CN111978317A - Imidazopyridine MNK1/MNK2 kinase inhibitor and preparation method and application thereof - Google Patents

Abstract

The present invention provides an imidazopyridine MNK1/MNK2 kinase inhibitor and a preparation method and application thereof, specifically, the present invention provides a compound represented by formula (I): or its stereoisomer, interconversion Isomers or pharmaceutically acceptable salts. The compounds of the present invention can be used to prepare pharmaceutical compositions for treating diseases or conditions related to MNK activity or expression.

Description

Imidazopyridine MNK1/MNK2 kinase inhibitor and preparation method and application thereof

technical field

The present invention belongs to the technical field of medicine, specifically, novel imidazopyridine compounds or their stereoisomers, geometric isomers, tautomers and their pharmaceutically acceptable salts, hydrates, prodrugs or Solvates, these compounds have good MNK1 and MNK2 kinase inhibitory activity.

Background technique

Protein kinases play an important role in various cellular functions, and their abnormal activation is associated with various diseases. Mitogen-activated protein kinases (MAPKs) can receive a variety of cellular signals (including growth factors, environmental stimuli and cytokines) and be activated, thereby regulating cell proliferation, differentiation, survival, cell cycle control and Programmed cell death. After receiving these stimulatory signals, MAPKs can activate downstream target proteins, namely the MAPK-activated protein kinases family (MAPKAPK), which includes mitogen-activated protein kinase-interacting kinases (MAPK-interacting kinases, MNKs). MNK kinase is a serine/threonine protein kinase that can specifically phosphorylate Ser209 of eukaryotic initiation factor eIF4E (eukaryotic initiation factor 4E), thereby indirectly regulating mRNA translation.

Eukaryotic initiation factor eIF4E, as an important transcription factor, can enhance the transcription of mRNA encoding cyclins and oncogenic proteins, thereby causing the up-regulation of tumor-associated protein expression. eIF4E forms the eukaryotic initiation factor complex eIF4F with the backbone protein eIF4G and the RNA helicase eIF4A. Since eIF4E is responsible for the binding of this complex to the cap structure at the 5' end of mRNA, it plays an irreplaceable regulatory role in RNA translation. In normal cells, the activity of eIF4E is restricted, and the transcription of these tumor-associated mRNAs is inhibited; while in tumor cells or tissues, high expression or overactivation of eIF4E can cause up-regulation of the transcription levels of these mRNAs. Upregulation of eIF4E expression levels was detected in a variety of tumors and tumor cell lines, including colon, breast, bladder, lung, prostate, gastric, Hodgkin's lymphoma, and neuroblastoma. In clinical practice, the up-regulation or over-activation of MNK kinase and eIF4E is often accompanied by drug resistance and poor prognosis. More importantly, although MNKs are essential for eIF4E-regulated tumorigenesis, inhibition of MNKs activity does not affect the survival and growth of normal cells and animals. Therefore, the inhibition of MNKs by small-molecule drugs is a promising tumor therapy.

As an important translational rate-limiting factor, eIF4E, the MNK/eIF4E signaling pathway can affect the synthesis of various chemokines, cytokines and immune checkpoint proteins, thereby regulating the immune response. MNK kinase inhibitors can significantly reduce the content of PD-L1 on the surface of tumor cells, but have no effect on the expression of PD-L1 mRNA, while MNK inhibitors can reduce the immune checkpoint proteins PD-1, TIM-3 and LAG3 on the surface of activated T cells expression. The results of tumor xenograft models also confirmed that MNK kinase inhibitors can reduce the content of PD-L1 in mice by 50%, and MNK inhibitors are more sensitive to tumor models with high PD-L1 expression. Meanwhile, MNK kinase inhibitors can significantly enhance the function of cytotoxic CD8 ⁺ T cells, inhibit the differentiation of activated regulatory T cells, and promote the formation of central memory T cells. In a mouse colon cancer allograft model, MNK inhibitors almost completely inhibited tumor proliferation. When the same tumor was re-inoculated 29 days after drug withdrawal, the tumor proliferation of mice was still completely controlled without drug administration. This also reflects that MNK inhibitors can activate long-lasting anti-tumor immune responses in model mice.

With the in-depth understanding of the structure and function of MNKs in recent years, a number of MNK inhibitors have been reported one after another, among which BAY1143269, Tomivosertib and ETC-206 have entered the clinic one after another. In mouse xenograft models, BAY1143269, Tomivosertib and ETC-206 can significantly inhibit the growth of tumor masses and prolong the survival period of mice. Judging from the published Phase I clinical results, both Tomivosertib and ETC-206 can significantly reduce the phosphorylation level of eIF4E in patients and show initial symptom relief. The current clinical results have further confirmed that MNK inhibitors can exert anti-tumor effects by regulating the tumor microenvironment under in vivo conditions. With the deepening of the understanding of the MNK/eIF4E pathway, the development of inhibitors based on this pathway will play a more important role in targeted therapy and tumor immunotherapy.

In conclusion, there is an urgent need in the art to develop new MNK kinase inhibitors.

SUMMARY OF THE INVENTION

The object of the present invention is to develop a new MNK kinase inhibitor.

The first aspect of the present invention provides a compound represented by general formula (I), or its stereoisomer, geometric isomer, tautomer, its pharmaceutically acceptable salt, and its prodrug and their hydrates or solvates:

in,

为选自下组的基团：

is a group selected from the group consisting of:

Ar is a group selected from the following group: substituted phenyl, substituted or unsubstituted 10-20 membered aryl, substituted or unsubstituted with 1-3 heteroatoms selected from the following group N, S and O 5-12-membered heteroaryl;

Wherein, the "substituted" refers to being substituted by one or more (such as 2, 3, 4, etc.) substituents selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1- C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 alkylamino, -C(O)C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C3 -C8cycloalkyl, oxo, -CN, hydroxy, amino, carboxyl, unsubstituted or substituted with one or more substituents selected from the group consisting of C6-C10 aryl, C3-C8 cycloalkyl , 5-10-membered heteroaryl groups with 1-3 heteroatoms selected from N, S and O, 5-10-membered heterocyclic groups with 1-3 heteroatoms selected from N, S and O; Described substituent is selected from following group: halogen, C1-C6 alkoxy;

And the compound is not the structure shown in the following formula:

In another preferred embodiment, the Ar is not a pyridyl group.

In another preferred embodiment, the Ar is not a group selected from the group consisting of benzofuranyl and benzothienyl.

In another preferred embodiment, described Ar is a group selected from the following group:

In another preference, the Ar group is selected from the following group:

In another preferred embodiment, the compound is selected from I-2 to I-25.

The second aspect of the present invention provides a pharmaceutical composition comprising: (i) a therapeutically effective amount of the compound of formula (I) described in the first aspect of the present invention, or a stereoisomer thereof, One or more of geometric isomers, tautomers, pharmaceutically acceptable salts thereof, prodrugs, hydrates or solvates thereof, and (ii) pharmaceutically acceptable carriers or excipients .

In another preferred embodiment, the pharmaceutical composition has a formulation form selected from the group consisting of tablets, pills, granules, films, dropping pills, capsules, injections, soft capsules, emulsions, liposomes, frozen Dry powder, polymer microspheres, or polyethylene glycol derivatives.

In another preferred embodiment, the pharmaceutical composition is used to treat diseases or conditions related to the activity or expression of MNK.

In another preferred embodiment, the MNK is MNK1 or MNK2.

The third aspect of the present invention provides a compound of formula (I) according to the first aspect of the present invention, or a stereoisomer, geometric isomer, tautomer, or a pharmaceutically acceptable isomer thereof. Use of the salt, its prodrug, hydrate or solvate for the preparation of a pharmaceutical composition for treating or preventing diseases or conditions related to the activity or expression level of MNK.

In another preferred embodiment, the disease is cancer.

In another preferred embodiment, the cancer is selected from the group consisting of: leukemia, lymphoma, Hodgkin's disease, myeloma, acute lymphoblastic leukemia, acute myeloid leukemia, polar promyelocytic leukemia, chronic lymphocytic leukemia Leukemia, chronic myeloid leukemia, chronic neutrophilic leukemia, polar undifferentiated cell leukemia, degenerative large cell lymphoma, adult T-cell ALL, AML with trilineage myelodysplasia, mixed lineage leukemia, Myelodysplastic syndrome, myelodysplasia, multiple myeloma and spinal sarcoma, chronic lymphocytic lymphoma, diffuse large B-cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia, mantle cell lymphoma, mediastinal (thymus) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma.

The fourth aspect of the present invention provides a method for preparing a compound of formula (I) as described in the first aspect of the present invention, the method comprising the steps of:

Under the catalysis of metal palladium catalyst (preferably Pd(PPh ₃ ) ₄ or Pd(dppf)Cl ₂ ), the compound of formula 7 is used for coupling reaction with Ar-B(OH) ₂ or aryl (Ar) boronate, The target compound (I) is obtained.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (eg, the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, it is not repeated here.

Detailed ways

After long-term and in-depth research, the present inventors discovered a new class of compounds with excellent inhibitory effect on MNK kinases (preferably MNK1 and MNK2). The compound can be used as an active ingredient to prepare a pharmaceutical composition for treating diseases related to MNK kinase activity or expression. On this basis, the inventors have completed the present invention.

definition

As used herein, the term "alkyl" includes straight or branched chain alkyl groups. For example C ₁ -C ₈ alkyl means straight or branched chain alkyl having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl Wait.

As used herein, the term "C3- _C8cycloalkyl " refers to a cycloalkyl group having _3-8 carbon atoms. It may be a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. Bicyclic forms, such as bridged or spiro forms, are also possible.

As used herein, the term "C ₁ -C ₆ alkoxy" refers to a straight or branched alkoxy group having 1-6 carbon atoms; for example, methoxy, ethoxy, propoxy, iso Propoxy, butoxy, isobutoxy, tert-butoxy, etc.

As used herein, the term "10-20 membered aryl" refers to an aryl group having 10-20 carbon atoms, eg, naphthyl, anthracenyl, phenanthryl, or the like.

As used herein, the term "5-12 membered heteroaryl having 1-3 heteroatoms selected from the following groups N, S and O" refers to having 5-10 atoms and wherein 1-3 atoms are selected from Cyclic aromatic groups of heteroatoms of the following groups N, S and O. It may be a single ring or a fused ring form. Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2, 4)-triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like.

Unless specifically stated that the group described in the present invention is "substituted or unsubstituted", the group of the present invention can be substituted by a substituent selected from the following group: halogen, nitrile, nitro, hydroxyl, amino , C ₁ -C ₆ alkyl-amino, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, halogenated C ₁ - C ₆ alkyl, halogenated C ₂ -C ₆ alkenyl, halogenated C ₂ -C ₆ alkynyl, halogenated C ₁ -C ₆ alkoxy, allyl, benzyl, C ₆ -C ₁₂ aryl , C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy-carbonyl, phenoxycarbonyl, C ₂ -C ₆ alkynyl-carbonyl, C ₂ -C ₆ alkenyl -carbonyl, C ₃ -C ₆ cycloalkyl-carbonyl, C ₁ -C ₆ alkyl-sulfonyl, etc.

As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br. "Halo" means substituted with an atom selected from F, Cl, Br, and I.

Unless otherwise specified, the structural formulas described herein are intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, those containing asymmetric R, S configuration of the center, (Z), (E) isomer of double bond, etc. Accordingly, individual stereochemical isomers or mixtures of enantiomers, diastereomers or geometric isomers (or conformational isomers) of the compounds of the present invention are within the scope of the present invention.

As used herein, the term "tautomer" means that structural isomers having different energies can exceed a low energy barrier, thereby interconverting. For example, proton tautomers (ie, protonation) include interconversion by migration of protons, such as 1H-indazole and 2H-indazole. Valence tautomers include interconversion by some bonding electron recombination.

As used herein, the term "solvate" refers to a complex in which a compound of the present invention coordinates with solvent molecules to form a complex in specified proportions.

As used herein, the term "hydrate" refers to a complex formed by the coordination of a compound of the present invention with water.

As used herein, the term "pharmaceutically acceptable salts" includes acid addition salts of compounds of formula (I) with the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, lactic acid , oxalic acid, adipic acid, glutaric acid, malonic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, Phenylacetic acid, mandelic acid, and also acid salts of inorganic bases.

As used herein, the term "prodrug" is a derivative of general formula (I), which may have weak or even no activity on their own, but after administration, under physiological conditions (eg by metabolism, solvolysis or otherwise) way) is converted into the corresponding biologically active form.

Active ingredient

As used herein, "compounds of the present invention" refers to compounds of formula I, and also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of compounds of formula I:

in,

为选自下组的基团：

is a group selected from the group consisting of:

Ar is a group selected from the following group: substituted phenyl, substituted or unsubstituted 10-20 membered aryl, substituted or unsubstituted with 1-3 heteroatoms selected from the following group N, S and O 5-12-membered heteroaryl; wherein, the "substituted" refers to being substituted by one or more (such as 2, 3, 4, etc.) substituents selected from the following group: halogen, C1-C6 Alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 alkylamino, -C(O)C1-C6 alkyl, C3-C8 Cycloalkyl, halogenated C3-C8cycloalkyl, oxo, -CN, hydroxy, amino, carboxyl, unsubstituted or substituted with one or more substituents selected from the group consisting of C6-C10 aryl base, C3-C8 cycloalkyl, 5-10 membered heteroaryl with 1-3 heteroatoms selected from N, S and O, 5-membered heteroaryl with 1-3 heteroatoms selected from N, S and O -10-membered heterocyclic group; the substituent is selected from the following group: halogen, C1-C6 alkoxy;

And the compound is not the structure shown in the following formula:

Preferably, the compound represented by formula (I) of the present invention is selected from the compounds in Table 1 below:

Table 1. Compound Structures

Preparation of compounds of formula (I)

The present invention relates to the preparation method of formula (I) compound, realizes through the following steps:

Starting from compounds 1 and 2, through ring closure, coupling with methoxycarbonyl benzene boronic acid, bromination, hydrolysis, condensation with morpholine and coupling with aryl boronic acid or aryl boronic acid ester, the target compound is obtained. Specifically, the preparation method comprises the following steps:

1. Take 2-amino 5-bromopyridine 1 and bromoacetaldehyde diethyl acetal 2 as raw materials, close the ring in hydrobromic acid to obtain compound 3;

2. Compound 3 is coupled with methoxycarbonylbenzeneboronic acid under the catalysis of Pd(PPh ₃ ) ₄ or Pd(dppf)Cl ₂ to obtain compound 4;

3. Compound 4 is brominated under the action of N-bromosuccinimide to obtain compound 5;

4. Compound 5 is hydrolyzed under the action of lithium hydroxide to obtain compound 6;

5. Compound 6 is condensed with morpholine under the action of condensing agent EDCI/HOBT or HATU to obtain compound 7.

6. Compound 7 is coupled with aryl boronic acid or aryl boronic acid ester under the catalysis of Pd(PPh ₃ ) ₄ or Pd(dppf)Cl ₂ to obtain the target compound (I).

Pharmaceutical compositions and methods of administration

Since the compound of the present invention has excellent inhibitory activity against MNK kinase, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and the compounds of the present invention as the main active ingredient The pharmaceutical composition can be used to prevent and/or treat (stabilize, alleviate or cure) diseases related to MNK kinase activity or expression (eg, colorectal cancer, gastric cancer, thyroid cancer, lung cancer, leukemia, B-cell lymphoma, T-cell lymphoma Tumor, Hairy Cell Lymphoma, Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Burkitt Lymphoma, Pancreatic Cancer, Melanoma, Multiple Myeloma, Brain Cancer, CNS Cancer, Kidney Cancer, Prostate Cancer, Ovarian cancer, breast cancer, uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, inappropriate cellular inflammatory response, leukemia and myelodysplastic syndromes, malignant lymphomas, head and neck tumors, Lung tumors and lung metastases, thoracic tumors, non-small cell tumors and small cell lung tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, kidney, bladder and prostate tumors, skin tumors, sarcomas, tumors metastases, neurodegenerative disorders).

The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention and a pharmaceutically acceptable excipient or carrier. The "safe and effective amount" refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-200 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。"Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gel substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility" as used herein means that the components of the composition are capable of admixture with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as

), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include, but are not limited to: oral, parenteral (intravenous, intramuscular, or subcutaneous).

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.

Besides these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds (eg, other anti-tumor or anti-inflammatory drugs).

When administered in combination, the pharmaceutical composition also includes one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (eg, other anti-tumor or anti-inflammatory drugs) . One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds may be used simultaneously, separately or sequentially with the compounds of the present invention for the prevention and/or treatment of MNK Kinase activity or expression related diseases.

When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dose is a pharmaceutically considered effective dose when administered, and in order to achieve the desired result, each kilogram per kilogram is required. The total amount of compound of formula (I) administered over 24 hours is about 0.01-800 mg, preferably 0.1-80 mg/kg. If necessary, it is administered in several single doses. Of course, the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions, or in accordance with the conditions suggested by the manufacturer. Percentages and parts are by weight unless otherwise indicated. Unless otherwise defined or indicated, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art.

Intermediate Preparation Example 1 6-Bromo-imidazo[1,2-a]pyridine

2-Amino-6-bromopyridine (3 g, 17.34 mmol, 1.0 equiv) was dissolved in a mixed solution of 30 mL of ethanol and 18 mL of water, and bromoacetaldehyde diethyl acetal (5.13 g, 26.01 mmol, 1.5 equiv) and 48 % aqueous solution of hydrobromic acid (3 mL), and the temperature was raised to 100° C. for 8 h after feeding. TLC plate monitoring reaction no longer proceeded, cooled the reaction solution to room temperature, concentrated under reduced pressure, added 100 mL of water, extracted with ethyl acetate (100 mL × 3), combined the organic phases and washed with saturated brine (50 mL × 3). It was dried over sodium sulfate, filtered and concentrated under reduced pressure, and the residue was separated by column chromatography to obtain 2.98 g of white solid powder, which was an intermediate 6-bromoimidazo[1,2-a]pyridine, and the yield was 87%.

¹ H NMR (300MHz, DMSO-d ₆ ) δ(ppm): 8.92(s, 1H), 7.93(s, 1H), 7.61(s, 1H), 7.56(d, J=9.6Hz, 1H), 7.33 (dd,J=9.5,1.8Hz,1H).

Intermediate Preparation Example 2 Methyl 4-(imidazo[1,2-a]pyridyl-6-yl)benzoate

6-Bromo-imidazo[1,2-a]pyridine (2.5g, 12.69mmol, 1.0equiv) was dissolved in a mixed solution of 45mL 1,4-dioxane and 4.5mL water, and 4-methoxy Carbonyl phenylboronic acid (2.74g, 15.23mmol, 1.2equiv) and potassium phosphate trihydrate (8.45g, 31.72mmol, 2.0equiv), fully replace the air in the reaction device with nitrogen, stir at room temperature for 15min, add tetrakistriphenylphosphine palladium (0.73 g, 0.63 mmol, 0.05 equiv), fully replace the air in the reaction device with nitrogen, continue stirring at room temperature for 15 min, and then heat up to 95° C. for 8 h. The reaction was no longer carried out by TLC plate monitoring, the reaction solution was cooled to room temperature, the insoluble matter was filtered off with celite, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to obtain 2.6 g of a white solid, which was the intermediate 4-(imidazo[ Methyl 1,2-a]pyridinyl-6-yl)benzoate in 81% yield.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 9.08 (s, 1H), 8.07 (d, J=8.4 Hz, 2H), 7.99 (s, 1H), 7.89 (d, J=8.4 Hz) ,2H),7.69–7.62(m,3H),3.89(s,3H).

Intermediate Preparation Example 3 Methyl 4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)benzoate

Methyl 4-(imidazo[1,2-a]pyridinyl-6-yl)benzoate (2.6 g, 10.31 mmol, 1.0 equiv) was dissolved in a mixed solution of 48 mL of acetonitrile and 16 mL of dichloromethane, and N was added. - Bromosuccinimide (2.38 g, 13.40 mmol, 1.3 equiv), the reaction was stirred at room temperature for 8 h. TLC plate monitoring reaction no longer proceeded, concentrated under reduced pressure, added 100 mL of water, extracted with dichloromethane (100 mL × 3), combined the organic phases, washed with saturated brine (50 mL × 3), dried the organic phase with anhydrous sodium sulfate, filtered Concentrated under reduced pressure, the residue was separated by column chromatography to obtain 3.1 g of yellow solid powder, which was the intermediate methyl 4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)benzoate, which was obtained The rate is 91%.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.34 (s, 1H), 8.24-8.11 (m, 2H), 7.75 (d, J=9.4 Hz, 1H), 7.68 (dd, J=5.4, 2.8Hz, 3H), 7.54(dd, J=9.4, 1.8Hz, 1H), 3.96(s, 3H).

Intermediate Preparation Example 4 4-(3-Bromoimidazo[1,2-a]pyridinyl-6-yl)benzoic acid

Methyl 4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)benzoate (1.89 g, 5.71 mmol, 1.0 equiv) was dissolved in a mixed solution of 20 mL of tetrahydrofuran and 10 mL of methanol, slowly Add dropwise 10 mL of LiOH (1.09 g, 45.66 mmol, 8.0 equiv) aqueous solution, and stir at room temperature for 4 h. After the TLC plate monitoring was completed, the reaction was concentrated under reduced pressure, diluted with 20 mL of water, 1M hydrochloric acid was slowly added dropwise, the pH was adjusted to 2 to 3, a large amount of white solid was precipitated, the filter cake was collected by filtration, washed with water, and dried at 60 °C to obtain a white solid 1.75g, which is the intermediate 4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)benzoic acid, the yield is 97%. Directly cast to the next step without further processing.

Intermediate Preparation Example 5 (4-(3-Bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone

4-(3-Bromoimidazo[1,2-a]pyridinyl-6-yl)benzoic acid (360 mg, 1.14 mmol, 1.0 equiv) was dissolved in 3 mL of N,N-dimethylformamide and added sequentially Phosphine (119 mg, 1.36 mmol, 1.2 equiv), EDCI (261 mg, 1.36 mmol, 1.2 equiv), HOBT (184 mg, 1.36 mmol, 1.2 equiv), triethylamine (138 mg, 1.36 mmol, 1.2 equiv) and DMAP (14 mg, 0.11 μmol, 0.1 equiv), and the temperature was raised to 40 °C for 8 h. After the completion of the reaction was monitored by TLC plate, 200 mL of dichloromethane was added to dilute, washed with saturated brine (20 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was separated by column chromatography to obtain 356 mg of yellow solid powder , which is the intermediate (4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone, with a yield of 81%.

Example 1 (4-(3-(pyridin-4-yl)azolo[1,2-a]pyridyl-6-yl)phenyl)(morpholinyl)methanone (I-1)

(4-(3-Bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (100 mg, 0.26 mmol, 1.0 equiv) was dissolved in 2 mL of 1,4 - To the mixed solution of dioxane and 0.2 mL of water, 4-pyridine boronic acid pinacol ester (64 mg, 0.31 mmol, 1.2 equiv) and potassium phosphate trihydrate (138 mg, 0.52 mmol) were added, and the reaction device was fully replaced with nitrogen The air inside was stirred at room temperature for 15 min, tetrakistriphenylphosphine palladium (30 mg, 26 μmol) was added, the air in the reaction device was fully replaced with nitrogen, and the temperature was raised to 95 °C for 8 h after stirring at room temperature for 15 min. After the completion of the reaction was monitored by TLC plate, the reaction solution was cooled to room temperature, the insoluble matter was filtered off with celite, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to obtain 52 mg of white solid, which was the target compound (4-(3-(pyridine) -4-yl)azolo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone 1-1 in 52% yield.

¹ H NMR (300MHz, CDCl ₃ )δ(ppm): 8.79(s, 2H), 8.60(s, 1H), 7.92(s, 1H), 7.83(d, J=8.6Hz, 1H), 7.62(s ,2H),7.56(s,5H),3.71(d,J=16.5Hz,8H); MS: found m/z[M+H] ⁺ 385.09, calcd.m/z[M]384.16.

Example 2 (4-(3-(pyridin-3-yl)imidazo[1,2-a]pyridyl-6-yl)phenyl)(morpholinyl)methanone (I-2)

Take (4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (110 mg, 0.28 mmol, 1.0 equiv) and pyridine-3-boronic acid ( 42 mg, 0.34 mmol, 1.2 equiv) was the starting material, and the specific synthesis method was referred to the synthesis of compound I-1 to obtain 81 mg of white solid powder, which was the target compound (4-(3-(pyridin-3-yl)imidazo[1] ,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone 1-2 in 74% yield.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.93 (s, 1H), 8.72 (d, J=4.4 Hz, 1H), 8.45 (s, 1H), 7.94 (d, J=7.9 Hz, 1H) ), 7.83(d, J＝6.1Hz, 2H), 7.60(d, J＝8.1Hz, 2H), 7.53(d, J＝8.2Hz, 4H), 3.66(d, J＝63.5Hz, 8H); MS: found m/z[M+H] ⁺ 385.03, calcd.m/z[M] 384.16.

Example 3 (4-(3-(pyrimidin-5-yl)imidazo[1,2-a]pyridyl-6-yl)phenyl)(morpholinyl)methanone (I-3)

With (4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (110 mg, 0.28 mmol, 1.0 equiv) and 5-pyrimidineboronic acid (43 mg , 0.34mmol, 1.2equiv) as starting material, the specific synthesis method refers to the synthesis of compound I-1 to obtain 48mg of white solid powder, which is the target compound (4-(3-(pyrimidin-5-yl)imidazo[1, 2-a]Pyridinyl-6-yl)phenyl)(morpholinyl)methanone 1-3 in 44% yield.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 9.30 (s, 1H), 9.05 (s, 2H), 8.42 (s, 1H), 7.95-7.78 (m, 2H), 7.57 (dd, J= 18.6, 7.9Hz, 5H), 3.65 (d, J=63.5Hz, 8H); MS: found m/z[M+H] ⁺ 386.20, calcd.m/z[M]385.15.

Example 4 (4-(3-(furan-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (I-4)

With (4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (100 mg, 0.26 mmol, 1.0 equiv) and 2-furanboronic acid (35 mg , 0.31 mmol, 1.2 equiv) as the starting material, the specific synthesis method refers to the synthesis of compound I-1 to obtain 48 mg of white solid powder, which is the target compound (4-(3-(furan-2-yl)imidazo[1, 2-a]Pyridinyl-6-yl)phenyl)(morpholinyl)methanone 1-4 in 43% yield.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.35 (s, 1H), 7.81 (s, 2H), 7.75 (s, 1H), 7.64 (d, J=10.4 Hz, 3H), 7.60-7.46 (m,3H),6.74(s,1H),3.71(d,J=16.3Hz,8H); MS: found m/z[M+H] ⁺ 374.11, calcd.m/z[M]373.14.

Example 5 (4-(3-(furan-3-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (I-5)

With (4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (110 mg, 0.28 mmol, 1.0 equiv) and 3-furanboronic acid (38 mg , 0.34 mmol, 1.2 equiv) as the starting material, the specific synthetic method refers to the synthesis of compound I-1 to obtain 62 mg of white solid powder, which is the target compound (4-(3-(furan-3-yl)imidazo[1, 2-a]Pyridinyl-6-yl)phenyl)(morpholinyl)methanone 1-5 in 58% yield.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.36 (s, 1H), 7.79 (d, J=24.7 Hz, 3H), 7.59 (d, J=23.2 Hz, 6H), 6.73 (s, 1H) ), 3.72(s, 8H); MS: found m/z[M+H] ⁺ 374.24, calcd.m/z[M]373.14.

Example 6 (4-(3-(5-Methylfuran-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (I-6 )

Take (4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (100 mg, 0.26 mmol, 1.0 equiv) and 2-methylfuran- 5-boronic acid pinacol ester (65mg, 0.31mmol, 1.2equiv) was the starting material, and the specific synthesis method was with reference to the synthesis of compound I-1 to obtain 52mg of white solid powder, which was the target compound (4-(3-(5- Methylfuran-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone 1-6 in 52% yield.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.71 (s, 1H), 7.87 (s, 1H), 7.78 (d, J=8.9 Hz, 1H), 7.66 (d, J=7.0 Hz, 2H) ),7.56(d,J＝7.0Hz,2H),7.49(d,J＝9.1Hz,1H),6.58(s,1H),6.19(s,1H),3.72(d,J＝15.7Hz,8H ), 2.45(s, 3H); MS: found m/z[MH] ^- 386.33, calcd.m/z[M] 387.16.

Example 7 (4-(3-(thiophen-2-yl)imidazo[1,2-a]pyridyl-6-yl)phenyl)(morpholinyl)methanone (I-7)

With (4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (100 mg, 0.26 mmol, 1.0 equiv) and thiophene-2-boronic acid Nadolester (65mg, 0.31mmol, 1.2equiv) was used as the starting material. For the specific synthesis method, refer to the synthesis of positive compound I-1 to obtain 57mg of white solid powder, which was the target compound (4-(3-(thiophen-2-yl) ) imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone 1-7 in 57% yield.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.59 (s, 1H), 7.86–7.75 (m, 2H), 7.65 (s, 1H), 7.62 (s, 1H), 7.58–7.47 (m, 4H), 7.35(d, J=3.5Hz, 1H), 7.25(dd, J=5.1, 3.6Hz, 1H), 3.74(s, 8H); MS: found m/z[M+H] ⁺ 390.16, calcd.m/z[M]389.12.

Example 8 (4-(3-(thiophen-2-yl)imidazo[1,2-a]pyridyl-6-yl)phenyl)(morpholinyl)methanone (I-8)

Take (4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (120 mg, 0.26 mmol, 1.0 equiv) and 3-thiopheneboronic acid (48 mg) , 0.37mmol, 1.4equiv) as the starting material, the specific synthesis method refers to the synthesis of compound I-1 to obtain 85mg of white solid powder, which is the target compound (4-(3-(thiophen-2-yl)imidazo[1, 2-a]Pyridinyl-6-yl)phenyl)(morpholinyl)methanone 1-8 in 70% yield.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.49 (s, 1H), 7.79 (d, J=7.4 Hz, 2H), 7.62 (d, J=8.1 Hz, 2H), 7.53 (dt, J =17.1,7.0Hz,5H),7.39(dd,J=4.7,1.6Hz,1H),3.74(s,8H); MS:found m/z[M+H] ⁺ 390.09,calcd.m/z[ M]389.12.

Example 9 (4-(3-(5-methylthien-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (I-9 )

Take (4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (56, 110 mg, 0.26 mmol, 1.0 equiv) and 5-methyl Thiophenol-2-boronic acid (49 mg, 0.34 mmol, 1.3 equiv) was used as the starting material. For the specific synthesis method, refer to the synthesis of compound I-1 to obtain 71 mg of white solid powder, which is the target compound (4-(3-(5-methyl) thiophen-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone 1-9 in 62% yield.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.58 (s, 1H), 7.76 (t, J=4.5 Hz, 2H), 7.64 (d, J=8.2 Hz, 2H), 7.54 (d, J ＝8.1Hz, 2H), 7.48(d, J＝10.7Hz, 1H), 7.12(d, J＝3.4Hz, 1H), 6.88(d, J＝2.7Hz, 1H), 3.64(d, J＝60.5 Hz, 8H), 2.59(s, 3H); MS: found m/z[M+H] ⁺ 404.06, calcd.m/z[M] 403.14.

Example 10 (4-(3-(5-cyanothiophen-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (I-10 )

Take (4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (110 mg, 0.26 mmol, 1.0 equiv) and 5-cyanothiophene- 2-boronic acid (52 mg, 0.34 mmol, 1.3 equiv) was used as the starting material. For the specific synthesis method, refer to the synthesis of compound I-1 to obtain 43 mg of white solid powder, which was the target compound (4-(3-(5-cyanothiophene- 2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone 1-10 in 36% yield.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.29 (s, 1H), 7.69 (dd, J=15.2, 8.3 Hz, 5H), 7.52 (dd, J=17.9, 8.4 Hz, 4H), 3.65 (d, J=59.1 Hz, 8H); MS: found m/z[M+H] ⁺ 415.37, calcd.m/z[M] 414.12.

Example 11 (4-(3-(benzothiophen-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (I-11)

Take (4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (110 mg, 0.26 mmol, 1.0 equiv) and benzothiophene-2- Boric acid (61 mg, 0.34 mmol, 1.2 equiv) was used as the starting material, and the specific synthesis method was referred to the synthesis of compound I-1 to obtain 55 mg of white solid powder, which was the target compound (4-(3-(benzothiophen-2-yl) Imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone 1-11 in 44% yield.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.75 (s, 1H), 7.97-7.79 (m, 4H), 7.66 (d, J=9.0 Hz, 2H), 7.55 (d, J=7.3 Hz) ,4H),7.49–7.34(m,2H),3.74(s,8H); MS: found m/z[M+H] ⁺ 440.05, calcd.m/z[M]439.14.

Example 12 (4-(3-(3,5-Dimethylisoxazol-2-yl)imidazo[1,2-a]pyridin-6-yl)phenyl)(morpholinyl)methan Ketone (I-12)

with, (4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (100 mg, 0.26 mmol, 1.0 equiv) and 3,5-di Methylisoxazole-4-boronic acid pinacol ester (69mg, 0.31mmol, 1.2equiv) was the starting material, and the specific synthesis method was with reference to the synthesis of compound I-1 to obtain 62mg of white solid powder, which was the target compound (4- (3-(3,5-Dimethylisoxazol-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone 1-12, received The rate is 60%.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 7.91 (s, 1H), 7.83 (d, J=9.3 Hz, 1H), 7.69 (s, 1H), 7.63-7.51 (m, 5H), 3.75 (s,8H), 2.39(s,3H), 2.21(s,3H); MS: found m/z[M+H] ⁺ 403.09, calcd.m/z[M]402.17.

Example 13 (4-(3-(1-Methyl-pyrazol-4-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (I -13)

With (4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (100 mg, 0.26 mmol, 1.0 equiv) and 1-methylpyrazole -4-boronic acid pinacol ester (64mg, 0.31mmol, 1.2equiv) was the starting material, and the specific synthesis method was referred to the synthesis of positive compound I-1 to obtain 66mg of white solid powder, which was the target compound (4-(3-( 1-Methyl-pyrazol-4-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone 1-13 in 66% yield.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 7.91 (s, 1H), 7.83 (d, J=9.3 Hz, 1H), 7.69 (s, 1H), 7.63-7.51 (m, 5H), 3.75 (s,8H), 2.39(s,3H), 2.21(s,3H); MS: found m/z[M+H] ⁺ 388.08, calcd.m/z[M]387.17.

Example 14 (4-(3-(biphenyl-4-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (I-14)

Take (4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (150 mg, 0.39 mmol, 1.0 equiv) and 4-biphenylboronic acid ( 115mg, 0.58mmol, 1.5equiv) as the starting material, the specific synthesis method refers to the synthesis of compound I-1 to obtain 120mg of white solid powder, which is the target compound (4-(3-(biphenyl-4-yl)imidazo[ 1,2-a]Pyridinyl-6-yl)phenyl)(morpholinyl)methanone 1-14 in 67% yield.

¹ H NMR (300MHz, DMSO) δ (ppm): 8.76 (s, 1H), 7.88 (d, J=5.5Hz, 5H), 7.85-7.73 (m, 5H), 7.69 (d, J=9.4Hz, 1H), 7.52(t, J=7.7Hz, 4H), 7.41(t, J=7.2Hz, 1H), 3.62(s, 8H); MS: found m/z[M+H] ⁺ 460.06, calcd. m/z[M]459.19.

Example 15 (4-(3-(4-(pyridin-2-yl)phenyl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (I -15)

With (4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (95 mg, 0.25 mmol, 1.0 equiv) and 4-(2-pyridine Base) phenylboronic acid pinacol ester (83mg, 0.29mmol, 1.2equiv) is the starting material, and the specific synthesis method refers to the synthesis of compound I-1 to obtain 81mg of white solid powder, which is the target compound (4-(3-(4 -(pyridin-2-yl)phenyl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone 1-15 in 72% yield.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.75 (d, J=5.9 Hz, 1H), 8.58 (s, 1H), 8.20 (d, J=8.3 Hz, 2H), 7.88-7.68 (m ,6H),7.62(d,J＝8.2Hz,2H),7.57-7.46(m,3H),7.36-7.28(m,1H),3.65(d,J＝53.6Hz,8H); MS:found m /z[M+H] ⁺ 460.39,calcd.m/z[M]460.19.

Example 16 (4-(3-(4-(naphthalen-2-yl)phenyl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (I -16)

With (4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (100 mg, 0.26 mmol, 1.0 equiv) and 2-naphthaleneboronic acid (67 mg , 0.39mmol, 1.5equiv) is the starting material, and the specific synthesis method refers to the synthesis of compound I-1 to obtain 55mg of white solid powder, which is the target compound ((4-(3-(4-(naphthalene-2-yl)benzene) yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone 1-16 in 49% yield.

¹ H NMR (300 MHz, DMSO) δ (ppm): 8.84 (s, 1H), 8.35 (s, 1H), 8.09 (dd, J=12.0, 7.0 Hz, 2H), 8.04–7.97 (m, 1H), 7.95(d,J＝1.6Hz,1H),7.90(d,J＝8.5Hz,1H),7.83(d,J＝9.1Hz,3H),7.71(d,J＝9.4Hz,1H),7.59( dd, J=4.7, 2.8Hz, 2H), 7.52 (d, J=8.0Hz, 2H), 3.61 (s, 8H);

MS: found m/z[M+H] ⁺ 434.14, calcd.m/z[M] 433.18.

Example 17 (4-(3-(4-(quinolin-3-yl)phenyl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone ( I-17)

Take (4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (100 mg, 0.26 mmol, 1.0 equiv) and quinoline-3-boronic acid (54mg, 0.31mmol, 1.2equiv) was the starting material, the specific synthesis method was with reference to the synthesis of compound I-1 to obtain 66mg of white solid powder, which was the target compound (4-(3-(4-(quinolin-3-yl) )phenyl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone 1-17 in 58.8% yield.

¹ H NMR (300MHz, DMSO) δ(ppm): 9.20(s, 1H), 8.53(s, 1H), 8.38(s, 1H), 8.21(d, J=8.0Hz, 1H), 8.01–7.74( m, 4H), 7.69–7.48 (m, 6H), 3.64 (d, J=75.9Hz, 8H).

MS: found m/z[M+H] ⁺ 434.17, calcd.m/z[M] 435.18.

Example 18 (4-(3-(4-(isoquinolin-6-yl)phenyl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (I-18)

With (4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (100 mg, 0.26 mmol, 1.0 equiv) and isoquinoline-6- Boronic acid (54 mg, 0.31 mmol, 1.2 equiv) was used as the starting material. The specific synthesis method was referred to the synthesis of compound I-1 to obtain 71 mg of white solid powder, which was the target compound (4-(3-(4-(isoquinoline-6). -yl)phenyl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone 1-18 in 63.1% yield.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 9.36 (s, 1H), 8.64 (d, J=4.7 Hz, 2H), 8.18 (d, J=8.4 Hz, 1H), 8.08 (s, 1H) ), 7.98–7.84 (m, 3H), 7.76 (d, J=5.5Hz, 1H), 7.69–7.50 (m, 5H), 3.68 (d, J=69.2Hz, 8H); MS: found m/z [M+H] ⁺ 434.17, calcd.m/z[M]435.05.

Example 19 (4-(3-(4-(quinolin-6-yl)phenyl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone ( I-19)

With (4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (100 mg, 0.26 mmol, 1.0 equiv) and isoquinoline-6- Boronic acid (54 mg, 0.31 mmol, 1.2 equiv) was used as the starting material. The specific synthesis method was referred to the synthesis of compound I-1 to obtain 52 mg of white solid powder, which was the target compound (4-(3-(4-(quinoline-6- yl)phenyl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone 1-19 in 46.2% yield.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 9.00 (d, J=3.7 Hz, 1H), 8.58 (s, 1H), 8.28 (dd, J=13.6, 9.0 Hz, 2H), 8.06 (s ,1H),7.97(d,J＝7.4Hz,1H),7.92–7.79(m,2H),7.61(d,J＝7.9Hz,2H),7.52(d,J＝7.9Hz,4H),3.64 (d, J=48.1 Hz, 8H); MS: found m/z[M+H] ⁺ 434.17, calcd.m/z[M] 435.31.

Example 20 (4-(3-(benzofuran-5-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (I-20)

Take (4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (110 mg, 0.28 mmol, 1.0 equiv) and benzofuran-5- Pinacol borate (83 mg, 0.34 mmol, 1.2 equiv) was the starting material, and the specific synthetic method was with reference to the synthesis of compound I-1 to obtain 43 mg of white solid powder, which was the target compound (4-(3-(benzofuran). -5-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone 1-20 in 36% yield.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.48 (s, 1H), 7.75 (td, J=19.2, 10.3 Hz, 5H), 7.54 (dt, J=17.3, 8.8 Hz, 6H), 6.89 (s, 1H), 3.64 (d, J=59.1Hz, 8H); MS: found m/z[M+H] ⁺ 424.27, calcd.m/z[M] 423.16.

Example 21 (4-(3-(1H-Indol-5-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (I-21)

With (4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (110 mg, 0.28 mmol, 1.0 equiv) and 5-indoleboronic acid ( 55mg, 0.34mmol, 1.2equiv) was the starting material, and the specific synthesis method was referred to the synthesis of compound I-1 to obtain 40mg of white solid powder, which was the target compound (4-(3-(1H-indol-5-yl)imidazole) [1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone 1-21 in 33% yield.

¹ H NMR (300MHz, DMSO-d ₆ )δ(ppm): 11.32(s, 1H), 8.64(s, 1H), 7.88(s, 1H), 7.79-7.71(m, 4H), 7.67-7.57( m,2H),7.54–7.38(m,4H),6.55(s,1H),3.60(s,8H); MS: found m/z[M+H] ⁺ 423.10,calcd.m/z[M] 422.17.

Example 22 (S)-(4-(3-(isoquinolin-6-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(3-aminopiperidinyl)methan Ketone (I-22)

Take (S)-(4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(3-tert-butoxycarbonylaminopiperidinyl)methanone (100 mg, 0.21 mmol , 1.0 equiv) and isoquinoline-6-boronic acid pinacol ester (77 mg, 0.30 mmol, 1.5 equiv) as starting materials, the specific synthesis method refers to the synthesis of compound I-1 to obtain 76 mg of yellow solid powder, which is (4 -(3-(Isoquinolin-6-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)((3-tert-butoxycarbonylaminopiperidinyl)methanone, yield was 69%.

(4-(3-(Isoquinolin-6-yl)imidazo[1,2-a]pyridyl-6-yl)phenyl)((3-tert-butoxycarbonylaminopiperidinyl)methanone (76 mg, 0.14 mmol, 1.0 equiv) was dissolved in 2 mL of dichloromethane, and trifluoroacetic acid (162 mg, 1.42 mmol, 10 equiv) was slowly added dropwise, and the reaction was stirred at room temperature for 4 h. After the TLC plate monitored the reaction, the reaction solution was concentrated to remove residual Trifluoroacetic acid, redissolved in 2 mL of dichloromethane, added triethylamine (16 mg, 0.17 mmol, 1.2 equiv), and continued stirring for 30 min. After concentration, the residue was subjected to column chromatography (dichloromethane/methanol=20/1～ 10/1) was separated to obtain 41 mg of yellow solid, (4-(3-(isoquinolin-6-yl)imidazo[1,2-a]pyridin-6-yl)phenyl)((3-amino piperidinyl) ketone in 66% yield.

¹ H NMR (400MHz, DMSO)δ9.38(s,1H),8.93(s,1H),8.57(d,J=5.7Hz,1H),8.42(s,1H),8.30(d,J=8.6 Hz, 1H), 8.09(dd, J＝8.5, 1.6Hz, 1H), 8.05(s, 1H), 7.96(d, J＝5.8Hz, 1H), 7.86(d, J＝8.2Hz, 3H), 7.75(dd,J=9.4,1.6Hz,1H),7.52(d,J=8.2Hz,2H),3.39(dd,J=14.0,7.0Hz,2H),3.18(s,1H),2.96–2.85 (m, 2H), 2.00–1.83 (m, 1H), 1.68 (s, 1H), 1.41 (d, J=10.1Hz, 2H).

Example 23 (4-(3-(isoquinolin-6-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(1-piperazinyl)methanone (I-23 )

Take (4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(1-tert-butoxycarbonylpiperazinyl)methanone (100 mg, 0.21 mmol, 1.0 equiv) and Isoquinoline-6-boronic acid pinacol ester (79 mg, 0.31 mmol, 1.5 equiv) was the starting material, and the specific synthetic method was with reference to the synthesis of compound I-22 to obtain 51 mg of yellow solid powder, which was the target compound (4-(3 -(Isoquinolin-6-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(1-piperazinyl)methanone in 56% yield.

1H NMR (400MHz, DMSO) δ9.38(s, 1H), 8.93(s, 1H), 8.57(d, J=5.7Hz, 1H), 8.42(s, 1H), 8.30(d, J=8.5Hz ,1H),8.09(dd,J＝8.5,1.4Hz,1H),8.06(s,1H),7.96(d,J＝5.7Hz,1H),7.91–7.83(m,3H),7.75(dd, J=9.4, 1.4Hz, 1H), 7.55 (d, J=8.2Hz, 2H), 3.60 (d, J=20.4Hz, 4H), 2.99 (d, J=24.9Hz, 4H).

Example 24 (4-(3-(4-(isoquinolin-6-yl))imidazo[1,2-a]pyridinyl-6-yl)phenyl)(4-morpholinylpiperidinyl) ) ketone (I-24)

With (4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(4-morpholinopiperidinyl)methanone (100 mg, 0.21 mmol, 1.0 equiv) and iso Quinoline-6-boronic acid pinacol ester (82 mg, 0.32 mmol, 1.5 equiv) was the starting material, and the specific synthetic method was referred to the synthesis of compound I-1 to obtain 57 mg of white solid powder, which was the target compound (4-(3- (Isoquinolin-6-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(4-morpholinopiperidinyl)methanone in 48% yield.

¹ H NMR (400MHz, DMSO) δ 9.39 (d, J=7.7Hz, 1H), 8.94 (d, J=7.1Hz, 1H), 8.57 (dd, J=7.7, 5.8Hz, 1H), 8.43 ( d, J=7.3Hz, 1H), 8.30 (t, J=8.1Hz, 1H), 8.16–8.04 (m, 2H), 8.03–7.94 (m, 1H), 7.85 (dd, J=10.1, 5.7Hz) ,3H),7.76(dd,J＝9.3,7.9Hz,1H),7.51(t,J＝8.0Hz,2H),4.48(s,1H),3.47(d,J＝90.0Hz,10H),2.95 (d, J=95.3Hz, 2H), 1.82 (d, J=39.6Hz, 2H), 1.48 (d, J=5.4Hz, 2H).

Example 25 (4-(3-(Isoquinolin-6-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(4-aminopiperidinyl)methanone (I- 25)

With (4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(4-aminopiperidinyl)methanone (100 mg, 0.21 mmol, 1.0 equiv) and isoquinoline -6-boronic acid pinacol ester (77mg, 0.30mmol, 1.5equiv) was the starting material, the specific synthesis method was referred to the synthesis of compound I-1 to obtain 15mg of yellow solid, (4-(3-(4-(isoquinoline) olin-6-yl))imidazo[1,2-a]pyridinyl-6-yl)phenyl)((4-aminopiperidinyl)methanone in 17% yield.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 9.39 (d, J=7.7 Hz, 1H), 8.94 (d, J=7.1 Hz, 1H), 8.57 (dd, J=7.7, 5.8 Hz) ,1H),8.43(d,J=7.3Hz,1H),8.30(t,J=8.1Hz,1H),8.16-8.04(m,2H),8.03-7.94(m,1H),7.85(dd, J=10.1, 5.7Hz, 3H), 7.76(dd, J=9.3, 7.9Hz, 1H), 7.51(t, J=8.0Hz, 2H), 4.48(s, 1H), 3.70(s, 1H), 3.23(s, 2H), 2.95(s, 1H), 1.82(s, 2H), 1.48(s, 2H).

Biological activity test case

Using the ADP-Glo kinase assay kit (Promega, catalog No. V6930), the compounds of the present invention were screened for their inhibitory activity on MNK1 and MNK2 enzymatic activities. All kinase reactions were performed in HEPES reaction buffer (15 mM HEPES pH 7.4, ₂₀ mM NaCl2, 1 mM EGTA, 10 mM _MgCl2 , 0.1 mg/mL BGG and 0.02% Tween-20). The final MNK1 reaction solution contained 10 nM MNK1 (Carna, catalog No. 02-145), 100 μM polypeptide substrate (TATKSGSTTKNR, Genscript), 300 μM ATP and compounds at different concentrations; the final MNK2 reaction solution contained 3 nM MNK1 (Carna, catalog No. 02-146 ), 50 μM polypeptide substrate (TATKSGSTTKNR, Genscript), 10 μM ATP and different concentrations of compounds. The final DMSO concentration in each reaction was 1%.

The specific operation steps are:

1. Add 4 μL of protein solution to each well of a 384-well plate, then add 2 μL of compound solution, centrifuge at 1000 rpm for 5 minutes, and incubate at room temperature for 10 minutes on a shaker;

2. Add 4 μL of substrate mixture (polypeptide substrate and ATP) to each well, centrifuge at 1000 rpm for 5 min, and incubate at room temperature for 60 min on a shaker;

3. Add 10 μL of ADP-Glo reagent to each well, centrifuge at 1000 rpm for 5 min, and incubate at room temperature on a shaker for 40 min (in the dark);

4. Add 20 μL Detection reagent to each well, centrifuge at 1000 rpm for 5 min, and incubate at room temperature on a shaker for 40 min (in the dark);

5. Read the RLU (Relative luminescence unit) value using the luminescence module of the multi-function microplate reader. The signal intensity was used to characterize the activity intensity of the MNK enzyme, and 8 concentrations of compound dilution were used to calculate the compound concentration ( _IC50 ) required to achieve 50% inhibition of enzyme activity. (The experimental results are shown in Table 2)

Table 2. Inhibitory activity of compounds on MNK1 and MNK2 enzymatic activities

From the above results, it can be seen that the compounds of the present invention have excellent inhibitory activities against both MNK1 and MNK2.

All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (10)

1. A compound represented by the general formula (I), or a stereoisomer, a geometric isomer, a tautomer, a pharmaceutically acceptable salt thereof, a prodrug thereof, and a hydrate or solvate thereof:

wherein,

is a group selected from:

ar is a group selected from the group consisting of: substituted phenyl, substituted or unsubstituted 10-20 membered aryl, substituted or unsubstituted 5-12 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O;

wherein "substituted" means substituted with one or more (e.g., 2, 3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 alkylamino, -C (O) C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxy, amino, carboxy, a group selected from the group consisting of unsubstituted or substituted by one or more substituents: C6-C10 aryl, C3-C8 cycloalkyl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, 5-10 membered heterocyclyl having 1-3 heteroatoms selected from N, S and O; the substituents are selected from the following group: halogen, C1-C6 alkoxy;

and the compound is not of the formula:

2. The compound of claim 1, or stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs and hydrates or solvates thereof, wherein Ar is a group selected from the group consisting of:

3. the compound of claim 1, or stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs and hydrates or solvates thereof, wherein said Ar group is selected from the group consisting of:

4. the compound of claim 1, or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug thereof, hydrate or solvate thereof, selected from the group consisting of:

5. a pharmaceutical composition, comprising: (i) a therapeutically effective amount of a compound of formula (I), as described in any one of claims 1-4, or one or more of a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt thereof, prodrug, hydrate, or solvate thereof, and (ii) a pharmaceutically acceptable carrier or excipient.

6. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition has a formulation form selected from the group consisting of: tablet, pill, granule, pellicle, dripping pill, capsule, injection, soft capsule, emulsion, liposome, lyophilized powder, polymer microsphere, or polyethylene glycol derivative.

7. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is for treating a disease or disorder associated with the activity or expression of MNK.

8. Use of a compound of formula (I), or a stereoisomer, a geometric isomer, a tautomer, a pharmaceutically acceptable salt thereof, a prodrug, a hydrate, or a solvate thereof according to any one of claims 1 to 4, for the preparation of a pharmaceutical composition for the treatment or prophylaxis of a disease or condition associated with the activity or amount of expression of MNK.

9. The use according to claim 8, wherein the disease is cancer.

10. A process for the preparation of a compound of formula (I) as claimed in any one of claims 1 to 4, characterized in that it comprises the steps of:

in a metal palladium catalyst (preferably Pd (PPh)₃)₄Or Pd (dppf) Cl₂) Catalytically, with a compound of formula 7 and Ar-B (OH)₂Or aryl (Ar) borate ester is subjected to coupling reaction to obtain the target compound (I).