WO2025218767A1 - Imidazopyridine derivatives and use thereof - Google Patents

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

Imidazolopyridine derivatives and uses thereof Technical Field

The present invention relates to novel imidazopyridine derivatives and use of the compounds for treating diseases, in particular for treating or preventing Acinetobacter baumannii infection and the diseases caused by the same.

Background Art

Acinetobacter baumannii is a Gram-negative bacterium. It is a strictly aerobic, non-lactose fermenting conditional pathogen. It does not have flagella, has low mobility, and has extremely strong vitality. It is widely present in nature.

Acinetobacter baumannii infections are common in hospitalized patients, and their most notable characteristic is multidrug resistance. Statistics show that the incidence of multidrug resistance is four times higher than that of other Gram-negative bacteria, such as Klebsiella pneumoniae and Pseudomonas aeruginosa. Furthermore, they have a high mortality rate and are difficult to treat. Acinetobacter baumannii infections account for over 10% of all hospital-acquired infections in the United States, with a mortality rate exceeding 50% in patients with sepsis and pneumonia. They are resistant to most first-line antibiotics, and the World Health Organization has designated them as one of the most threatening strains to humans.

Acinetobacter baumannii infections often occur in intensive care units and surgical wards, and are mainly manifested as bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection.

The genome of Acinetobacter baumannii mutates rapidly when faced with adversity and stress, which gives it extremely strong environmental adaptability. This is the basis for its ability to adapt to harsh environments that other pathogens cannot adapt to, and its strong drug resistance and infectivity. It is mainly manifested in the ability to resist dry environments, movement and transfer capabilities, and biofilm formation capabilities. Acinetobacter baumannii is defined by the Antimicrobial Drug Availability Working Group of the Infectious Diseases Society of America (IDSA) and remains "a major example of a mismatch between unmet medical needs and current antimicrobial drug development pipelines." Therefore, the clinical development of anti-Acinetobacter baumannii drugs is imminent. The present invention provides novel compounds that exhibit activity against Acinetobacter baumannii.

Summary of the Invention

The technical problem solved by the present invention is to provide an imidazopyridine derivative and a preparation method thereof and use thereof in treating bacterial infection.

In order to solve the technical problems of the present invention, the present invention provides the following technical solutions:

In a first aspect, the present invention provides an imidazopyridine compound having a structure shown in general formula (I):

wherein _R 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-morpholinyl, N-thiomorpholinyl, N-oxidothiomorpholinyl, N-piperazinyl, N-methylpiperidine-4-carboxamide, and N,N-dimethylpiperidine-4-carboxamide;

R ₂ is selected from hydrogen, halogen, C ₁ -C ₆ alkyl;

R ₃ , R ₄ and R ₅ are each independently selected from hydrogen;

R ₆ and R ₇ are each independently selected from hydrogen, halogen, cyano, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy;

R ₈ is halogen, cyano, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl, or phenyl;

R ₃ , R ₄ , R ₅ , R ₉ and R ₁₀ are hydrogen;

In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein R ₁ is methylamino, N-morpholinyl, N-methylpiperidine-4-carboxamide and N,N-dimethylpiperidine-4-carboxamide.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R ₂ is methyl.

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

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R ₄ is hydrogen.

In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein R ₅ is hydrogen.

In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein R ₆ is hydrogen.

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

In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein R ₈ is C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkyl, trifluoromethoxy, cyclopropyloxy, cyclopropylmethoxy and phenyl.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R ₈ is methoxy.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R ₉ is hydrogen, halogen, trifluoromethyl and cyano.

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

In a preferred embodiment, the compound has the following structure:

In a second aspect, the present invention provides a pharmaceutical composition comprising the imidazopyridine compound and a pharmaceutically acceptable salt thereof as described in the first aspect and a pharmaceutically acceptable carrier or excipient, and further comprising one or more other active ingredients.

The compound of the present invention or the pharmaceutical composition containing the same can be administered in unit dosage form, and the administration route can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eyes, lungs and respiratory tract, skin, vagina, rectum, etc.

The dosage form can be a liquid dosage form, a solid dosage form, or a semisolid dosage form. Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o/w, w/o, and multiple emulsions), suspensions, injections (including aqueous injections, powder injections, and infusions), eye drops, nasal drops, lotions, and liniments; solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, and orally disintegrating tablets), capsules (including hard capsules, soft capsules, and enteric-coated capsules), granules, powders, micropills, dropping pills, suppositories, films, patches, aerosols (powders), and sprays; semisolid dosage forms can be ointments, gels, pastes, and the like.

The compound of the present invention can be prepared into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle delivery systems.

In order to prepare the compound of the present invention into tablets, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, and solubilizers. The diluent may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent may be water, ethanol, isopropyl alcohol, etc.; the binder may be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinyl pyrrolidone, polyethylene glycol, etc.; the disintegrant may 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 sorbitan fatty acid ester, sodium lauryl sulfate, etc.; the lubricant and solubilizing agent may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

The tablets can be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

To prepare a dosing unit as a capsule, the active ingredient compound of the present invention can be mixed with a diluent and a cosolvent, and the mixture can be placed directly in a hard or soft capsule. Alternatively, the active ingredient compound of the present invention can be first mixed with a diluent, a binder, and a disintegrant to form granules or pellets, which can then be placed in a hard or soft capsule. The same diluents, binders, wetting agents, disintegrants, and cosolvents used to prepare tablets of the compound of the present invention can also be used to prepare capsules of the compound of the present invention.

To prepare the compounds of the present invention as injections, water, ethanol, isopropanol, propylene glycol, or mixtures thereof can be used as solvents, and appropriate amounts of solubilizers, cosolvents, pH adjusters, and osmotic pressure regulators commonly used in the art can be added. Examples of solubilizers or cosolvents include poloxamer, lecithin, and hydroxypropyl-β-cyclodextrin; pH adjusters include phosphates, acetates, hydrochloric acid, and sodium hydroxide; and osmotic pressure regulators include sodium chloride, mannitol, glucose, phosphates, and acetates. For lyophilized powder injections, mannitol, glucose, and the like can also be added as support agents.

Furthermore, if necessary, colorants, preservatives, perfumes, flavorings or other additives may be added to the pharmaceutical preparations.

To achieve the purpose of medication and enhance the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known method of administration.

The dosage of the pharmaceutical compositions of the compounds of the present invention 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 route of administration, and the dosage form. Generally speaking, a suitable daily dosage range of the compounds of the present invention is 0.1-50 mg/kg body weight. This dosage can be administered as a single dosage unit or divided into several dosage units, depending on the physician's clinical experience and the dosage regimen selected from other treatment options. The compounds or compositions of the present invention can be taken alone or in combination with other therapeutic agents or symptomatic drugs. When the compounds of the present invention have a synergistic effect with other therapeutic agents, the dosage should be adjusted accordingly.

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 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.

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

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.

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

Solution 1

a) Boronic acid II is reacted with an imidazopyridine derivative III in the presence of a coupling agent (such as DAPCy) and a base (K ₃ PO ₄ ) to form compound IV.

b) conveniently reacting with IV in the presence of a transition metal catalyst (e.g., Pd(OAc) ₂ ), a base (e.g., NaOtBu), and a ligand (BINAP) to obtain an imidazopyridine derivative (I). These imidazopyridines (I) can be the final desired compounds or can be further derivatized to obtain the final imidazopyridine derivative (I).

Option II

b) tert-Butyl 4-amino-2-methylbenzoate is commercially available or can be obtained by methods known in the art, and can be conveniently reacted with intermediate IV under metal catalytic reaction conditions to obtain intermediate VI.

C) Acid derivative VII can be obtained in the presence of acid. The example of acid includes trifluoroacetic acid. Acid derivative VII is conveniently reacted with piperidine-4-carboxylic acid tert-butyl ester under the coupling reaction conditions of variation (coupling reaction conditions include: HATU, HBTU etc. in the presence of a base such as DIPEA, NEt ₃ etc.), 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 reacts with diethylamine or methylamine etc. under coupling conditions (coupling reaction conditions include: HATU, HBTU etc. in the presence of a base such as DIPEA, NEt ₃ etc.), to provide compound of formula (I).

the term

The term "alkyl" refers to a monovalent or polyvalent (e.g., monovalent or divalent) straight or branched chain saturated hydrocarbon radical (" _Ci - _C6 -alkyl") containing from 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms). In some examples, the alkyl group contains from 1 to 3 carbon atoms, such as 1, 2, or 3 carbon atoms. Some non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. A particularly preferred, but non-limiting example of an alkyl group is methyl.

The term "alkoxy" refers to an alkyl group as defined above attached to the parent molecular moiety through an oxygen atom. Unless otherwise indicated, an alkoxy group contains from 1 to 6 carbon atoms (" _Ci - _C6 -alkoxy"). In some preferred embodiments, the alkoxy group contains from 1 to 4 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. A particularly preferred, but non-limiting example of an alkoxy group is methoxy.

The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). Preferably, the term "halogen" or "halo" refers to fluorine (F), chlorine (Cl) or bromine (Br). Particularly preferred but non-limiting examples of "halogen" or "halo" are fluorine (F) and chlorine (Cl). The term "cycloalkyl" refers to a saturated or unsaturated monocyclic or bicyclic hydrocarbon radical having 3-12 ring carbon atoms ("C ₃ -C ₁₂ -cycloalkyl"). In some preferred embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon radical 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., the bridge separating the two rings is a single bond or a chain of one or two ring atoms, and a spirocyclic moiety, i.e., the two rings are connected by a common ring atom. Preferably, cycloalkyl group is a saturated monocyclic hydrocarbon radical with 3 to 6 ring carbon atoms (such as 3,4,5 or 6 carbon atoms).Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.Term " heterocycloalkyl " and " heterocyclic radical " are used interchangeably, refer to saturated or partially unsaturated monocycle or bicyclic, preferably monocyclic system with 3 to 10 ring atoms, preferably 3 to 8 ring atoms, wherein 1,2 or 3 in the ring atoms are heteroatoms selected from N, O and S, and all the other ring atoms are carbon.Preferably, 1-2 in the ring atoms are selected from N and O, and all the other ring atoms are carbon." bicyclic heterocyclic radical " refers to the heterocyclic moiety formed by two rings with two common ring atoms, and the bridge that promptly separates two rings is the chain of single bond or one or two ring atoms, and spirocyclic moiety, i.e. two rings are 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.

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

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

The term "oxo" refers to an oxygen atom (=0) double bonded to the parent molecule.

The term "amino" refers to a _-NH2 group.

The term "carboxy" refers to a -COOH group.

The term "carbamoyl" refers to a -C(O) _NH2 group.

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

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.

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.

Beneficial technical effects

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

Figure 1: In vivo drug efficacy survival curves in mice infected with Acinetobacter baumannii in Example 7 and Example 27

Figure 2 Acute toxicity survival curve in mice

DETAILED DESCRIPTION

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.

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

The following abbreviations are used in this article:

(R)-BINAP = (R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, ACN = acetonitrile, aq. = aqueous, Boc = tert-butyloxycarbonyl, CAS = Chemical Abstracts 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 mode, ESP = electrospray ionization negative mode, _H2 = hydrogen, h = hour, _H2O = water, K _3PO4 = tripotassium phosphate, LC-MS = liquid chromatography coupled to mass spectrometry, MeOH = methanol _{, min} = minute, mL = milliliter, MS = mass spectrometry, _N2 = nitrogen, _Na2SO4 = sodium sulfate, Pd/C = palladium on carbon, DAPCy = trans-bis(dicyclohexylamino)palladium(II) acetate, Pd(OAc) ₂ = palladium acetate, PE = petroleum ether, _Rf = retention factor, RM = reaction mixture, RT = room temperature, prep-TLC = preparative thin layer chromatography, UV = ultraviolet.

Intermediate 13: 5-(8-bromoimidazo[1,2-a]pyridin-3-yl)-2-methoxybenzonitrile

8-Bromo-3-iodoimidazo[1,2-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 cooled to room temperature, diluted with 20 mL of dichloromethane, and filtered through 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. The title compound was isolated by column chromatography (201 mg, 66% yield) as a light yellow solid. MS (ESI, m/z): 328.17 [M+H] ^⁺ .

The following intermediates were prepared similarly:

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

Step 1: 4-Nitro-2-methylphenyl(morpholinyl)methanone

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 and stirred at 75°C for 10 minutes, then returned to room temperature and stirred for 1.5 hours. Morpholine (480.35 mg, 5.52 mmol) was added to the mixture and stirred at room temperature for 12 hours. The mixture was diluted with water and extracted with EA (20 mL x 2). The organic phases were 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(morpholino)methanone (655.73 mg, 95% yield) as a light pink solid. MS (ESI, m/z): 251.10 [M+H] ⁺ .

Step 2: 4-amino-2-methylphenyl(morpholinyl)methanone

4-Nitro-2-methylphenyl(morpholino)methanone (500 mg) was dissolved in 10 mL of methanol, and 10% Pd/C (50 mg) was added. The mixture was then reacted in a medium-pressure hydrogenator for 8 hours. The mixture was filtered through Celite and concentrated under reduced pressure to yield 4-amino-2-methylphenyl(morpholino)methanone (426.80 mg, 97% yield) as a light pink solid. MS (ESI, m/z): 221.12 [M+H] ⁺ .

The following intermediates were prepared similarly:

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

4-Amino-2-methylphenyl(morpholinyl)methanone (302.05 mg, 1.37 mmol) was added to a toluene solution (6 mL) with Intermediate 13 (300 mg, 0.91 mmol), NaOtBu (351.42 mg, 3.66 mmol), BINAP (71.15 mg, 0.11 mmol), and _Pd (OAc) (20.52 mg, 0.091 mmol). The mixture was purged with _N₂ for 5 min. The reaction mixture was stirred and heated at 100°C under an _N₂ atmosphere for 12 h. Upon completion of the reaction, the mixture was poured into water (20 mL), and the aqueous solution was extracted with dichloromethane (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 afford the title compound as a pale pink solid (160 mg, 37.5% yield).

MS (ESI, m/z): 468.20[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-D ₆ )δ8.43(s,1H),7.99(dd,J＝11.59,4.50Hz,2H),7.91(dd,J＝8.77,2.36Hz,1H),7.70(s,1H),7.37(d,J＝8.87Hz,1H),7.34–7.26(m,1H),7.26–7.1 5(m,2H),7.08(d,J＝8.22Hz,1H),6.97(d,J＝7.49Hz,1H),6.81(t,J＝7.16 Hz, 1H), 3.95 (s, 3H), 3.54 (d, J = 46.89Hz, 6H), 3.18 (s, 2H), 2.18 (s, 3H).

The following examples were prepared similarly to Example 7

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

Example 1 was obtained from Intermediate 1 and Intermediate B by the synthetic method of Example 7.

MS(ESI,m/z):387.18[M+H] ⁺ . ¹ H NMR(500MHz,DMSO-D ₆ )δ8.45(s,1H),8.03(q,J＝4.53Hz,1H),7.96(dd,J＝6.85,0.90Hz,1H),7.62(s,1H),7.59(d,J ＝2.13Hz,1H),7.57(d,J＝2.13Hz,1H),7.31(d,J＝8.23Hz,1H),7.22(d,J＝2.21Hz,1H),7.19(dd ,J＝8.24,2.28Hz,1H),7.13(d,J＝2.15Hz,1H),7.12(d,J＝2.10Hz,1H),6.98(dd,J＝7.48,0.89H z,1H),6.84(t,J＝7.13Hz,1H),5.28(s,1H),3.84(s,3H),2.74(d,J＝4.50Hz,3H),2.35(s,3H).

Example 2: 4-((3-(3-chloro-4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-8-yl)amino)-N,2-dimethylbenzamide

Example 2 was obtained from Intermediate 2 and Intermediate B by the synthetic method of Example 7.

MS(ESI,m/z):475.11[M+H] ⁺ . ¹ H NMR(500MHz,DMSO-D ₆ )δ8.45(s,1H),7.99(q,J＝4.49Hz,1H),7.94(dd,J＝6.83,0.88Hz,1H),7.90(dd,J ＝8.67,2.33Hz,1H),7.79(d,J＝2.25Hz,1H),7.70(s,1H),7.42(d,J＝8.77Hz,1H),7 .28(d,J＝8.25Hz,1H),7.18(d,J＝2.26Hz,1H),7.16(dd,J＝8.23,2.29Hz,1H),6.97 (dd,J＝7.48,0.89Hz,1H),6.85–6.81(m,1H),2.70(d,J＝4.55Hz,3H),2.31(s,3H).

Example 3: 4-((3-(3-chloro-4-(cyclopropylmethoxy)phenyl)imidazo[1,2-a]pyridin-8-yl)amino)-N,2-dimethylbenzamide

Example 3 was obtained from Intermediate 3 and Intermediate B by the synthetic method of Example 7.

MS(ESI,m/z):461.17[M+H]+. ¹ H NMR(500MHz,DMSO-D ₆ )δ8.43(s,1H),7.99(q,J＝4.54Hz,1H),7.94(dd,J＝6.83,0.88Hz,1H),7.67(d,J＝2.21Hz,1H) ,7.65(s,1H),7.53(dd,J＝8.52,2.23Hz,1H),7.26(dd,J＝9.78,8.44Hz,2H),7.18(d,J＝2.27Hz ,1H),7.15(dd,J＝8.26,2.29Hz,1H),6.96(dd,J＝7.54,0.90Hz,1H),6.82(t,J＝7.15Hz,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).

Example 4: N-ethyl-4-(3-(4-methoxyphenyl)imidazo[1,2-a]pyridin-8-amino)-2-methylbenzamide

Example 4 was obtained by using Intermediate 1 and Intermediate C through the synthetic method of Example 7.

MS(ESI,m/z):401.19[M+H]+. ¹ H NMR(500MHz,DMSO-D ₆ )δ8.44(s,1H),8.09(t,J＝5.59Hz,1H),7.96(dd,J＝6.79,0.91Hz,1H),7.62 (s,1H),7.60–7.55(m,2H),7.30(d,J＝8.19Hz,1H),7.24–7.18(m,2H),7.15 –7.11(m,2H),6.97(dd,J＝7.53,0.92Hz,1H),6.84(t,J＝7.14Hz,1H),3.84( s,3H),3.23(qd,J＝7.20,5.56Hz,2H),2.35(s,3H),1.11(t,J＝7.19Hz,3H).

Example 5: 4-(3-(4-methoxyphenyl)imidazo[1,2-a]pyridine-8-amino)-N,N,2-trimethylbenzamide

Example 5 was obtained by the synthetic method of Example 7 using Intermediate 1 and directly purchased 4-amino-N,N,2-trimethylbenzamide.

MS(ESI,m/z):401.19[M+H]+. ¹ H NMR (400MHz, DMSO) δ8.31(s,1H),8.10(d,J＝6.68Hz,1H),7.64(d,J＝8.42Hz,2H),7.51(d ,J＝7.86Hz,1H),7.30–7.11(m,7H),3.86(s,3H),3.00(s,3H),2.82(s,3H),2.21(s,3H).

Example 6: (4-(3-(4-methoxyphenyl)imidazo[1,2-a]pyridin-8-yl)amino)-2-methylphenyl)(morpholinyl)methanone

Example 6 was obtained by using Intermediate 1 and Intermediate A through the synthetic method of Example 7.

MS(ESI,m/z):443.20[M+H]+. ¹ H NMR(500MHz,DMSO-D ₆ )δ8.41(s,1H),7.91(dd,J＝6.79,0.88Hz,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(d d,J＝7.51,0.91Hz,1H),6.79(t,J＝7.12Hz,1H),3.80(s,3H),3.54(d,J＝59.24Hz,6H),3.20(d,J＝18.41Hz,2H),2.18(s,3H).

Example 8: (4-(3-(4-methoxyphenyl)imidazo[1,2-a]pyridin-8-yl)amino)-2-methylphenyl)(thiomorpholinyl)methanone

Example 8 was obtained by using Intermediate 1 and Intermediate D through the synthetic method of Example 7.

MS(ESI,m/z):459.18[M+H]+. ¹ H NMR(500MHz,DMSO-D ₆ )δ8.44(s,1H),7.62(s,1H),7.59(d,J＝2.09Hz,1H),7.57(d,J＝2.15Hz,1H),7.27(d,J＝2.19Hz,1H),7.23(dd,J＝8.19,2.25Hz,1H),7. 14–7.11(m,3H),6.99(dd,J＝7.48,0.89Hz,1H),6.83(t,J＝7.14Hz,1H),3.84(s,3H),3.58(d,4H),2.68(d,J＝6.77Hz,4H),2.20(s,3H).

Example 9: (4-(3-(4-methoxyphenyl)imidazo[1,2-a]pyridin-8-yl)amino)-2-methylphenyl)(piperazin-1-yl)methanone

Intermediate 1 and Intermediate H were synthesized using the same method as in Example 7 to obtain Intermediate I. 200 mg of Intermediate I was dissolved in 2 mL of dichloromethane, and 0.925 mL of 4 mol/L HCl, 1,4-dioxane solution was added. As the reaction proceeded, a precipitated solid was precipitated. After 4 h of reaction, the precipitate was filtered to obtain 150 mg of a light yellow solid, Example 9.

MS(ESI,m/z):442.22[M+H]+. ¹ H NMR(500MHz,DMSO-D ₆ )δ8.82(s,1H),8.06–7.98(m,1H),7.84(s,1H),7.62–7.60(m,1H),7.60–7.58(m,1H),7.26(s,1H),7.23(d,J＝1.16Hz,2H),7.2 1–7.15(m,2H),7.14(q,J＝1.41Hz,1H),6.98(d,J＝7.80Hz,1H),3.84(s,3H),3.57–3.42(m,4H),3.20–3.05(m,4H),2.23(s,3H).

Example 10: (4-(3-(4-ethoxyphenyl)imidazo[1,2-a]pyridin-8-ylamino)-2-methylphenyl)(morpholinyl)methanone

Example 10 was obtained by using Intermediate 4 and Intermediate A through the synthetic method of Example 7.

MS(ESI,m/z):457.22[M+H]+. ¹ H NMR(500MHz,DMSO-D ₆ )δ8.40(s,1H),7.91(dd,J＝6.86,0.90Hz,1H),7.58(s,1H),7.53(d,J＝2.12Hz,1H), 7.52(d,J＝2.12Hz,1H),7.23(d,J＝2.20Hz,1H),7.19(dd,J＝8.21,2.23Hz,1H),7.10 –7.04(m,3H),6.95(dd,J＝7.48,0.90Hz,1H),6.79(t,J＝7.12Hz,1H),4.07(q,J＝6.9 7Hz, 2H), 3.54 (d, J = 59.61Hz, 7H), 3.18 (s, 2H), 2.18 (s, 3H), 1.33 (t, J = 6.96Hz, 3H).

Example 11: (4-(3-chloro-4-cyclopropyloxyphenyl)imidazo[1,2-a]pyridin-8-yl)amino)-2-methylphenyl)(morpholinyl)methanone

Example 11 was obtained from Intermediate 5 and Intermediate A by the synthetic method of Example 7.

MS(ESI,m/z):503.18[M+H]+. ¹ H NMR(500MHz,DMSO-D ₆ )δ8.51(s,1H),8.12(dd,J＝6.80,0.90Hz,1H),8.03(q,J＝4.54Hz,1H),7.78(s,1H),7.65(d,J＝2.0 0Hz,1H),7.58(d,J＝8.18Hz,1H),7.28(dd,J＝8.17,2.00Hz,1H),7.23(d,J＝2.27Hz,1H),7.20(dd, J＝8.28,2.27Hz,1H),7.02(dd,J＝7.52,0.89Hz,1H),6.89(t,J＝7.16Hz,1H),4.12(dq,J＝5.96,3.0 3Hz,1H),3.58(d,J＝61.79Hz,6H),3.22(s,2H),2.35(s,3H),0.89–0.82(m,2H),0.82–0.75(m,2H).

Example 12: (4-(3-chloro-4-methoxyphenyl)imidazo[1,2-a]pyridin-8-yl)amino)-2-methylphenyl)(morpholinyl)methanone

Example 12 was obtained by using Intermediate 6 and Intermediate A through the synthetic method of Example 7.

MS(ESI,m/z):477.16[M+H]+. ¹ H NMR(500MHz,DMSO-D ₆ )δ8.46(s,1H),7.99–7.97(m,1H),7.91(d,J＝8.42Hz,1H),7.72(d,J＝2.21Hz,1H),7. 70(s,1H),7.61(dd,J＝8.50,2.22Hz,1H),7.26(d,J＝2.19Hz,1H),7.23(dd,J＝8.26,2. 23Hz,1H),7.00(d,J＝7.34Hz,1H),6.85(t,J＝7.16Hz,1H),6.77(ddd,J＝8.38,6.81,1. 27Hz, 1H), 3.94 (s, 3H), 3.58 (d, J = 58.96Hz, 7H), 3.23 (d, J = 7.69Hz, 1H), 2.22 (s, 3H).

Example 13: 4-(3-(2-chloro-[1,1′-biphenyl]-4-yl)imidazo[1,2-a]pyridin-8-yl)amino)-2-methylphenyl)(morpholinyl)methanone

Example 13 was obtained from Intermediate 7 and Intermediate A by the synthetic method of Example 7.

MS(ESI,m/z):523.18[M+H]+. ¹ H NMR(500MHz,DMSO-D ₆ )δ8.50(s,1H),8.13(dd,J＝6.80,0.88Hz,1H),7.88(s,1H),7.86(s,1H),7.8 2–7.77(m,5H),7.57(d,J＝2.03Hz,1H),7.56(d,J＝2.01Hz,1H),7.28(d,J＝2. 20Hz,1H),7.23(d,J＝2.25Hz,1H),7.13(d,J＝8.21Hz,1H),7.03(dd,J＝7.49, 0.89Hz,1H),6.89(t,J=7.16Hz,1H),3.53(s,6H),3.23(s,2H),2.22(s,3H).

Example 14: (4-(3-chloro-4-methylphenyl)imidazo[1,2-a]pyridin-8-yl)amino)-2-methylphenyl)(morpholinyl)methanone

Example 14 was obtained from Intermediate 8 and Intermediate A by the synthetic method of Example 7.

MS(ESI,m/z):461.16[M+H]+. ¹ H NMR(500MHz,DMSO-D ₆ )δ8.44(s,1H),8.00(dd,J＝6.80,0.87Hz,1H),7.72(s,1H),7.67(d,J＝1.74Hz, 1H),7.52(dd,J＝7.83,1.78Hz,1H),7.49(d,J＝7.82Hz,1H),7.23(d,J＝2.17Hz,1 H),7.19(dd,J＝8.23,2.24Hz,1H),7.08(d,J＝8.16Hz,1H),6.98(d,J＝7.47Hz,1 H), 6.83 (t, J = 7.17Hz, 1H), 3.60 (s, 4H), 3.18 (s, 4H), 2.37 (s, 3H), 2.18 (s, 3H).

Example 15: (4-(3-(3,4-dichlorophenyl)imidazo[1,2-a]pyridin-8-yl)amino)-2-methylphenyl)(morpholinyl)methanone

Example 15 was obtained from Intermediate 9 and Intermediate A by the synthetic method of Example 7.

MS(ESI,m/z):481.11[M+H]+. ¹ H NMR(500MHz,DMSO-D ₆ )δ8.47(s,1H),8.05(dd,J＝6.85,0.88Hz,1H),7.92(d,J＝2.09Hz,1H),7.81(s,1H) ,7.78–7.74(m,1H),7.66(dd,J＝8.35,2.11Hz,1H),7.23(d,J＝2.19Hz,1H),7.19(d d,J＝8.25,2.21Hz,1H),7.08(d,J＝8.18Hz,1H),7.00(dd,J＝7.54,0.89Hz,1H),6.8 5(t,J＝7.17Hz,1H),3.62(d,J＝16.91Hz,6H),3.16(d,J＝23.37Hz,2H),2.18(s,3H).

Example 16: (4-(4-methoxy-3-trifluoromethylphenyl)imidazo[1,2-a]pyridin-8-amino)-2-methylphenyl)(morpholinyl)methanone

Example 16 was obtained from Intermediate 10 and Intermediate A by the synthetic method of Example 7.

MS(ESI,m/z):511.19[M+H]+. ¹ H NMR(500MHz,DMSO-D ₆ )δ8.52(s,1H),8.14(dd,J＝6.79,0.87Hz,1H),8.03(d,J＝4.61Hz,1H),8.02(d,J＝2 .17Hz,1H),7.87(s,1H),7.53–7.47(m,1H),7.32(d,J＝9.07Hz,1H),7.22(d,J＝2.2 2Hz,1H),7.19(dd,J＝8.23,2.30Hz,1H),7.04(dd,J＝7.55,0.86Hz,1H),6.95–6.88 (m,1H),3.94(s,3H),3.58(d,J＝58.96Hz,7H),3.23(d,J＝7.69Hz,1H)2.35(s,3H).

Example 17: 5-methoxy-2-(8-((3-methyl-4-(morpholine-4-carbonyl)phenyl)amino)imidazo[1,2-a]pyridin-3-yl)benzonitrile

Example 17 was obtained from Intermediate 11 and Intermediate A by the synthetic method of Example 7.

MS(ESI,m/z):511.19[M+H]+. ¹ H NMR(500MHz,DMSO-D ₆ )δ8.45(s,1H),7.95(dd,J＝6.81,0.90Hz,1H),7.62(s,1H),7.60–7.53(m,2H),7.27(d,J＝2.18Hz,1H),7.23(dd,J＝8.20,2.23Hz,1H),7. 15–7.08(m,3H),6.98(dd,J＝7.47,0.87Hz,1H),6.82(t,J＝7.13Hz,1H),3.83(s,3H),3.58(d,J＝61.79Hz,6H),3.22(s,2H),2.22(s,3H).

Example 19: N-(2-(2-aminoethoxy)ethyl)-4-(3-(4-methoxyphenyl)imidazo[1,2-a]pyridin-8-yl)amino)-2-methylbenzamide

Step 1: Intermediate 14 was synthesized from Intermediate 1 and tert-butyl 4-amino-2-methylbenzoate using the method described in Example 7. MS (ESI, m/z): 430.21 [M+H] ⁺ .

Step 2: Intermediate 14 (600 mg, 1.39 mmol) was dissolved in 5 mL of dichloromethane. 3.34 mL of trifluoroacetic acid was added. After stirring at room temperature for 6 h, the reaction solution was concentrated under reduced pressure to obtain 900 mg of a brownish-black crude product, Intermediate 15. MS (ESI, m/z): 374.14 [M+H] ⁺ .

Step 3: Dissolve 900 mg of crude Intermediate 15 in 6 mL of N,N-dimethylformamide. Add 1.83 g of HATU and 1.26 mL of DIPEA, stir at room temperature for 1 hour, then add 984.67 mg of tert-butyl (2-(2-aminoethoxy)ethyl)carbamate. React at room temperature for 6 hours. Upon completion of the reaction, pour the mixture into water (20 mL), and extract the aqueous solution 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 yield 672 mg of a light yellow solid, Intermediate 16, in a 79% yield. MS (ESI, m/z): 560.28 [M+H] ^⁺ .

Step 4: 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 and stirred at room temperature for 6 h. During this period, a white solid precipitated. The solid was filtered, washed, and dried to obtain 420 mg of Example 19.

MS(ESI,m/z):460.23[M+H] ⁺ . ¹ H NMR(500MHz,DMSO-D ₆ )δ9.39(s,1H),8.23(t,J＝5.59Hz,2H),8.13(d,J＝6.71Hz,1H),7.68–7.60(m,2H),7.40(d,J＝8.01Hz,1H),7.20(d,J＝3.93Hz,2H),7. 18(d,J＝2.10Hz,1H),3.86(s,3H),3.64(t,2H),3.57(t,J＝5.77Hz,2H),3.44(t,J＝5.65Hz,2H),2.98(p,J＝5.64Hz,2H),2.37(s,3H).

Example 20: 4-(3-(3-cyano-4-methoxyphenyl)imidazo[1,2-a]pyridin-8-amino)-N,2-dimethylbenzamide

Example 20 was synthesized using Intermediate 13 and Intermediate B by the synthetic method of Example 7.

MS(ESI,m/z):412.17[M+H] ⁺ . ¹ H NMR(500MHz,DMSO-D ₆ )δ8.44(s,1H),7.62(s,1H),7.59(d,J＝2.09Hz,1H),7.57(d,J＝2.15Hz,1H),7.27(d,J＝2.19Hz,1H),7.23(dd,J＝8.19,2.25Hz,1 H),7.14–7.11(m,3H),6.99(dd,J＝7.48,0.89Hz,1H),6.83(t,J＝7.14Hz,1H),3.84(s,3H),2.74(d,J＝4.50Hz,3H),2.35(s,3H).

Example 21: 2-methoxy-5-(8-((3-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)imidazo[1,2-a]pyridin-3-yl)benzonitrile

Example 21 was synthesized using Intermediate 13 and Intermediate G by the synthetic method of Example 7.

MS(ESI,m/z):484.19[M+H] ⁺ . ¹ H NMR(500MHz,DMSO-D ₆ )δ8.58(s,1H),8.08–8.00(m,2H),7.96(dd,J＝8.78,2.32Hz,1H),7.75(s,1H),7.42(d,J＝8.90Hz,1H),7.13(d,J＝8.20Hz,1H),7.11– 7.08(m,2H),7.01(dd,J＝8.20,1.94Hz,1H),6.86(t,J＝7.16Hz,1H),3.99(s,3H),3.78(s,3H),3.56(d,J＝40.84Hz,6H),3.20(s,2H).

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

Step 1: Intermediate 14 was synthesized from Intermediate 1 and tert-butyl 4-amino-2-methylbenzoate using the method described in Example 7. MS (ESI, m/z): 430.21 [M+H]+.

Step 2: Intermediate 14 (600 mg, 1.39 mmol) was dissolved in 5 mL of dichloromethane. 3.34 mL of trifluoroacetic acid was added. After stirring at room temperature for 6 h, the reaction solution was concentrated under reduced pressure to obtain 900 mg of a brownish-black crude product, Intermediate 15. MS (ESI, m/z): 374.14 [M+H].

Step 3: Dissolve 900 mg of crude Intermediate 15 in 6 mL of N,N-dimethylformamide. Add 1.83 g of HATU and 1.26 mL of DIPEA, stir at room temperature for 1 hour, then add 894 mg of tert-butyl piperidine-4-carboxylate. React at room temperature for 6 hours. After the reaction, pour the mixture into 20 mL of water, and extract the aqueous solution with ethyl acetate (20 mL x 2). The combined organic layers are washed with water and _brine , dried over anhydrous _Na₂SO₄ , concentrated under reduced pressure, and separated by column chromatography to yield 567 mg of a light yellow solid, Intermediate 19, in a 75% yield. MS (ESI, m/z): 541.27 [M+H]⁺.

Step 4: Dissolve intermediate 16 (450 mg, 1.39 mmol) in 5 mL of dichloromethane. Add 2.00 mL of trifluoroacetic acid. Stir at room temperature for 6 h. Concentrate the reaction mixture under reduced pressure to obtain 675 mg of intermediate 17 as a brownish-black crude product. MS (ESI, m/z): 485.56 [M+H].

Step 5: Dissolve 250 mg of the crude intermediate 17 in 4 mL of N,N-dimethylformamide solution, then add 351.64 mg of HATU and 250 μL of DIPEA. Stir at room temperature for 1 hour. Add 463 μL of 2 mol/L dimethylamine solution, and react at room temperature for 6 hours. After the reaction is complete, pour the mixture into water (20 mL), and extract the aqueous solution with ethyl acetate (20 mL x 2). The organic layers are combined, washed with water and brine, dried _over anhydrous _Na₂SO₄ , concentrated under reduced pressure, and separated by column chromatography to obtain 187 mg of a light yellow solid, Example 23, in a 75% yield.

MS (ESI, m/z): 512.26 [M+H] +. ¹ H NMR(400MHz,MeOD)δ8.00(d,J＝6.83Hz,1H),7.93(d,J＝7.55Hz,2H),7.70(s ,1H),7.42(d,J＝8.85Hz,1H),7.31–7.13(m,4H),6.97(t,J＝7.21Hz,1H),4.0 8(s,3H),3.76(hept,J＝6.65Hz,3H),3.18(s,3H),3.08(s,1H),2.99(s,2H), 2.97(s,3H),2.35(d,J＝31.29Hz,3H),1.92(d,J＝13.93Hz,1H),1.71(s,4H).

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

Intermediate 1 and tert-butyl 4-amino-2-methylbenzoate were synthesized using the same method as in Example 7 to obtain Intermediate 14. Intermediate 14 was then converted to Intermediate 17 using the method described in Example 23. Subsequently, 250 mg of crude Intermediate 17 was dissolved in 4 mL of N,N-dimethylformamide solution, followed by the addition of 351.64 mg of HATU and 250 μL of DIPEA. The mixture was stirred at room temperature for 1 hour, and 106.83 mg of ethanolic methylamine solution was added, followed by reaction at room temperature for 6 hours. Upon completion of the reaction, 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 165 mg of a light yellow solid, Example 27, in a 61% yield.

MS(ESI,m/z):498.25[M+H]+. ¹ H NMR (400MHz, MeOD) δ8.21(d,J＝6.76Hz,1H),7.94(s,1H),7.63(d,J＝2.25Hz,1H),7.61(s,1H),7.56(d,J＝7.73Hz,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＝32.28Hz,3H),2.03–1.83(m,2H),1.70(d,J＝11.28Hz,3H).

Example 28: 1-(4-((3-(3-chloro-4-methoxyphenyl)imidazo[1,2-a]pyridin-8-yl)amino)-2-methylbenzoyl)-N-methylpiperidine-4-carboxamide

Example 28 was obtained from Intermediate 6 by the same synthetic method as Example 23.

MS(ESI,m/z):537.25[M+H]+. ¹ H NMR (400MHz, MeOD) δ8.18(d,J＝6.76Hz,1H),7.94(d,J＝1.70Hz,1H),7.73(d,J＝1.93H z,1H),7.68–7.58(m,1H),7.52(d,J＝7.65Hz,1H),7.33(d,J＝8.54Hz,1H),7.24(t,J＝ 7.24Hz,2H),7.12(s,3H),4.00(d,J＝1.72Hz,3H),3.15(d,J＝1.83Hz,4H),2.94(s,5H ),2.31(d,J＝30.72Hz,3H),1.89(d,J＝13.54Hz,1H),1.67(s,3H),1.43–1.23(m,1H).

Example 29: 1-(4-((3-(3-cyano-4-methoxyphenyl)imidazo[1,2-a]pyridin-8-yl)amino)-2-methylbenzoyl)-N-methylpiperidine-4-carboxamide

Example 29 was obtained from Intermediate 13 by the same synthetic method as Example 23.

MS(ESI,m/z):532.21[M+H]+. ¹ H NMR(400MHz,MeOD)δ8.07(d,J＝6.80Hz,1H),7.77(s,1H),7.68(s,1H),7.59(d,J＝8.32Hz,1 H),7.32(dd,J＝14.12,8.11Hz,2H),7.19(d,J＝28.13Hz,3H),7.08(t,J＝7.25Hz,1H),3.99(s ,3H),3.64(s,1H),3.21–3.07(m,1H),2.93(t,J＝26.57Hz,1H),2.72(s,3H),2.52(d,J＝22.2 4Hz,1H),2.31(d,J＝32.72Hz,3H),1.92(d,J＝13.60Hz,1H),1.72(s,3H),1.43–1.23(m,2H).

Example 30: 1-(4-((3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyridin-8-yl)amino)-2-methylbenzoyl)-N-methylpiperidine-4-carboxamide

Example 30 was obtained from Intermediate 16 by the same synthetic method as Example 23.

MS(ESI,m/z):530.25[M+H] ⁺ . ¹ H NMR (400MHz, MeOD) δ8.13(d,J＝6.79Hz,1H),7.82(s,1H),7.46(d,J＝4.24Hz,1H),7.43(s,1H),7.39( d,J＝7.71Hz,1H),7.33(t,J＝8.55Hz,1H),7.23(s,1H),7.14(d,J＝6.88Hz,3H),3.97(s,3H),3.61(q,J ＝7.57Hz,2H),3.13(t,J＝12.76Hz,1H),2.92(s,1H),2.72(s,3H),2.49(s,1H),2.30(d,J＝32.79Hz,3H ),1.92(d,J＝13.49Hz,1H),1.67(d,J＝38.76Hz,3H),1.27(d,J＝13.22Hz,1H),1.18(t,J＝7.03Hz,1H).

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

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

Intermediate 35: (4-((3-bromoimidazo[1,2-a]pyrazin-8-yl)amino)-2-methylphenyl)(morpholinyl)methanone

3-Bromo-8-chloroimidazo[1,2-a]pyrazine (500 mg, 2.15 mmol), Intermediate A (569 mg, 2.58 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (158 mg, 215 μmol) were added to a 100 mL two-necked flask and dissolved in 8 mL of ultra-dry 1,4-dioxane. Anhydrous sodium carbonate (454 mg, 4.30 mmol) was dissolved in purified water to form a saturated solution, which was then added to the reaction flask. The reaction mixture was stirred and heated at 110°C under a _nitrogen atmosphere for 12 h. Upon completion of the reaction, the mixture was poured into water (20 mL), and the aqueous solution was extracted with dichloromethane (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 Comparative Example 1. It was obtained as a light yellow solid (528 mg, yield 62.6%). MS (ESI, m/z): 416.06 [M+H] ⁺ .

Intermediate 35 (300 mg, 721 μmol), 3-cyano-4-methoxyphenylboronic acid (153 mg, 865 μmmol), and 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (52.7 mg, 72.1 μmol) were added to a 25 mL two-necked flask and dissolved in 5% ultra-dry 1,4-dioxane. Anhydrous sodium carbonate (153 mg, 1.44 mmol) was dissolved in purified water to make a saturated solution, which was then added to the reaction flask. The reaction mixture was stirred and heated at 110°C under a _nitrogen atmosphere for 12 h. Upon completion of the reaction, the mixture was poured into water (20 mL), and the aqueous solution was extracted with dichloromethane (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 yield the title compound. It was obtained as a brown solid (220 mg, 65.3% yield). MS (ESI, m/z): 469.19 [M+H] +.

Comparative Example 2: N-(4-(3-chloro-4-methoxyphenyl)-1H-pyrrolo[2,3-c]pyridin-7-amino)-2-methylphenyl)acetamide

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

7-Chloro-1H-pyrrolo[2,3-c]pyridine (500 mg, 3.30 mmol) was placed in a 50 mL two-necked flask and dissolved in 10 mL of anhydrous methanol. N-iodosuccinimide (855 mg, 4.95 mmol) was dissolved in 5 mL of anhydrous methanol solution and added dropwise to the two-necked flask. As the reaction proceeded, the reaction solution changed from an orange turbid liquid to a red turbid liquid. After 8 hours of reaction, TLC monitored the reaction to be complete. After the reaction was completed, the mixture was poured into water (20 mL), and the aqueous solution was extracted with dichloromethane (20 mL × 2). The organic layers were combined, washed with water, saturated sodium thiosulfate solution and brine, dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, and separated by column chromatography to obtain the title compound. It was a light yellow solid (606 mg, yield 66.1%)

Intermediate 38: 7-chloro-3-(3-chloro-4-methoxyphenyl)-1H-pyrrolo[2,3-c]pyridine

Intermediate 38 was obtained by following the synthetic method of intermediate 35.

Intermediate 19 (200 mg, 682 μmol), Intermediate G (224 mg, 136 μmol), tris(dibenzylideneacetone)dipalladium (312 mg, 341 μmol), BINAP (420 mg, 680 μmol), and potassium tert-butoxide (115 mg, 1.02 mmol) were added to a 50 mL two-necked flask and dissolved in toluene solution (10 mL). The reaction mixture was purged with _N₂ for 5 min. The reaction mixture was stirred and heated at 100°C under an _N₂ atmosphere for 12 h. Upon completion of the reaction, the mixture was poured into water (20 mL), and the aqueous solution was extracted with dichloromethane (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 the comparative product. Pale yellow solid (32 mg, 11.2% yield) MS (ESI, m/z): 421.14 [M+H] +.

Experimental Example 1 Evaluation of in vitro antibacterial activity

Minimum Inhibitory Concentration (MIC) Test: Inoculate Acinetobacter baumannii (ATCC 19606) into 10 mL of beef peptone medium and incubate with shaking at 200 rpm in a 37°C incubator for 20 hours. When the clarified medium becomes turbid, it indicates vigorous bacterial proliferation. At this point, dilute the culture medium with fresh beef peptone medium to an _OD600 value between 0.3 and 0.5. Dilute the culture medium again with fresh tryptone soy broth to prepare the test culture. In a clean, sterile 96-well cell culture plate, add 200 μL of the prepared test culture to each well in the first column and 100 μL to each well in columns 2 through 12. Add 4 μL of a pre-prepared 1.6 mg/mL DMSO solution of the test sample to each well in column 1 (triplicate for each sample). A positive control (4 μL of the same concentration of levofloxacin) and a blank control (no drug) were also established. 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).

Results: Table 1 provides the minimum inhibitory concentrations (MICs) of the example compounds of the present invention obtained relative to Acinetobacter baumannii ATCC 19606 strain in micrograms/ml. Table 2 provides the minimum inhibitory concentrations (MICs) of the comparative compounds of the present invention obtained relative to Acinetobacter baumannii ATCC 19606 strain in micrograms/ml. Most of the specific compounds of the present invention exhibited MICs < 1 μg/mL (Acinetobacter baumannii 19606). Compared with the comparative examples, the example compounds have significant advantages in in vitro activity.

Table 1 Example Compound MIC

Table 2 MIC of comparative compounds

Experimental Example 2 Evaluation of antibacterial activity in mice

Experimental animals: Beijing Weitonglihua Experimental Animal Technology Co., Ltd., ICR mice, weighing between 20-22 g, uniform weight, male mice.

Model: Sepsis model infected with Acinetobacter baumannii (ATCC 19606)

Modeling method: mice were infected with 1×10 ⁵ CFU/mL Acinetobacter baumannii (ATCC 19606) to form a sepsis model (0.5 mL of bacterial solution was injected intraperitoneally into each mouse).

Experimental plan: The compound is first dissolved in DMSO and then diluted with other solvents so that the solvent ratio is

Saline: Tween 80: DMSO = 9:0.5:0.5. Mice were divided into five groups, each consisting of six male mice. One hour after model establishment, the drug-treated groups received intraperitoneal injections of 0.4 mL of Example 1 solution at doses of 10 mg/mL, 30 mg/kg, and 50 mg/kg, respectively. The negative control group received 0.4 mL of blank solvent after model establishment. The survival rate of the mice was observed for 7 days.

Results: As shown in Figure 1, Example Compound 7 showed a complete protective effect when administered at a dose of 10 mg/kg. Example Compound 27 also showed a complete protective effect when administered at a dose of 10 mg/kg.

Experimental Example 3 Acute toxicity test in mice

Experimental animals: Beijing Weitonglihua Experimental Animal Technology Co., Ltd., ICR mice, weighing between 20-22 g, uniform weight, male mice.

Experimental plan: A total of 6 groups, including 5 experimental groups and 1 blank group. In Example 1, mice were administered at doses of 300 mg/kg, 200 mg/kg, 100 mg/kg, 50 mg/kg, and 10 mg/kg (solvent: normal saline: Tween 80: DMSO = 9:0.5:0.5) via intraperitoneal administration with a dosing volume of 0.4 mL. The blank group was injected intraperitoneally with 0.4 mL of blank solvent, and the survival rate of the mice was observed for 7 days.

Results: See Figure 2. After intraperitoneal injection of 300 mg/kg of Example Compound 7, the mice showed normal activities and no death was observed.

Claims (8)

An imidazopyridine derivative and a pharmaceutically acceptable salt thereof, characterized in that the compound structure is shown in general formula (I): _R1 is selected from C1 _{- C6} alkylamino, _C1 - _C6 cycloalkylamino, N,N-dialkylamino, wherein the dialkyl group can form a cyclic structure with a heteroatom, the dialkyl group is _C1 - _C6 alkyl, and the heteroatom is N, O and S; _R2 , _R3 , R4, _R5 , _R6 , _{R7 , R8 , R9} and _R10 are each independently selected from hydrogen, halogen, cyano, _C1 - _C3 alkyl, _C1 - _C3 alkoxy, and phenyl. The imidazopyridine derivative and pharmaceutically acceptable salt thereof according to claim 1, characterized in that: _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-piperazinyl, N-methylpiperidine-4-carboxamide, N,N-dimethylpiperidine-4-carboxamide. The imidazopyridine derivative and pharmaceutically acceptable salt thereof according to any one of claims 1-2, characterized in that: _R2 is methyl, methoxy, or halogen; R ₆ and R ₇ are each independently selected from hydrogen, halogen, cyano, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy; R ₈ is halogen, cyano, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl, or phenyl; R ₃ , R ₄ , R ₅ , R ₉ and R ₁₀ are hydrogen. The imidazopyridine derivative and pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: _R2 is methyl; R ₈ is methoxy; R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₉ and R ₁₀ are hydrogen. The imidazopyridine derivative and pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound is selected from: [Corrected 12.05.2025 in accordance with Article 91]
A pharmaceutical composition, characterized in that it comprises the imidazopyridine derivative and pharmaceutically acceptable salts thereof according to any one of claims 1 to 5, and one or more pharmaceutically acceptable carriers or excipients. [Corrected 12.05.2025 in accordance with Article 91]
Use of the imidazopyridine derivative according to any one of claims 1 to 5 and its pharmaceutically acceptable salt and the pharmaceutical composition according to claim 6 in the preparation of a medicament for treating bacterial infection. [Corrected 12.05.2025 in accordance with Article 91]
The use according to claim 7, characterized in that the bacteria are selected from sensitive or resistant Acinetobacter baumannii.