CN111978318A - 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, the present invention provides a new class of imidazopyridine compounds or stereoisomers, geometric isomers, tautomers and pharmaceutically acceptable salts thereof, Hydrates, prodrugs or solvates, and their use as MNK1 and MNK2 kinase inhibitors.

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 4E (eukaryotic initiation factor4E), 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,

X is S or O;

R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C10 aryl , substituted or unsubstituted 5-10-membered heteroaryl with 1-3 heteroatoms selected from N, S and O, substituted or unsubstituted with 1-3 heteroatoms selected from N, S and O 5-10 membered heterocyclyl, -CN, -OR, -SR, -N(R) ₂ , -NO ₂ , -COR, -CO ₂ R, -CON(R) ₂ , -CONROR, -SOR, -SO ₂ R, -SO ₂ N(R) ₂ , -OCOR, -NRCOR, -NRSO ₂ R or -NRCON(R) ₂ ; or R ₁ and R ₂ together with the N atom to which they are attached form a substituted or unsubstituted 5-6 membered heterocyclyl;

Each R is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted with 1- 5-10 membered heteroaryl with 3 heteroatoms selected from N, S and O, substituted or unsubstituted 5-10 membered heterocyclyl with 1-3 heteroatoms selected from N, S and O;

R ₃ is H, or has a structure represented by -NR ₄ R ₅ , wherein R ₄ and R ₅ are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl; or R ₁ and R ₂ forms a substituted or unsubstituted 5-6 membered heterocyclic group with the N atom to which it is attached;

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; Said substituents are selected from the group consisting of halogen, C1-C6 alkoxy.

In another preferred embodiment, the X is O.

In another preferred example, the R ₁ and R ₂ are each independently a substituted or unsubstituted C1-C6 alkyl group; or the N atoms to which R1 and R2 are connected together form a substituted or unsubstituted 5-6-membered Heterocyclyl.

In another preferred example, the -NR ₁ R ₂ has the following structure:

wherein Y is selected from the group consisting of none (ie chemical bond), O, S, _NR6 , or CHR6 _;

Said R ₆ is selected from the following group: C1-C6 alkyl, C1-C6 alkylamino, -C(O)C1-C6 alkyl, amino, having 1-3 hetero compounds selected from N, S and O A 5- to 10-membered heterocyclic group of atoms.

In another preferred embodiment, the compound has the structure shown in the following formula II:

In another preferred embodiment, the compound is selected from I-1 to I-20.

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:

进行偶联反应，得到目标化合物(I)。Under the catalysis of metal palladium catalyst (preferably Pd(PPh ₃ ) ₄ or Pd(dppf)Cl ₂ ), the compound of formula 7 is combined with

The coupling reaction is carried out to obtain the target compound (I).

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.

Active ingredient

The present invention synthesizes a series of compounds of general structural formula (I) or their stereoisomers, geometric isomers, tautomers and their pharmaceutically acceptable salts, hydrates, prodrugs or solvates Object:

in,

X is S or O;

R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C10 aryl , substituted or unsubstituted 5-10-membered heteroaryl with 1-3 heteroatoms selected from N, S and O, substituted or unsubstituted with 1-3 heteroatoms selected from N, S and O 5-10 membered heterocyclyl, -CN, -OR, -SR, -N(R) ₂ , -NO ₂ , -COR, -CO ₂ R, -CON(R) ₂ , -CONROR, -SOR, -SO ₂ R, -SO ₂ N(R) ₂ , -OCOR, -NRCOR, -NRSO ₂ R or -NRCON(R) ₂ ; or R ₁ and R ₂ together with the N atom to which they are attached form a substituted or unsubstituted 5-6 membered heterocyclyl;

Each R is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted with 1- 5-10 membered heteroaryl with 3 heteroatoms selected from N, S and O, substituted or unsubstituted 5-10 membered heterocyclyl with 1-3 heteroatoms selected from N, S and O;

R ₃ is H, or has a structure represented by -NR ₄ R ₅ , wherein R ₄ and R ₅ are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl; or R ₁ and R ₂ forms a substituted or unsubstituted 5-6 membered heterocyclic group with the N atom to which it is attached;

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; Said substituents are selected from the group consisting of halogen, C1-C6 alkoxy.

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 compound of formula (I) of the present invention can be prepared by the following steps:

Starting from compounds 1 and 2, through ring closure, coupling with methoxycarbonyl phenylboronic acid, bromination, hydrolysis, condensation with the corresponding amine and then coupling to obtain the target compound. 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 the corresponding amine under the action of condensing agent EDCI/HOBT or HATU to obtain compound 7.

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

Wherein, the definitions of X, R ₁ and R ₂ above are as described above.

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.

Example 1

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

Step 1: Preparation of 6-bromoimidazo[1,2-a]pyridine

2-Amino-6-bromopyridine (3 g, 17.34 mmol) 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) and 48% aqueous hydrobromic acid ( 3 mL), the temperature was raised to 100 °C for 8 h. After monitoring the completion of the reaction by TLC plate, the reaction solution was cooled to room temperature, concentrated under reduced pressure, added with 100 mL of water, extracted with ethyl acetate, combined with the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The compound was separated by column chromatography to obtain 2.98 g of white solid powder, which was the intermediate 6-bromoimidazo[1,2-a]pyridine, and the yield was 87.2%.

¹ H NMR (300MHz, DMSO-d ₆ )δ: 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).

Step 2: Preparation of methyl 4-(imidazo[1,2-a]pyridinyl-6-yl)benzoate

6-Bromoimidazo[1,2-a]pyridine (2.5 g, 12.69 mmol) was dissolved in a mixed solution of 45 mL of 1,4-dioxane and 4.5 mL of water, and 4-methoxycarbonylbenzeneboronic acid (2.74 mL) was added. g, 15.23mmol) and potassium phosphate trihydrate (8.45g, 31.72mmol), fully replace the air in the reaction device with nitrogen, stir at room temperature for 15min, add tetrakistriphenylphosphine palladium (0.73g, 0.63mmol), fully The air in the reaction device was replaced, and stirring was continued at room temperature for 15 min, and then the temperature was raised to 95 °C for 8 h. After monitoring the completion of the reaction 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 2.6 g of a white solid, which was the intermediate 4-(imidazo[1] ,2-a]Pyridinyl-6-yl)benzoic acid methyl ester in 81.2% yield.

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

Step 3: Preparation of methyl 4-(3-bromoimidazo[1,2-a]pyridin-6-yl)benzoate

Methyl 4-(imidazo[1,2-a]pyridinyl-6-yl)benzoate (2.6 g, 10.31 mmol) was dissolved in a mixed solution of 48 mL of acetonitrile and 16 mL of dichloromethane, and N-bromo Succinimide (2.38 g, 13.40 mmol) was stirred at room temperature for 8 h. After monitoring the completion of the reaction by TLC plate, concentrate under reduced pressure, add 100 mL of water, extract with dichloromethane, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter and concentrate under reduced pressure, and separate the residue by column chromatography , 3.1 g of yellow solid powder was obtained, which was the intermediate methyl 4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)benzoate, and the yield was 90.8%.

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

Step 4: Preparation of 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) was dissolved in a mixed solution of 20 mL of tetrahydrofuran and 10 mL of methanol, and 10 mL of methanol was slowly added dropwise. LiOH (1.09 g, 45.66 mmol) in aqueous solution was stirred at room temperature for 4 h. After monitoring the reaction by TLC plate, concentrate under reduced pressure, add 20 mL of water to dilute, slowly add 1M hydrochloric acid dropwise, and adjust the pH to 2 to 3. A large amount of white solids are precipitated. The filter cake is collected by filtration, washed with water, and dried to obtain 1.75 g of white solids. , which is the intermediate 4-(3-bromoimidazo[1,2-a]pyridyl-6-yl)benzoic acid with a yield of 96.7%.

Step 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) was dissolved in 3 mL of N,N-dimethylformamide, followed by the addition of morpholine (119 mg). , 1.36 mmol), EDCI (261 mg, 1.36 mmol), HOBT (184 mg, 1.36 mmol), triethylamine (138 mg, 1.36 mmol) and DMAP (14 mg, 0.11 μmol), 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 subjected to column chromatography (dichloromethane/methanol= 100/1～100/3) were separated to obtain 356 mg of yellow solid powder, which was the intermediate (4-(3-bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl) Methyl ketone, the yield was 81.2%.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 7.72 (dd, J=21.1, 8.4 Hz, 4H), 7.55 (dd, J=13.8, 9.4 Hz, 3H), 3.67 (d, J=47.9Hz, 8H).

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

(4-(3-Bromoimidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (110 mg, 0.26 mmol) was dissolved in 2 mL of 1,4-dioxane In the mixed solution of 0.2 mL of water, benzothiophene-2-boronic acid (61 mg, 0.34 mmol) and potassium phosphate trihydrate (138 mg, 0.52 mmol) were added, and the air in the reaction device was fully replaced with nitrogen, stirred at room temperature for 15 min, and added Tetrakistriphenylphosphine palladium (30 mg, 26 μmol), fully replaced the air in the reaction device with nitrogen, continued stirring at room temperature for 15 min, and then heated to 95° C. for 8 h. 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 55 mg of white solid powder, (4-(3-(benzothiophene). -2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone in 43.9% 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 2

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

(4-(3-(benzofuran-2-yl)imidazo[1,2-a]pyridin-6-yl)phenyl)(morpholinyl) can be prepared by a method similar to that in Example 1 ketone.

¹ H NMR (300MHz, DMSO-d ₆ )δ: 9.01(s, 1H), 8.22(s, 1H), 7.99-7.84(m, 3H), 7.85-7.67(m, 3H), 7.66-7.49(m ,3H),7.43–7.27(m,2H),3.64(s,8H); MS: found m/z[M+H] ⁺ 424.01, calcd.m/z[M]423.16.

Example 3

(4-(3-(benzofuran-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone (I -3)

(4-(3-(benzofuran-2-yl)imidazo[1,2-a]pyridin-6-yl)phenyl)(4-methyl) can be prepared by a method similar to that in Example 1 piperazin-1-yl)methanone.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 9.01 (s, 1H), 8.22 (s, 1H), 7.89 (t, J=7.9 Hz, 3H), 7.74 (dd, J=23.3, 7.1Hz, 3H), 7.63–7.47 (m, 3H), 7.41–7.26 (m, 2H), 3.53 (d, J=42.9Hz, 4H), 2.34 (s, 4H), 2.22 (s, 3H); MS: found m/z[M+H] ⁺ 437.19, calcd.m/z[M]436.19.

Example 4

(4-(3-(benzofuran-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(piperidinyl)methanone (I-4)

(4-(3-(benzofuran-2-yl)imidazo[1,2-a]pyridin-6-yl)phenyl)(piperidinyl) can be prepared by a method similar to that in Example 1 ketone.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 9.30 (s, 1H), 9.09 (s, 1H), 8.24 (s, 1H), 8.07 (d, J=7.1 Hz, 2H), 7.75-7.63 (m, 2H), 7.59(d, J=7.3Hz, 2H), 7.48–7.31(m, 2H), 7.29(s, 1H), 7.17(s, 1H), 3.76(s, 2H), 3.45( s, 2H), 1.67 (d, J=33.8Hz, 6H); MS: found m/z[M+H] ⁺ 422.06, calcd.m/z[M] 421.18.

Example 5

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

(4-(3-(benzofuran-2-yl)imidazo[1,2-a]pyridin-6-yl)phenyl)(N,N- dimethylamino) ketone.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.95 (s, 1H), 8.12 (s, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.68 (s, 3H), 7.60 (d , J=5.7Hz, 4H), 7.34(t, J=6.4Hz, 2H), 7.05(s, 1H), 3.17(s, 3H), 3.10(s, 3H); MS: found m/z[M +H]+382.10,calcd.m/z[M]381.15.

Example 6

(4-(3-(benzofuran-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(pyrrolidinyl)methanone (I-6)

(4-(3-(benzofuran-2-yl)imidazo[1,2-a]pyridin-6-yl)phenyl)(pyrrolidinyl) can be prepared by a method analogous to that in Example 1 ketone.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.94 (s, 1H), 8.12 (s, 1H), 7.85 (d, J=8.9 Hz, 1H), 7.76-7.54 (m, 6H), 7.40 –7.28(m, 2H), 7.05(s, 1H), 3.71(t, J=6.7Hz, 2H), 3.53(t, J=6.5Hz, 2H), 1.99(ddd, J=18.9, 13.2, 7.5 Hz,4H); MS: found m/z[M+H] ⁺ 408.22, calcd.m/z[M]407.16.

Example 7

(4-(3-(benzofuran-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(4-acetylpiperazin-1-yl)methanone (I -7)

(4-(3-(benzofuran-2-yl)imidazo[1,2-a]pyridin-6-yl)phenyl)(4-acetyl) can be prepared by a method similar to that in Example 1 piperazin-1-yl)methanone.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.93 (s, 1H), 8.10 (s, 1H), 7.83 (d, J=9.3 Hz, 1H), 7.70 (dd, J=6.4, 1.9 Hz ,2H),7.68–7.62(m,1H),7.57(tt,J=8.2,6.1Hz,4H),7.33(ddd,J=14.6,7.1,1.4Hz,2H),7.03(s,1H), 3.62(d, J=32.4Hz, 8H), 2.15(s, 3H); MS: found m/z[M+H] ⁺ 465.26, calcd.m/z[M]464.18.

Example 8

(4-(3-(benzofuran-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(4-dimethylaminopiperidinyl)methanone (I-8 )

(4-(3-(benzofuran-2-yl)imidazo[1,2-a]pyridin-6-yl)phenyl)(4-dimethyl) can be prepared by a method similar to that in Example 1 aminopiperidinyl) ketone.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.92 (s, 1H), 8.10 (s, 1H), 7.81 (d, J=9.3 Hz, 1H), 7.72-7.52 (m, 7H), 7.34 (dd, J=14.6, 6.1Hz, 2H), 7.03(s, 1H), 4.79(s, 1H), 3.92(s, 1H), 3.02(s, 2H), 2.53(t, J=10.9Hz, 1H), 2.32(d, J=22.8Hz, 6H), 1.96(s, 2H), 1.57(d, J=9.9Hz, 2H); MS: found m/z[M+H] ⁺ 465.32, calcd. m/z[M]464.22.

Example 9

(4-(3-(benzofuran-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(4-methylpiperidinyl)methanone (I-9)

(4-(3-(benzofuran-2-yl)imidazo[1,2-a]pyridin-6-yl)phenyl)(4-methyl) can be prepared by a method similar to that in Example 1 piperidinyl) ketone.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.95 (s, 1H), 8.12 (s, 1H), 7.86 (d, J=9.3 Hz, 1H), 7.73-7.45 (m, 7H), 7.35 (t, J＝7.9Hz, 2H), 7.06(s, 1H), 4.72(s, 1H), 3.82(s, 1H), 2.95(d, J＝71.1Hz, 2H), 2.09(s, 2H) ,1.74(d,J=36.4Hz,3H),1.02(d,J=6.2Hz,3H); MS:found m/z[M+H] ⁺ 436.28,calcd.m/z[M]435.19.

Example 10

(4-(3-(benzofuran-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(4-isopropylpiperazin-1-yl)methanone ( I-10)

(4-(3-(benzofuran-2-yl)imidazo[1,2-a]pyridin-6-yl)phenyl)(4-isopropyl) can be prepared by a method similar to that in Example 1 ylpiperazin-1-yl)methanone.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.94 (s, 1H), 8.12 (s, 1H), 7.83 (d, J=9.3 Hz, 1H), 7.68 (t, J=7.8 Hz, 3H) ), 7.59(q, J＝6.6Hz, 4H), 7.35(dd, J＝13.9, 6.6Hz, 2H), 7.05(s, 1H), 3.71(d, J＝93.4Hz, 4H), 2.80(dt , J=13.1, 6.5Hz, 1H), 2.60 (d, J=33.0Hz, 4H), 1.10 (d, J=6.5Hz, 6H); MS: found m/z[M+H] ⁺ 465.26, calcd .m/z[M]464.22.

Example 11

(4-(3-(benzofuran-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(4-piperidinylpiperidinyl)methanone (I-11 )

(4-(3-(benzofuran-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(4-piperidine can be prepared by a method similar to that in Example 1 piperidinyl) ketone.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.94 (s, 1H), 8.12 (s, 1H), 7.83 (d, J=9.3 Hz, 1H), 7.67 (dd, J=10.3, 4.9 Hz) ,3H),7.59(dd,J＝12.3,8.3Hz,4H),7.42-7.30(m,2H),7.05(s,1H),4.81(s,1H),3.92(s,1H),3.08( s, 1H), 2.82(s, 1H), 2.57(s, 5H), 1.88(s, 4H), 1.63(d, J=4.9Hz, 6H); MS: found m/z[M+H] ⁺ 505.22,calcd.m/z[M]504.25.

Example 12

(4-(3-(benzofuran-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(4-morpholinopiperidinyl)methanone (I-12 )

(4-(3-(benzofuran-2-yl)imidazo[1,2-a]pyridin-6-yl)phenyl)(4-morpholine can be prepared by a method similar to that in Example 1 piperidinyl) ketone.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.94 (s, 1H), 8.12 (s, 1H), 7.82 (d, J=9.8 Hz, 1H), 7.63 (dt, J=17.9, 8.1 Hz) ,6H),7.45–7.30(m,2H),7.05(s,1H),4.78(s,2H),3.94(s,1H),3.76(s,4H),3.02(d,J=58.3Hz, 2H), 2.56(d, J＝26.5Hz, 4H), 2.47(s, 1H), 1.96(s, 2H), 1.56(s, 2H); MS: found m/z[M+H] ⁺ 507.10, calcd.m/z[M]506.23.

Example 13

(4-(3-(benzofuran-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(piperazinyl)methanone trifluoroacetate (I-13 )

(4-(3-(benzofuran-2-yl)imidazo[1,2-a]pyridin-6-yl)phenyl)(piperazinyl) can be prepared by a method similar to that in Example 1 Ketone trifluoroacetate.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.94 (s, 1H), 8.12 (s, 1H), 7.82 (d, J=9.8 Hz, 1H), 7.63 (dt, J=17.9, 8.1 Hz) ,6H),7.45–7.30(m,2H),7.05(s,1H),6.51(s,1H),3.55(s,4H),3.45(s,4H); MS:found m/z[M+ H] ⁺ 423.16,calcd.m/z[M]422.17.

Example 14

(4-(3-(benzofuran-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(4-aminopiperidinyl)methanone trifluoroacetate ( I-14)

(4-(3-(benzofuran-2-yl)imidazo[1,2-a]pyridin-6-yl)phenyl)(4-aminopiperyl) can be prepared by a method similar to that in Example 1 pyridyl)methanone trifluoroacetate.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 9.03 (s, 1H), 8.23 (s, 1H), 7.91 (dd, J=14.0, 8.8 Hz, 3H), 7.80 (dd, J=9.4, 1.6Hz, 1H), 7.72(t, J=6.8Hz, 2H), 7.61(s, 1H), 7.54(d, J=8.2Hz, 2H), 7.41–7.28(m, 2H), 6.85(s, 2H), 4.47(s, 1H), 3.72(s, 1H), 3.22(s, 2H), 2.96(s, 1H), 1.92(s, 2H), 1.43(s, 2H); MS: found m/ z[M+H] ⁺ 437.26, calcd.m/z[M]436.19.

Example 15

(R)-(4-(3-(benzofuran-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(3-aminopiperidinyl)methanonetrifluoro Acetate (I-15)

(R)-(4-(3-(benzofuran-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)( 3-Aminopiperidinyl)methanone trifluoroacetate.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.94 (s, 1H), 8.12 (s, 1H), 7.82 (d, J=9.8 Hz, 1H), 7.63 (dt, J=17.9, 8.1 Hz) ,6H),7.45–7.30(m,2H),7.05(s,1H),4.28(d,J=46.0Hz,2H),3.13–2.80(m,3H),1.95(s,1H),1.71( s,1H),1.48(s,2H); MS: found m/z[M+H] ⁺ 437.13, calcd.m/z[M]436.19.

Example 16

(S)-(4-(3-(benzofuran-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(3-aminopiperidinyl)methanonetrifluoro Acetate (I-16)

(S)-(4-(3-(benzofuran-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)( 3-Aminopiperidinyl)methanone trifluoroacetate.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 9.03 (s, 1H), 8.23 (s, 1H), 7.92 (d, J=8.2 Hz, 3H), 7.81 (d, J=9.4 Hz, 1H) ), 7.72(t, J＝7.0Hz, 2H), 7.62(s, 1H), 7.57(d, J＝8.0Hz, 2H), 7.43–7.28(m, 2H), 4.27(d, J＝46.0Hz ,2H),3.10–2.78(m,3H),1.94(s,1H),1.69(s,1H),1.45(s,2H); MS:found m/z[M+H] ⁺ 437.13,calcd. m/z[M]436.19.

Example 17

(4-(3-(7-Morpholinylbenzofuran-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (I-17 )

(7-Isopropylbenzofuran-2-yl)boronic acid (4-(3-(7-morpholinobenzofuran-2-yl)imidazo[1] can be prepared by a method similar to that in Example 1 ,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.98 (s, 1H), 8.15 (s, 1H), 7.86 (d, J=7.7 Hz, 1H), 7.70 (d, J=6.5 Hz, 2H) ), 7.65–7.52(m, 3H), 7.28(s, 2H), 7.05(s, 1H), 6.85(d, J=7.7Hz, 1H), 3.90(d, J=3.5Hz, 4H), 3.68 (d, J=53.0Hz, 8H), 3.39 (d, J=3.5Hz, 4H); MS: found m/z[M+H] ⁺ 509.37, calcd.m/z[M] 508.21.

Example 18

(4-(3-(7-(Piperazin-1yl)benzofuran-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone Trifluoroacetate (I-18)

(4-(3-(7-(Piperazin-1 yl)benzofuran-2-yl)imidazo[1,2-a]pyridinyl-6-yl can be prepared by a method similar to that in Example 1 )phenyl)(morpholinyl)methanone trifluoroacetate.

¹ H NMR (300MHz, CDCl ₃ )δ(ppm): 9.92(s, 2H), 8.99(s, 1H), 8.22(s, 1H), 8.14(d, J=7.4Hz, 1H), 7.75(d ,J=9.5Hz,1H),7.67(d,J=6.1Hz,2H),7.60(d,J=9.1Hz,2H),7.36(d,J=7.4Hz,1H),7.29(s,1H ), 7.15(s, 1H), 6.88(d, J=7.1Hz, 1H), 3.81(s, 4H), 3.64(d, J=32.1Hz, 8H), 3.27(s, 4H); MS: found m/z[M+H] ⁺ 508.27, calcd.m/z[M]507.23.

Example 19

(4-(3-(7-Piperidinylbenzofuran-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (I-19 )

(4-(3-(7-Piperidinylbenzofuran-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl) can be prepared by a method similar to that in Example 1 (morpholinyl) ketone.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 9.04 (s, 1H), 8.11 (s, 1H), 7.83 (d, J=9.3 Hz, 1H), 7.72 (d, J=8.1 Hz, 2H) ), 7.61–7.54(m, 3H), 7.28(s, 1H), 7.02(s, 1H), 6.86(d, J=6.5Hz, 1H), 3.76(s, 8H), 3.34(s, 4H) ,1.78(d,J=4.1Hz,4H),1.63(dd,J=10.7,5.5Hz,2H); MS:found m/z[M+H] ⁺ 507.30,calcd.m/z[M]506.23 .

Example 20

(4-(3-(7-(Dimethylamino)benzofuran-2-yl)imidazo[1,2-a]pyridinyl-6-yl)phenyl)(morpholinyl)methanone (I -20)

(4-(3-(7-(dimethylamino)benzofuran-2-yl)imidazo[1,2-a]pyridinyl-6-yl)benzene can be prepared by a method similar to that in Example 1 group) (morpholinyl) ketone.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 9.07 (s, 1H), 8.24 (s, 1H), 7.95-7.75 (m, 5H), 7.59 (d, J=8.2 Hz, 2H) ,7.52(s,1H),7.15(dd,J=6.7,3.7Hz,2H),3.63(s,8H),3.08(s,6H); MS:found m/z[M+H] ⁺ 467.14, calcd.m/z[M]466.2.

Biological Activity Test Example 1 Kinase Level Test

The following are the inhibitory activities of the compounds of the present invention on MNK1 and MNK2 enzymatic activities. Compounds were screened for activity using the ADP-Glo Kinase Assay Kit (Promega, catalog No. V6930). All kinase reactions were performed in HEPES reaction buffer (15 mM HEPES pH7.4, 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 implementation method is:

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 min, and incubate at room temperature on a shaker for 10 min;

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;

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);

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);

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.

Biological Activity Test Example 2 Liver Microparticle Stability Test

Tolbutamide was selected as the reference compound. The specific method is as follows:

Prepare 0.1MK ₃ PO ₄ (pH7.4) buffer and 3×NADPH stock solution (6mM, 5mg/mL), and preheat in a 37°C water bath;

Configuration of test compound and reference compound spiking solution: 5 μL compound stock solution (10 nM) was added to 95 μL acetonitrile;

Configuration of 1.5μM spiking solution in microsomes (0.75mg/mL): add 1.5μL spikingsolution and 18.75μL liver microsome solution (20mg/mL) to 479.75μL K ₃ PO ₄ buffer;

Add 30μL of spiking solution in microsomes to the multi-well plate and incubate at 37°C for 5min;

Add 15 μL of NADPH stock solution to each well to start the reaction and time it;

Add 150 μL of IS-containing acetonitrile solution at 0min, 5min, 15min, 30min and 45min respectively to terminate the reaction;

After shaking for 10 min, centrifuge at 6000 rpm for 15 min; take 80 μL of supernatant from each well for LC/MS detection, and calculate T _1/2 .

(The experimental results are shown in Table 3)

Table 3. Compound Liver Microsome Stability

From the above results, it can be seen that the compounds of the present invention have good metabolic stability in the liver microsomal model.

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

in, X is S or O; R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C10 aryl , substituted or unsubstituted 5-10-membered heteroaryl with 1-3 heteroatoms selected from N, S and O, substituted or unsubstituted with 1-3 heteroatoms selected from N, S and O 5-10 membered heterocyclyl, -CN, -OR, -SR, -N(R) ₂ , -NO ₂ , -COR, -CO ₂ R, -CON(R) ₂ , -CONROR, -SOR, -SO ₂ R, -SO ₂ N(R) ₂ , -OCOR, -NRCOR, -NRSO ₂ R or -NRCON(R) ₂ ; or R ₁ and R ₂ together with the N atom to which they are attached form a substituted or unsubstituted 5-6 membered heterocyclyl; Each R is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted with 1- 5-10 membered heteroaryl with 3 heteroatoms selected from N, S and O, substituted or unsubstituted 5-10 membered heterocyclyl with 1-3 heteroatoms selected from N, S and O; R ₃ is H, or has a structure represented by -NR ₄ R ₅ , wherein R ₄ and R ₅ are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl; or R ₁ and R ₂ forms a substituted or unsubstituted 5-6 membered heterocyclic group with the N atom to which it is attached; 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; Said substituents are selected from the group consisting of halogen, C1-C6 alkoxy. 2. The compound of claim 1, or its stereoisomer, geometric isomer, tautomer, its pharmaceutically acceptable salt, its prodrug and its hydrate or solvate, which It is characterized in that the X is O. 3. The compound of claim 1, or its stereoisomer, geometric isomer, tautomer, its pharmaceutically acceptable salt, its prodrug and its hydrate or solvate, which It is characterized in that said R1 and R2 are each independently substituted or unsubstituted C1-C6 alkyl; or R1 and R2 together with the N atom to which they are connected together form a substituted or unsubstituted 5-6 membered heterocyclic group. 4. The compound of claim 1, or its stereoisomer, geometric isomer, tautomer, its pharmaceutically acceptable salt, its prodrug and its hydrate or solvate, which It is characterized in that the compound has the structure shown in the following formula II:

5. The compound of claim 1, or its stereoisomer, geometric isomer, tautomer, its pharmaceutically acceptable salt, its prodrug and its hydrate or solvate, which It is characterized in that, described compound is selected from following group:

6. A pharmaceutical composition, characterized in that, the pharmaceutical composition comprises: (i) a therapeutically effective amount of the compound of formula (I) according to any one of claims 1-5, 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 . 7. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is used to treat diseases or conditions related to the activity or expression of MNK. 8. The compound of formula (I) as described in any one of claims 1-5, or its stereoisomer, geometric isomer, tautomer, its pharmaceutically acceptable salt, its prodrug, hydrated The use of the compound or solvate, characterized in that the compound is used to prepare a pharmaceutical composition for the treatment or prevention of diseases or conditions related to the activity or expression of MNK. 9. The use of claim 8, wherein the disease is cancer. 10. the preparation method of the compound of formula (I) as described in any one of claim 1-5, is characterized in that, described method comprises the step:

Under the catalysis of metal palladium catalyst (preferably Pd(PPh ₃ ) ₄ or Pd(dppf)Cl ₂ ), the compound of formula 7 is combined with

The coupling reaction is carried out to obtain the target compound (I).