 7.47 (m, 1H), 7.32 (d, J = 9.07 Hz, 1H), 7.22 (d, J = 2.22 Hz, 1H), 7.19 (dd, J = 8.23, 2.30 Hz, 1H), 7.04 (dd, J = 7.55, 0.86 Hz, 1H), 6.95 - 6.88 (m, 1H), 3.94 (s, 3H), 3.58 (d, J = 58.96 Hz, 7H), 3.23 (d, J = 7.69 Hz, 1H) 2.35 (s, 3H).

[0127] Example 17: 5-Methoxy-2-(8-((3-methyl-4-(morpholine-4-carbonyl)phenyl)amino)imidazo[l,2- a]pyridin-3-yl)benzonitrile

[0128] Example 17 was obtained from Intermediate 11 and Intermediate A by the synthetic method as in Example 7.

[0129] MS (ESI, m / z): 511.19 [M+H]+. 1 H NMR (500 MHz, DMSO-D6) δ 8.52 (s, 1H), 8.14 (dd, J = 6.79, 0.87 Hz, 1H), 8.03 (d, J = 4.61 Hz, 1H), 8.02 (d, J = 2.17 Hz, 1H), 7.87 (s, 1H), 7.53 - 7.47 (m, 1H), 7.32 (d, J = 9.07 Hz, 1H), 7.22 (d, J = 2.22 Hz, 1H), 7.19 (dd, J = 8.23, 2.30 Hz, 1H), 7.04 (dd, J = 7.55, 0.86 Hz, 1H), 6.95 - 6.88 (m, 1H), 3.94 (s, 3H), 3.58 (d, J = 58.96 Hz, 7H), 3.23 (d, J = 7.69 Hz, 1H) 2.35 (s, 3H).

[0130] Example 19: N-(2-(2-Aminoethoxy)ethyl)-4-(3-(4-methoxyphenyl)imidazo[l,2-a]pyridin-8-ylamino)-2- methylbenzamide

[0131] Step one: Synthesis of intermediate 14 from intermediate 1 and tert-butyl 4-amino-2-methylbenzoate by the synthetic method as in Example 7. MS (ESI, m / z): 430.21 [M+H] + .

[0132] Step two: Intermediate 14 (600 mg, 1.39 mmol) was dissolved in 5 mL of dichloromethane solution, 3.34 mL of trifluoroacetic acid solution was added, stirred at room temperature for 6 h, then the reaction solution was concentrated under reduced pressure to obtain 900 mg of brown-black crude product, which was intermediate 15. MS (ESI, m / z): 374.14 [M+H] + .

[0133] Step three: 900 mg of intermediate 15 crude product was dissolved in 6 mL of N,N- dimethylformamide solution, then 1.83 g of HATU, 1.26 mL of DIPEA was added, stirred at room temperature for 1 h, then 984.67 mg of tert-butyl (2-(2-aminoethoxy)ethyl)carbamate was added, and reacted at room temperature for 6 h. After the reaction was completed, the mixture was poured into water (20 mL), and the aqueous solution was extracted with ethyl acetate (20 mL x 2). The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and separated by column chromatography to obtain 672 mg of light yellow solid, which was intermediate 16, with a yield of 79%. MS (ESI, m / z): 560.28 [M+H] + .

[0134] Step four: Intermediate 16 (600 mg, 1.39 mmol) was dissolved in 5 mL of dichloromethane solution, 8.00 mL of 4 moL / L hydrochloric acid 1,4-dioxane solution was added, stirred at room temperature for 6 h, during which white solid was precipitated, filtered, washed and dried to obtain 420 mg of Example 19.

[0135] MS (ESI, m / z): 460.23 [M+H] + . 1 H NMR (500 MHz, DMSO-D6) δ 9.39 (s, 1H), 8.23 (t, J = 5.59 Hz, 2H), 8.13 (d, J = 6.71 Hz, 1H), 7.68 - 7.60 (m, 2H), 7.40 (d, J = 8.01 Hz, 1H), 7.20 (d, J = 3.93 Hz, 2H), 7.18 (d, J = 2.10 Hz, 1H), 3.86 (s, 3H), 3.64 (t, 2H), 3.57 (t, J = 5.77 Hz, 2H), 3.44 (t, J = 5.65 Hz, 2H), 2.98 (p, J = 5.64 Hz, 2H), 2.37 (s, 3H).

[0136] Example 20: 4-(3-(3-cyano-4-methoxyphenyl)imidazo[l,2-a]pyridin-8- amino)-N,2-dimethylbenzamide

[0137] Example 20 was synthesized from Intermediate 13 and Intermediate B by the method of synthesis as in Example 7.

[0138] MS (ESI, m / z): 412.17 [M+H] + . 1 H NMR (500 MHz, DMSO-D6) δ 8.44 (s, 1H), 7.62 (s, 1H), 7.59 (d, J = 2.09 Hz, 1H), 7.57 (d, J = 2.15 Hz, 1H), 7.27 (d, J = 2.19 Hz, 1H), 7.23 (dd, J = 8.19, 2.25 Hz, 1H), 7.14 - 7.11 (m, 3H), 6.99 (dd, J = 7.48, 0.89 Hz, 1H), 6.83 (t, J = 7.14 Hz, 1H), 3.84 (s, 3H), 2.74 (d, J = 4.50 Hz, 3H), 2.35 (s, 3H).

[0139] Example 21: 2-methoxy-5-(8-((3-methoxy-4-(morpholine-4-carbonyl)phenyl) amino)imidazo[l,2-a]pyridin-3-yl)benzonitrile

[0140] Example 21 was synthesized from Intermediate 13 and Intermediate G by the method of synthesis as in Example 7.

[0141] MS (ESI, m / z): 484.19 [M+H] + . 1 H NMR (500 MHz, DMSO-D6) δ 8.44 (s, 1H), 7.62 (s, 1H), 7.59 (d, J = 2.09 Hz, 1H), 7.57 (d, J = 2.15 Hz, 1H), 7.27 (d, J = 2.19 Hz, 1H), 7.23 (dd, J = 8.19, 2.25 Hz, 1H), 7.14 - 7.11 (m, 3H), 6.99 (dd, J = 7.48, 0.89 Hz, 1H), 6.83 (t, J = 7.14 Hz, 1H), 3.84 (s, 3H), 2.74 (d, J = 4.50 Hz, 3H), 2.35 (s, 3H).

[0142] Example 23: 1-(4-((3-(4-methoxyphenyl)imidazo[1,2-a]pyridin-8-yl)amino)-2- methylbenzoyl)-N,N-dimethylpiperidine-4-carboxamide

[0143] Step one: Synthesis of intermediate 14 from intermediate 1 and tert-butyl 4-amino-2- methylbenzoate by the synthetic method as in Example 7. MS (ESI, m / z): 430.21 [M+H]+.

[0144] Step two: Intermediate 14 (600 mg, 1.39 mmol) was dissolved in 5 mL of dichloromethane solution, 3.34 mL of trifluoroacetic acid solution was added, stirred at room temperature for 6 h, the reaction solution was concentrated under reduced pressure to obtain 900 mg of brown-black crude product, which was intermediate 15. MS (ESI, m / z): 374.14 [M+H]+.

[0145] Step three: 900 mg of intermediate 15 crude product was dissolved in 6 mL of N,N- dimethylformamide solution, followed by the addition of 1.83 g of HATU, 1.26 mL of DIPEA, stirred at room temperature for 1 h, 894 mg of tert-butyl piperidine-4-carboxylate was added, and reacted at room temperature for 6 h. After the reaction was completed, the mixture was poured into water (20 mL), and the aqueous solution was extracted with ethyl acetate (20 mL x 2). The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and separated by column chromatography to obtain 567 mg of light yellow solid, which was intermediate 19, with a yield of 75%. MS (ESI, m / z): 541.27 [M+H]+.

[0146] Step four: Intermediate 16 (450 mg, 1.39 mmol) was dissolved in 5 mL of dichloromethane solution, 2.00 mL of trifluoroacetic acid solution was added, stirred at room temperature for 6 h, and the reaction solution was concentrated under reduced pressure to obtain 675 mg of intermediate 17 as a brown-black crude product. MS (ESI, m / z): 485.56 [M+H]+.

[0147] Step five: 250 mg of intermediate 17 crude product was dissolved in 4 mL of N,N- dimethylformamide solution, followed by the addition of 351.64 mg of HATU, 250 μL of DIPEA, and stirred at room temperature for 1 h, 463 μL of 2 mol / L dimethylamine solution was added, and reacted at room temperature for 6 h. After the reaction was completed, the mixture was poured into water (20 mL), and the aqueous solution was extracted with ethyl acetate (20 mL x 2). The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and separated by column chromatography to obtain 187 mg of light yellow solid, which was Example 23, with a yield of 75%.

[0148] MS (ESI, m / z): 512.26 [M+H]+. 1 H NMR (400 MHz, MeOD) δ 8.00 (d, J = 6.83 Hz, 1H), 7.93 (d, J = 7.55 Hz, 2H), 7.70 (s, 1H), 7.42 (d, J = 8.85 Hz, 1H), 7.31 - 7.13 (m, 4H), 6.97 (t, J = 7.21 Hz, 1H), 4.08 (s, 3H), 3.76 (hept, J = 6.65 Hz, 3H), 3.18 (s, 3H), 3.08 (s, 1H), 2.99 (s, 2H), 2.97 (s, 3H), 2.35 (d, J = 31.29 Hz, 3H), 1.92 (d, J = 13.93 Hz, 1H), 1.71 (s, 4H).

[0149] Example 27: 1-(4-((3-(4-methoxyphenyl)imidazo[l,2-a]pyridin-8-yl)amino)-2- methylbenzoyl)-N-methylpiperidine-4-carboxamide

[0150] Intermediate 14 was obtained from Intermediate 1 and tert-butyl 4-amino-2- methylbenzoate by the synthetic method as in Example 7. Intermediate 14 was obtained to Intermediate 17 by the method described in Example 23 above. Then, 250 mg of Intermediate 17 crude was dissolved in 4 mL of N,N-dimethylformamide solution, followed by the addition of 351.64 mg of HATU, 250 μL of DIPEA and stirring at room temperature for 1 h, 106.83 mg of methylamine ethanol solution was added and reacted at room temperature for 6 h. After the reaction was completed, the mixture was poured into water (20 mL), and the aqueous solution was extracted with ethyl acetate (20 mL x 2). The organic layer was washed with water and brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and separated by column chromatography to obtain 165 mg of a light yellow solid, which was Example 27, with a yield of 61%.

[0151] MS (ESI, m / z): 512.26 [M+H]+. 1H NMR (400 MHz, MeOD) δ 8.21 (d, J = 6.76 Hz, 1H), 7.94 (s, 1H), 7.63 (d, J = 2.25 Hz, 1H), 7.61 (s, 1H), 7.56 (d, J = 7.73 Hz, 1H), 7.31 - 7.13 (m, 4H), 7.10 (s, 2H), 3.90 (s, 3H), 3.14 (s, 2H), 2.94 (s, 2H), 2.72 (s, 3H), 2.49 (s, 1H), 2.30 (d, J = 32.28 Hz, 3H), 2.03 - 1.83 (m, 2H), 1.70 (d, J = 11.28 Hz, 3H).

[0152] Example 28: l-(4-((3-(3-chloro-4-methoxyphenyl)imidazo[l,2- a]pyridin-8-yl)amino)-2-methylbenzoyl)-N-methylpiperidine-4-carboxamide

[0153] Example 28 was obtained from Intermediate 6 by the synthetic method as in Example 23.

[0154] MS (ESI, m / z): 537.25 [M+H]+. 1 H NMR (400 MHz, MeOD) δ 8.18 (d, J = 6.76 Hz, 1H), 7.94 (d, J = 1.70 Hz, 1H), 7.73 (d, J = 1.93 Hz, 1H), 7.68 - 7.58 (m, 1H), 7.52 (d, J = 7.65 Hz, 1H), 7.33 (d, J = 8.54 Hz, 1H), 7.24 (t, J = 7.24 Hz, 2H), 7.12 (s, 3H), 4.00 (d, J = 1.72 Hz, 3H), 3.15 (d, J = 1.83 Hz, 4H), 2.94 (s, 5H), 2.31 (d, J = 30.72 Hz, 3H), 1.89 (d, J = 13.54 Hz, 1H), 1.67 (s, 3H), 1.43 - 1.23 (m, 1H).

[0155] Example 29: l-(4-((3-(3-cyano-4-methoxyphenyl)imidazo[l,2- a]pyridin-8-yl)amino)-2-methylbenzoyl)-N-methylpiperidine-4-carboxamide

[0156] Example 29 was obtained from Intermediate 13 by the synthetic method as in Example 23.

[0157] MS (ESI, m / z): 532.21 [M+H]+. 1H NMR (400 MHz, MeOD) δ 8.07 (d, J = 6.80 Hz, 1H), 7.77 (s, 1H), 7.68 (s, 1H), 7.59 (d, J = 8.32 Hz, 1H), 7.32 (dd, J = 14.12, 8.11 Hz, 2H), 7.19 (d, J = 28.13 Hz, 3H), 7.08 (t, J = 7.25 Hz, 1H), 3.99 (s, 3H), 3.64 (s, 1H), 3.21 - 3.07 (m, 1H), 2.93 (t, J = 26.57 Hz, 1H), 2.72 (s, 3H), 2.52 (d, J = 22.24 Hz, 1H), 2.31 (d, J = 32.72 Hz, 3H), 1.92 (d, J = 13.60 Hz, 1H), 1.72 (s, 3H), 1.43 - 1.23 (m, 2H).

[0158] Example 30: l-(4-((3-(3-fluoro-4-methoxyphenyl)imidazo[l,2-a]pyridin-8-yl)amino)-2- methylbenzoyl)-N-methylpiperidine-4-carboxamide

[0159] Example 30 was obtained from Intermediate 16 by the synthetic method as in Example 23.

[0160] MS (ESI, m / z): 530.25 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 8.07 (d, J = 6.80 Hz, 1H), 7.77 (s, 1H), 7.68 (s, 1H), 7.59 (d, J = 8.32 Hz, 1H), 7.32 (dd, J = 14.12, 8.11 Hz, 2H), 7.19 (d, J = 28.13 Hz, 3H), 7.08 (t, J = 7.25 Hz, 1H), 3.99 (s, 3H), 3.64 (s, 1H), 3.21 - 3.07 (m, 1H), 2.93 (t, J = 26.57 Hz, 1H), 2.72 (s, 3H), 2.52 (d, J = 22.24 Hz, 1H), 2.31 (d, J = 32.72 Hz, 3H), 1.92 (d, J = 13.60 Hz, 1H), 1.72 (s, 3H), 1.43 - 1.23 (m, 2H).

[0161] The advantages of the present application in terms of pharmaceutical efficacy will be more fully understood by reference to the following examples of comparison.

[0162] Comparative Example 1: 2-methoxy-5-(8-((3-methyl-4-(morpholine-4-carbonyl)phenyl)amino)imidazo[l,2- a]pyrazin-3-yl)benzonitrile

[0163] Intermediate 35: (4-((3-bromoimidazo[l,2-a]pyrazin-8-yl)amino)-2-methylphenyl)(morpholino)methanone

[0164] To a 100 mL two-necked flask, 3-bromo-8-chloroimidazo[l,2-a]pyrazine (500 mg, 2.15 mmol), intermediate A (569 mg, 2.58 mmol), l,l'-bis(diphenylphosphino)ferrocene palladium dichloride (158 mg, 215 μmol) were added, dissolved in 8 mL super dry 1,4-dioxane. Anhydrous sodium carbonate (454 mg, 4.30 mmol) was dissolved in pure water to make a saturated solution and then added to the reaction flask. The reaction mixture was stirred and heated at 110 °C under N2atmosphere for 12 h. The reaction was completed, the mixture was poured into water (20 mL), and the aqueous solution was extracted with dichloromethane (20 mL x 2). The organic layers were combined, washed with water and brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and separated by column chromatography to give comparative example 1. It was a light yellow solid (528 mg, 62.6% yield. MS (ESI, m / z): 416.06 [M+H]+. + .

[0165] To a 25 mL two-necked flask, intermediate 35 (300 mg, 721 μmol), 3-cyano-4-methoxyphenyl boronic acid (153 mg, 865 μmmol), l,l'-bis(diphenylphosphino)ferrocene]palladium dichloride (52.7 mg, 72.1 μmol) were added, dissolved in 5 mL super dry 1,4-dioxane. Anhydrous sodium carbonate (153 mg, 1.44 mmol) was dissolved in pure water to make a saturated solution and then added to the reaction flask. The reaction mixture was stirred and heated at 110 °C under N2atmosphere for 12 h. The reaction was completed, the mixture was poured into water (20 mL), and the aqueous solution was extracted with dichloromethane (20 mL x 2). The organic layers were combined, washed with water and brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and separated by column chromatography to give the title compound. It was a brown solid (220 mg, 65.3% yield MS (ESI, m / z): 469.19 [M+H]+.

[0166] Comparative Example 2: N-(4-(3-chloro-4-methoxyphenyl)-lH-pyrrolo[2,3-c]pyridin-7-ylamino)-2- methylphenyl)acetamide

[0167] Intermediate 37: 7-Chloro-3-iodopyrrolo[2,3-c]pyridine

[0168] Intermediate 37: 7-Chloro-3-iodopyrrolo[2,3-c]pyridine

[0169] Intermediate 38: 7-Chloro-3-(3-chloro-4-methoxyphenyl)-lH-pyrrolo[2,3- c]pyridine

[0170] Intermediate 38 was obtained according to the synthetic procedure of Intermediate 35.

[0171] Intermediate 38: 7-Chloro-3-(3-chloro-4-methoxyphenyl)-lH-pyrrolo[2,3- c]pyridine

[0172] Example 1: Evaluation of in vitro antibacterial activity

[0173] Minimum growth inhibition concentration (MIC) test: Acinetobacter baumannii (ATCC 19606) was inoculated into 10 mL of tryptone medium and incubated in a 37 °C incubator with shaking at 200 rpm for 20 hours. When the clear medium became turbid, it indicated that the bacteria proliferated significantly and grew vigorously. At this time, the bacterial solution was diluted with new tryptone medium to make its OD600 value less than 0.1. Then, the diluted bacterial solution was inoculated into 96-well plates, and the final volume of each well was 200 μL. The plates were incubated in a 37 °C incubator with shaking at 200 rpm. After 20 hours, the OD600 value of each well was measured. The MIC was defined as the lowest concentration of the test compound that inhibited the growth of the bacteria by more than 50% compared to the control group. 600The value is between 0.3 to 0.5, again dilute with new tryptone soya broth medium by equal volume, as test bacteria liquid. Take clean and sterile 96-well cell culture plate, add 200 μL of prepared test bacteria liquid to each well of the first column, add 100 μL of test bacteria liquid to each well of the second column to the twelfth column. Take 4 μL of 1.6 mg / mL DMSO solution of the sample to be tested prepared in advance and add to each well of the first column (three replicates for each sample), and set up a positive control group (i.e. 4 μL of levofloxacin of the same concentration) and a blank control (i.e. without adding drugs). Starting from each well of the first column, sequentially add 100 μL of sample from the previous column to each well of the next column with 8 micro-pipettes to perform 2-fold gradient dilution, and set up 32 μg / mL, 16 μg / mL, 4 μg / mL, 2 μg / mL, 1 μg / mL, 0.5 μg / mL, 0.25 μg / mL, 0.125 μg / mL, 0.0625 μg / mL, 0.0313 μg / mL, 0.0156 μg / mL, 0.008 μg / mL, 12 different concentrations of compound solutions. Place the 96-well cell culture plate in a 37°C incubator and incubate for 18 h, and observe the growth of Acinetobacter baumannii in each well of the 96-well plate. For each compound, the concentration of the compound corresponding to the well in which no bacteria grow is the minimum bacteriostatic concentration of the compound.

[0174] Results: Table 1 provides the minimum bacteriostatic concentration (MIC) in micrograms per milliliter of the example compounds of the present application obtained with respect to the Acinetobacter baumannii ATCC 19606 strain. Table 2 provides the minimum bacteriostatic concentration (MIC) in micrograms per milliliter of the comparative example compounds of the present application obtained with respect to the Acinetobacter baumannii ATCC 19606 strain. Most of the specific compounds of the present application exhibit a MIC < 1 μg / mL (Acinetobacter baumannii 19606). The example compounds have a significant advantage in in vitro activity compared to the comparative examples.

[0175] Table 1 Example compound MIC

[0176] Table 2 Comparative example compound MIC

[0177] Experimental Example 2 Evaluation of antibacterial activity in vivo in mice

[0178] Experimental animals: Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., ICR mice, body weight between 20-22 g, uniform body weight, male mice.

[0179] Model: septicemia model infected with Acinetobacter baumannii (ATCC 19606)

[0180] Modeling method: 1 x 10 5CFU / mL of Acinetobacter baumannii (ATCC 19606) to infect mice to form a sepsis model (0.5 mL of bacterial solution was injected intraperitoneally to each mouse).

[0181] Experimental scheme: the compound was first dissolved in DMSO and then diluted with other solvents, so that the solvent ratio was physiological saline: Tween 80: DMSO = 9:0.5:0.5.

[0182] Physiological saline: Tween 80: DMSO = 9:0.5:0.5. The mice were divided into 5 groups, 6 male mice in each group. The mice in the drug administration group were injected intraperitoneally with 0.4 mL of Example 1 solution at a dose of 10 mg / mL, 30 mg / kg and 50 mg / kg at 1 hour after modeling. The negative control group was injected with 0.4 mL of blank solvent after modeling. The survival rate of the mice was observed for 7 days.

[0183] Results: see Figure 1. Example compound 7 showed complete protection when administered at a dose of 10 mg / kg. Example compound 27 also showed complete protection when administered at a dose of 10 mg / kg.

[0184] Experimental Example 3 Acute toxicity test in mice

[0185] Experimental animals: Beijing Vantoll Life Science and Technology Co., Ltd., ICR mice, weighing between 20-22 g, uniform in weight, male mice.

[0186] Experimental scheme: a total of 6 groups, including 5 experimental groups and 1 blank group. Example 1 was administered at a dose of 300 mg / kg, 200 mg / kg, 100 mg / kg, 50 mg / kg and 10 mg / kg (solvent: physiological saline: Tween 80: DMSO = 9:0.5:0.5), and was administered intraperitoneally at a volume of 0.4 mL. The blank group was injected with 0.4 mL of blank solvent intraperitoneally, and the survival rate of the mice was observed for 7 days.

[0187] Results: see Figure 2. Intraperitoneal injection of 300 mg / kg of example compound 7, the mice were normal after administration, and no deaths were observed.

Claims

1. An imidazopyridine derivative and a pharmaceutically acceptable salt thereof, characterized in that: The compound structure is shown as general formula (I): R1is selected from the group consisting of C1-C6alkylamino, C1-C6cycloalkylamino, N,N-dialkylamino wherein the dialkyl can form a cyclic structure with a heteroatom, the dialkyl being C1-C6alkyl, the heteroatom being N, O and S; R2, R3, R4, R5, R6, R7, R8, R9and R 10 each independently selected from the group consisting of hydrogen, halogen, cyano, C1-C3alkyl, C1-C3alkoxy, phenyl.

2. The imidazopyridine derivative and pharmaceutically acceptable salt thereof according to claim 1, characterized by: R1 is selected from the group consisting of methylamino, ethylamino, propylamino, butylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, N-(2-(2- aminoethoxy)ethylamino, N,N-dimethylamino, N,N-diethylamino, N-methyl-N- ethylamino, N-methylformamido, N-morpholino, N-thiomorpholino, N-oxidothiomorpholino, N-piperazino, N-methylpiperidin-4-formamido, N,N-dimethylpiperidin-4- formamido.

3. The imidazopyridine derivative and pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, characterized by: R2 is methyl, methoxy, halogen; R6 and R7 are each independently selected from the group consisting of hydrogen, halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy; R8 is halogen, cyano, C1-C3 alkoxy, C1-C3 alkyl, phenyl; R3, R4, R5, R9 and R 10 is hydrogen.

4. The imidazopyridine derivative and pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized by: R2 is methyl; R8 is methoxy; R3, R4, R5, R6, R7, R9 and R 10 is hydrogen.

5. The imidazopyridine derivative and pharmaceutically acceptable salt thereof according to Claim 1, characterized by, The compound is selected from:

6. [R 91 CORRECTED 12.05.2025] A pharmaceutical composition characterized in that, The pharmaceutical composition comprises the imidazopyridine derivative and pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, and one or more pharmaceutically acceptable carriers or excipients.

7. [Amended according to Rule 91 12.05.2025] Use of the imidazopyridine derivative and pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and the pharmaceutical composition according to claim 6 for the manufacture of a medicament for the treatment of bacterial infection.

8. Use according to claim 7, characterized in that the compound is applied to the skin of the human body. The bacteria are selected from the group consisting of susceptible or resistant Acinetobacter baumannii. The bacteria are selected from the group consisting of susceptible or resistant Acinetobacter baumannii.

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