Imidazopyridine derivative and application thereof

Abstract

The invention belongs to the technical field of medicines, and discloses an imidazopyridine derivative and application thereof. The invention specifically relates to an imidazopyridine derivative as shown in a general formula (I) and pharmaceutically acceptable salts thereof. The invention also relates to the use of the compound in the treatment or prevention of bacterial infections and diseases caused by bacterial infections, in particular in the treatment or prevention of diseases infected by Acinetobacter baumannii (Acinetobacter baumannii).

Description

TECHNICAL FIELD

[0001] The present application relates to novel imidazopyridine derivatives and the use of the compounds for the treatment of diseases, in particular for the treatment or prevention of Acinetobacter baumannii infections and the 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 multidrug resistance. According to statistics, the probability of multidrug 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 faced with 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. The present application provides novel compounds that exhibit activity against Acinetobacter baumannii. SUMMARY

[0006] The technical problem solved by the present application is to provide imidazopyridine derivatives, a preparation method thereof and the use thereof in the treatment of bacterial infections.

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

[0008] In a first aspect, the present application provides an imidazopyridine compound having the structure shown in general formula (I),

[0009]

[0010] 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-formamido, N,N-dimethylpiperidin-4-formamido;

[0011] R2is selected from hydrogen, halogen, C1-C6alkyl;

[0012] R3, R4, and R5are each independently selected from hydrogen;

[0013] R6and R7are each independently selected from hydrogen, halogen, cyano, C1-C3alkyl, C1-C3alkoxy;

[0014] R8is halogen, cyano, C1-C3alkoxy, C1-C3alkyl, phenyl;

[0015] R3, R4, R5, R9, and R 10 are hydrogen;

[0016] 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-formamido, and N,N-dimethylpiperidin-4-formamido.

[0017] In preferred embodiments, the present application provides a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2is methyl.

[0018] In preferred embodiments, the present application provides a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen.

[0019] In preferred embodiments, the present application provides a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen.

[0020] In preferred embodiments, the present application provides a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R5is hydrogen.

[0021] In preferred embodiments, the present application provides a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R6is hydrogen.

[0022] In preferred embodiments, the present application provides a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R7is hydrogen.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] In a preferred embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R

[0028]

[0029]

[0030]

[0031]

[0032]

[0033]

[0034]

[0035]

[0036]

[0037] 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.

[0038] 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.

[0039] The administration form can be a liquid form, a solid form or a semi-solid form. The liquid 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 form can be a tablet (including ordinary tablet, enteric-coated tablet, chewable 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 form can be an ointment, a gel, a paste, etc.

[0040] The compound of the present application can be prepared into a common preparation, a sustained-release preparation, a controlled-release preparation, a targeted preparation and various micro-particle administration systems.

[0041] In order to prepare the tablet of the compound of the present application, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, co-solvents. 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, polyvinyl pyrrolidone, polyethylene glycol, etc.; the disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; the lubricants and co-solvents can be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0042] The tablet can be further prepared into a coated tablet, such as a sugar-coated tablet, a film-coated tablet, an enteric-coated tablet, or a double-layer tablet and a multi-layer tablet.

[0043] In order to prepare the capsule of the administration unit, the effective component, the compound of the present application, can be mixed with diluents and co-solvents, and the mixture can be directly placed in a hard capsule or a soft capsule. The effective component, the compound of the present application, can also be mixed with diluents, binders and disintegrants to prepare granules or pellets, and then placed in a hard capsule or a soft capsule. The various diluents, binders, wetting agents, disintegrants and co-solvents used for preparing the tablet of the compound of the present application can also be used for preparing the capsule of the compound of the present application.

[0044] For injection, the compounds of the present application can be dissolved in water, ethanol, isopropanol, propylene glycol or a mixture thereof, and an appropriate amount of solubilizers, co-solvents, pH adjusters, osmotic pressure adjusters commonly used in the art can be added. The solubilizers or co-solvents can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; the pH adjusters can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure adjusters can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. If a lyophilized powder injection is prepared, mannitol, glucose, etc. can also be added as a supporting agent.

[0045] In addition, if necessary, coloring agents, preservatives, fragrances, flavoring agents or other additives can also be added to the pharmaceutical preparation.

[0046] For the purpose of medication and enhancement of therapeutic effect, the pharmaceutical or pharmaceutical composition of the present application can be administered by any known administration method.

[0047] The administration dose of the pharmaceutical composition of the compound of the present application can vary widely 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 the dosage form, etc. Generally, the suitable dose of the compound of the present application per day is in the range of 0.1-50 mg / Kg body weight. The above dose 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 the use of other therapeutic means. The compound or composition of the present application can be taken alone or in combination with other therapeutic drugs or symptomatic drugs. When the compound of the present application has a synergistic effect with other therapeutic drugs, its dose should be adjusted according to the actual situation.

[0048] In a third aspect, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, having valuable pharmacological properties, for use in treating or preventing infections caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli or a combination thereof and the use of diseases caused thereby. In particular, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, for use in treating or preventing infections caused by Gram-negative bacteria and diseases caused thereby. Most particularly, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, for use in treating or preventing infections caused by Acinetobacter baumannii and diseases caused thereby. Particularly bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections.

[0049] In a fourth aspect, the present invention provides a method for preparing the imidazopyridine compound of the first aspect.

[0050] The preparation of the compounds of formula (I) of the present invention can be carried out according to sequential or convergent synthetic routes. The synthesis of the compounds of the present invention is shown in the following scheme. The skills required for performing the reactions and purifying the resulting products are known to those skilled in the art. Unless otherwise indicated, the substituents used in the following method descriptions have the meanings provided herein. In more detail, the compounds of formula (I) can be prepared by the methods described below, the methods provided in the examples, or similar methods. The appropriate reaction conditions for each reaction step are known to those skilled in the art. The reaction sequence is not limited to the sequence shown in the scheme, but, depending on the starting material and its corresponding reactivity, the order of the reaction steps can be freely changed. The starting material is commercially available or can be prepared by methods similar to those described below, by methods described in this specification, or by methods known in the art.

[0051] The synthesis of compounds of formula (I) can be accomplished according to the general synthetic routes outlined in Schemes I and II below.

[0052] Solution 1

[0053]

[0054] a) reacting boronic acid II with imidazopyridine derivative III in the presence of a coupling agent (such as DAPCy) and a base (K3PO4) to form compound IV.

[0055] b) conveniently reacting IV in the presence of a transition metal catalyst (such as Pd(OAc)2) and a base (such as NaOtBu), a ligand (BINAP) to obtain imidazopyridine derivatives (I). These imidazopyridines (I) can be the final desired compounds or can be further derivatized to obtain the final imidazopyridine derivatives (I).

[0056] Scheme II

[0057]

[0058] b) 4-amino-2-methylbenzoic acid tert-butyl ester is either commercially available or can be obtained by methods known in the art and can be conveniently reacted with intermediate IV under metal catalyzed reaction conditions to obtain intermediate VI.

[0059] 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, NEt3and 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, 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, NEt3and the like) to provide a compound of formula (I).

[0060] The term

[0061] The term "alkyl" means a monovalent or polyvalent (e.g., monovalent or divalent) straight-chain or branched-chain saturated hydrocarbon radical ("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.

[0062] The term "alkoxy" refers to an alkyl group as previously defined attached to the parent molecular moiety through an oxygen atom. Unless otherwise indicated, an alkoxy group contains 1 to 6 carbon atoms ("Ci-C6-alkoxy"). In some preferred embodiments, the alkoxy group contains 1 to 4 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, and t-butyloxy. One particularly preferred, but non-limiting example of an alkoxy group is methoxy.

[0063] The term "halogen" or "halo" refers to fluorine (F), chlorine (CI), bromine (Br), or iodine (I). Preferably, the term "halogen" or "halo" refers to 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" refers to a saturated or unsaturated monocyclic or bicyclic hydrocarbon group having 3-12 ring carbon atoms ("C3-C 12 The term "cycloalkyl" refers to a saturated or unsaturated monocyclic or bicyclic hydrocarbon group having 3-12 ring carbon atoms ("C3-C

[0064] The term "aminoalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group has been replaced with an amino group. One preferred, but non-limiting example of an aminoalkyl group is aminomethyl, aminoethyl, and N,N-dimethylamino.

[0065] The term "cyano" refers to a -CN (nitrile) group.

[0066] The term "oxo" refers to an oxygen atom (=0) bound to the parent molecule through a double bond.

[0067] The term "amino" refers to a -NH2 group.

[0068] The term "carboxy" refers to a -COOH group.

[0069] The term "carbamoyl" refers to a -C(O)NH2 group.

[0070] The term "carbonyl" refers to a -C(O)- group.

[0071] The term "prevent" includes preventing or delaying the onset of clinical symptoms of a condition, disease or disorder in a mammal, and particularly a human who may have or be susceptible to a condition, disease or disorder but has not yet developed or displayed clinical or subclinical symptoms of the condition, disease or disorder.

[0072] The term "mammal" includes humans and non-humans, and includes but is not limited to humans, non-human primates, canines, felines, murines, bovines, equines, and swine. In a particularly preferred embodiment, the term "mammal" refers to humans.

[0073] Beneficial technical effects

[0074] The imidazopyridine derivatives of the present invention have novel structures, show significant inhibitory effects on Acinetobacter baumannii both in vitro and in vivo in mice, and have good safety, and are expected to become new anti-Acinetobacter baumannii therapeutic drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0075] Figure 1 In vivo drug efficacy survival curves of Acinetobacter baumannii infection model mice in Example 7 and Example 27

[0076] Figure 2 Acute toxicity survival curve in mice DETAILED DESCRIPTION

[0077] The present invention will be further described by way of the following examples, however, the scope of the present invention is not limited to the following examples. It will be appreciated by those skilled in the art that various changes and modifications may be made to the present invention without departing from the spirit and scope of the present invention.

[0078] Unless otherwise stated, all metal coupled reaction examples and intermediates were prepared under a nitrogen atmosphere.

[0079] The following abbreviations are used in this article:

[0080] (R)-BINAP = (R)-2,2'-bis(diphenylphosphino)-l,l'-binaphthyl, ACN = acetonitrile, aq. = aqueous, Boc = tert-butyloxycarbonyl, CAS = Chemical Abstracts Service, DCM = dichloromethane, DMF = N,N-dimethylformamide, DMSO = dimethyl sulfoxide, DMSO-d6 = deuterated dimethyl sulfoxide, HATU = N,N,N',N'-tetramethyl-0-(7-azabenzotriazol-l-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(s), H2O = water, K3PO4 = potassium phosphate tribasic, LC-MS = liquid chromatography-mass spectrometry, MeOH = methanol, min = minute(s), mL = milliliter(s), MS = mass spectrometry, N2 = nitrogen, Na2SO4 = sodium sulfate, Pd / C = palladium on carbon, Pd(DAPCy) = trans-bis(dicyclohexylphosphino)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.

[0081] Intermediate 13: 5-(8-bromoimidazo[l,2-a]pyridin-3-yl)-2-methoxybenzonitrile

[0082]

[0083] 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 Na2SO4 and 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] + .

[0084] The following intermediates were prepared similarly:

[0085]

[0086] The following intermediates were prepared similarly:

[0087]

[0088] Intermediate A: 4-amino-2-methylphenyl(morpholinyl)methanone

[0089] Step 1: 4-nitro-2-methylphenyl(morpholinyl)methanone

[0090] 2-methyl-4-nitrobenzoic acid (500 mg, 2.76 mmol) and CDI (537 mg, 3.31 mmol) were dissolved in 5 mL of anhydrous DMF, stirred at 75 °C for 10 min, and then stirred at room temperature for 1.5 h. Morpholine (480.35 mg, 5.52 mmol) was added to the mixture, which was stirred at room temperature for 12 h. The mixture was diluted with water and extracted with EA (20 mL x 2). The organic phase was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography gave 4-nitro-2-methylphenyl(morpholinyl)methanone (655.73 mg, 95% yield) as a light pink solid. MS (ESI, m / z): 251.10 [M+H] + .

[0091] Step 2: 4-amino-2-methylphenyl(morpholinyl)methanone

[0092] 4-nitro-2-methylphenyl(morpholinyl)methanone (500 mg) was dissolved in 10 mL of methanol, 10% Pd / C (50 mg) was added, and the mixture was placed in a medium-pressure hydrogenation instrument for reaction for 8 h. The mixture was filtered through diatomite, and concentrated under reduced pressure to give 4-amino-2-methylphenyl(morpholinyl)methanone (426.80 mg, 97% yield) as a light pink solid. MS (ESI, m / z): 221.12 [M+H] + .

[0093] The following intermediates were prepared similarly:

[0094]

[0095]

[0096] Example 7: 2-methoxy-5-(8-((3-methyl-4-(morpholine-4-carbonyl)phenyl)amino)imidazo[l,2-a]pyridin-3-yl)benzonitrile

[0097]

[0098] 4-amino-2-methylphenyl(morpholinyl)methanone (302.05 mg, 1.37 mmol) with intermediate 13 (300 mg, 0.91 mmol) NaOtBu (351.42 mg, 3.66 mmol), BINAP (71.15 mg, 0.11 mmol), Pd(OAc)2(20.52 mg, 0.091 mmol) were added to toluene (6 mL) and the mixture was purged with N2for 5 min. The reaction mixture was stirred and heated under N2atmosphere at 100 °C for 12 h. The reaction was complete, 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 obtain the title compound. Off-white solid (160 mg, 37.5% yield).

[0099] 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).

[0100] The following examples were prepared in analogy to example 7

[0101] Example 1: 4-((3-(4-methoxyphenyl)imidazo[l,2-a]pyridin-8-yl)amino)-N,2- dimethylbenzamide

[0102]

[0103] Example 1 was obtained from intermediate 1 and intermediate B by the synthetic procedure as in example 7.

[0104] MS (ESI, m / z): 387.18 [M+H] + . 1H 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).

[0105] Example 2: 4-((3-(3-chloro-4-(trifluoromethoxy)phenyl)imidazo[l,2- a]pyridin-8-yl)amino)-N,2-dimethylbenzamide

[0106]

[0107] Example 2 was obtained from Intermediate 2 and Intermediate B by the synthetic method as in Example 7.

[0108] MS (ESI, m / z): 475.11 [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).

[0109] Example 3: 4-((3-(3-chloro-4-(cyclopropylmethoxy)phenyl)imidazo[l,2- a]pyridin-8-yl)amino)-N,2-dimethylbenzamide

[0110]

[0111] Example 3 was obtained from Intermediate 3 and Intermediate B by the synthetic method as in Example 7.

[0112] MS (ESI, m / z): 461.17 [M+H]+. 1 H 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).

[0113] Example 4: N-ethyl-4-(3-(4-methoxyphenyl)imidazo[l,2-a]pyridin-8-ylamino)-2- methylbenzamide

[0114]

[0115] Example 4 was obtained from Intermediate 1 and Intermediate C by the synthetic method as in Example 7. 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).

[0116] Example 5: 4-(3-(4-methoxyphenyl)imidazo[l,2-a]pyridin-8-amino)-N,N,2- trimethylbenzamide

[0117]

[0118] Example 5 was obtained by the synthetic method as in Example 7 from Intermediate 1 and 4-amino-N,N,2-trimethylbenzamide, which was purchased directly.

[0119] 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).

[0120] Example 6: (4-(3-(4-methoxyphenyl)imidazo[l,2-a]pyridin-8-yl)amino)-2- methylphenyl)(morpholino)methanone

[0121]

[0122] Example 6 was obtained by the synthetic method as in Example 7 from Intermediate 1 and Intermediate A.

[0123] 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).

[0124] Example 8: (4-(3-(4-methoxyphenyl)imidazo[l,2-a]pyridin-8-yl)amino)-2- methylphenyl)(thiomorpholino)methanone

[0125]

[0126] Example 8 was obtained from Intermediate 1 and Intermediate D by the synthetic method as in Example 7.

[0127] MS (ESI, m / z): 459.18 [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).

[0128] Example 9: (4-(3-(4-methoxyphenyl)imidazo[l,2-a]pyridin-8-yl)amino)-2- methylphenyl)(piperazin-l-yl)methanone

[0129]

[0130] 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 HCl, 1,4-dioxane solution was added, and as the reaction proceeded, a precipitated solid was separated out. The precipitate was filtered out after 4 h of reaction to obtain 150 mg of a light yellow solid, which was Example 9.

[0131] 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).

[0132] Example 10: (4-(3-(4-ethoxyphenyl)imidazo[l,2-a]pyridin-8-ylamino)-2- methylphenyl)(morpholinyl)methanone

[0133]

[0134] Example 10 was obtained from Intermediate 4 and Intermediate A by the synthetic method as in Example 7.

[0135] 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).

[0136] Example 11: (4-(3-chloro-4-cyclopropoxyphenyl)imidazo[l,2-a]pyridin-8-yl)amino)-2- methylphenyl)(morpholinyl)methanone

[0137]

[0138] Example 11 was obtained from Intermediate 5 and Intermediate A by the synthetic method as in Example 7.

[0139] MS (ESI, m / z): 503.18 [M+H]+. 1H 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).

[0140] Example 12: (4-(3-chloro-4-methoxyphenyl)imidazo[l,2-a]pyridin-8-yl)amino)-2- methylphenyl)(morpholinyl)methanone

[0141]

[0142] Example 12 was obtained from Intermediate 6 and Intermediate A by the synthetic method as in Example 7.

[0143] MS (ESI, m / z): 477.16 [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).

[0144] Example 13: 4-(3-(2-chloro-[l,l'-biphenyl]-4-yl)imidazo[l,2-a]pyridin-8-yl)amino)-2- methylphenyl)(morpholinyl)methanone

[0145]

[0146] Example 13 was obtained from Intermediate 7 and Intermediate A by the synthetic method as in Example 7.

[0147] 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).

[0148] Example 14: (4-(3-chloro-4-methylphenyl)imidazo[l,2-a]pyridin-8-yl)amino)-2- methylphenyl)(morpholinyl)methanone

[0149]

[0150] Example 14 was obtained from Intermediate 8 and Intermediate A by the synthetic method as in Example 7.

[0151] 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).

[0152] Example 15: (4-(3-(3,4-dichlorophenyl)imidazo[l,2-a]pyridin-8-yl)amino)-2- methylphenyl)(morpholinyl)methanone

[0153]

[0154] Example 15 was obtained from Intermediate 9 and Intermediate A by the synthetic method as in Example 7.

[0155] 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).

[0156] Example 16: (4-(4-methoxy-3-trifluoromethylphenyl)imidazo[l,2-a]pyridin-8-ylamino)- 2-methylphenyl)(morpholinyl)methanone

[0157]

[0158] Example 16 was obtained from Intermediate 10 and Intermediate A by the synthetic method as in Example 7.

[0159] MS (ESI, m / z): 511.19 [M+H]+. 1H 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).

[0160] Example 17: 5-Methoxy-2-(8-((3-methyl-4-(morpholine-4-carbonyl)phenyl)amino)imidazo[l,2- a]pyridin-3-yl)benzonitrile

[0161]

[0162] Example 17 was obtained from Intermediate 11 and Intermediate A by the method of synthesis as in Example 7.

[0163] MS (ESI, m / z): 511.19 [M+H]+. 1 H NMR (500 MHz, DMSO-D6) δ 8.45 (s, 1H), 7.95 (dd, J = 6.81, 0.90 Hz, 1H), 7.62 (s, 1H), 7.60 - 7.53 (m, 2H), 7.27 (d, J = 2.18 Hz, 1H), 7.23 (dd, J = 8.20, 2.23 Hz, 1H), 7.15 - 7.08 (m, 3H), 6.98 (dd, J = 7.47, 0.87 Hz, 1H), 6.82 (t, J = 7.13 Hz, 1H), 3.83 (s, 3H), 3.58 (d, J = 61.79 Hz, 6H), 3.22 (s, 2H), 2.22 (s, 3H).

[0164] Example 19: N-(2-(2-Aminoethoxy)ethyl)-4-(3-(4-methoxyphenyl)imidazo[l,2- a]pyridin-8-ylamino)-2-methylbenzamide

[0165]

[0166] 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] + .

[0167] 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] + .

[0168] 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] + .

[0169] 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.

[0170] 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).

[0171] Example 20: 4-(3-(3-cyano-4-methoxyphenyl)imidazo[l,2-a]pyridin-8- amino)-N,2-dimethylbenzamide

[0172]

[0173] Example 20 was synthesized from Intermediate 13 and Intermediate B by the method of synthesis as in Example 7.

[0174] 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).

[0175] Example 21: 2-methoxy-5-(8-((3-methoxy-4-(morpholine-4-carbonyl)phenyl) amino)imidazo[l,2-a]pyridin-3-yl)benzonitrile

[0176]

[0177] Example 21 was synthesized from Intermediate 13 and Intermediate G by the method of synthesis as in Example 7.

[0178] 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).

[0179] Example 23: 1-(4-((3-(4-methoxyphenyl)imidazo[l,2-a]pyridin-8-yl)amino)-2- methylbenzoyl)-N,N-dimethylpiperidine-4-carboxamide

[0180]

[0181] 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]+.

[0182] 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]+.

[0183] 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 layers were 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]+.

[0184] 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]+.

[0185] 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 layers were 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%.

[0186] 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).

[0187] Example 27: 1-(4-((3-(4-methoxyphenyl)imidazo[l,2-a]pyridin-8-yl)amino)-2- methylbenzoyl)-N-methylpiperidine-4-carboxamide

[0188]

[0189] Example 27: 1-(4-((3-(4-methoxyphenyl)imidazo[l,2-a]pyridin-8-yl)amino)-2- methylbenzoyl)-N-methylpiperidine-4-carboxamide

[0190] 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).

[0191] Example 28: l-(4-((3-(3-chloro-4-methoxyphenyl)imidazo[l,2-a]pyridin-8-yl)amino)-2- methylbenzoyl)-N-methylpiperidine-4-carboxamide

[0192]

[0193] Example 28 was obtained from Intermediate 6 by the synthetic method as in Example 23.

[0194] MS (ESI, m / z): 537.25 [M+H]+. 1 H 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).

[0195] Example 29: l-(4-((3-(3-cyano-4-methoxyphenyl)imidazo[l,2-a]pyridin-8-yl)amino)-2- methylbenzoyl)-N-methylpiperidine-4-carboxamide

[0196]

[0197] Example 29 was obtained from Intermediate 13 by the synthetic method as in Example 23.

[0198] MS (ESI, m / z): 532.21 [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).

[0199] Example 30: l-(4-((3-(3-fluoro-4-methoxyphenyl)imidazo[l,2-a]pyridin-8-yl)amino)-2- methylbenzoyl)-N-methylpiperidine-4-carboxamide

[0200]

[0201] Example 30 was obtained from Intermediate 16 by the method of synthesis as in Example 23.

[0202] 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).

[0203] The advantages of the present application in terms of pharmaceutical efficacy will be more fully understood by reference to the following comparative examples.

[0204] Comparative Example 1: 2-methoxy-5-(8-((3-methyl-4-(morpholine-4-carbonyl)phenyl)amino)imidazo[l,2- a]pyrazin-3-yl)benzonitrile

[0205]

[0206] Intermediate 35: (4-((3-bromoimidazo[l,2-a]pyrazin-8-yl)amino)-2-methylphenyl)(morpholino)methanone

[0207]

[0208] Comparative Example 1: 2-methoxy-5-(8-((3-methyl-4-(morpholine-4-carbonyl)phenyl)amino)imidazo[l,2- a]pyrazin-3-yl)benzonitrile + .

[0209] Comparative Example 1: 2-methoxy-5-(8-((3-methyl-4-(morpholine-4-carbonyl)phenyl)amino)imidazo[l,2- a]pyrazin-3-yl)benzonitrile

[0210] Comparative Example 2: N-(4-(3-chloro-4-methoxyphenyl)-lH-pyrrolo[2,3- c]pyridin-7-amino)-2-methylphenyl)acetamide

[0211]

[0212] Intermediate 37: 7-chloro-3-iodopyrrolo[2,3-c]pyridine

[0213]

[0214] Intermediate 37: 7-chloro-3-iodopyrrolo[2,3-c]pyridine

[0215] Intermediate 38: 7-chloro-3-(3-chloro-4-methoxyphenyl)-lH-pyrrolo[2,3- c]pyridine

[0216]

[0217] Intermediate 38 was obtained according to the synthetic procedure of Intermediate 35.

[0218] Intermediate 38: 7-chloro-3-(3-chloro-4-methoxyphenyl)-lH-pyrrolo[2,3- c]pyridine

[0219] Experimental Example 1 Evaluation of in vitro antibacterial activity

[0220] Minimum Inhibitory Concentration (MIC) Test: Inoculate Acinetobacter baumannii (ATCC 19606) into 10 mL of beef peptone medium and incubate at 37°C in a shaker at 200 rpm for 20 hours. When the clarified medium becomes turbid, it indicates that the bacteria are proliferating and growing vigorously. At this time, dilute the bacterial solution with fresh beef peptone medium to an OD of 600 If the value is between 0.3 and 0.5, dilute the sample again with fresh tryptone soy broth medium in equal multiples to prepare the test bacterial solution. Take a clean, sterile 96-well cell culture plate and add 200 μL of the prepared test bacterial solution to each well in the first column and 100 μL to each well in columns 2 through 12. Add 4 μL of the pre-prepared 1.6 mg / mL DMSO solution of the test sample to each well in column 1 (each sample is repeated in triplicate). Also set up a positive control group (i.e., 4 μL of the same concentration of levofloxacin) and a blank control (i.e., no drug). Starting with each well in the first column, use an 8-channel micropipette to pipette 100 μL of sample from the previous column into each well in the next column, performing a two-fold serial dilution. A total of 12 different compound concentrations were set, including 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, and 0.008 μg / mL. The 96-well cell culture plate was placed in a 37°C incubator for 18 hours. The growth of Acinetobacter baumannii in each well was observed. For each compound, the well where no bacterial growth was observed was the minimum inhibitory concentration (MIC).

[0221] Results: Table 1 provides the minimum inhibitory concentrations (MICs) of the example compounds of the present invention obtained against Acinetobacter baumannii ATCC 19606 in micrograms / ml. Table 2 provides the minimum inhibitory concentrations (MICs) of the comparative examples of the present invention obtained against Acinetobacter baumannii ATCC 19606 in micrograms / ml. Most of the specific compounds of the present invention exhibited MICs < 1 μg / mL (Acinetobacter baumannii 19606). The example compounds had significant advantages in in vitro activity compared to the comparative examples.

[0222] Table 1 MIC of example compounds

[0223] Example compounds ATCC 19606 (pg / mL) Example compounds ATCC 19606 (pg / mL) 1 0.0313 17 <0.0156 2 0.5 18 2 3 8 19 0.5 4 0.25 20 4 5 0.5 21 4 6 0.0313 22 4 7 0.0625 23 <0.0313 8 0.25 24 <0.0313 9 0.5 25 <0.0313 10 0.125 26 <0.0313 11 2 27 <0.0156 12 2 28 <0.0156 13 4 29 <0.0156 14 4 30 <0.0156 15 1 31 <0.0156 16 4

[0224] Table 2 MIC of comparative compounds

[0225] Comparative example ATCC 19606 (pg / mL) 1 8 2 >128

[0226] Evaluation of antibacterial activity in vivo in mice

[0227] Experimental animals: ICR mice, weighing between 20-22 g, uniform weight, male mice, Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0228] Model: septicemia model infected with Acinetobacter baumannii (ATCC 19606)

[0229] Modeling method: 1 x 10 5 The mice were infected with 1 x 10

[0230] 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. The mice were divided into 5 groups, 6 male mice in each group, and the drug administration group was injected intraperitoneally with 0.4 mL of a solution of Example 1 at a dose of 10 mg / mL, 30 mg / kg and 50 mg / kg 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. Results: see attached 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.

[0231] Experimental Example 3 Acute toxicity test in mice in vivo

[0232] Experimental animals: ICR mice, weighing between 20-22 g, uniform weight, male mice, Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0233] 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 ratio physiological saline: Tween 80: DMSO = 9:0.5:0.5), and the volume of intraperitoneal administration was 0.4 mL. The blank group was injected with 0.4 mL of blank solvent by intraperitoneal administration, and the survival rate of the mice was observed for 7 days.

[0234] Results: see attached Figure 2 Example compounds ATCC 19606 (pg / mL) Example compounds ATCC 19606 (pg / mL) Comparative example ATCC 19606 (pg / mL) Figure 1 Figure 2 Example compounds ATCC 19606 (pg / mL) 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 its pharmaceutically acceptable salt according to claim 1, wherein: R1 is 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-oxidothiomorpholino, N-piperazino, N-methylpiperidin-4-formamido, N,N-dimethylpiperidin-4-formamido.

3. The imidazopyridine derivative and its pharmaceutically acceptable salt according to any one of claims 1-2, wherein: R2 is methyl, methoxy, halogen; R6 and R7 are each independently selected from 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 its pharmaceutically acceptable salt according to any one of claims 1-3, wherein: 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. A pharmaceutical composition, characterized by, The pharmaceutical composition comprises the imidazopyridine derivative and its pharmaceutically acceptable salt according to any one of claims 1-5, and one or more pharmaceutically acceptable carriers or excipients.

7. Use of the imidazopyridine derivative and its pharmaceutically acceptable salt according to any one of claims 1-5 and the pharmaceutical composition according to claim 6 in the preparation of a medicament for treating bacterial infection.

8. Use according to claim 7, characterised in that, The bacteria are selected from sensitive or drug-resistant Acinetobacter baumannii.

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