WO2021249558A1 - Pteridone derivative as rsk inhibitor and application thereof - Google Patents

Abstract

The present invention relates to a pteridone derivative as an RSK protein kinase inhibitor and an application thereof. Specifically, the present invention relates to a compound represented by formula I, a pharmaceutical composition comprising a compound represented by formula I, and a use of the compound in the preparation of a drug for treating RSK-related diseases or for inhibiting RSK.

Description

Pteridone derivatives as RSK inhibitors and their applications Technical field

The present invention relates to the field of medicinal chemistry; specifically, the present invention relates to a novel pteridone derivative, its synthesis method and its application as an RSK inhibitor in the preparation of drugs for tumor-related diseases.

Background technique

Cardiovascular diseases, cancer, respiratory diseases and diabetes are the main components of non-communicable diseases (NCDs). At present, the main cause of human death is non-communicable diseases, and cardiovascular diseases among non-communicable diseases cause the largest number of human deaths, and cancer is the second leading cause of death related to human survival. There are three main traditional methods of treating cancer: surgery, radiotherapy and chemotherapy. In recent years, with the development of science and technology, targeted therapy and immunotherapy have gradually become effective methods for the treatment of cancer. Targeted therapies are mainly small molecule drugs or monoclonal antibody treatments, which control the growth and spread of tumor cells in the body by interfering with specific proteins to treat cancer. As researchers learn more about cancer-related proteins, the design of small-molecule drugs targeting these proteins for cancer treatment has also become more and more promising.

The Ras-MAPK signaling pathway is involved in the regulation of a variety of cancer types. RSK is the most downstream effector, and its abnormal expression and activity are related to the occurrence and development of a variety of diseases. The Ras-MAPK signaling pathway is activated by stimulation of growth factors, mitogen hormones and neurotransmitters. Activation of cell surface receptors leads to increased autophosphorylation of Tyr kinase and creates docking sites for growth factor receptor binding protein-2 (GRB2), which connect the receptor to serum-free guanine nucleotide exchange factor (SOS) . SOS catalyzes the binding of GTP to Ras. GTP binds to Ras and activates its effector Raf kinase. Raf phosphorylates and activates MAPK and extracellular signal-regulated kinase (MEK1/2). Ribosomal S6 kinase (RSK) is directly phosphorylated and activated by ERK1/2 and 3-phosphoinositide-dependent kinase-1 (PDK1). Activated RSK is still membrane-related, free in the cytoplasm, or transported to the nucleus, mediating cell differentiation, proliferation, survival, and transformation of proto-oncogenes. The Ras signal transduction pathway has the effect of promoting cell proliferation and protecting cells from apoptosis, and is of great significance to the occurrence and development of human tumors and the maintenance of biological behavior.

The p90 ribosomal S6 protein kinase (RSK) is a member of the serine/threonine kinase family widely expressed in tissues. As an important regulator downstream of the Ras signal transduction pathway, it plays an important role in the occurrence and development of tumors. effect. In mammals, there are four subtypes, RSK1, RSK2, RSK3 and RSK4. Each of the four subtypes has two kinase domains with different functions: N-terminal kinase domain (NTKD) and C-terminal kinase domain (CTKD), and a linker domain (linker domain). ). The C-terminal tail contains a specific extracellular signal regulated kinase (ERK) binding site, which binds to ERK to make RSK further under the control of ERK.

At present, there are no drugs that target RSK in clinical practice. The small-molecule inhibitors of RSK under development mainly include two types. One is RSK2 selective inhibitors including SL0101, CMK, etc., and the other is RSK pan-inhibitors including BID- 1870, FMK, LJH308, LJH685, etc., these small molecule inhibitors have all entered clinical research.

Therefore, the research and development of drugs targeting RSK has great clinical significance and application prospects.

Summary of the invention

The purpose of the present invention is to provide pteridone derivatives as RSK inhibitors.

Another object of the present invention is to provide a pharmaceutical composition containing the above-mentioned compound.

Another object of the present invention is to provide the use of the above compound in the preparation of drugs for treating RSK-related diseases or inhibiting RSK.

In the first aspect, the present invention provides a compound represented by formula I or a pharmaceutically acceptable salt thereof:

R ^{1 is} selected from the following group: hydrogen, optionally substituted C ₁ -C ₁₀ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₃ -C ₆ cycloalkenyl group, optionally substituted C ₃ -C ₈ lactone group, C ₁ -C ₁₀ amide group, optionally substituted C ₁ -C ₁₀ amide group, optionally substituted C _5- C ₁₀ aryl, optionally substituted C ₃ -C ₈ heterocyclic group, optionally substituted aromatic heterocyclic group;

R ^{2 is} selected from the following group: hydrogen, optionally substituted C ₁ -C ₁₀ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₅ -C ₁₀ aryl or heteroaryl, Optionally substituted C ₃ -C ₈ heterocyclic group;

R ^{3 is} selected from the following group: hydrogen, optionally substituted C ₁ -C ₁₀ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₁ -C ₁₀ alkyl formyl, optionally Substituted aryl formyl, optionally substituted C ₅ -C ₁₀ aryl, optionally substituted C ₃ -C ₈ heterocyclic group;

X is selected from N and CH.

In a specific embodiment, the compound is a compound represented by Formula II:

Where

R ^{1 is} selected from the following group: hydrogen, optionally substituted C ₁ -C ₁₀ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₃ -C ₆ cycloalkenyl group, optionally substituted C ₅ -C ₁₀ aryl group, optionally substituted C ₃ -C ₈ heterocyclic group, optionally substituted aromatic heterocyclic group;

R ^{4 is} selected from the following group: hydrogen, halogen (preferably F), hydroxyl, optionally substituted C ₁ -C ₃ alkoxy, optionally substituted C ₁ -C ₃ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₃ -C ₆ cycloalkenyl, COOH, C ₁ -C ₃ alkoxyformyl, optionally substituted carbamoyl , An optionally substituted C ₅ -C ₁₀ aryl group, an optionally substituted C ₃ -C ₈ heterocyclic group, an optionally substituted aromatic heterocyclic group, a cyano group; or two adjacent R ⁴ are connected to them The carbon atoms of together form a 5- or 6-membered carbocyclic or aromatic ring containing 1-3, preferably 1-2 heteroatoms independently selected from N, O or S;

R ^{3 is} selected from the group consisting of hydrogen, substituted C ₁ -C ₁₀ alkyl, C ₃ -C ₈ cycloalkyl, substituted C ₁ -C ₁₀ alkyl formyl, optionally substituted aryl formyl, any Optional substituted C ₅ -C ₁₀ aryl, optionally substituted C ₃ -C ₈ heterocyclic group;

m is selected from 1-5.

In a preferred embodiment, the R ⁴ is located in the meta or para position of the phenyl substituted; or two adjacent R ⁴ and the carbon atom to which they are connected together form a group containing 1-2 independently selected from A 5- or 6-membered carbocyclic or aromatic ring of heteroatoms of N, O, or S.

In a specific embodiment, in the compound,

R ^{1 is} selected from the following group: optionally substituted C ₁ -C ₁₀ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₅ -C ₁₀ aryl.

In a specific embodiment, the compound is a compound selected from the following group or a pharmaceutically acceptable salt thereof:

In a specific embodiment, in the compound,

Where

R ^{1 is} selected from the following group: optionally substituted C ₁ -C ₈ alkyl, optionally substituted C ₅ -C ₇ cycloalkyl, optionally substituted phenyl;

R ^{4 is} selected from the following group: halogen (preferably F), hydroxyl, optionally substituted C ₁ -C ₃ alkoxy, optionally substituted C ₁ -C ₃ alkyl, optionally substituted C ₅ -C ₇ hetero Cyclic, optionally substituted carbamoyl;

R ^{3 is} selected from the group consisting of hydrogen, substituted C ₁ -C ₆ alkyl, C ₅ -C ₇ cycloalkyl, optionally substituted C ₅ -C ₁₀ aryl, optionally substituted C ₅ -C ₇ hetero Ring base.

m is selected from 1-3.

In a preferred embodiment, the substitution is C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogen, hydroxyl, nitro, C ₃ -C ₅ cycloalkyl, C ₃ -C ₅ Heterocyclyl, C ₅ -C ₇ aryl, optionally substituted carbamoyl, optionally substituted alkanoylamino substitution.

In a specific embodiment, the compound is a compound selected from the following group or a pharmaceutically acceptable salt thereof:

Preferred

In a second aspect, the present invention provides a pharmaceutical composition comprising the compound described in the first aspect or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

In a preferred embodiment, the pharmaceutical composition is a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, and powders.

In the fourth aspect, the present invention provides the use of the compound described in the first aspect in the preparation of drugs for treating or preventing RSK protein kinase-mediated diseases, or drugs for inhibiting RSK protein kinase, or for inhibiting RSK1, RSK2, RSK3, RSK4 One of the uses in medicine.

In a specific embodiment, the RSK protein kinase-mediated disease is cancer.

In a specific embodiment, the cancer is selected from the group consisting of esophageal cancer, renal cell carcinoma, pancreatic cancer, colon cancer, breast cancer, lung cancer, prostate cancer, ovarian cancer, endometrial cancer, head and neck squamous cell Cancer, acute myeloid leukemia and solid tumors; or breast cancer where RSK1 and RSK4 are involved in regulation, ovarian cancer where RSK3 and RSK4 are involved in regulation, prostate cancer where RSK1 and RSK2 are involved in regulation, lung cancer where RSK1 and RSK2 and RSK4 are involved in regulation, RSK2 is involved Regulated head and neck squamous cell carcinoma and acute myeloid leukemia, RSK4 involved in the regulation of esophageal cancer, kidney cancer, endometrial cancer, colon cancer and other cancers and solid tumors.

In the fifth aspect, the present invention provides a method for treating or preventing RSK protein kinase-mediated diseases using the compounds described in the first aspect.

In a preferred embodiment, the RSK protein kinase is one of RSK1, RSK2, RSK3, and RSK4.

In a preferred embodiment, the RSK-mediated disease is cancer; preferably, the cancer is selected from the group consisting of breast cancer in which RSK1 and RSK4 are involved in regulation, ovarian cancer in which RSK3 and RSK4 are involved in regulation, and RSK1 and RSK2 in regulation. Regulated prostate cancer, RSK1, RSK2 and RSK4 involved in regulation of lung cancer, RSK2 involved in regulation of head and neck squamous cell carcinoma and acute myeloid leukemia, RSK4 involved in regulation of esophageal cancer, kidney cancer, endometrial cancer, colon cancer, etc. Cancer and solid tumors.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as the embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, I will not repeat them here.

detailed description

After extensive and in-depth research, the inventor found a batch of pteridone derivatives with brand-new structures. These derivatives have RSK kinase inhibitory activity, and the IC ₅₀ value of some compounds for RSK kinase inhibitory activity reaches the nM level. The present invention has been completed on this basis.

The inventors synthesized candidate compounds with RSK inhibitory activity. The structure of the obtained candidate compounds was optimized, and a series of 7(8H)-pteroidone compounds that had not been reported in the literature were designed and synthesized, and the structure was characterized. This series of compounds have been tested at the molecular level, and a batch of compounds that can inhibit the activity of RSK kinase have been obtained. _{The IC 50 of} compound 001 for RSK1-4 kinase inhibitory activity was 110.4, 143.2, 141.2 and 89nM, respectively.

Definition of Terms

Some groups involved in this article are defined as follows:

As used herein, "alkyl" refers to a saturated branched or straight chain or cyclic alkyl group with a carbon chain length of 1-10 carbon atoms. Preferred alkyl groups include 1-5, 1-2, 1-6. One, 1-4, 3-8 alkyl groups with varying carbon atoms. Examples of alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, heptyl and the like. The alkyl group may be substituted by one or more substituents, for example by halogen or haloalkyl. For example, the alkyl group may be an alkyl group substituted with 1-4 fluorine atoms, or the alkyl group may be an alkyl group substituted with a fluoroalkyl group.

Herein, "alkenyl" generally means a monovalent hydrocarbon group with at least one double bond, usually containing 2-8 carbon atoms, preferably containing 2-6 carbon atoms, and may be straight or branched. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.

In this context, "ester group" generally refers to a carboxylic acid derivative having at least one ester group, usually containing 3-8 carbon atoms, preferably containing 3-6 carbon atoms, and may be linear or branched. Examples of ester groups include, but are not limited to, methyl formate, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, and the like.

In this context, "hydroxyl" refers to a branched or straight chain alcohol with a carbon chain length of 1-10 carbon atoms, usually containing 1-10 carbon atoms, preferably containing 1-6 carbon atoms, and can be straight or branched. . Examples of ester hydroxyl groups include, but are not limited to, 1-hydroxyn-butyl, 1-hydroxyisobutyl, and the like.

In this context, "amido" refers to a group with the structural formula "-R'-NH-C(O)-R", wherein R'can be selected from hydrogen or alkyl, and R can be selected from alkyl and alkenyl , alkynyl, NR _c R _d is substituted alkyl, NR _c R _d is substituted alkenyl and NR _c R _d group substituted alkynyl, halogen substituted alkyl, alkenyl substituted with cyano group, Among them, R _c and R _{d can be} selected from alkyl and alkenyl groups.

As used herein, "aryl" refers to a monocyclic, bicyclic or tricyclic aromatic group containing 6 to 14 carbon atoms, including phenyl, naphthyl, phenanthryl, anthracenyl, indenyl, stilbene, tetralin Base, indanyl, etc. The aryl group may be optionally substituted with 1-5 (for example, 1, 2, 3, 4, or 5) substituents selected from the group consisting of halogen, C _1-4 aldehyde, C _1-6 alkyl, cyano Group, nitro, amino, amido, hydroxy, hydroxymethyl, halogen-substituted alkyl (e.g. trifluoromethyl), halogen-substituted alkoxy (e.g. trifluoromethoxy), carboxyl, C _1-4 Alkoxy, ethoxyformyl, N(CH ₃ ) and C _1-4 acyl, etc., heterocyclic group or heteroaryl group, etc. Similarly, the "heteroaryl group" herein refers to an aryl group containing one or more, preferably 1-3, more preferably 1-2 heteroatoms independently selected from N, O or S.

As used herein, "heterocyclic group" includes but is not limited to 5-membered or 6-membered heterocyclic groups containing 1-3 heteroatoms selected from O, S or N, including but not limited to furyl, thienyl, pyrrolyl , Pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, piperidinyl, morpholinyl, etc.

In this context, "aromatic heterocyclic group" means that it contains 5-14 ring atoms and has 6, 10, or 14 electrons shared in the ring system. Moreover, the ring atoms contained are carbon atoms and optionally 1-3 heteroatoms from oxygen, nitrogen, and sulfur. Useful aromatic heterocyclic groups include piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, including but not limited to In pyrimidinyl and so on. The aromatic heterocyclic group may be optionally substituted with 1-5 (for example, 1, 2, 3, 4, or 5) substituents selected from the group consisting of halogen, C _1-4 aldehyde, C _1-6 straight chain Or branched chain alkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, halogen-substituted alkyl (e.g. trifluoromethyl), halogen-substituted alkoxy (e.g. trifluoromethoxy), carboxyl, C _1-4 alkoxy, ethoxyformyl, N(CH ₃ ) and C _1-4 acyl.

As used herein, "alkoxy" refers to an oxy group substituted by an alkyl group. Preferred alkoxy groups are alkoxy groups having 1 to 6 carbon atoms in length, more preferably alkoxy groups having 1 to 3 carbon atoms in length. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, propoxy and the like. The alkoxy group may be substituted by one or more substituents, for example by halogen or haloalkyl. For example, the alkoxy group may be an alkyl group substituted with 1 to 4 fluorine atoms, or the alkyl group may be an alkyl group substituted with a fluoroalkyl group.

As used herein, "halogen" refers to fluorine, chlorine, bromine or iodine.

As used herein, "optionally substituted" means that the modified substituent may be optionally substituted with 1-5 (for example, 1, 2, 3, 4, or 5) substituents selected from the following: halogen, C _1-4 aldehyde groups, C _1-6 straight or branched chain alkyl groups, cyano groups, nitro groups, amino groups, hydroxyl groups, hydroxymethyl groups, halogen-substituted alkyl groups (e.g. trifluoromethyl), halogen-substituted alkoxy groups Group (e.g. trifluoromethoxy), carboxy, C _1-4 alkoxy, ethoxyformyl, N(CH ₃ ) and C _1-4 acyl.

In a preferred embodiment, the substitution refers to C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogen, hydroxyl, nitro, C ₃ -C ₅ cycloalkyl, C _3- C ₅ heterocyclyl, C ₅ -C ₇ aryl, optionally substituted carbamoyl, optionally substituted alkanoylamino substituted.

Unless otherwise specified, the structural formula described in the present invention is intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, containing asymmetry The R and S configuration of the center, the (Z) and (E) isomers of the double bond, etc. Therefore, a single stereochemical isomer of the compound of the present invention or a mixture of its enantiomers, diastereomers or geometric isomers (or conformational isomers) all belong to the scope of the present invention.

As used herein, the term "tautomers" means that structural isomers with different energies can exceed the low energy barrier to convert into each other. For example, proton tautomers (ie, proton transfer) include interconversion through proton transfer, such as 1H-indazole and 2H-indazole. Valence tautomers include interconversion through some bond-forming electron recombination.

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

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

Compound of the present invention

In order to provide candidate compounds with RSK inhibitory activity, the present invention provides compounds represented by general formula I:

^{R 1} , R ² , R ³ , and X in formula I are as described above.

In the compound represented by the general formula I, R ² is preferably an aryl group, more preferably a phenyl group. Therefore, in a preferred embodiment, the present invention provides a compound represented by the general formula II:

^{R 1} , R ³ , R ⁴ and m in Formula II are as described above.

Preferably, in the compound represented by the general formula II, R ⁴ is located at the meta or para position of the phenyl group it replaces.

In addition, in the compound represented by the general formula I, R ¹ is preferably an optionally substituted alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group.

Therefore, in a specific embodiment, the present invention provides a compound selected from the following group or a pharmaceutically acceptable salt thereof:

In a preferred embodiment, the compound of the present invention is the following compound:

More preferred

Based on the teachings of the present invention and the common knowledge in the field, those skilled in the art will understand that each group in the compound of the present invention can be further substituted to obtain derivatives capable of having the same or similar activity as the compounds specifically disclosed in the present invention. Things. Each group in the compound of the present invention can be substituted by various substituents conventional in the art, as long as the substitution does not violate the rules of chemical synthesis or the rules of valence.

The term "substituted" as used herein refers to the replacement of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent may be the correspondingly described substituent in the foregoing, or may be a specific substituent appearing in each embodiment or a conventional substituent in the art. Therefore, in the present invention, the substituents in the general formula can also each independently be the corresponding groups in the specific compounds in the examples; that is, the present invention includes not only the combination of the substituents in the above general formula, but also the general formula Combinations of some of the substituents shown in the examples and other specific substituents appearing in the examples. It is not difficult for those skilled in the art to prepare compounds having such a combination of substituents and to detect that the resulting compound is active based on the usual technical means in this field. In other words, based on the teachings of the present invention, those skilled in the art can synthesize various compounds falling within the protection scope of the present invention. These compounds are not limited to the specific compounds disclosed in the Examples section of the specification; the compounds of the present invention include both the Examples section. The disclosed specific compounds also include various compounds composed of specific substituents at a certain substitution position in these specific compounds and substituents at other substitution positions in the general formula. Due to space limitations, they will not be listed here.

As a compound with pharmacological activity, the compound of the present invention can obviously be used as a medicine. Therefore, in addition to the various properties that have been tested in the examples, the compound of the present invention can also possess various activities inherent in medicine. For example, in vivo activity, bioavailability, druggability, toxicity, differential toxicity, etc. Based on the teachings of the present invention and conventional technical means in the field, those skilled in the art know how to obtain various compounds within the scope of the present invention and detect various activities of various compounds within the scope of the present invention; in other words, based on the teachings of the present invention With conventional technical means in the field, those skilled in the art know how to repeat, verify, and implement the present invention.

On the basis of the compound of the present invention, the present invention provides a pharmaceutical composition containing a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient .

Examples of pharmaceutically acceptable salts of the compounds of the present invention include, but are not limited to, inorganic and organic acid salts, such as hydrochloride, hydrobromide, sulfate, citrate, lactate, tartrate, and maleate , Fumarate, mandelate and oxalate; and inorganic and alkalis such as sodium hydroxyl, tris(hydroxymethyl)aminomethane (TRIS, tromethamine) and N-methylglucamine Organic alkali salt.

The pharmaceutical composition of the present invention can be formulated into a formulation suitable for various administration routes, including but not limited to being formulated for parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, intrathecal, and cranial use. In the form of internal, nasal or external route of administration, it is used to treat tumors and other diseases. The dosage is the amount of medicine that is effective to improve or eliminate one or more conditions. For the treatment of a specific disease, an effective amount is an amount sufficient to ameliorate or in some way alleviate the symptoms associated with the disease. Such a dose can be administered as a single dose, or it can be administered according to an effective treatment regimen. The dosage may cure the disease, but the administration is usually to improve the symptoms of the disease. Generally, repeated administration is required to achieve the desired symptom improvement. The dosage of the medicine will be determined according to the patient's age, health and weight, the type of concurrent treatment, the frequency of treatment, and the desired treatment benefit.

The pharmaceutical preparation of the present invention can be administered to any mammal as long as they can obtain the therapeutic effect of the compound of the present invention. The most important of these mammals is humans.

The compound of the present invention or its pharmaceutical composition can be used to treat various diseases mediated by RSK protein kinase. Herein, diseases mediated by RSK protein kinase are various cancers. The cancers include, but are not limited to: breast cancer in which RSK1 and RSK4 are involved in regulation, ovarian cancer in which RSK3 and RSK4 are involved in regulation, prostate cancer in which RSK1 and RSK2 are involved in regulation, lung cancer in which RSK1 and RSK2 and RSK4 are involved in regulation, and head in which RSK2 is involved in regulation. Neck squamous cell carcinoma and acute myeloid leukemia, esophageal cancer, kidney cancer, endometrial cancer, colon cancer and other cancers and solid tumors that RSK4 participates in the regulation.

The pharmaceutical preparation of the present invention can be manufactured in a known manner. For example, it is manufactured by traditional mixing, granulating, ingoting, dissolving, or freeze-drying processes. When manufacturing oral preparations, solid excipients and active compounds can be combined to selectively grind the mixture. After adding an appropriate amount of additives if needed or necessary, the granule mixture is processed to obtain tablets or dragee cores.

Suitable auxiliary materials are especially fillers, for example sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations or calcium phosphates, such as tricalcium phosphate or dibasic calcium phosphate; and binders, such as starch pastes, including corn starch , Wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, or polyvinylpyrrolidone. If necessary, disintegrating agents can be added, such as the starch mentioned above, as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salt, such as sodium alginate. Auxiliary agents are especially flow regulators and lubricants, for example, silica, talc, stearates, such as magnesium calcium stearate, stearic acid or polyethylene glycol. If necessary, the tablet core can be provided with a suitable coating that can resist gastric juices. For this purpose, concentrated sugar solutions can be used. This solution may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, a lacquer solution and a suitable organic solvent or solvent mixture. In order to prepare a coating resistant to gastric juice, a suitable cellulose solution such as cellulose acetate phthalic acid or hydroxypropyl methylcellulose phthalic acid can be used. Dyestuffs or pigments can be added to the coating of tablets or lozenge cores. For example, for identification or to characterize combinations of active ingredient doses.

Based on the above-mentioned compound and pharmaceutical composition, the present invention further provides a method for treating RSK protein kinase-mediated diseases, which method comprises administering the compound or pharmaceutical composition of the present invention to a subject in need.

The administration method includes, but is not limited to, various administration methods known in the art, which can be determined according to the actual condition of the patient. These methods include, but are not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, intrathecal, intracranial, nasal or topical routes of administration.

The present invention also includes the use of the compounds of the present invention in the preparation of drugs for preventing or treating RSK-mediated diseases or inhibiting RSK4 activity.

The advantages of the present invention:

1. The compound provided by the present invention is a 7(8H)-pteridone compound with a completely new structure;

2. The compound provided by the present invention has excellent inhibitory activity on RSK protein kinase;

3. The compound provided by the present invention lays a foundation for the development of drugs capable of inhibiting targeted RSK, has great industrialization and commercialization prospects and market value, and has significant economic benefits.

The technical solution of the present invention will be further described below in conjunction with specific implementation cases, but the following implementation cases do not constitute a limitation to the present invention. All various application methods adopted in accordance with the principles and technical means of the present invention belong to the scope of the present invention. The experimental methods that do not indicate specific conditions in the following examples are usually in accordance with conventional conditions or in accordance with the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

Materials and Methods

The synthesis of the 7(8H)-pteroidone compound of the present invention is as follows:

Synthetic Route One

Reagents and conditions: (a) DIPEA, CH ₃ CN, room temperature; (b) DIPEA, THF, room temperature, (c) H ₂ , Pd/C, CH ₃ OH/DCM; (d) ethyl formate, AcOH, EtOH, reflux.

Synthetic Route Two

Reagents and conditions: (f) CH ₃ ONa, MeOH, room temperature; (g) Pd/C, H ₂ , EA, room temperature; (h) ethyl glyoxylate, AcOH, PhMe, reflux; (i) 48% HBr , AcOH, reflux; (j) SOCl ₂ , 0℃to 80℃; (k) Pd(OAc) ₂ , BINAP, sodium tert-butoxide, PhMe, reflux; (l) TEA, MeOH, reflux; (m) TFA , IPA, reflux.

Example 1

The specific synthesis method of the above steps a-d is as follows:

1. Synthesis of 2-chloro-N-isopentyl-5-nitropyrimidin-4-amine

Weigh 2,4-dichloro-5-nitropyrimidine (5.00g, 25.78mmol), DIPEA (4.53mL) in a 250mL round bottom flask, add acetonitrile to dissolve. 3-Methylbutylamine (2.25g, 25.78mmol) was added dropwise under ice bath, and TLC tracked to the complete conversion of the raw material immediately after the dropwise addition was completed. A solid precipitated out, filtered with suction, the filter cake was washed with acetonitrile, and the filtrate was rotary evaporated to remove the solvent. The product was separated by 300-400 mesh silica gel column chromatography (PE/EA=150/1, v/v) to obtain 4.12 g of 2-chloro-N-isopentyl-5-nitropyrimidin-4-amine as a yellow solid. The yield was 65.3%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ9.04 (s, 1H), 8.37 (s, 1H), 3.70-3.65 (m, 2H), 1.75-1.65 (m, 1H), 1.59 (q, J=7.2Hz,2H),0.96(d,J=6.8Hz,6H).LC-MS:m/z:245.1(M+H) ⁺ .

2. Synthesis of 2,6-difluoro-4-((4-(isoprene)-5-nitrosulfan-2-yl)amine)phenol

Weigh 2-chloro-N-isopentyl-5-nitropyrimidin-4-amine (2.30g, 9.40mmol), DIPEA (3.27mL) in a 50mL round bottom flask, add tetrahydrofuran to dissolve. Another 4-amino-2,6-difluorophenol (1.82 g, 9.40 mmol, 75%) was added to the above reaction solution, and stirring was continued at room temperature. TLC tracks until the raw material conversion is complete. After the reaction is complete, the solvent is removed by rotary evaporation. The product was separated by 300-400 mesh silica gel column chromatography (DCM/MeOH=200/1, v/v) to obtain 2,6-difluoro-4-((4-(isoprene)-5-nitro Sulfa-2-yl)amine)phenol yellow solid 0.81g, yield 24%.

¹ H NMR(400MHz,DMSO-d ₆ ): δ10.40(s,1H),9.91(s,1H),9.00(s,1H),7.50(d,J=9.6Hz,2H),3.57(q ,J=6.0Hz,2H),3.17(d,J=3.6Hz,1H),1.70-1.60(m,1H),1.57-1.48(m,2H),0.91(d,J=6.8Hz,6H) .LC-MS:m/z:354.1(M+H) ⁺ .

3. Synthesis of 4-((5-amino-4-(isopentylamino)pyrimidin-2-yl)amino)-2,6-difluorophenol

Weigh 2,6-difluoro-4-((4-(isoprene)-5-nitrosulfonamide-2-yl)amine)phenol (2e) (0.81g, 2.29mmol), add methanol and two Chloromethane (methanol/dichloromethane = 1/2, v/v), and palladium carbon (10%), hydrogen gas was introduced, and the mixture was stirred at room temperature. TLC tracks until the raw material conversion is complete. After the completion of the reaction, it was filtered through diatomaceous earth, and the filtrate was rotary evaporated to remove the solvent. The obtained product was directly used in the next reaction without purification.

4. Synthesis of 2-((4-hydroxyphenyl)amino)-8-isoamylpteridine-7(8H)-one

Put the 4-((5-amino-4-(isopentylamino)pyrimidin-2-yl)amino)-2,6-difluorophenol obtained in the previous step into a 50mL round bottom flask, add glacial acetic acid, anhydrous Ethanol (glacial acetic acid/absolute ethanol = 1/15, v/v), then add ethyl glyoxylate (50% toluene solution), and heat to reflux. TLC tracks until the raw material conversion is complete. After the reaction, it was cooled to room temperature, and then the solvent was removed by rotary evaporation. The product was separated by 300-400 mesh silica gel column chromatography (DCM/MeOH=100/1, v/v) to obtain 2-((3,5-difluoro-4-hydroxyphenyl)amino)-8-isopentyl Gypteridine-7(8H)-one is a yellow solid 0.10g, and the two-step yield is 12%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.29 (s, 1H), 9.81 (s, 1H), 8.81 (s, 1H), 7.95 (s, 1H), 7.47 (d, J = 6.4Hz) ,2H),4.16(t,J=7.6Hz,2H),1.75-1.67(m,1H),1.57-1.51(m,2H),0.95(d,J=6.4Hz,6H).HRMS(ESI) : Calculated value C ₁₇ H ₁₇ F ₂ N ₅ O ₂ [M+H] ⁺ 362.1429, experimental value 362.1427.

The following compounds (compounds 002-004 and 006) were all synthesized according to the above steps a-d:

3-(2-((3,5-Difluoro-4-hydroxyphenyl)amino)-7-oxopyridine-8(7H)-yl)-N-methylbenzamide (Compound 002)

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.28 (s, 1H), 9.63 (s, 1H), 8.93 (s, 1H), 8.54 (d, J = 4.0 Hz, 1H), 8.11 (s ,1H), 8.06(d,J=7.2Hz,1H),7.93(s,1H),7.70(t,J=7.6Hz,1H),7.60(d,J=7.2Hz,1H),7.00(d , J = 4.0Hz, 2H), 2.79 (d, J = 3.6Hz, 3H) .HRMS (ESI) calcd _{14 F 2 N 6 O 3 [} MH] C 20 H - 423.1017, Found 423.1018.

2-((3,5-Difluoro-4-hydroxyphenyl)amino)-8-isoamylpteridine-7(8H)-one (Compound 003)

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.08 (s, 1H), 9.24 (s, 1H), 8.78 (s, 1H), 7.90 (s, 1H), 7.56 (d, J = 7.6 Hz ,2H),6.73(d,J=9.2Hz,2H),4.16(t,J=5.2Hz,2H),1.71-1.63(m,1H),1.56-1.50(m,2H),0.96(d, J=6.8Hz,6H).HRMS(ESI): Calculated value C ₁₇ H ₂₀ N ₅ O ₂ [M+H] ⁺ 326.1617, experimental value 326.1618.

8-cyclopentyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pteridine-7(8H)-one (Compound 004)

¹ H NMR (400MHz, DMSO-d ₆ ): δ9.94(d,J=1.2Hz,1H),8.76(s,1H),7.83(s,1H),7.50(d,J=6.0Hz,2H ), 6.93(d,J=6.0Hz,2H),5.65-5.64(m,1H),3.10(t,J=3.2Hz,4H),2.46(t,J=3.2Hz,4H),2.26-2.25 (m, 2H), 2.22 (s, 3H), 1.80-1.78 (m, 2H), 1.60-1.58 (m, 2H), 1.25-1.23 (m, 2H).HRMS (ESI) calculated value C ₂₂ H _{28 ^{N 7 O [MH] - 406.2355}} , Found 406.2356.

8-cyclopentyl-2-((3,5-difluoro-4-methoxyphenyl)amino)pteridine-7(8H)-one (Compound 006)

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.36 (s, 1H), 8.87 (s, 1H), 7.93 (s, 1H), 7.60-7.45 (m, 2H), 5.65 (p, J = 8.7 Hz, 1H), 3.87 (s, 3H), 2.24 (dt, J = 16.0, 7.8 Hz, 2H), 1.95 (t, J = 14.7 Hz, 2H), 1.84 (dd, J = 12.5, 7.1 Hz, 2H ), 1.69-1.54 (m, 2H). ¹³ C NMR (101MHz, DMSO-d ₆ ) δ159.66,158.33,156.78,154.29,150.70,148.12,135.73,121.87,104.14(d,J=28.3),62.46,53.40 ,27.68,25.40.HRMS(ESI)(m/z): Calculated value C ₁₈ H ₁₇ F ₂ N ₅ O ₂ [M+H] ⁺ 374.1429, experimental value 374.1428.

8-cyclopentyl-2-((3,5-difluoro-4-hydroxyphenyl)amino)pteridine-7(8H)-one (Compound 007)

Weigh 8-cyclopentyl-2-((3,5-difluoro-4-methoxyphenyl)amino)pteridine-7(8H)-one) (0.5mg, 1.34mmol) in a 50mL single-mouth round bottom In the flask, add 1 mL of glacial acetic acid as a solvent, and raise the temperature to 28°C to dissolve it. Slowly add 0.5 mL of hydrobromic acid, and heat to reflux for reaction. TLC monitors the progress of the reaction. The reaction was completely quenched with ice water, extracted with ethyl acetate/water, the organic layer was spin-dried, and separated by silica gel column chromatography (DCM/MeOH=100/1, v/v) to obtain 8-cyclopentyl-2-((3 ,5-Difluoro-4-hydroxyphenyl)amino)pteridine-7(8H)-one yellow solid (3.26g, 0.91mmol), yield 67.9%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ 10.19 (s, 1H), 9.85 (s, 1H), 8.83 (s, 1H), 7.92 (d, J = 22.8 Hz, 1H), 7.54-7.32 (m,2H),5.64(s,1H),2.40-2.10(m,2H),1.92(s,2H),1.88-1.73(m,2H),1.71-1.50(m,2H).LC-MS :m/z:360.15[M+H] ⁺ . ¹³ C NMR(151MHz,DMSO)δ162.78,159.76,158.55,156.88,153.31,153.25,151.72,151.66,150.71,121.65,104.36(d,J=25.7), 40.51,36.26,31.24,27.68,25.34.HRMS(ESI)(m/z): Calculated value C ₁₇ H ₁₅ F ₂ N ₅ O ₂ [M+H] ⁺ 360.1275, experimental value 360.1274.

The specific synthesis method of compound 005 is as follows:

Reagents and conditions: (a)-(d) as mentioned above; (e) CH ₃ I, Cs ₂ CO ₃ , DMF, room temperature.

Synthesis of 2-((3,5-difluoro-4-methoxyphenyl)amino)-8-isoamylpteridine-7(8H)-one

Weigh out 2-((3,5-difluoro-4-hydroxyphenyl)amino)-8-isoamylpteridine-7(8H)-one (0.050g, 0.14mmol), Cs ₂ CO ₃ (0.0070 g, 0.21mmol) in a 10mL single-necked flask, add 3mL DMF to dissolve, add iodomethane (10μL, 0.17mmol, stirring for 1h at room temperature. TLC tracked the conversion of the raw materials, add ice water, extract with dichloromethane, collect the organic phase, Rotate to dry, the crude product is separated by silica gel column chromatography (DCM/CH ₃ OH=150:1, v/v) to obtain 2-((3,5-difluoro-4-methoxyphenyl)amino)-8 -Isoamylpteridine-7(8H)-one 40mg, the yield is 77.0%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ 10.46 (s, 1H), 8.86 (s, 1H), 8.00 (s, 1H), 7.55 (d, J = 10.8 Hz, 2H), 4.16 (q ,J=6.8Hz,2H),3.87(s,3H),1.72-1.65(m,1H),1.55-1.54(m,2H),0.95(d,J=6.4Hz,6H).HRMS(ESI) Calculated value C ₁₈ H ₂₀ F ₂ N ₅ O ₂ [M+H] ⁺ 376.1585, experimental value 376.1586.

Example 2

The specific synthesis method of the above steps l-m is as follows:

Synthesis of 2-methoxy-N-cyclopentyl-5-nitropyrimidin-4-amine

Accurately weigh 2-chloro-N-cyclopentyl-5-nitropyrimidin-4-amine (5.00 g, 20.7 mmol) into a 100 mL single-neck round bottom flask, and add 10 mL of anhydrous methanol to dissolve it. At room temperature, use a constant pressure dropping funnel to slowly drop sodium methoxide into the reaction solution. After the addition is complete, react at 50°C. Solids gradually formed in the reaction liquid. TLC monitoring showed that the reaction was complete in 2.5 hours. Add a small amount of water to the reaction solution to produce more solids, filter to obtain a light yellow filter residue, and spin dry to obtain 2-methoxy-N-cyclopentyl-5-nitro-4-aminopyrimidine (3.90g, 16.40mmol) , The yield is 79.2%.

¹ H NMR(400MHz,CDCl ₃ )δ9.09(s,1H),8.44(s,1H),4.62-4.50(m,1H),4.04(s,3H),2.15(dd,J=12.6,5.8 Hz, 2H), 1.86-1.75 (m, 2H), 1.71 (dd, J = 14.2, 7.3 Hz, 2H), 1.61 (dt, J = 18.9, 6.2 Hz, 2H). LC-MS: m/z: 239.10[M+H] ⁺ .

Synthesis of 2-methoxy-N-cyclopentyl-5-amino-4-aminopyrimidine

Accurately weigh 2-methoxy-N-cyclopentyl-5-nitro-4-aminopyrimidine (3.00 g, 12.60 mmol) into a 100 mL single-neck round bottom flask, and add 15 mL of ethyl acetate to dissolve it. Add 10% palladium on carbon. Pass hydrogen and react at 25°C. TLC monitoring showed that the reaction was complete in 14 hours. The palladium-carbon was filtered off through a Celite pad, and the filtrate was spin-dried to obtain a dark green oily 2-methoxy-N-cyclopentyl-5-amino-4-aminopyrimidine. Just vote for the next step. LC-MS: m/z: 243.20[M+H] ⁺

Synthesis of 8-cyclopentyl-2-methoxy-7(8H)-pteroidone

Accurately weigh 2-methoxy-N-cyclopentyl-5-amino-4-aminopyrimidine (3.00g, 14.4mmol) into a 100mL single-neck round bottom flask, dissolve in 10mL absolute ethanol, and add 1mL glacial acetic acid as dehydration Agent. Ethyl glyoxylate (50% toluene solution) (2.94 g, 28.80 mmol) was added dropwise to the reaction solution, and the reaction was refluxed at 110° C. using a water trap. The reaction liquid is wine yellow. TLC monitoring showed that the reaction was complete after 12 hours. Separated by silica gel column chromatography (PE/EA=5:1, v/v) to obtain 8-cyclopentyl-2-methoxy-(8H)-pteroidone (2.16g, 8.70mmol) as a yellow-white solid, The two-step yield was 50.4%.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.09(s,1H),8.29(s,1H),5.64-5.52(m,1H), 2.14(td,J=14.9,7.4Hz,2H), 2.07-1.95(m,2H),1.86(dt,J=11.7,8.6Hz,2H),1.70-1.57(m,2H).LC-MS:m/z:247.10[M+H] ⁺ .

Synthesis of 8-cyclopentyl-2-hydroxy-7(8H)-pteroidone

Accurately weigh 8-cyclopentyl-2-methoxy-7(8H)-pteroidone (5.00 g, 20.3 mmol) into a 250 mL single-neck round bottom flask. Add 15 mL of glacial acetic acid at room temperature and increase the temperature to 50° C. until the acetic acid completely dissolves 8-cyclopentyl-2-methoxy-7(8H)-pteroidone. 10 mL of hydrobromic acid was slowly added dropwise to the reaction solution. After the addition is complete, the temperature is raised to 120°C and refluxed. TLC monitoring showed that the reaction was complete after 1 hour. The reaction liquid was slowly added dropwise to ice water, and a solid precipitated out. The gray filter residue was obtained by filtration, namely 8-cyclopentyl-2-hydroxy-7(8H)-pteroidone (2.25 g, 9.70 mmol), and the yield was 48%. Just vote for the next step.

Synthesis of 8-cyclopentyl-2-chloro-7(8H)-pteroidone

Accurately weigh 8-cyclopentyl-2-hydroxy-7(8H)-pteroidone (2.25 g, 9.69 mmol) into a 250 mL single-neck round bottom flask. Under an ice bath, thionyl chloride (11.53 g, 96.90 mmol) was slowly added dropwise to the compound, and the reaction liquid was turbid and yellowish. Slowly add 6 drops of DMF to the reaction solution as a catalyst. After the addition is complete, the temperature is raised to 80°C for reaction. TLC monitoring, the reaction was complete in 30 minutes. The thionyl chloride was removed by rotary evaporation, extracted with ethyl acetate/water, and the EA layer was rotary dried. Separated by silica gel column chromatography (PE/EA=5/1, v/v) to obtain white crystals, 8-cyclopentyl-2-chloro-7(8H)-pteroidone (1.946g, 7.78mmol), The rate is 80.3%.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.09(s,1H),8.29(s,1H),5.64-5.52(m,1H), 2.14(td,J=14.9,7.4Hz,2H), 2.07-1.95(m,2H),1.86(dt,J=11.7,8.6Hz,2H),1.70-1.57(m,2H).LC-MS:m/z:251.10[M+H] ⁺ .

8-cyclopentyl-2-(2,6-difluoropyridin-4-yl)amino)pteridine-7(8H)-one (Compound 008)

Accurately weigh 8-cyclopentyl-2-chloro-7(8H)-pteroidone (100mg, 0.40mmol) into a 25mL two-necked round bottom flask, add 2,6-difluoro-4-aminopyridine (62.4 mg, 0.48mmol), palladium acetate (4.5mg, 0.02mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (12.5mg, 0.02mmol), sodium tert-butoxide (46mg, 0.48mmol) ), dissolved with 10 mL of toluene. Under the protection of nitrogen, the temperature was raised to 110°C for reaction. TLC monitoring. The reaction was complete in 12 hours. The palladium catalyst was filtered off through a pad of diatomaceous earth. Spin dry the filtrate. Separated by silica gel column chromatography (DCM/MeOH=150/1, v/v) to obtain a yellow solid, namely 8-cyclopentyl-2-(2,6-difluoropyridin-4-yl)amino)pteridine-7 (8H)-ketone (27mg, 0.08mmol), yield 20.0%, melting point: 272.2-272.4°C.

¹ H NMR(400MHz,DMSO-d ₆ )δ11.07(s,1H),9.01(s,1H),8.05(s,1H),7.43(s,2H),5.67(p,J=8.9Hz, 1H), 2.25 (dt, J = 15.4, 7.6 Hz, 2H), 1.99 (d, J = 7.8 Hz, 2H), 1.87 (dd, J = 12.6, 7.2 Hz, 2H), 1.69-1.58 (m, 2H ). ¹³ C NMR (151MHz, DMSO-d ₆ ) δ 163.04 (d, J = 19.6), 161.47, 161.44, 159.49, 157.76, 156.59, 154.89, 150.90, 150.16, 122.80, 95.11 (d, J = 45.3) ,53.62,27.73,25.48.HRMS(ESI) calculated value C ₁₆ H ₁₄ F ₂ N ₆ O[M+H] ⁺ 345.1275, experimental value 345.1274.

The following compounds (compound 008-010) were synthesized according to the method of step f-k above:

Synthesis of 8-cyclopentyl-2-(2-fluoropyridin-4-yl)amino)pteridine-7(8H)-one (Compound 009)

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.83 (s, 1H), 8.98 (s, 1H), 8.14-8.06 (m, 1H), 8.02 (s, 1H), 7.64 (d, J = 1.4 Hz, 1H), 7.54 (d, J = 5.7 Hz, 1H), 5.70 (p, J = 8.8 Hz, 1H), 2.36-2.16 (m, 2H), 1.98 (s, 3H), 1.92-1.77 (m , 2H), 1.76-1.56 (m, 3H). ¹³ C NMR (151MHz, DMSO-d ₆ ) δ165.37,163.85,159.54,158.13,156.66,151.44(d,J=12.1),150.85,149.62,148.07(d , J = 18.1), 122.52, 112.34, 97.56 (d, J = 43.8), 53.52, 27.75, 25.52. HRMS (ESI) calculated value C ₁₆ H ₁₅ FN ₆ O[M+H] ⁺ 327.1372, experimental value 327.1371.

Synthesis of 8-cyclopentyl-2-(pyridin-4-yl)amino)pteridine-7(8H)-one (compound 010)

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.56 (s, 1H), 8.94 (s, 1H), 8.43 (d, J = 5.5 Hz, 2H), 7.98 (s, 1H), 7.75 (d, J = 5.9 Hz, 2H), 5.72 (p, J = 8.8 Hz, 1H), 2.25 (dd, J = 11.6, 7.9 Hz, 2H), 1.98 (s, 2H), 1.91-1.79 (m, 2H), 1.73-1.59 (m, 2H). ¹³ _{C NMR (151MHz, DMSO-d 6} ) δ 159.56, 158.42, 156.72, 150.80, 150.48, 148.99, 146.78, 122.23, 113.75, 53.37, 27.80, 25.61. HRMS (ESI) calculated value C ₁₆ H ₁₆ N ₆ O[M+H] ⁺ 309.1464, experimental value 309.1465.

The specific synthesis method of compound 011 is as follows:

Synthesis of 1-chloro-3-fluoro-2-methoxy-5-nitrobenzene

The raw material 2-chloro-6-fluoroanisole (2 g, 0.12 mmol) was placed in a 100 mL single-neck round bottom flask, and 8 mL of concentrated sulfuric acid was taken to dissolve it. Take concentrated nitric acid (0.90mL, 0.02mmol) in a 10mL single-necked round bottom flask, and add concentrated sulfuric acid (0.74mL, 0.14mmol) dropwise to concentrated nitric acid under an ice bath. Under ice bath conditions, add 2-chloro-6-fluoroanisole dropwise to the mixed acid. After the addition is complete, react at 0°C. TLC monitors the progress of the reaction. The reaction was completed in 3 hours, and the reaction solution was slowly added dropwise to ice water, extracted with ethyl acetate, and dried with anhydrous sodium sulfate. After the organic phase is spin-dried, proceed directly to the next reaction.

Synthesis of 3-chloro-5-fluoro-4-methoxyaniline

Place 1-chloro-3-fluoro-2-methoxy-5-nitrobenzene (2.56g, 12.50mmol) in a 100mL single-neck round bottom flask, add ethanol and water (ethanol/water = 4/1, v /v) Dissolve. Add reducing iron powder (3.48 g, 62.14 mmol), NH ₄ Cl (2.66 g, 49.72 mmol), and react at 90°C under argon protection. The progress of the reaction was monitored by TLC, and the reaction was complete in 12 hours. The pH of the reaction solution was adjusted to 9 with sodium carbonate. Diatomite suction filtration, ethyl acetate/water extraction, silica gel column chromatography (PE/EA=100/5, v/v) separation. A white solid, 3-chloro-5-fluoro-4-methoxyaniline (1.3 g, 7.42 mmol) was obtained. The two-step yield is 55.4%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 6.47-6.43 (m, 1H), 6.39 (dd, J = 13.0, 2.6 Hz, 1H), 5.33 (s, 2H), 3.69 (s, 3H). LC-MS: m/z:176.05[M+H] ⁺ .

Synthesis of 4-amino-2-chloro-6-fluorophenol

Place 3-chloro-5-fluoro-4-methoxyaniline (0.30 g, 1.71 mmol) in a 25 mL single-neck round bottom flask, add 2 mL of acetic acid to dissolve, and slowly add 1 mL of hydrobromic acid dropwise. Reflux at 117°C, monitored by TLC. The reaction was complete in 6 hours. A gray solid precipitated in the reaction liquid. Filtration with suction and washing with isopropanol to obtain off-white filter residue, namely 4-amino-2-chloro-6-fluorophenol (compound 3c) (0.22 mg, 1.36 mmol), with a yield of 79.5%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.63 (s, 1H), 7.18 (d, J = 2.2 Hz, 1H), 7.16 (t, J = 3.5 Hz, 1H), 4.24 (s, 2H) .

Synthesis of 8-cyclopentyl-2-((3-chloro-5-fluoro-4-hydroxyphenyl)amino)pteridine-7(8H)-one (Compound 011)

Weigh 8-cyclopentyl-2-chloro-7(8H)-pteroidone (0.08g, 0.32mmol), 4-amino-2-chloro-6-fluorophenol (0.62mg, 3.85mmol) in 10mL Round-bottomed flask, add 3mL isopropanol to dissolve. Pass N ₂ and slowly add TFA at room temperature. After the addition was completed, the temperature was raised to 85° C. to reflux, and the reaction progress was monitored by TLC. The reaction was completed within 7 hours, and the reaction liquid changed from clear to yellow and turbid. After standing, it was filtered with suction, and the filter cake was washed with anhydrous isopropanol to obtain a yellow solid, namely 8-cyclopentyl-2-((3-chloro-5-fluoro-4-hydroxyphenyl)amino)pteridine-7( 8H)-ketone (compound G6) (0.05 g, 0.13 mmol), the yield is 40.6%.

¹ H NMR(400MHz,DMSO-d ₆ )δ10.20(s,1H),10.05(s,1H),8.84(s,1H),7.90(s,1H),7.67(d,J=2.0Hz, 1H),7.52(d,J=12.5Hz,1H),5.79–5.51(m,1H),2.33–2.17(m,2H),1.93(s,2H),1.87–1.77(m,2H),1.69 –1.54(m,2H). ¹³ C NMR(151MHz, DMSO-d ₆ )δ159.78,158.55,156.86,152.88,151.29,150.68,147.55,137.39(d,J=15.1),132.13,122.42(d,J= 6.0), 121.61, 116.98, 107.69 (d, J = 24.1), 53.38, 27.69, 25.43. HRMS (ESI) calculated value C ₁₆ H ₁₆ N ₆ O[M+H] ⁺ 376.0978, experimental value 376.0978.

The following compounds (compounds 012 and 013) were synthesized according to the method of step m above:

Synthesis of 8-cyclopentyl-2-((3-cyano-5-fluoro-4-hydroxyphenyl)amino)pteridine-7(8H)-one (Compound 012)

¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ 10.26 (s, 1H), 8.83 (s, 1H), 8.20 (s, 1H), 7.89 (s, 1H), 7.73 (s, 1H), 5.79-5.65(m,1H), 2.17(d,J=11.3Hz,2H), 1.89(d,J=11.4Hz,3H), 1.83(d,J=4.0Hz,1H),1.71-1.51(m , 2H). ¹³ _{C NMR (151MHz, DMSO-d 6} ) δ 171.62, 159.85, 158.70, 156.83, 151.41, 150.68, 149.81, 147.39, 145.68, 116.53, 114.21, 62.47, 27.87, 25.96, 25.73.

Synthesis of 8-cyclopentyl-2-((3-trifluoromethyl-5-fluoro-4-hydroxyphenyl)amino)pteridine-7(8H)-one (compound G013):

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.52 (s, 1H), 10.30 (s, 1H), 8.85 (s, 1H), 7.90 (s, 2H), 7.75 (s, 1H), 5.74 5.59 (m, 1H), 2.20 (dt, J = 15.1, 7.6 Hz, 2H), 1.92 (s, 2H), 1.82 (dd, J = 12.3, 7.4 Hz, 2H), 1.65-1.50 (m, 2H) . ¹³ C NMR(151MHz,DMSO)δ159.86,158.60,156.78,152.66,152.66,151.08,150.68,147.69,139.26,131.76,124.77,121.62,118.63,113.48,112.40(d,J=22.7),53.31,27.74, 25.57. HRMS (ESI) calculated value C ₁₆ H ₁₆ N ₆ O[M+H] ⁺ 410.1240, experimental value 410.1239.

The specific synthesis method of compound 014 is as follows:

Synthesis of 3-fluoro-2-hydroxy-5-nitrobenzaldehyde

Accurately weigh the raw material 3-fluoro-2-hydroxybenzaldehyde (1.00 g, 7.14 mmol) into a 25 mL single-neck round bottom flask. Under ice bath, add 3mL glacial acetic acid to dissolve. Slowly add concentrated nitric acid (2.7 g, 42.8 mmol) dropwise. The reaction liquid gradually changed from colorless to pale yellow. The progress of the reaction was monitored by TLC, and the reaction was complete in 4 hours. The reaction solution was slowly added dropwise to ice water, and a light yellow solid precipitated. A light yellow filter residue was obtained by filtration, namely 3-fluoro-2-hydroxy-5-nitrobenzaldehyde (800 mg, 4.32 mmol), with a yield of 60.5%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.30 (s, 1H), 8.37 (dd, J = 10.6, 2.8 Hz, 1H), 8.28 (dd, J = 2.6, 1.1 Hz, 1H). LC- MS:m/z:184.10[M+H] ^- .

Synthesis of 3-fluoro-5-nitrocatechol

Dissolve 3-fluoro-2-hydroxy-5-nitrobenzaldehyde (0.80 g, 4.32 mmol) in tetrahydrofuran. Add 0.05N sodium hydroxide (0.026g, 0.65mmol) dropwise at 0°C. Slowly add 30% hydrogen peroxide (2.55 g, 22.52 mmol), and react at room temperature. TLC monitors the progress of the reaction. The reaction was complete in 6 hours. Quench the hydrogen peroxide with sodium sulfite until the starch potassium iodide test paper does not turn blue. The tetrahydrofuran was distilled off, and it was directly cast to the next step.

Synthesis of 4-fluoro-6-nitrobenzo[d][1,3]dioxazole

3-Fluoro-5-nitrocatechol (0.40 g, 2.30 mmol) was placed in a 25 mL single-neck round bottom flask, and DMF (2.00 mL) was added to dissolve it. Add dibromomethane (0.60g, 3.45mmol), cesium carbonate (1.12g, 3.45mmol), and react at 110°C. The progress of the reaction was monitored by TLC, and the reaction was complete in 5 hours. The solvent was removed by rotary evaporation, extracted with ethyl acetate/water, and the ethyl acetate layer was rotary dried. Separated by silica gel column chromatography (PE/EA=400/1, v/v) to obtain white crystals, namely 4-fluoro-6-nitrobenzo[d][1,3]dioxazole (0.20mg, 1.80 mmol), the two-step yield is 42.0%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.94 (dd, J = 10.1, 2.0 Hz, 1H), 7.73 (d, J = 1.9 Hz, 1H), 6.36 (s, 2H).

Synthesis of 4-fluoro-6-aminobenzo[d][1,3]dioxazole

Place 4-fluoro-6-nitrobenzo[d][1,3]dioxazole (0.15g, 0.83mmol) in a 10mL double round bottom flask, add dichloromethane and methanol to dissolve it (two Methyl chloride/methanol = 2/1, v/v). Add palladium on carbon (10%) and stir at room temperature under hydrogen. TLC monitors the progress of the reaction. The reaction was complete in 12 hours. The palladium carbon was filtered off with a celite pad, and the solvent was removed by rotary evaporation to obtain a yellow solid, which was directly used in the next reaction.

Synthesis of 8-cyclopentyl-2-(((7-fluorobenzo[d][1,3]dioxol-5-yl)amino)pteridine-7(8H)-one (Compound 014)

Accurately weigh 4-fluoro-6-aminobenzo[d][1,3]dioxazole (0.18g, 1.19mmol), 4-amino-2-chloro-6-fluorophenol (0.30g, 1.19mmol) In a 10 mL double-necked round bottom flask, 3 mL of methanol was added to dissolve, and triethylamine (0.12 g, 1.19 mmol) was added dropwise. After the addition was completed, the temperature was raised to 80° C. to reflux, and the reaction progress was monitored by TLC. The reaction was complete in 10 hours, and a large amount of precipitation was formed in the reaction solution. After standing and suction filtration, a yellow solid, 8-cyclopentyl-2-(((7-fluorobenzo[d][1,3]dioxol-5-yl)amino)pteridine-7( 8H)-ketone.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.21 (s, 1H), 8.84 (s, 1H), 7.90 (s, 1H), 7.26 (d, J = 12.7 Hz, 1H), 7.20 (s, 1H), 6.09 (s, 2H), 5.72-5.57 (m, 1H), 2.24 (d, J = 8.1 Hz, 2H), 1.93 (s, 2H), 1.87-1.76 (m, 2H), 1.65-1.54 (m, 2H). ¹³ C NMR (151MHz, CDCl ₃ ) δ159.06,158.07,157.14,150.98,150.36,147.57,146.59,144.98,132.98,130.63,121.53,103.13(d,J=22.7),102.52,98.94, 54.15, 27.86, 25.29. HRMS (ESI) calculated value C ₁₈ H ₁₆ FN ₅ O ₃ [M+H] ⁺ 370.1316, experimental value 370.1316.

The following compounds (compounds 015-017) were synthesized according to the method of step 1 above:

Synthesis of 8-cyclopentyl-2-((benzo[d][1,3]dioxolan-5-yl)amino)pteridine-7(8H)-one (Compound 015)

¹ H NMR(400MHz,CDCl ₃ )δ8.74(s,1H),7.92(s,1H),7.68(s,1H),7.23(s,1H),6.83(dd,J=20.3,8.3Hz, 2H),6.00(s,2H),5.66(p,J=8.8Hz,1H),2.30(dt,J=16.3,8.0Hz,2H),2.04-1.80(m,4H),1.73-1.56(m , 2H). ¹³ _{C NMR (151MHz, CDCl 3} ) δ 159.31, 158.56, 157.03, 150.89, 147.99, 147.24, 144.60, 132.22, 121.54, 114.61, 108.20, 103.88, 101.47, 53.70, 29.70, 27.86, 25.31.HRMS (ESI ) Calculated value C ₁₈ H ₁₇ N ₅ O ₃ [M+H] ⁺ 352.1410, experimental value 352.1411.

Synthesis of 8-cyclopentyl-2-((1H-indazol-5-yl)amino)pteridine-7(8H)-one (Compound 016)

¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.03 (s, 1H), 10.16 (s, 1H), 8.81 (s, 1H), 8.10 (s, 1H), 8.01 (s, 1H), 7.85 ( s, 1H), 7.65 - 7.40 (m, 2H), 5.66 (s, 1H), 2.24 (s, 2H), 1.80 (s, 4H), 1.54 (s, 2H). ¹³ C NMR (151MHz, DMSO- d ₆ )δ159.86,159.33,157.02,150.72,146.57,137.47,133.68,132.63,123.29,122.57,121.36,111.60,110.51,53.05,27.73,25.38.HRMS(ESI) calculated value C ₁₈ H ₁₇ N ₇ O(M +H) ⁺ 348.1576,, the experimental value is 348.1575.

Synthesis of 2-(benzo[d]isoxazol-5-ylamino)-8-cyclopentylpteridine-7(8H)-one (compound 017)

¹ H NMR (600MHz, DMSO-d ₆ ) δ10.34 (s, 1H), 9.22 (d, J = 0.7Hz, 1H), 8.85 (s, 1H), 8.23 (s, 1H), 7.88 (d, J = 9.9Hz, 1H), 7.86 (dd, J = 9.0, 2.0 Hz, 1H), 7.77 (d, J = 8.9 Hz, 1H), 5.67 (s, 1H), 2.20 (dt, J = 31.1, 11.6 Hz, 2H), 1.91-1.75 (m, 4H), 1.57 (d, J = 4.5 Hz, 2H). ¹³ C NMR (151MHz, DMSO) δ 159.82, 159.06, 158.57, 156.90, 150.80, 147.70, 147.35, 136.12, 125.48,121.94,121.71,113.20,109.93,53.06,27.82,25.52.HRMS (ESI) calculated value C ₁₈ H ₁₇ N ₇ O[M+H] ⁺ 349.1413, experimental value 349.1412.

Synthesis of 2,6-Difluoro-4-nitrophenyl dimethyl carbamate (Compound 019)

2,6-Difluoro-4-nitrophenol (0.44g, 2.53mmol) was placed in a 25mL two-necked round bottom flask, and DCM ultra-dry solvent was added to dissolve it. N,N-dimethylformyl chloride (1.09g, 10.14mmol) was added dropwise under ice bath, and 1 drop of pyridine was added as a catalyst. 80°C reaction. TLC monitors the progress of the reaction. The reaction was complete in 10 hours. The solvent was removed by rotary evaporation, and silica gel column chromatography (PE/EA=50/1, v/v) was separated to obtain a white solid, namely 2,6-difluoro-4-nitrophenyl dimethyl carbamate ( 2v) (0.25 mg, 1.00 mmol), the yield is 39.5%.

¹ H NMR (400MHz, DMSO) δ8.31-8.23 (m, 2H), 3.11 (s, 3H), 2.96 (s, 3H).

Synthesis of 2,6-Difluoro-4-aminophenyl dimethyl carbamate

2,6-Difluoro-4-nitrophenyl dimethyl carbamate (0.24 g, 0.98 mmol) was placed in a 25 mL double-necked round bottom flask, and 3 mL ethyl acetate was added as a solvent. Pd/C (10%) was added, hydrogen gas was added, and the reaction was carried out at room temperature. TLC monitoring. The reaction was complete in 12 hours. The palladium carbon was filtered off through a Celite pad, and the solvent was removed by rotary evaporation to obtain a light yellow solid solid, which was directly cast to the next step.

4-((8-Cyclopentyl-7-oxo-7,8-dihydropterin-2-yl)amino)-2,6-difluorophenyl dimethyl carbamate (Compound 020) Synthesis

Weigh 8-cyclopentyl-2-chloro-7(8H)-pteroidone (0.11g, 0.45mmol), 4-amino-2-chloro-6-fluorophenol (0.10g, 0.45mmol) in 10mL Round-bottomed flask, add 3mL isopropanol to dissolve. Pass N ₂ and add trifluoroacetic acid dropwise at room temperature. After the dropwise addition was completed, the temperature was raised to 85°C for the reaction, and the reaction progress was monitored by TLC. The reaction was completed within 7 hours, and a large amount of precipitation was formed in the reaction solution. After standing, it was filtered with suction, and the filter cake was washed with anhydrous isopropanol to obtain a yellow solid, namely 4-((8-cyclopentyl-7-oxo-7,8-dihydropterin-2-yl)amino) -2,6-Difluorophenyl dimethyl carbamate (117 mg, 0.27 mmol), the two-step yield is 28.3%.

¹ H NMR (400MHz, DMSO) δ 10.50 (s, 1H), 8.92 (s, 1H), 7.96 (s, 1H), 7.63 (d, J = 10.6 Hz, 2H), 5.73-5.61 (m, 1H) ),3.08(s,3H),2.94(s,3H),2.26(s,2H),1.96(s,2H),1.85(s,2H),1.61(d,J=5.0Hz,2H). ¹³ C NMR (151MHz, CDCl ₃ ) δ159.25, 157.73, 156.91, 156.46, 156.42, 154.82, 154.78, 153.46, 150.84, 148.30, 136.64, 123.35, 121.82, 103.59, 103.48, 103.45, 103.30, 54.32, 37.15, 36.70, 27.80, 25.33. HRMS (ESI) calculated value C ₂₀ H ₂₀ F ₂ N ₆ O ₃ [M+H] ⁺ 431.1643, experimental value 431.164.

4-((8-Cyclopentyl-7-oxo-7,8-dihydropterin-2-yl)amino)-2,6-difluorophenyl 4-methylbenzoate (Compound 021 )Synthesis

The product 4-((8-cyclopentyl-7-oxo-7,8-dihydropterin-2-yl)amino)-2,6-difluorophenyl 4-methylbenzoate is yellow Solid (0.14g, 0.30mol), the two-step yield is 28.0%. Melting point: 174.8-175.0°C.

¹ H NMR (400MHz, DMSO) δ 10.58 (s, 1H), 8.94 (s, 1H), 8.06 (d, J = 8.2 Hz, 2H), 7.97 (s, 1H), 7.72 (d, J = 10.5 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 5.69 (dd, J = 17.5, 8.8 Hz, 1H), 2.45 (s, 3H), 2.32-2.20 (m, 2H), 1.96 (s , 2H), 1.91-1.80 (m, 2H), 1.67-1.55 (m, 2H). ¹³ C NMR (151MHz, DMSO) δ163.74,159.69,158.28,156.77,154.03,150.81,148.66,146.14,130.67,130.36, 124.63,122.15,103.59(d,J=25.7),40.52,27.71,25.41,21.82.HRMS (ESI) calculated value C ₂₅ H ₂₁ F ₂ N ₅ O ₃ [M+H] ⁺ 478.1691, experimental value 478.1692.

Example 3. Biological Activity Test

The in vitro inhibitory effect experiment of the compound provided by the present invention on RSK4 kinase activity is carried out as follows, RSK1-3 adopts the same method as RSK4 (Kashem, M.A. et al. J. Biomol. Screen. 12, 70-83):

In vitro enzyme activity analysis:

All enzyme reactions were performed at 30°C for 40 minutes. The 50 μL reaction mixture contained 40 mM Tris, pH 7.4 _{, 10 mM MgCl 2} , 0.1 mg/ml BSA, 1 mM DTT, 10 μM ATP, 0.2 ug/mL kinase, and 100 μM lipid substrate. The compound was diluted in 10% DMSO, and 5 μl of the dilution was added to 50 μl reactions so that the final concentration of DMSO in all reactions was 1%. Kinase-Glo reagent was added to the reaction system for detection. It measures the kinase activity by quantifying the amount of ATP remaining in the solution after the kinase reaction. _{The IC 50} value was calculated using nonlinear regression, and each experiment was repeated more than 2 times. The test results are shown in Table 1 below.

Table 1: Inhibitory activity of 7(8H)-pteridone compounds on RSK4

Table 2: Inhibitory activity of compound 001 on RSK1-4

discuss:

After extensive and in-depth research, the inventors designed and synthesized a series of 7(8H)-pteroidone compounds that have not been reported in the literature. The obtained compounds were tested on the molecular level activity, and a batch of RSK inhibitors was obtained. Compound. It laid the foundation for the treatment of cancer mediated by RSK.

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

Claims (10)

1. The compound represented by the general formula I or a pharmaceutically acceptable salt thereof:

   

   R ^{1 is} selected from the following group: hydrogen, optionally substituted C ₁ -C ₁₀ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₃ -C ₆ cycloalkenyl group, optionally substituted C ₃ -C ₈ lactone group, C ₁ -C ₁₀ amide group, optionally substituted C ₁ -C ₁₀ amide group, optionally substituted C _5- C ₁₀ aryl, optionally substituted C ₃ -C ₈ heterocyclic group, optionally substituted aromatic heterocyclic group;

   R ^{2 is} selected from the following group: hydrogen, optionally substituted C ₁ -C ₁₀ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₅ -C ₁₀ aryl or heteroaryl, Optionally substituted C ₃ -C ₈ heterocyclic group;

   R ^{3 is} selected from the following group: hydrogen, optionally substituted C ₁ -C ₁₀ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₁ -C ₁₀ alkyl formyl, optionally Substituted aryl formyl, optionally substituted C ₅ -C ₁₀ aryl, optionally substituted C ₃ -C ₈ heterocyclic group;

   X is selected from N and CH.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound represented by the general formula II:

   

   Where

   R ^{1 is} selected from the following group: hydrogen, optionally substituted C ₁ -C ₁₀ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₃ -C ₆ cycloalkenyl group, optionally substituted C ₅ -C ₁₀ aryl group, optionally substituted C ₃ -C ₈ heterocyclic group, optionally substituted aromatic heterocyclic group;

   R ^{4 is} selected from the following group: hydrogen, halogen (preferably F), hydroxyl, optionally substituted C ₁ -C ₃ alkoxy, optionally substituted C ₁ -C ₃ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₃ -C ₆ cycloalkenyl, COOH, C ₁ -C ₃ alkoxyformyl, optionally substituted carbamoyl , An optionally substituted C ₅ -C ₁₀ aryl group, an optionally substituted C ₃ -C ₈ heterocyclic group, an optionally substituted aromatic heterocyclic group, a cyano group; or two adjacent R ⁴ are connected to them The carbon atoms of together form a 5- or 6-membered carbocyclic or aromatic ring containing 1-3, preferably 1-2 heteroatoms independently selected from N, O or S;

   R ^{3 is} selected from the group consisting of hydrogen, substituted C ₁ -C ₁₀ alkyl, C ₃ -C ₈ cycloalkyl, substituted C ₁ -C ₁₀ alkyl formyl, optionally substituted aryl formyl, any Optional substituted C ₅ -C ₁₀ aryl, optionally substituted C ₃ -C ₈ heterocyclic group;

   m is selected from 1-5.
3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein:

   R ^{1 is} selected from the following group: optionally substituted C ₁ -C ₁₀ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₅ -C ₁₀ aryl.
4. A compound selected from the following group or a pharmaceutically acceptable salt thereof:

   

   
5. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein:

   Where

   R ^{1 is} selected from the following group: optionally substituted C ₁ -C ₈ alkyl, optionally substituted C ₅ -C ₇ cycloalkyl, optionally substituted phenyl;

   R ^{4 is} selected from the following group: halogen (preferably F), hydroxyl, optionally substituted C ₁ -C ₃ alkoxy, optionally substituted C ₁ -C ₃ alkyl, optionally substituted C ₅ -C ₇ hetero Cyclic group, optionally substituted carbamoyl group;

   R ^{3 is} selected from the group consisting of hydrogen, substituted C ₁ -C ₆ alkyl, C ₅ -C ₇ cycloalkyl, optionally substituted C ₅ -C ₁₀ aryl, optionally substituted C ₅ -C ₇ hetero Ring base.

   m is selected from 1-3.
6. A compound selected from the following group or a pharmaceutically acceptable salt thereof:

   

   Preferred

   

   
7. A pharmaceutical composition comprising the compound according to any one of claims 1-6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
8. Use of the compound according to any one of claims 1-6 in the preparation of drugs for treating or preventing RSK protein kinase-mediated diseases, or drugs for inhibiting RSK protein kinase, or inhibiting one of RSK1, RSK2, RSK3, RSK4 One of the uses in medicine.
9. The use according to claim 8, wherein the disease mediated by RSK protein kinase is cancer.
10. The use according to claim 8, wherein the cancer is selected from the group consisting of esophageal cancer, renal cell carcinoma, pancreatic cancer, colon cancer, breast cancer, lung cancer, prostate cancer, ovarian cancer, endometrial cancer, Head and neck squamous cell carcinoma, acute myeloid leukemia and solid tumors; or breast cancer where RSK1 and RSK4 are involved in regulation, ovarian cancer where RSK3 and RSK4 are involved in regulation, prostate cancer where RSK1 and RSK2 are involved in regulation, RSK1, RSK2 and RSK4 are involved Regulated lung cancer, RSK2 involved in the regulation of head and neck squamous cell carcinoma and acute myeloid leukemia, RSK4 involved in regulation of esophageal cancer, kidney cancer, endometrial cancer, colon cancer and other cancers and solid tumors.