CN111978318A - Imidazopyridine MNK1/MNK2 kinase inhibitor and preparation method and application thereof - Google Patents

Abstract

The invention provides an imidazopyridine MNK1/MNK2 kinase inhibitor, a preparation method and application thereof, and particularly provides a compound shown as a formula (I): or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. The compounds of the invention may be used in the preparation of pharmaceutical compositions for the treatment of diseases or disorders associated with MNK activity or expression.

Description

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

Technical Field

The invention belongs to the technical field of medicines, and particularly provides a novel imidazopyridine compound or a stereoisomer, a geometric isomer, a tautomer, a pharmaceutically acceptable salt, a hydrate, a prodrug or a solvate thereof, and application thereof as an MNK1 and MNK2 kinase inhibitor.

Background

Protein kinases (protein kinases) play an important role in a variety of cellular functions, and their abnormal activation is associated with a variety of diseases. Mitogen-activated protein kinases (MAPKs) are capable of receiving a variety of cellular signals including growth factors, environmental stimuli, and cytokines and are activated to regulate cell proliferation, differentiation, survival, cell cycle control, and programmed cell death. Upon receiving these stimulation signals, MAPKs are capable of activating downstream target proteins, the MAPK-activated protein kinase family (MAPKAPK), which includes mitogen-activated protein kinase-acting kinases (MNKs). The MNK kinase belongs to serine/threonine protein kinases and can specifically phosphorylate Ser209 of eukaryotic initiation factor eIF4E (eukaryotic initiation factor4E) so as to indirectly regulate mRNA translation.

The eukaryotic initiation factor eIF4E is an important transcription factor, and can strengthen the transcription of mRNA encoding and controlling cyclin and oncogenic protein so as to cause the up-regulation of the expression of tumor-associated protein. eIF4E, together with the scaffold protein eIF4G and RNA helicase eIF4A, make up the eukaryotic initiation factor complex eIF 4F. Since eIF4E is responsible for binding of this complex to the 5' terminal cap structure of mRNA, it plays an irreplaceable regulatory role in RNA translation. In normal cells, eIF4E activity is restricted and transcription of these tumor-associated mrnas is inhibited; in tumor cells or tissues, however, high expression or over-activation of eIF4E causes upregulation of the level of transcription 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, stomach, hodgkin's lymphoma and neuroblastoma. Clinically, upregulation or over-activation of MNK kinase and eIF4E expression is often accompanied by drug resistance and poor prognosis. More importantly, while MNKs are an essential condition for eIF 4E-regulated tumor formation, inhibition of MNKs activity does not affect normal cell and animal survival and growth. Therefore, the inhibition of MNKs by small molecular drugs is a promising tumor treatment means.

The eIF4E is an important translation rate-limiting factor, and the MNK/eIF4E signal pathway can influence the synthesis of various chemokines, cytokines and immune checkpoint proteins so as to regulate and control immune response. The MNK kinase inhibitor can obviously reduce the content of PD-L1 on the surface of tumor cells without influencing the expression of PD-L1mRNA, and simultaneously, the MNK kinase inhibitor can reduce the expression of the activation T cell surface immune checkpoint proteins PD-1, TIM-3 and LAG 3. Tumor xenograft model results also demonstrate that MNK kinase inhibitors can reduce PD-L1 levels by 50% in mice, and that MNK inhibitors are more sensitive to tumor models with high PD-L1 expression. Meanwhile, MNK kinase inhibitor can remarkably enhance cytotoxic CD8⁺T cell function, inhibiting differentiation of activated regulatory T cells, and promoting the formation of central memory T cells. MNK inhibitors almost completely inhibited tumor proliferation in a mouse colon cancer allograft model. On the other hand, when the same tumor was inoculated again 29 days after the withdrawal, the tumor proliferation of the mice was still completely controlled without the administration of the drug. This also laterally reflects the ability of MNK inhibitors to activate a durable anti-tumor immune response in model mice.

With the intensive understanding of the structure and function of MNKs in recent years, several MNK inhibitors have been reported in succession, of which BAY1143269, Tomivosertib and ETC-206 have entered the clinic. BAY1143269, Tomivosertib and ETC-206 all were able to significantly inhibit tumor mass growth and prolong the survival of mice in a mouse xenograft model. From published phase I clinical results, both Tomivosertib and ETC-206 were able to significantly reduce the phosphorylation levels of eIF4E in patients and showed initial symptomatic relief. However, the current clinical results further prove that under in vivo conditions, the MNK inhibitor can play an anti-tumor effect by regulating the tumor microenvironment. With the increasing understanding of the MNK/eIF4E pathway, inhibitor development based on this pathway will play a more important role in targeted therapy and tumor immunotherapy.

In view of the above, there is an urgent need in the art for the development of novel MNK kinase inhibitors.

Disclosure of Invention

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

In a first aspect of the present invention, there is provided 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 the content of the first and second substances,

x is S or O;

R₁and R₂Each 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-to 10-membered heteroaryl having 1-3 heteroatoms selected from N, S and O, substituted OR unsubstituted 5-to 10-membered heterocyclyl having 1-3 heteroatoms selected from N, S and O, -CN, -OR, -SR, -N (R)₂、-NO₂、-COR、-CO₂R、-CON(R)₂、-CONROR、-SOR、-SO₂R、-SO₂N(R)₂、-OCOR、-NRCOR、-NRSO₂R or-NRCON (R)₂(ii) a Or R₁And R₂Together with the N atom to which they are attached form a substituted or unsubstituted 5-6 membered heterocyclic group;

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 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, substituted or unsubstituted 5-10 membered heterocyclyl having 1-3 heteroatoms selected from N, S and O;

R₃is H, or has-NR₄R₅In the structure shown, wherein R₄And R₅Each independently selected from the group consisting of: hydrogen, substituted or unsubstituted C1-C6 alkyl; or R₁And R₂Together with the N atom to which they are attached form a substituted or unsubstituted 5-6 membered heterocyclic group;

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.

In another preferred embodiment, X is O.

In another preferred embodiment, R is₁And R₂Each independently substituted or unsubstituted C1-C6 alkyl; or R1 and R2 taken together with the N atom to which they are attached form a substituted or unsubstituted 5-6 membered heterocyclic group.

In another preferred embodiment, the-NR is₁R₂Has the following structure:

wherein Y is selected from the group consisting of: none (i.e. chemical bond), O, S, NR₆Or CHR₆；

Said R₆Selected from the group consisting of: C1-C6 alkyl, C1-C6 alkylamino, -C (O) C1-C6 alkyl, amino, having 1-3A 5-10 membered heterocyclyl having a heteroatom selected from N, S and O.

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

in another preferred embodiment, the compound is selected from the group consisting of I-1 to I-20.

In a second aspect of the present invention, there is provided a pharmaceutical composition comprising: (i) a therapeutically effective amount of a compound of formula (I), as described in the first aspect of the invention, 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.

In another preferred embodiment, 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.

In another preferred embodiment, the pharmaceutical composition is used for treating a disease or disorder associated with the activity or expression level of MNK.

In another preferred example, the MNK is MNK1 or MNK 2.

In a third aspect of the present invention, there is provided a use of a compound of formula (I) as described in the first aspect of the present invention, or a stereoisomer, a geometric isomer, a tautomer, a pharmaceutically acceptable salt thereof, a prodrug, a hydrate, or a solvate thereof, for the manufacture of a pharmaceutical composition for the treatment or prevention of a disease or condition associated with an activity or an 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 lymphocytic leukemia, acute myelocytic leukemia, polar promyelocytic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic neutrophilic leukemia, polar undifferentiated cell leukemia, anaplastic large cell lymphoma, adult T cell ALL, AML with three lineage myelodysplasia, mixed lineage leukemia, myelodysplastic syndrome, myelodysplasia, multiple myeloma and myelosarcoma, chronic lymphocytic lymphoma, diffuse large B cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma.

In a fourth aspect of the invention, there is provided a process for the preparation of a compound of formula (I) as described in the first aspect of the invention, said process comprising the steps of:

in a metal palladium catalyst (preferably Pd (PPh)₃)₄Or Pd (dppf) Cl₂) Catalyzed by a compound of formula 7 with

Carrying out coupling reaction to obtain the target compound (I).

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Detailed Description

The present inventors have conducted extensive and intensive studies for a long time and have found a novel class of compounds having an excellent inhibitory effect on MNK kinases (preferably MNK1 and MNK 2). The compound can be used as an active ingredient for preparing a pharmaceutical composition for treating diseases related to the activity or expression amount of MNK kinase. On this basis, the inventors have completed the present invention.

Definition of

As used herein, the term "alkyl" includes straight or branched chain alkyl groups. E.g. C₁-C₈Alkyl represents a straight or branched chain alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.

As used herein, the term "C₃-C₈Cycloalkyl "refers to cycloalkyl groups having 3 to 8 carbon atoms. It may be a single ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. It may also be in the form of a double ring, for example a bridged or spiro ring.

As used herein, the term "C₁-C₆Alkoxy "means a straight or branched chain alkoxy group having 1 to 6 carbon atoms; for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy and the like.

The term "10-20 membered aryl" as used herein refers to an aryl group having 10-20 carbon atoms, for example, naphthyl, anthryl, phenanthryl or the like.

As used herein, the term "5-12 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to a cyclic aromatic group having 5-10 atoms and wherein 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be a single ring or a condensed 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 to be "substituted or unsubstituted", the groups of the present invention may be substituted with a substituent selected from the group consisting of: halogen, nitrile group, nitro group, hydroxyl group, amino group, C₁-C₆Alkyl-amino, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Alkoxy, halo C₁-C₆Alkyl, halo C₂-C₆Alkenyl, halo C₂-C₆Alkynyl, halo C₁-C₆Alkoxy, allyl, benzyl, C₆-C₁₂Aryl radical, C₁-C₆alkoxy-C₁-C₆Alkyl radical, C₁-C₆Alkoxy-carbonyl, phenoxycarbonyl, C₂-C₆Alkynyl-carbonyl, C₂-C₆Alkenyl-carbonyl, C₃-C₆Cycloalkyl-carbonyl, C₁-C₆Alkyl-sulfonyl, and the like.

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. "halogenated" means substituted with an atom selected from F, Cl, Br, and I.

Unless otherwise specified, the structural formulae depicted herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, R, S configuration containing an asymmetric center, (Z), (E) isomers of double bonds, and the like. Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers or geometric isomers (or conformers) thereof are within the scope of the present invention.

As used herein, the term "tautomer" means that structural isomers having different energies may exceed the low energy barrier, thereby converting with each other. For example, proton tautomers (i.e., proton transmutations) include interconversion by proton shift, such as 1H-indazoles and 2H-indazoles. Valence tautomers include interconversion by recombination of some of the bonding electrons.

As used herein, the term "solvate" refers to a complex of a compound of the present invention coordinated to solvent molecules in a specific ratio.

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 salt" includes acid addition salts of the 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 in addition acid salts of inorganic bases.

Active ingredient

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

Wherein the content of the first and second substances,

x is S or O;

R₁and R₂Each 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-to 10-membered heteroaryl having 1-3 heteroatoms selected from N, S and O, substituted OR unsubstituted 5-to 10-membered heterocyclyl having 1-3 heteroatoms selected from N, S and O, -CN, -OR, -SR, -N (R)₂、-NO₂、-COR、-CO₂R、-CON(R)₂、-CONROR、-SOR、-SO₂R、-SO₂N(R)₂、-OCOR、-NRCOR、-NRSO₂R or-NRCON (R)₂(ii) a Or R₁And R₂Together with the N atom to which they are attached form a substituted or unsubstituted 5-6 membered heterocyclic group;

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 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, substituted or unsubstituted 5-10 membered heterocyclyl having 1-3 heteroatoms selected from N, S and O;

R₃is H, or has-NR₄R₅In the structure shown, wherein R₄And R₅Each independently selected from the group consisting of: hydrogen, substituted or unsubstituted C1-C6 alkyl; or R₁And R₂Together with the N atom to which they are attached form a substituted or unsubstituted 5-6 membered heterocyclic group;

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.

Preferably, the compounds of formula (I) according to the invention are selected from the compounds of table 1 below:

TABLE 1 Structure of the compounds

Preparation of Compounds of formula (I)

The compounds of formula (I) according to the invention can be prepared by the following steps:

starting from the compounds 1 and 2, the target compound is obtained by ring closing, coupling with methoxycarbonylphenylboronic acid, bromination, hydrolysis, condensation with corresponding amine and re-coupling. Specifically, the preparation method comprises the following steps:

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

2. compound 3 in Pd (PPh)₃)₄Or Pd (dppf) Cl₂Coupling with methoxycarbonyl phenylboronic acid under the catalysis to obtain a compound 4;

3. brominating the compound 4 under the action of N-bromosuccinimide to obtain a compound 5;

4. hydrolyzing the compound 5 under the action of lithium hydroxide to obtain a compound 6;

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

6. Compound 7 in Pd (PPh)₃)₄Or Pd (dppf) Cl₂Coupling with benzofuran-2-boric acid or benzothiophene-2-boric acid under catalysis to obtain a target compound (I);

wherein, X, R above₁And R₂As defined above.

Pharmaceutical compositions and methods of administration

Since the compound of the present invention has excellent inhibitory activity of MNK kinase, the compound of the present invention and various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the prevention and/or treatment (stabilization, alleviation or cure) of diseases associated with MNK kinase activity or expression amount (e.g., colorectal cancer, gastric cancer, thyroid cancer, lung cancer, leukemia, B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, burkitt's lymphoma, pancreatic cancer, melanoma, multiple myeloma, brain cancer, CNS cancer, renal 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, breast 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, tumor metastases, neurodegenerative disorders).

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

"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like

) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

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 the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells 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 delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. 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 compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.

In addition to 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 as, for example, 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 nonaqueous carriers, diluents, solvents or vehicles 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, such as 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 (e.g., 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 invention for the prevention and/or treatment of diseases associated with MNK kinase activity or expression.

In using the pharmaceutical compositions, a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment at a dosage which is pharmaceutically acceptable and effective to achieve the desired result, the total amount of compound of formula (I) administered per kilogram of 24 hours is about 0.01 to 800mg, preferably about 0.1 to 80 mg/kg. If necessary in the form of several single doses. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight. Unless defined or otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

Example 1

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

Step 1: preparation of 6-bromoimidazo [1,2-a ] pyridines

2-amino-6-bromopyridine (3g, 17.34mmol) was dissolved in a mixed solution of 30mL of ethanol and 18mL of water, bromoacetaldehyde diethyl acetal (5.13g, 26.01mmol) and 48% aqueous hydrobromic acid (3mL) were added, and the temperature was raised to 100 ℃ to react for 8 hours. After the completion of the reaction was monitored by TLC plate, the reaction mixture was cooled to room temperature and then concentrated under reduced pressure, 100mL of water was added, ethyl acetate was used for extraction, the organic phases were combined and washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was separated by column chromatography to give 2.98g of a white solid powder as an intermediate 6-bromoimidazo [1,2-a ] pyridine with a yield of 87.2%.

¹H NMR(300MHz,DMSO-d₆):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 (2.5g, 12.69mmol) was dissolved in a mixed solution of 45mL of 1, 4-dioxane and 4.5mL of water, 4-methoxycarbonylphenylboronic acid (2.74g, 15.23mmol) and potassium phosphate trihydrate (8.45g, 31.72mmol) were added, the air in the reaction apparatus was sufficiently replaced with nitrogen, stirring was carried out at room temperature for 15min, tetratriphenylphosphine palladium (0.73g, 0.63mmol) was added, the air in the reaction apparatus was sufficiently replaced with nitrogen, stirring was continued at room temperature for 15min, and then, the temperature was raised to 95 ℃ to react for 8 h. After completion of the reaction was monitored by TLC plate, the reaction mixture was cooled to room temperature, insoluble matter was removed with celite, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give 2.6g of a white solid as intermediate methyl 4- (imidazo [1,2-a ] pyridin-6-yl) benzoate in 81.2% yield.

¹H NMR(300MHz,DMSO-d₆):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).

And step 3: preparation of methyl 4- (3-bromoimidazo [1,2-a ] pyridinyl-6-yl) benzoate

Methyl 4- (imidazo [1,2-a ] pyridin-6-yl) benzoate (2.6g, 10.31mmol) was dissolved in a mixed solution of 48mL of acetonitrile and 16mL of dichloromethane, N-bromosuccinimide (2.38g, 13.40mmol) was added, and the reaction was stirred at room temperature for 8 hours. After the completion of the reaction was monitored by TLC plate, concentration was carried out under reduced pressure, 100mL of water was added, extraction was carried out with methylene chloride, the organic phases were combined and washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure by filtration, and the residue was separated by column chromatography to give 3.1g of a yellow solid powder as an intermediate methyl 4- (3-bromoimidazo [1,2-a ] pyridin-6-yl) benzoate in a yield of 90.8%.

¹H NMR(300MHz,CDCl₃):8.34(s,1H),8.24–8.11(m,2H),7.75(d,J＝9.4Hz,1H),7.68(dd,J＝5.4,2.8Hz,3H),7.54(dd,J＝9.4,1.8Hz,1H),3.96(s,3H).

And 4, step 4: preparation of 4- (3-bromoimidazo [1,2-a ] pyridinyl-6-yl) benzoic acid

Methyl 4- (3-bromoimidazo [1,2-a ] pyridin-6-yl) benzoate (1.89g, 5.71mmol) was dissolved in a mixed solution of 20mL of tetrahydrofuran and 10mL of methanol, and 10mL of an aqueous solution of LiOH (1.09g, 45.66mmol) was slowly added dropwise thereto, followed by stirring at room temperature for 4 hours. After the TLC plate monitoring reaction is completed, decompressing and concentrating, adding 20mL of water for dilution, slowly dropwise adding 1M hydrochloric acid, adjusting the pH to 2-3, separating out a large amount of white solid, filtering and collecting a filter cake, washing with water, and drying to obtain 1.75g of white solid which is intermediate 4- (3-bromoimidazo [1,2-a ] pyridyl-6-yl) benzoic acid, wherein the yield is 96.7%.

And 5: (4- (3-bromoimidazo [1,2-a ] pyridinyl-6-yl) phenyl) (morpholinyl) methanone

4- (3-Bromoimidazo [1,2-a ] pyridin-6-yl) benzoic acid (360mg, 1.14mmol) was dissolved in 3mL of N, N-dimethylformamide, morpholine (119mg, 1.36mmol), EDCI (261mg, 1.36mmol), HOBT (184mg, 1.36mmol), triethylamine (138mg, 1.36mmol) and DMAP (14mg, 0.11. mu. mol) were added in this order, and the mixture was heated to 40 ℃ for reaction for 8 hours. After completion of the reaction was monitored by TLC plate, 200mL of dichloromethane was added to dilute the reaction solution, washed with saturated brine (20mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was separated by column chromatography (dichloromethane/methanol ═ 100/1 to 100/3) to obtain 356mg of a yellow solid powder as an intermediate (4- (3-bromoimidazo [1,2-a ] pyridin-6-yl) phenyl) (morpholino) methanone in 81.2% yield.

¹H NMR(300MHz,CDCl₃)8.32(s,1H),7.72(dd,J＝21.1,8.4Hz,4H),7.55(dd,J＝13.8,9.4Hz,3H),3.67(d,J＝47.9Hz,8H).

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

(4- (3-bromoimidazo [1,2-a ] pyridin-6-yl) phenyl) (morpholino) methanone (110mg, 0.26mmol) was dissolved in a mixed solution of 2mL1, 4-dioxane and 0.2mL water, benzothiophene-2-boronic acid (61mg, 0.34mmol) and potassium phosphate trihydrate (138mg, 0.52mmol) were added, the air in the reaction apparatus was sufficiently replaced with nitrogen, the mixture was stirred at room temperature for 15min, tetratriphenylphosphine palladium (30mg, 26. mu. mol) was added, the air in the reaction apparatus was sufficiently replaced with nitrogen, the mixture was further stirred at room temperature for 15min, and then the temperature was raised to 95 ℃ to react for 8 h. After completion of the reaction was monitored by TLC plate, the reaction mixture was cooled to room temperature, insoluble matter was removed with celite, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give 55mg of (4- (3- (benzothien-2-yl) imidazo [1,2-a ] pyridin-6-yl) phenyl) (morpholino) methanone as a white solid in 43.9% yield.

¹H NMR(300MHz,CDCl₃)(ppm):8.75(s,1H),7.97–7.79(m,4H),7.66(d,J＝9.0Hz,2H),7.55(d,J＝7.3Hz,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) methanone can be prepared by an analogous method to that in example 1.

¹H NMR(300MHz,DMSO-d₆):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-methylpiperazin-1-yl) methanone can be prepared by a method similar to that in example 1.

¹H NMR(300MHz,DMSO-d₆)(ppm):9.01(s,1H),8.22(s,1H),7.89(t,J＝7.9Hz,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) methanone can be prepared by a similar method to that in example 1.

¹H NMR(300MHz,CDCl₃)(ppm):9.30(s,1H),9.09(s,1H),8.24(s,1H),8.07(d,J＝7.1Hz,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) methanone can be prepared by a method similar to that in example 1.

¹H NMR(300MHz,CDCl₃)(ppm):8.95(s,1H),8.12(s,1H),7.84(d,J＝8.8Hz,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) methanone can be prepared by a method similar to that in example 1.

¹H NMR(300MHz,CDCl₃)(ppm):8.94(s,1H),8.12(s,1H),7.85(d,J＝8.9Hz,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＝18.9,13.2,7.5Hz,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-acetylpiperazin-1-yl) methanone can be prepared by a similar method to that in example 1.

¹H NMR(300MHz,CDCl₃)(ppm):8.93(s,1H),8.10(s,1H),7.83(d,J＝9.3Hz,1H),7.70(dd,J＝6.4,1.9Hz,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-dimethylaminopiperidinyl) methanone may be prepared by a similar method to that in example 1.

¹H NMR(300MHz,CDCl₃)(ppm):8.92(s,1H),8.10(s,1H),7.81(d,J＝9.3Hz,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-methylpiperidinyl) methanone may be prepared by a similar method to that in example 1.

¹H NMR(300MHz,CDCl₃)(ppm):8.95(s,1H),8.12(s,1H),7.86(d,J＝9.3Hz,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-isopropylpiperazin-1-yl) methanone can be prepared by a similar method to that in example 1.

¹H NMR(300MHz,CDCl₃)(ppm):8.94(s,1H),8.12(s,1H),7.83(d,J＝9.3Hz,1H),7.68(t,J＝7.8Hz,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-piperidinyl) methanone (I-11)

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

¹H NMR(300MHz,CDCl₃)(ppm):8.94(s,1H),8.12(s,1H),7.83(d,J＝9.3Hz,1H),7.67(dd,J＝10.3,4.9Hz,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-morpholinylpiperidinyl) methanone (I-12)

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

¹H NMR(300MHz,CDCl₃)(ppm):8.94(s,1H),8.12(s,1H),7.82(d,J＝9.8Hz,1H),7.63(dt,J＝17.9,8.1Hz,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) methanone trifluoroacetate can be prepared by a similar method to that in example 1.

¹H NMR(300MHz,CDCl₃)(ppm):8.94(s,1H),8.12(s,1H),7.82(d,J＝9.8Hz,1H),7.63(dt,J＝17.9,8.1Hz,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-aminopiperidinyl) methanone trifluoroacetate can be prepared by a similar method to that in example 1.

¹H NMR(300MHz,CDCl₃)(ppm):9.03(s,1H),8.23(s,1H),7.91(dd,J＝14.0,8.8Hz,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) methanone trifluoroacetate (I-15)

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

¹H NMR(300MHz,CDCl₃)(ppm):8.94(s,1H),8.12(s,1H),7.82(d,J＝9.8Hz,1H),7.63(dt,J＝17.9,8.1Hz,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 ] pyridin-6-yl) phenyl) (3-aminopiperidinyl) methanone trifluoroacetate (I-16)

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

¹H NMR(300MHz,CDCl₃)(ppm):9.03(s,1H),8.23(s,1H),7.92(d,J＝8.2Hz,3H),7.81(d,J＝9.4Hz,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-Morpholinobenzofuran-2-yl) imidazo [1,2-a ] pyridin-6-yl) phenyl) (morpholinyl) methanone (I-17)

(7-isopropylbenzofuran-2-yl) boronic acid (4- (3- (7-morpholinobenzofuran-2-yl) imidazo [1,2-a ] pyridin-6-yl) phenyl) (morpholino) methanone can be prepared by a method similar to that in example 1.

¹H NMR(300MHz,CDCl₃)(ppm):8.98(s,1H),8.15(s,1H),7.86(d,J＝7.7Hz,1H),7.70(d,J＝6.5Hz,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-1 yl) 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 ] pyridin-6-yl) phenyl) (morpholinyl) methanone trifluoroacetate can be prepared by a similar method to that in example 1.

¹H NMR(300MHz,CDCl₃)(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 ] pyridin-6-yl) phenyl) (morpholinyl) methanone (I-19)

(4- (3- (7-piperidinylbenzofuran-2-yl) imidazo [1,2-a ] pyridin-6-yl) phenyl) (morpholinyl) methanone can be prepared by a similar method to that in example 1.

¹H NMR(300MHz,CDCl₃)(ppm):9.04(s,1H),8.11(s,1H),7.83(d,J＝9.3Hz,1H),7.72(d,J＝8.1Hz,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 ] pyridin-6-yl) phenyl) (morpholinyl) methanone (I-20)

(4- (3- (7- (dimethylamino) benzofuran-2-yl) imidazo [1,2-a ] pyridin-6-yl) phenyl) (morpholino) methanone can be prepared by a similar method to that in example 1.

¹H NMR(300MHz,DMSO-d₆)(ppm):9.07(s,1H),8.24(s,1H),7.95–7.75(m,5H),7.59(d,J＝8.2Hz,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 inhibitory activity of the compounds of the present invention on the enzymatic activities of MNK1 and MNK2 is as follows. The activity of the compounds was screened using the ADP-Glo kinase test kit (Promega, catalog No. V6930). All kinase reactions were performed in HEPES reaction buffer (15mM HEPES pH7.4, 20mM NaCl)₂，1mM EGTA，10mMMgCl₂0.1mg/mL BGG and 0.02% Tween-20). The final MNK1 reaction solution contained 10nM MNK1(Carna, catalog No.02-145), 100 μ M polypeptide substrate (TATKSGSTTKNR, Genscript), 300 μ M ATP and varying concentrations of compounds; the final MNK2 reaction solution contained 3nM MNK1(Carna, catalog No.02-146), 50. mu.M polypeptide substrate (TATKSGSTTKNR, Genscript), 10. mu.M ATP and varying concentrations of compounds. The final DMSO concentration in each reaction was 1%. The specific implementation method comprises the following steps:

Adding 4 μ L protein solution into each well of 384-well plate, adding 2 μ L compound solution, centrifuging at 1000rpm for 5min, and incubating at room temperature for 10min on shaking table;

adding 4 μ L of substrate mixture (polypeptide substrate and ATP) to each well, centrifuging at 1000rpm for 5min, and incubating on a shaker at room temperature for 60 min;

add 10. mu.L ADP-Glo reagent into each well, centrifuge for 5min at 1000rpm, incubate 40min at room temperature on shaker (avoid light);

adding 20 μ L Detection reagent into each well, centrifuging at 1000rpm for 5min, and incubating on a shaker at room temperature for 40min (in the dark);

the RLU (relative luminescence unit) value is read by using a multifunctional microplate reader cold luminescence module. The signal intensity was used to characterize the intensity of MNK enzyme activity and 8 concentrations of compound dilution were used to calculate the concentration of compound required to achieve 50% inhibition of enzyme activity (IC)₅₀). (the results are shown in Table 2)

TABLE 2 inhibitory Activity of Compounds on MNK1 and MNK2 enzyme Activity

As can be seen from the above results, the compounds of the present invention have excellent inhibitory activity against both MNK1 and MNK 2.

Biological Activity test example 2 liver microparticle stability test

Tolbutamide is selected as a reference compound. The specific method comprises the following steps:

configuration 0.1M K₃PO₄(pH7.4) buffer and 3 XNADPH stock (6mM, 5mg/mL) and pre-heated in a 37 ℃ water bath;

configuration of test and reference compounds spiking solution: add 5 μ L of compound stock (10nM) to 95 μ L acetonitrile;

1.5 μ M spiking solutions in microspheres (0.75 mg/mL): mu.L of spiking solution and 18.75. mu.L of liver microparticle solution (20 mg)/mL) was added to 479.75. mu. L K₃PO₄In a buffer solution;

adding 30 μ L of spiking solutions in the microsomes into a multi-well plate, and incubating at 37 deg.C for 5 min;

adding 15 mu L of NADPH stock solution into each hole to start reaction, and timing;

adding 150 μ L of IS-containing acetonitrile solution at 0min, 5min, 15min, 30min and 45min, respectively, and terminating the reaction;

oscillating for 10min, and centrifuging at 6000rpm for 15 min; 80 μ L of supernatant was collected from each well and subjected to LC/MS detection to calculate T_1/2。

(the results are shown in Table 3)

TABLE 3 Compound liver microsome stability

As can be seen from the above results, the compounds of the present invention have good metabolic stability in the liver microsome model.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

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 the content of the first and second substances,

x is S or O;

R₁and R₂Each 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-to 10-membered heteroaryl having 1-3 heteroatoms selected from N, S and O, substituted OR unsubstituted 5-to 10-membered heterocyclyl having 1-3 heteroatoms selected from N, S and O, -CN, -OR, -SR, -N (R)₂、-NO₂、-COR、-CO₂R、-CON(R)₂、-CONROR、-SOR、-SO₂R、-SO₂N(R)₂、-OCOR、-NRCOR、-NRSO₂R or-NRCON (R)₂(ii) a Or R₁And R₂Together with the N atom to which they are attached form a substituted or unsubstituted 5-6 membered heterocyclic group;

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 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, substituted or unsubstituted 5-10 membered heterocyclyl having 1-3 heteroatoms selected from N, S and O;

R₃is H, or has-NR₄R₅In the structure shown, wherein R₄And R₅Each independently selected from the group consisting of: hydrogen, substituted or unsubstituted C1-C6 alkyl; or R₁And R₂Together with the N atom to which they are attached form a substituted or unsubstituted 5-6 membered heterocyclic group;

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.

2. The compound of claim 1, or stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs and hydrates or solvates thereof, wherein X is O.

3. The compound of claim 1, or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt thereof, prodrug thereof, hydrate thereof, or solvate thereof, wherein R1 and R2 are each independently substituted or unsubstituted C1-C6 alkyl; or R1 and R2 taken together with the N atom to which they are attached form a substituted or unsubstituted 5-6 membered heterocyclic group.

4. The compound of claim 1, or stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs and hydrates or solvates thereof, wherein said compound has the structure shown in formula II below:

5. 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:

6. a pharmaceutical composition, comprising: (i) a therapeutically effective amount of a compound of formula (I), as described in any one of claims 1-5, 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.

7. The pharmaceutical composition of claim 6, 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 5, 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 5, characterized in that it comprises the steps of:

in a metal palladium catalyst (preferably Pd (PPh)₃)₄Or Pd (dppf) Cl₂) Catalyzed by a compound of formula 7 with

Carrying out coupling reaction to obtain the target compound (I).