CN111978325B - Imidazopyridazine MNK1/MNK2 kinase inhibitor, and preparation method and application thereof - Google Patents
Imidazopyridazine MNK1/MNK2 kinase inhibitor, and preparation method and application thereof Download PDFInfo
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- CN111978325B CN111978325B CN201910431113.XA CN201910431113A CN111978325B CN 111978325 B CN111978325 B CN 111978325B CN 201910431113 A CN201910431113 A CN 201910431113A CN 111978325 B CN111978325 B CN 111978325B
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- compound
- acid
- pharmaceutically acceptable
- pyridazin
- alkyl
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application provides an imidazopyridazine MNK1/MNK2 kinase inhibitor, and a preparation method and application thereof. Specifically, the application provides a compound shown as a formula (I): or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. The compounds of the present application may be used for the preparation of pharmaceutical compositions for the treatment of diseases or conditions associated with MNK (preferably including MNK1 and MNK 2) activity or expression levels.
Description
Technical Field
The application belongs to the technical field of medicines, and particularly provides a novel imidazopyridazine compound or a stereoisomer, a geometric isomer, a tautomer thereof, and pharmaceutically acceptable salts, hydrates, prodrugs or solvates thereof, and application thereof as MNK1 and MNK2 kinase inhibitors.
Background
Protein kinases (protein kinases) play an important role in a variety of cellular functions, and their aberrant activation is associated with a variety of diseases. Mitogen-activated protein kinases (mipgen-activated protein kinases, MAPKs) are capable of receiving a variety of cellular signals including growth factors, environmental stimuli and cytokines and are activated, thereby regulating proliferation, differentiation, survival, cell cycle control and programmed cell death of cells. Upon receipt of these stimulus signals, MAPKs are able to activate downstream target proteins, the MAPK-activated protein kinase family (MAPK-activated protein kinases family, MAPKAPK), which includes mitogen-activated protein kinase-acting kinases (MAPK-interacting kinases, MNKs). MNK kinases belong to serine/threonine protein kinases and are capable of specifically phosphorylating Ser209 of eukaryotic initiation factor eIF4E (eukaryotic initiation factor E) to indirectly regulate mRNA translation.
Eukaryotic initiation factor eIF4E is an important transcription factor and can enhance and regulate the transcription of cyclin and oncogenic protein mRNA, thereby causing the up-regulation of tumor-associated protein expression. eIF4E forms the eukaryotic initiation factor complex eIF4F with the framework proteins eIF4G and RNA helicase eIF 4A. Since eIF4E is responsible for binding of the complex to the 5' end cap structure of mRNA, it plays an irreplaceable regulatory role in RNA translation. In normal cells, the activity of eIF4E is restricted and transcription of these tumor-associated mRNA is inhibited; whereas in tumor cells or tissues, high expression or excessive activation of eIF4E may cause up-regulation of these mRNA transcript levels. Upregulation of eIF4E expression levels was detected in a variety of tumors and tumor cell lines, including colon cancer, breast cancer, bladder cancer, lung cancer, prostate cancer, gastric cancer, hodgkin's lymphoma, and neuroblastoma. Whereas clinically, upregulation or excessive 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 survival and growth of normal cells and animals. Therefore, the inhibition of MNKs by small molecule drugs is a promising approach to tumor treatment.
eIF4E acts as an important translational rate limiting factor and MNK/eIF4E signaling pathway can affect the synthesis of various chemokines, cytokines, and immune checkpoint proteins, thereby regulating immune responses. MNK kinase inhibitors can significantly reduce the content of PD-L1 on the surface of tumor cells without affecting the expression of PD-L1mRNA, and MNK inhibitors can reduce the expression of activated 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 content by 50% in mice, and that MNK inhibitors are more sensitive to tumor models with high PD-L1 expression. At the same time, MNK kinase inhibitors can significantly enhance cytotoxic CD8 + T cell function, inhibits differentiation of activated regulatory T cells, and promotes formation of central memory T cells. In the mouse colon cancer allograft model, MNK inhibitors almost completely inhibited tumor proliferation. And atThe same tumor was vaccinated again 29 days after drug withdrawal, and tumor proliferation in mice was still completely controlled without drug administration. This also reflects from the side that MNK inhibitors are able to activate a permanent anti-tumor immune response in model mice.
With the recent advances in understanding the structure and function of MNKs, a number of MNK inhibitors have been reported, with BAY1143269, tomivosertib and ETC-206 entering the clinic. In the mouse xenograft model, BAY1143269, tomivosertib and ETC-206 were all able to significantly inhibit tumor mass growth and extend the survival of mice. From published phase I clinical results, both Tomivoservib and ETC-206 were able to significantly reduce the level of phosphorylation of eIF4E in patients and exhibited primary symptomatic relief. The clinical results at present further prove that the MNK inhibitor can exert the anti-tumor effect by regulating the tumor microenvironment under in vivo conditions. With the continued depth of 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 foregoing, there is a great need in the art to develop new MNK kinase inhibitors.
Disclosure of Invention
The object of the present application is to develop a novel MNK kinase inhibitor.
In a first aspect of the present application, there is provided a compound of formula (I), or a stereoisomer, a geometric isomer, a tautomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, and a hydrate or solvate thereof:
wherein,
x is S or O;
R 1 and R is 2 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 5-1 having 1 to 3 heteroatoms selected from N, S and O0 membered heteroaryl, substituted OR unsubstituted 5-10 membered heterocyclyl having 1-3 heteroatoms selected from N, S and O, -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 The method comprises the steps of carrying out a first treatment on the surface of the Or R is 1 And R is 2 Together with the N atom to which it is attached, form a substituted or unsubstituted 5-6 membered heterocyclic group;
each R is independently selected from the group consisting of 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;
R 3 is H, or has-NR 4 R 5 The structure shown, wherein R 4 And R is 5 Each independently selected from the group consisting of: hydrogen, substituted or unsubstituted C1-C6 alkyl; or R is 1 And R is 2 Together with the N atom to which it is attached, form a substituted or unsubstituted 5-6 membered heterocyclic group;
wherein "substituted" refers to substitution 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 with 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 group consisting of: halogen, C1-C6 alkoxy.
In another preferred embodiment, X is O.
In another preferred embodiment, R is 1 And R is 2 Each independently is a substituted or unsubstituted C1-C6 alkyl group; or R is 1 And R is 2 With N atoms bound thereto to form a substitution orUnsubstituted 5-6 membered heterocyclyl.
In another preferred embodiment, the said-NR 1 R 2 Has the following structure:
wherein Y is selected from the group consisting of: no (i.e. chemical bond), O, S, NR 6 Or CHR (CHR) 6 ;
Said R is 6 Selected from the group consisting of: C1-C6 alkyl, C1-C6 alkylamino, -C (O) C1-C6 alkyl, amino, 5-to 10-membered heterocyclyl having 1-3 heteroatoms selected from N, S and O.
In another preferred embodiment, the compound has the structure shown in formula II:
in another preferred embodiment, R 3 Is a five-membered or six-membered heterocyclic ring containing N.
In another preferred embodiment, the compound is selected from I-1 to I-17.
In a second aspect of the present application, there is provided a pharmaceutical composition comprising: (i) A therapeutically effective amount of one or more 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 the first aspect of the application, 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: tablets, pills, granules, films, dripping pills, capsules, injections, soft capsules, emulsions, liposomes, freeze-dried powders, polymeric microspheres, or polyethylene glycol derivatives.
In another preferred embodiment, the pharmaceutical composition is used for treating a disease or condition associated with the activity or expression level of MNK.
In another preferred embodiment, the MNK is MNK1 or MNK2.
In a third aspect of the present application there is provided the 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 the first aspect of the present application, for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of a disease or condition associated with the activity or expression of MNK.
In another preferred embodiment, the disease is cancer.
In another preferred embodiment, the cancer is selected from the group consisting of: leukemias, lymphomas, hodgkins disease, myelomas, acute lymphoblastic leukemias, acute myelogenous leukemia, polar promyelocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic neutrophilic leukemia, polar undifferentiated leukemia, degenerative developmental large cell lymphoma, adult T-cell ALL, AML with trilinear myelodysplasia, mixed lineage leukemia, myelodysplastic syndrome, myelodysplasia, multiple myeloma and myelema sarcoma, 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 exudative lymphoma, burkitt lymphoma.
In a fourth aspect of the present application there is provided a process for the preparation of a compound of formula (I) according to the first aspect of the present application, the process comprising the steps of:
in the presence of a metallic palladium catalyst (preferably Pd (PPh) 3 ) 4 Or Pd (dppf) Cl 2 ) Catalyzed by compounds of the formula 7And (3) performing a coupling reaction to obtain the target compound (I).
It is understood that within the scope of the present application, the above-described technical features of the present application and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Detailed Description
The present inventors have conducted intensive studies for a long time and have found a novel compound having an excellent inhibitory effect on MNK kinase (preferably MNK1 and MNK 2). The compound can be used as an active ingredient for preparing a pharmaceutical composition for treating diseases related to MNK kinase activity or expression level. On this basis, the inventors completed the present application.
Definition of the definition
As used herein, the term "alkyl" includes straight or branched chain alkyl groups. For example C 1 -C 8 Alkyl means a straight or branched alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.
As used herein, the term "C 3 -C 8 Cycloalkyl "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. But also in the form of a bicyclic ring, for example a bridged or spiro ring.
As used herein, the term "C 1 -C 6 Alkoxy "refers to straight or branched chain alkoxy groups having 1 to 6 carbon atoms; for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy and the like.
As used herein, the term "10-20 membered aryl" 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 following groups N, S and O" refers to a cyclic aromatic group having 5-10 atoms and wherein 1-3 atoms are heteroatoms selected from the following groups N, S and O. It may be a single ring or may be in the form of a fused ring. 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 otherwise indicated as "substituted or unsubstituted", the radicals according to the application may be substituted by substituents selected from the group consisting of: halogen, nitrile, nitro, hydroxy, 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, halo C 1 -C 6 Alkyl, halogenated C 2 -C 6 Alkenyl, halo C 2 -C 6 Alkynyl, halo 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, 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 described herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example R, S configuration containing asymmetric centers, the (Z), (E) isomers of double bonds, etc. Thus, individual stereochemical isomers of the compounds of the application or mixtures of enantiomers, diastereomers or geometric isomers (or conformational isomers) thereof are all within the scope of the application.
As used herein, the term "tautomer" means that structural isomers having different energies may exceed the low energy barrier, thereby interconverting. For example, proton tautomers (i.e., proton transfer) include tautomers by proton transfer, such as 1H-indazole and 2H-indazole. Valence tautomers include tautomers that undergo interconversion by recombination of some of the bond-forming electrons.
As used herein, the term "solvate" refers to a compound of the application that coordinates to a solvent molecule to form a complex in a specific ratio.
As used herein, the term "hydrate" refers to a complex of a compound of the present application coordinated to water.
As used herein, the term "pharmaceutically acceptable salt" includes acid addition salts of compounds of formula (I) with: 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 acid salts of inorganic bases.
Active ingredient
The application synthesizes a series of compounds shown in the general structural formula (I) or stereoisomers, geometric isomers, tautomers and pharmaceutically acceptable salts, hydrates, prodrugs or solvates thereof:
wherein,
x is S or O;
R 1 and R is 2 Independently selected from hydrogen, halogen, optionally substituted aliphatic, optionally substituted aromatic, optionally substituted heteroaromatic, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, -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 ;
Each R is independently selected from hydrogen, optionally substituted aliphatic, optionally substituted aromatic, optionally substituted heteroaromatic, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl;
R 1 and R is 2 Optionally substituted 5-6 membered cycloalkane, aryl, heterocycloalkyl or heteroaryl groups may be formed together.
In another aspect, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of one or more of a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, and pharmaceutically acceptable salt thereof, a prodrug thereof, and a hydrate or solvate thereof, and optionally a pharmaceutically acceptable carrier or excipient.
In yet another aspect, the "pharmaceutically acceptable salts" of the present application include acid addition salts of the compounds of formula (I) with: 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 acid salts of inorganic bases.
Prodrugs of the derivatives of the application are derivatives of formula (I) which may themselves have relatively weak or even no activity, but are converted to the corresponding biologically active form under physiological conditions (e.g. by metabolism, solvolysis or otherwise) after administration.
The compound or the pharmaceutically acceptable salt, the hydrate and the prodrug thereof can be used singly as the sole antitumor drug or can be used in combination with the antitumor drugs on the market at present for treating and/or preventing tumors and the like.
In a further aspect, the present application relates to a process for the preparation of a compound of formula (I), by:
starting from compounds 1 and 2, the target compound is obtained through ring closure, coupling with methoxycarbonyl phenylboronic acid, bromination, hydrolysis, condensation with corresponding amine and re-coupling. Specifically, the preparation method comprises the following steps:
3-amino 6-chloropyrazine 1 and bromoacetaldehyde diethyl acetal 2 are taken as raw materials, and are cyclized in hydrobromic acid to obtain a compound 3;
compound 3 was purified on Pd (PPh 3 ) 4 Or Pd (dppf) Cl 2 Coupling with methoxycarbonyl phenylboronic acid under the catalysis to obtain a compound 4;
brominating the compound 4 under the action of N-bromosuccinimide to obtain a compound 5;
the compound 5 is hydrolyzed under the action of lithium hydroxide to obtain a compound 6;
the compound 6 is condensed with the corresponding amine under the action of condensing agent EDCI/HOBT or HATU to obtain the compound 7.
Compound 7 in Pd (PPh 3 ) 4 Or Pd (dppf) Cl 2 Coupling with benzofuran-2-boric acid or benzothiophene-2-boric acid under the catalysis to obtain a target compound (I);
therein, the above X, R 1 And R is 2 Is defined as before.
Preferably, the compound of formula (I) according to the application is selected from the compounds in table 1 below:
TABLE 1 Structure of Compounds
Preparation of Compounds of formula (I)
The compound of formula (I) according to the application can be prepared by the following steps:
starting from compounds 1 and 2, the target compound is obtained through ring closure, coupling with methoxycarbonyl phenylboronic acid, bromination, hydrolysis, condensation with corresponding amine and re-coupling. Specifically, the preparation method comprises the following steps:
1. 2-amino 5-bromopyridine 1 and bromoacetaldehyde diethyl acetal 2 are taken as raw materials, and the ring is closed in hydrobromic acid to obtain a compound 3;
2. compound 3 was purified on Pd (PPh 3 ) 4 Or Pd (dppf) Cl 2 Coupling 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. the compound 5 is hydrolyzed under the action of lithium hydroxide to obtain a compound 6;
5. the compound 6 is condensed with the corresponding amine under the action of condensing agent EDCI/HOBT or HATU to obtain the compound 7.
6. Compound 7 in Pd (PPh 3 ) 4 Or Pd (dppf) Cl 2 Coupling with benzofuran-2-boric acid or benzothiophene-2-boric acid under the catalysis to obtain a target compound (I);
therein, the above X, R 1 And R is 2 Is defined as before.
Pharmaceutical compositions and methods of administration
Because of the excellent inhibitory activity of MNK kinase, the compounds of the present application and various crystalline forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compounds of the present application as a major active ingredient are useful for preventing and/or treating (stabilizing, alleviating or curing) MNK kinase activity or expression level-related diseases (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, kidney cancer, prostate cancer, ovarian cancer, breast cancer, uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, inappropriate cellular inflammatory responses, leukemia and myelodysplastic syndrome, malignant lymphoma, head and neck tumors, lung tumors and lung metastases, tumors, non-small cell tumors and small cell lung tumors, gastrointestinal tumors, endocrine tumors and tumors, urinary bladder, bladder tumors, skin disorders, skin-related to other conditions, prostate cancer, tumor or tumor cell tumors, and lung tumors.
The pharmaceutical compositions of the present application comprise a safe and effective amount of a compound of the present application within 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 compositions contain 1-2000mg of the compound of the application per dose, more preferably 10-200mg of the compound of the application per dose. Preferably, the "one dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present application without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, and the like), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, and the like), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, and the like), emulsifiers (e.g.) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present application 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 admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, 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 with 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 released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used 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 these substances and the like.
In addition to these inert diluents, the compositions can also include 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-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 excipients include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the application may be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., other antineoplastic or anti-inflammatory agents).
When administered in combination, the pharmaceutical composition also includes a combination with one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (e.g., other antineoplastic or anti-inflammatory agents). 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 application for the prevention and/or treatment of diseases associated with MNK kinase activity or expression levels.
When a pharmaceutical composition is used, a safe and effective amount of a compound of the present application is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage to be administered, and the total amount of the compound of formula (I) administered per kilogram per 24 hours is about 0.01 to 800mg, preferably 0.1 to 80mg/kg, to achieve the desired result. If necessary, in the form of several single doses. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
The application will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present application and are not intended to limit the scope of the present application. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
Example 1
(4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (morpholinyl) methanone (I-1)
Step 1: preparation of 6-chloroimidazo [1,2-b ] pyridazine
To a mixed solution of 30mL of ethanol and 18mL of water was added bromoacetaldehyde diethyl acetal (5.11 g,25.94 mmol) and 48% aqueous hydrobromic acid (3 mL), and the mixture was heated to 100℃and reacted for 8 hours. After completion of the reaction, the reaction mixture was cooled to room temperature by TLC plate, concentrated under reduced pressure, 100mL of water was added, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure by filtration, and the residue was separated by column chromatography to give 2.05g of a white solid powder as intermediate 6-chloroimidazo [1,2-b ] pyridazine in a yield of 61.8%.
1 H NMR(300MHz,DMSO-d 6 )δ(ppm):8.35(s,1H),8.23(d,J=9.5Hz,1H),7.85(d,J=1.1Hz,1H),7.36(d,J=9.5Hz,1H).
Step 2: preparation of methyl 4- (imidazo [1,2-b ] pyridazinyl-6-yl) benzoate
6-Chloroimidazo [1,2-b ] pyridazine (2.0 g,13.01 mmol) was dissolved in a mixed solution of 45mL of 1, 4-dioxane and 4.5mL of water, 4-methoxycarbonylphenylboronic acid (2.81 g,15.63 mmol) and potassium phosphate trihydrate (6.94 g,26.05 mmol) were added, the air in the reaction apparatus was sufficiently replaced with nitrogen, stirring was carried out at room temperature for 15 minutes, and tetrakis triphenylphosphine palladium (0.72 g,0.65 mmol) was added, the air in the reaction apparatus was sufficiently replaced with nitrogen, stirring was continued at room temperature for 15 minutes and then the temperature was raised to 95℃for reaction for 8 hours. After completion of the reaction, the reaction mixture was cooled to room temperature by TLC plate, insoluble matter was filtered off with celite, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give 1.9g of a white solid as intermediate methyl 4- (imidazo [1,2-b ] pyridazin-6-yl) benzoate in a yield of 57.6%.
1 H NMR(300MHz,CDCl 3 )δ(ppm):8.42(dd,J=1.6,0.9Hz,1H),8.19–8.17(m,1H),8.16–8.14(m,1H),7.78(d,J=9.4Hz,1H),7.72(d,J=1.1Hz,1H),7.70(s,1H),7.69–7.67(m,1H),7.67–7.64(m,1H),3.98(s,3H).
Step 3: preparation of methyl 4- (3-bromoimidazo [1,2-b ] pyridazin-6-yl) benzoate
Methyl 4- (imidazo [1,2-b ] pyridazin-6-yl) benzoate (1.5 g,5.92 mmol) was dissolved in a mixed solution of 24mL of acetonitrile and 8mL of methylene chloride, N-bromosuccinimide (1.26 g,7.11 mmol) was added, and the reaction was stirred at room temperature for 8 hours. After completion of the reaction, the TLC plate was monitored, concentrated under reduced pressure, extracted with 100mL of water, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was separated by column chromatography to give 1.62g of a yellow solid powder as intermediate methyl 4- (3-bromoimidazo [1,2-b ] pyridazin-6-yl) benzoate in 82.3% yield.
Step 4: preparation of 4- (3-bromoimidazo [1,2-b ] pyridazin-6-yl) benzoic acid
Methyl 4- (3-bromoimidazo [1,2-b ] pyridazin-6-yl) benzoate (1.6 g,4.82 mmol) was dissolved in a mixed solution of 20mL of tetrahydrofuran and 10mL of methanol, and 10mL of an aqueous solution of LiOH (0.92 g,38.54 mmol) was slowly added dropwise thereto and stirred at room temperature for 4 hours. After the TLC plate monitors the completion of the reaction, the reaction is concentrated under reduced pressure, 20mL of water is added for dilution, 1M hydrochloric acid is slowly added dropwise to adjust the pH to 2-3, a large amount of white solid is precipitated, a filter cake is collected by filtration, water washing and drying are carried out to obtain 1.52g of white solid which is intermediate 4- (3-bromoimidazo [1,2-b ] pyridazinyl-6-yl) benzoic acid, and the yield is 100%.
Step 5: (4- (3-bromoimidazo [1,2-b ] pyridazin-6-yl) phenyl) (morpholinyl) methanone
4- (3-Bromoimidazo [1,2-b ] pyridazin-6-yl) benzoic acid (360 mg,1.14 mmol) was dissolved in 3mL of N, N-dimethylformamide, and 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. Mu. Mol) were added in this order and reacted at 40℃for 8 hours. After completion of the reaction, which was monitored by TLC plate, 200mL of methylene chloride was added to dilute, saturated brine (20 ml×3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure by filtration, and the residue was separated by column chromatography (methylene chloride/methanol=100/1 to 100/3) to give 356mg of yellow solid powder as intermediate (4- (3-bromoimidazo [1,2-b ] pyridazin-6-yl) phenyl) (morpholinyl) methanone in a yield of 65.9%.
Step 6: preparation of (4- (3- (benzothien-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (morpholinyl) methanone (I-1)
(4- (3-Bromoimidazo [1,2-b ] pyridazinyl-6-yl) phenyl) (morpholinyl) methanone (110 mg,0.28 mmol) was dissolved in a mixed solution of 2mL of 1, 4-dioxane and 0.2mL of water, benzofuran-2-boric acid (55 mg,0.34 mmol) and potassium phosphate trihydrate (138 mg,0.52 mmol) were added, the air in the reaction apparatus was sufficiently replaced with nitrogen, stirring was carried out at room temperature for 15min, and tetrakis triphenylphosphine palladium (30 mg, 26. Mu. Mol) 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℃for reaction for 8h. After completion of the reaction, the reaction mixture was cooled to room temperature by TLC plate, insoluble matter was filtered off with celite, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give 67mg of (4- (3- (benzothien-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (morpholinyl) methanone as a white solid in a yield of 55.6%.
1 H NMR(300MHz,CDCl 3 )δ(ppm):8.60(s,1H),7.86–7.76(m,2H),7.64(d,J=7.9Hz,2H),7.52(dd,J=12.7,6.7Hz,4H),7.35(d,J=3.5Hz,1H),7.31–7.20(m,2H),3.67(d,J=50.8Hz,8H);MS:found m/z[M+H] + 425.04,calcd.m/z[M]424.15.
Example 2
(4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (4-methylpiperazin-1-yl) methanone (I-2)
(4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (4-methylpiperazin-1-yl) methanone can be prepared by a similar method to that described in example 1.
1 H NMR(300MHz,CDCl 3 )δ(ppm):8.40(s,1H),8.16(dd,J=8.7,4.1Hz,3H),7.80–7.53(m,6H),7.35(dd,J=17.6,7.8Hz,2H),3.74(d,J=89.8Hz,4H),2.51(s,4H),2.39(s,3H);MS:found m/z[M+H] + 438.17,calcd.m/z[M]437.19.
Example 3
(4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (piperidinyl) methanone (I-3)
(4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (piperidinyl) methanone can be prepared in analogy to example 1.
1 H NMR(300MHz,CDCl 3 )δ(ppm):8.39(s,1H),8.14(d,J=5.3Hz,3H),7.76(s,1H),7.72(d,J=7.2Hz,1H),7.69–7.53(m,4H),7.34(dd,J=17.8,8.4Hz,2H),3.62(s,4H),1.71(d,J=19.0Hz,4H),1.59(s,2H);MS:found m/z[M-H] - 421.02,calcd.m/z[M]422.17.
Example 4
(4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (N, N-dimethylamino) methanone (I-4)
(4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (N, N-dimethylamino) methanone can be prepared by a similar method to that described in example 1.
1 H NMR(300MHz,CDCl 3 )δ(ppm):8.41(s,1H),8.23(d,J=9.4Hz,1H),8.16(d,J=8.4Hz,2H),7.79(d,J=0.8Hz,1H),7.76–7.63(m,4H),7.60(d,J=8.2Hz,1H),7.41–7.30(m,2H),3.21(s,3H),3.11(s,3H);MS:found m/z[M+H] + 383.08,calcd.m/z[M]382.14.
Example 5
(4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (pyrrolidinyl) methanone (I-5)
(4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (pyrrolidinyl) methanone can be prepared by a similar method to that described in example 1.
1 H NMR(300MHz,CDCl 3 )δ(ppm):8.38(s,1H),8.15(t,J=9.0Hz,3H),7.89–7.64(m,4H),7.64–7.46(m,2H),7.34(dd,J=17.9,7.3Hz,2H),3.74(t,J=6.5Hz,2H),3.55(t,J=6.2Hz,2H),2.08–1.92(m,4H);MS:found m/z[M+H] + 408.54,calcd.m/z[M]408.16.
Example 6
(4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (4-acetylpiperazin-1-yl) methanone (I-6)
(4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (4-acetylpiperazin-1-yl) methanone can be prepared by a similar method to that described in example 1.
1 H NMR(300MHz,CDCl 3 )δ(ppm):8.40(s,1H),8.18(dd,J=8.8,3.5Hz,3H),7.71(dd,J=15.7,8.3Hz,4H),7.60(t,J=8.5Hz,2H),7.42–7.28(m,2H),3.65(d,J=32.4Hz,8H),2.18(s,3H);MS:found m/z[M+H] + 465.97,calcd.m/z[M]465.18.
Example 7
(4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (4-dimethylaminopiperidinyl) methanone (I-7)
(4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (4-dimethylaminopiperidinyl) methanone can be prepared in analogy to example 1.
1 H NMR(300MHz,CDCl 3 )δ(ppm):8.41(s,1H),8.17(dd,J=8.8,7.1Hz,3H),7.67(ddd,J=20.4,17.7,8.9Hz,6H),7.35(dd,J=18.0,7.2Hz,2H),4.81(s,1H),3.93(s,1H),3.02(d,J=63.5Hz,2H),2.52(dd,J=15.5,9.5Hz,1H),2.38(s,6H),2.01(d,J=45.9Hz,4H);MS:found m/z[M+H] + 466.30,calcd.m/z[M]465.22.
Example 8
(4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (4-methylpiperidinyl) methanone (I-8)
(4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (4-methylpiperidinyl) methanone can be prepared by a similar method to that described in example 1.
1 H NMR(300MHz,CDCl 3 )δ(ppm):8.39(s,1H),8.16(dd,J=13.3,5.7Hz,3H),7.80–7.53(m,6H),7.35(dd,J=17.7,8.2Hz,2H),4.73(s,1H),3.82(s,1H),2.96(d,J=68.5Hz,2H),1.79(d,J=47.1Hz,5H),1.03(s,3H);MS:found m/z[M+H] + 437.13,calcd.m/z[M]436.19.
Example 9
(4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (4-isopropylpiperazin-1-yl) methanone (I-9)
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(4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (4-isopropylpiperazin-1-yl) methanone can be prepared in analogy to example 1.
1 H NMR(300MHz,CDCl 3 )δ(ppm):8.40(s,1H),8.23–8.10(m,3H),7.67(ddd,J=30.9,15.6,7.3Hz,6H),7.35(dd,J=17.5,8.2Hz,2H),3.88(s,2H),3.57(s,2H),2.82(dd,J=13.3,6.4Hz,1H),2.62(d,J=33.5Hz,4H),1.11(d,J=6.3Hz,6H);MS:found m/z[M+H] + 466.30,calcd.m/z[M]465.22.
Example 10
(4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (4-piperidyl piperidinyl) methanone (I-10)
(4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (4-piperidyl piperidinyl) methanone can be prepared in analogy to example 1.
1 H NMR(300MHz,CDCl 3 )δ(ppm):8.40(s,1H),8.15(t,J=8.0Hz,3H),7.66(ddd,J=19.0,16.6,8.0Hz,6H),7.35(dd,J=17.7,7.9Hz,2H),4.85(s,1H),3.93(s,1H),3.09(s,1H),2.84(s,1H),2.62(s,5H),1.69(s,4H),1.27(s,6H);MS:found m/z[M+H] + 506.26,calcd.m/z[M]505.25.
Example 11
(4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (4-morpholinylpiperidinyl) methanone (I-11)
(4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (4-morpholinylpiperidinyl) methanone can be prepared by a similar method to that described in example 1.
1 H NMR(300MHz,CDCl 3 )δ(ppm):8.40(s,1H),8.16(dd,J=8.8,7.0Hz,3H),7.66(ddd,J=19.4,16.2,7.9Hz,6H),7.42–7.29(m,2H),4.79(s,1H),3.92(s,1H),3.77(s,4H),3.04(d,J=55.0Hz,2H),2.59(d,J=15.4Hz,4H),2.51(d,J=6.2Hz,1H),1.90(s,2H),1.58(s,2H);MS:found m/z[M+H] + 508.34,calcd.m/z[M]507.23.
Example 12
(4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (piperazinyl) methanone trifluoroacetate (I-12)
(4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (piperazinyl) methanone trifluoroacetate can be prepared by a similar method to that described in example 1.
1 H NMR(300MHz,CDCl 3 )δ(ppm):8.40(s,1H),8.23–8.10(m,3H),7.67(ddd,J=30.9,15.6,7.3Hz,6H),7.35(dd,J=17.5,8.2Hz,2H),5.98(s,1H),3.49(d,J=9.8Hz,8H);MS:found m/z[M+H] + 424.14,calcd.m/z[M]423.17.
Example 13
(4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (4-aminopiperidinyl) methanone trifluoroacetate (I-13)
(4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (piperazinyl) methanone trifluoroacetate can be prepared by a similar method to that described in example 1.
1 H NMR(300MHz,CDCl 3 )δ(ppm):8.48–8.38(m,2H),8.33(d,J=8.3Hz,2H),8.04(d,J=9.6Hz,1H),7.87–7.79(m,2H),7.70(d,J=7.9Hz,1H),7.64(d,J=8.3Hz,2H),7.36(dt,J=15.6,7.2Hz,2H),4.40(s,1H),3.65(s,1H),3.16–2.92(m,3H),1.84(s,2H),1.35(s,2H);MS:found m/z[M+H] + 438.04,calcd.m/z[M]437.19.
Example 14
(R) - (4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (4-aminopiperidinyl) methanone trifluoroacetate (I-14)
(4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (piperazinyl) methanone trifluoroacetate can be prepared by a similar method to that described in example 1.
1 H NMR(300MHz,CDCl 3 )δ(ppm):8.44(dd,J=12.3,6.3Hz,2H),8.34(d,J=7.1Hz,2H),8.05(d,J=9.6Hz,1H),7.88–7.80(m,2H),7.70(t,J=7.4Hz,3H),7.37(dt,J=14.9,6.7Hz,2H),4.23(d,J=98.7Hz,2H),3.08–2.91(m,3H),1.99(s,1H),1.74(s,1H),1.51(s,2H);MS:found m/z[M+H] + 438.04,calcd.m/z[M]437.19.
Example 15
(S) - (4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (4-aminopiperidinyl) methanone trifluoroacetate (I-15)
(4- (3- (benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (piperazinyl) methanone trifluoroacetate can be prepared by a similar method to that described in example 1.
1 H NMR(300MHz,CDCl 3 )δ(ppm):8.41(dd,J=35.2,9.5Hz,4H),8.07(d,J=9.2Hz,1H),7.75(dd,J=31.3,22.7Hz,5H),7.52–7.25(m,2H),4.31(d,J=42.1Hz,2H),2.99(d,J=62.7Hz,3H),1.87(d,J=58.0Hz,2H),1.45(d,J=40.8Hz,2H);MS:found m/z[M+H] + 438.17,calcd.m/z[M]437.19.
Example 16
(4- (3- (7- (pyrrolidin-1-yl) benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (piperazinyl) methanone trifluoroacetate (I-16)
(4- (3- (7- (pyrrolidin-1-yl) benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (piperazinyl) methanone trifluoroacetate can be prepared by a similar method to that described in example 1.
1 H NMR(400MHz,CDCl 3 )δ(ppm):9.07(s,1H),8.14(s,1H),7.99(d,J=11.0Hz,1H),7.77(d,J=7.4Hz,2H),7.61(d,J=8.1Hz,2H),7.30(s,2H),7.10(s,1H),6.90(d,J=7.0Hz,1H),4.01(s,4H),3.35(d,J=31.2Hz,8H),1.66(s,4H);MS:found m/z[M+H] + 492.94,calcd.m/z[M]492.23.
Example 17
(4- (3- (7- (piperidin-1-yl) benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (piperazinyl) methanone trifluoroacetate (I-17)
(4- (3- (7- (piperidin-1-yl) benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl) phenyl) (piperazinyl) methanone trifluoroacetate can be prepared by a similar method as in example 1.
1 H NMR(400MHz,CDCl 3 )δ(ppm):9.05(s,1H),8.14(s,1H),7.98(d,J=11.1Hz,1H),7.75(d,J=7.3Hz,2H),7.59(d,J=8.1Hz,2H),7.29(s,2H),7.07(s,1H),6.89(d,J=7.0Hz,1H),3.99(s,4H),3.30(d,J=31.2Hz,8H),1.79(s,4H),1.64(s,2H);MS:found m/z[M+H] + 507.04,calcd.m/z[M]506.24.
Biological Activity test example 1 kinase level test
Compound activity was screened using ADP-Glo kinase assay kit (Promega, catalog No. v 6930). All kinase reactions were performed in HEPES reaction buffer (15 mM HEPES pH7.4, 20mM NaCl) 2 ,1mM EGTA,10mM MgCl 2 0.1mg/mL BGG and 0.02% Tween-20). The final MNK1 reaction solution contained 10nM MNK1 (Carna, catalog No. 02-145), 100. Mu.M polypeptide substrate (TATKSGSTTKNR, genscript), 300. Mu.M ATP and various 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 various concentrations of compounds. The final DMSO concentration in each reaction was 1%. The specific implementation method comprises the following steps:
adding 4 mu L of protein solution into each well of a 384-well plate, adding 2 mu L of compound solution, centrifuging at 1000rpm for 5min, and incubating for 10min at room temperature on a shaking table;
adding 4 μl of substrate mixture (polypeptide substrate and ATP) into each well, centrifuging at 1000rpm for 5min, and incubating at room temperature on a shaker for 60min;
10 mu L of ADP-Glo reagent is added into each hole, and the mixture is centrifuged at 1000rpm for 5min, and incubated on a shaking table at room temperature for 40min (in the absence of light);
add 20. Mu.L Detection reagent per well, centrifuge at 1000rpm for 5min, incubate on shaker at room temperature for 40min (protected from light);
the RLU (Relative luminescence unit) value was read using a multifunctional microplate reader cold light emitting module. The signal intensity was used to characterize the activity intensity of MNK enzyme and the compound concentration required to achieve 50% inhibition of enzyme activity was calculated using 8 concentrations of compound dilution (IC 50 ). (see experimental resultsTable 2)
TABLE 2 inhibitory Activity of Compounds on MNK1 and MNK2 enzyme Activity
From the above results, it can be seen that the compounds of the present application have excellent inhibitory activity against both MNK1 and MNK2.
Biological Activity test example 2 liver microparticle stability test
Tolbutamide was used as the reference compound. The specific method comprises the following steps:
configuration 0.1M K 3 PO 4 (pH 7.4) buffer and 3 XNADPH stock (6 mM,5 mg/mL) and pre-heated in a 37℃water bath;
configuration of test compound and reference compound spiking solution: mu.L of the compound stock solution (10 nM) was added to 95. Mu.L of acetonitrile;
1.5 mu M spiking solution in microsomes (0.75 mg/mL) configuration: 1.5 mu L spiking solution and 18.75 mu L of liver particulate solution (20 mg/mL) were added to 479.75 mu L K 3 PO 4 Buffer solution;
30 mu L spiking solution in microsomes was added to a multiwell plate and incubated at 37℃for 5min;
the reaction was started by adding 15. Mu.L of NADPH stock per well and timed;
adding 150 mu L of acetonitrile solution containing IS at 0min, 5min, 15min, 30min and 45min respectively, and stopping the reaction;
centrifuging at 6000rpm for 15min after shaking for 10min; 80 mu L of supernatant liquid is taken from each hole for LC/MS detection, and T is calculated 1/2 . (see Table 3 for experimental results)
TABLE 3 Compound liver microsome stability
From the above results, it can be seen that the compounds of the present application have good metabolic stability in liver microsomal models.
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.
Claims (10)
1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:
wherein,
R 1 and R is 2 Each independently selected from the group consisting of: unsubstituted C1-C6 alkyl, or said-NR 1 R 2 Has the following structure:
wherein Y is selected from the group consisting of: a bond, O, N, or CH;
said R is 6 Selected from the group consisting of: H. C1-C6 alkyl, C1-C6 alkylamino, -C (O) C1-C6 alkyl, amino.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 And R is 2 Each independently is unsubstituted C1 alkyl.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said-NR 1 R 2 Has the following structure:
wherein Y is selected from the group consisting of: a bond, O, N, or CH;
said R is 6 Selected from the group consisting of: C1-C6 alkyl, C1-C6 alkylamino, -C (O) C1-C6 alkyl.
4. A compound, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
5. a pharmaceutical composition, the pharmaceutical composition comprising: (i) A therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-4, and (ii) a pharmaceutically acceptable carrier or excipient.
6. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is used for treating a disease or disorder associated with the activity or expression of MNK.
7. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 4, for the preparation of a pharmaceutical composition for the treatment or prophylaxis of a disease or condition associated with the activity or expression of MNK.
8. The use according to claim 7, wherein the disease is cancer.
9. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 4, comprising the steps of:
catalyzed by a metallic palladium catalyst with a compound of formula 7And (3) performing a coupling reaction to obtain the target compound (I).
10. The method of claim 9, wherein the metallic palladium catalyst is selected from the group consisting of: pd (PPh) 3 ) 4 、Pd(dppf)Cl 2 。
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