TW202321244A - Wnt pathway inhibitor compound - Google Patents

Abstract

The present invention relates to a Wnt pathway inhibitor compound represented by formula (I) and a pharmaceutical composition comprising the compound, and use of the compound of formula (I) in preventing and/or treating cancers, tumors, inflammatory diseases, and autoimmune diseases or immune-mediated diseases.

Description

A kind of Wnt pathway inhibitor compound

The invention relates to a heterocyclic compound, in particular to a highly active Wnt pathway inhibitor and its application.

This application claims the priority of the Chinese patent application 202110847130.9 with the title of "a Wnt pathway inhibitor compound" submitted to the China National Intellectual Property Office on July 26, 2021, the content of which is incorporated herein by reference in its entirety.

Wnt/β-catenin signal transduction pathway is a pathway conserved in biological evolution. In normal somatic cells, β-catenin is only a cytoskeleton protein that forms a complex with E-cadherin at the cell membrane to maintain the adhesion of the same type of cells and prevent cell movement. When the Wnt signaling pathway is not activated, the β-catenin in the cytoplasm is phosphorylated and forms a β-catenin degradation complex with APC (Adenomatous polyposis coli), Axin and GSK3β, thereby initiating the degradation of the ubiquitin system through the proteasome pathway β-catenin, to maintain a low level of β-catenin in the cytoplasm. When cells are stimulated by Wnt signal, Wnt protein binds to the specific receptor Frizzled protein on the cell membrane, and the activated Frizzled receptor recruits intracellular Dishevelled protein, inhibits the degradation activity of the β-catenin degradation complex formed by GSK3β and other proteins, and stabilizes Free β-catenin protein in the cytoplasm. The stably accumulated β-catenin in the cytoplasm enters the nucleus and binds to the LEF/TCF transcription factor family to initiate the transcription of downstream target genes (such as c-myc, c-jun, Cyclin D1, etc.). Excessive activation of the Wnt/β-catenin signaling pathway is closely related to the occurrence of various cancers (including colon cancer, gastric cancer, breast cancer, etc.). For example, abnormal activation of Wnt canonical signaling pathway and nuclear accumulation of β-catenin protein widely exist in colorectal cancer. Proliferation of cancers such as colon cancer can be suppressed by inhibiting the activity of the Wnt signaling pathway. APC mutations exist in more than 85% of colorectal cancers, and the mutated APC blocks the phosphorylation and degradation of β-catenin and induces the occurrence of colorectal cancer. In addition, mutations of Axin and β-catenin itself can also cause the intracellular accumulation of β-catenin and activate the Wnt/β-catenin pathway.

Although it is known that inhibiting the Wnt signaling pathway can effectively prevent and/or treat cancer, tumors, inflammatory diseases, autoimmune diseases and immune-mediated diseases, there is still a lack of satisfactory and effective Wnt pathway inhibitors in the current state of the art compound. Therefore, it is a need in the prior art to study effective Wnt pathway inhibitor compounds.

The present invention provides a compound having a structure of formula (I) for inhibiting Wnt pathway activity or pharmaceutically acceptable salts, isotopic derivatives, and stereoisomers thereof:

其中：

in:

--- Indicates the presence or absence of a single bond;

R1 represents C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 3-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, and said R1 can be Optionally 0, 1, 2, 3 selected from: hydrogen, halogen, OR ^a , nitro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) Haloalkyl, (C ₃ -C ₆ ) cycloalkyl, halo (C ₃ -C ₆ ) cycloalkyl, 3-6 membered heterocycloalkyl, halogenated 3-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, cyano, S R ^a , halo(C ₁ -C ₆ )alkoxy, halo(C ₃ -C ₆ )cycloalkoxy, halo (C ₁ -C ₆ )alkylthio, (C ₃ -C ₆ )cycloalkyloxy, (C ₃ -C ₆ )cycloalkylthio, halo(C ₃ -C ₆ )cycloalkylthio The substituent of the group is substituted;

X represents a covalent bond or -(CR ^a R ^a' ) _m -, -(CR ^a R ^a' ) _m -O-(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m -N (R ^b )-(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m -S-(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m C(O) (CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m S(O) ₂ (CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m C(O)N(R ^b )(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m S(O) ₂ N(R ^b )(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m N(R ^b )C(O)(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m N(R ^b )S(O) ₂ (CR ^a R ^a' ) _n -, -( CR ^a R ^a' ) _m OC(O)N(R ^b )(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m N(R ^b )C(O)O(CR ^a R ^{a '} ) _n -, -(CR ^a R ^a' ) _m N(R ^b )C(O)N(R ^b' )(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m N( R ^b )S(O) ₂ N(R ^b' )(CR ^a R ^a' ) _n -;

Cy represents C ₃ -C ₅ cycloalkyl or 4-5 membered cycloheteroalkyl, and it can be arbitrarily replaced by 0, 1 or 2 selected from hydrogen, halogen, -OR ^a , (C ₁ -C ₆ ) alkane Substituents of radical, (C ₁ -C ₆ ) haloalkyl, (C ₃ -C ₆ ) cycloalkyl, cyano and hydroxy (C ₁ -C ₆ ) alkyl;

R ² represents hydrogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) haloalkyl, (C ₃ -C ₆ ) cycloalkyl or hydroxy (C ₁ -C ₆ ) alkyl;

R ³ and R ^3' each independently represent hydrogen, halogen, OR ^a , (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, hydroxy C ₁ -C ₆ alkyl or (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl;

Or R ³ and R ^3' form a 3-6 membered saturated or unsaturated ring together with the carbon atom connected to it, and the ring can also optionally contain 1 or 2 heteroatoms selected from O, S and N, And the ring can be optionally substituted by 0, 1 or 2 substituents selected from halogen, hydroxyl and C ₁ -C ₆ alkyl;

Or R ² , R ³ or R ² , R ^3' together form a 4-6 membered saturated or unsaturated ring with the atoms connected to it, and the ring can also optionally contain 1 or 2 members selected from O, S and N heteroatoms, and the ring can also be optionally substituted by 0, 1, 2 halogens, hydroxyl, C ₁ -C ₆ alkyl;

R ⁴ and R ^4' each independently represent hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, hydroxyl C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl;

or R ⁴ and R ^4' together form =O;

^RT and ^RT' each independently represent hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxy C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogen, OR ^a ;

or ^RT and RT ^' together form a 3-6 membered ring with the atom attached to it;

Wherein, when --- represents the absence of a single bond, A represents (CR ^L R ^L' ) _p , wherein ^RL and ^RL' each independently represent hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ Haloalkyl, hydroxy C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogen, OR ^a , or ^RL and ^RL' together form a 3-6 membered ring with the carbon atom connected to it, in which Can optionally contain 0, 1 or 2 heteroatoms selected from O, S and N, and the ring can also be optionally substituted by 0, 1 or 2 substituents selected from halogen and hydroxyl;

Among them, when --- indicates the presence of a single bond, A indicates CR ^H , wherein R ^H indicates hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxyl C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogen, OR ^a ;

Wherein, R ^a , R ^a' , R ^b , R ^b' each independently represent hydrogen or C ₁ -C ₆ alkyl;

wherein m, n, and p represent 0, 1 or 2 each independently.

Among the above-mentioned compounds of the formula (I) or their pharmaceutically acceptable salts, isotopic derivatives, and stereoisomers, it is preferably a compound with the following formula (II) or its pharmaceutically acceptable salts, isotopes derivatives, stereoisomers,

其中R¹、R²、R³、R^3’、R⁴、R^4’、X、Cy具有如上述定義。

Wherein R ¹ , R ² , R ³ , R ^3' , R ⁴ , R ^4' , X, Cy have the above definitions.

Further, the present invention also provides a compound having the following formula (III) and pharmaceutically acceptable salts, isotopic derivatives, and stereoisomers:

其中R¹、R²、R³、R^3’、R⁴、R^4’、R^T、R^T’、R^L、R^L’、X、Cy如上述所定義。

wherein R ¹ , R ² , R ³ , R ^3′ , R ⁴ , R ^4′ , ^RT , RT ^′ , ^RL , RL ^′ , X, and Cy are as defined above.

In some technical solutions of the present invention, R ² represents hydrogen, C ₁ -C ₆ alkyl, hydroxyl (C ₁ -C ₆ alkyl) or C ₃ -C ₆ cycloalkyl.

In some embodiments of the present invention, wherein, R ³ , R ^3' each independently represent hydrogen, C ₁ -C ₆ alkyl, hydroxyl (C ₁ -C ₆ alkyl) or C ₃ -C ₆ cycloalkyl .

In some embodiments of the present invention, wherein, R ⁴ and R ^4' each independently represent hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, or R ⁴ and R ^4' together form = O.

、

、

、 In some embodiments of the present invention, wherein Cy represents C ₃ -C ₅ cycloalkyl or 4-5 membered cycloheteroalkyl; preferably, Cy represents

,

,

,

In some embodiments of the invention, X represents a covalent bond or -(CR ^a R ^a' ) _m -, -(CR ^a R ^a' ) _m -O-(CR ^a R ^a' ) _n -, -( CR ^a R ^a' ) _m -N(R ^b )-(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m -S-(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m C(O)N(R ^b )(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m S(O) ₂ N(R ^b )(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m N(R ^b )C(O)(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m N(R ^b )S(O) ₂ (CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m OC(O)N(R ^b )(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m N(R ^b )C(O)O(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m N(R ^b )C(O)N(R ^b' )(CR ^a R ^a' ) _n - , -(CR ^a R ^a' ) _m N(R ^b )S(O) ₂ N(R ^b' )(CR ^a R ^a' ) _n -.

In some embodiments of the present invention, X represents -O-, -NR ^b -, -CR ^a R ^a' -, -OCR ^a R ^a' -, -CR ^a R ^a' O-, -C(O) -, -C(O)NR ^b -, -NR ^b C(O)-, -NR ^b -C(O)-NR ^b -, -CR ^a R ^a' -C(O)NR ^b -, -CR ^a R ^a' -NR ^b C(O)-, -S-, -NR ^b S(O) ₂ -, -SO ₂ NR ^b , -OC(O)NR ^b -, -S(O) ₂ , - C(O)NR ^b -, -C(O)CR ^a R ^a' -, -CR ^a R ^a' C(O)NR ^b -, -NR ^b C(O)CR ^a R ^a' -, -NR ^b C(O)O-; wherein R ^a , R ^a' , and R ^b each independently represent hydrogen or C ₁ -C ₆ alkyl.

In some embodiments of the present invention, X represents -(CR ^a R ^a' ) _m -O-(CR ^a R ^a' ) _n -, preferably -O-, -OCR ^a R ^a' -, -CR ^a R ^a' O-, more preferably -O- or -O-CH ₂ -.

In some embodiments of the invention, ^RT and ^RT' represent hydrogen.

In some embodiments of the invention, ^RL and RL ^' represent hydrogen.

In some embodiments of the invention, R ^H represents hydrogen.

In some embodiments of the present invention, R ¹ represents C ₃ -C ₆ cycloalkyl, 3-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl substituted by 0, 1, 2 or 3 substituents , 5-10 membered heteroaryl, wherein the substituent is selected from halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) haloalkyl, (C ₃ -C ₆ ) cycloalkyl, Halogenated (C ₃ -C ₆ )cycloalkyl, 3-6 membered heterocycloalkyl, halogenated 3-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl.

In some embodiments of the present invention, R ¹ represents C ₃ -C ₆ cycloalkyl, 3-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, and said R ¹ can be optionally 0, 1, 2, 3 selected from: hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) haloalkyl, (C ₃ -C ₆ ) cycloalkane Substituents of groups, halo(C ₃ -C ₆ )cycloalkyl groups.

In some embodiments of the invention, R ^is selected from:

In some embodiments of the invention, R ^is selected from:

In some preferred aspects, the present invention provides a compound having the following structure:

Furthermore, the present invention also provides a pharmaceutical composition, comprising the compound of the present invention or its pharmaceutically acceptable salt, isotope derivative or stereoisomer.

Further, the present invention also provides the compounds described in the present invention or their pharmaceutically acceptable salts, isotopic derivatives, stereoisomers or pharmaceutical compositions described in the present invention for the prevention and/or treatment of cancer , tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases in medicine. It should be noted that in this article, when referring to the "compound" of the structure of formula (I) to formula (III), it generally also covers its stereoisomers, diastereomers and enantiomers. , racemic mixtures and isotopic derivatives.

Accordingly, the present invention provides a method for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease, comprising administering the compound described in the present invention or its pharmaceutically acceptable salts, isotopic derivatives, stereoisomers or pharmaceutical compositions of the present invention.

It is well known to those skilled in the art that a compound's salt, solvate, and hydrate are alternative forms of the compound, and they can all be converted into the compound under certain conditions. Compounds of formula (I) to formula (III) generally include their pharmaceutically acceptable salts, and further include their solvates and hydrates.

Similarly, when referring to a compound herein, its prodrugs, metabolites and nitroxides are also generally included.

The pharmaceutically acceptable salts of the present invention may be formed using, for example, the following inorganic or organic acids: "Pharmaceutically acceptable salt" means a salt which, within the scope of reasonable medical judgment, is suitable for use in contact with humans and lower Such animal tissues, without undue toxicity, irritation, allergic reaction, etc., can be called a reasonable benefit / risk ratio. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or alone by reacting the free base or acid with a suitable reagent, as outlined below. For example, a free base function can be reacted with a suitable acid. Examples of pharmaceutically acceptable inorganic acid addition salts are amino acids with inorganic acids (e.g., hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric) or organic acids (e.g., acetic, oxalic, maleic, tartaric, lemon acid, succinic acid or malonic acid), or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include Alginate, Sodium Alginate, Ascorbate, Aspartate, Besylate, Benzoate, Bisulfate, Borate, Butyrate, Camphorate, Camphorsulfonate, Citrate, Cyclopentane propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lactobionate, Lactate, Laurate, Lauryl Sulfate, Malate, Maleate, Malonate Salt, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulfate, 3-phenylpropanoid salt, phosphate, bitter salt, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, pentanoate salt etc. Representative alkali or alkaline earth metal salts include those of sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, where appropriate, nontoxic ammonium salts, quaternary ammonium salts, and amine cations formed with counterions, for example, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkanes sulfonates and arylsulfonates.

The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example, by dissolving the compound of the present invention in a water-miscible organic solvent (such as acetone, methanol, ethanol and acetonitrile), adding an excess of organic acid or inorganic Aqueous acid solution, so that the salt is precipitated from the resulting mixture, the solvent and remaining free acid are removed therefrom, and the precipitated salt is isolated.

The precursors or metabolites described in the present invention may be precursors or metabolites known in the art, as long as the precursors or metabolites are transformed into compounds through in vivo metabolism. For example, "prodrugs" refer to those prodrugs of the compounds of the present invention which, within the scope of sound medical judgment, are suitable for use in contact with human and lower animal tissues without undue toxicity, irritation, allergic response, etc., Qualified as having a reasonable benefit/risk ratio and valid for its intended use. The term "prodrug" refers to a compound that is rapidly transformed in vivo to yield the parent compound of the above formula, for example by in vivo metabolism, or N-demethylation of a compound of the invention.

"Solvate" as used herein means a physical association of a compound of the present invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bond. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, solvates will be able to be isolated. Solvent molecules in solvates may exist in regular and/or disordered arrangements. Solvates may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses both solution-phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

"Stereoisomerism" described in the present invention is divided into conformational isomerism and configurational isomerism, and configurational isomerism can also be divided into cis-trans isomerism and optical isomerism (i.e. optical isomerism), conformational isomerism refers to having A stereoisomerism phenomenon in which the atoms or atomic groups of molecules of a certain configuration are arranged in different ways in space due to the rotation or twisting of carbon and carbon single bonds. The common structures are alkane and cycloalkane compounds, such as The chair and boat conformations that occur in the cyclohexane structure. "Stereoisomer" means when a compound of the present invention contains one or more asymmetric centers and is thus available as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and single Diastereomers. The compound of the present invention has an asymmetric center, and each asymmetric center can produce two optical isomers, and the scope of the present invention includes all possible optical isomers and diastereoisomer mixtures and pure or partially pure compounds . The compounds described herein may exist in tautomeric forms having different points of attachment of hydrogens by displacement of one or more double bonds. For example, a ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included in the compounds of the present invention. Enantiomers, diastereoisomers, racemates, mesoforms, cis-trans isomers, tautomers, geometric isomers of all compounds of formula (I) to formula (III) , epimers and their mixtures, etc., are included in the scope of the present invention.

An "isotopic derivative" of the present invention refers to an isotopically labeled molecule of a compound herein. Isotopes commonly used for isotopic labeling are: Hydrogen isotopes, ² H and ³ H; Carbon isotopes: ¹¹ C, ¹³ C and ¹⁴ C; Chlorine isotopes: ³⁵ Cl and ³⁷ Cl; Fluorine isotopes: ¹⁸ F; Iodine isotopes: ¹²³ I and ¹²⁵ I; nitrogen isotopes: ¹³ N and ¹⁵ N; oxygen isotopes: ¹⁵ O, ¹⁷ O and ¹⁸ O and sulfur isotope ³⁵ S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Especially deuterium ³ H and carbon ¹³ C are more widely used because of their easy labeling and convenient detection. The substitution of some heavy isotopes, such as deuterium ( ² H), can enhance the stability of metabolism, prolong the half-life and thus achieve the purpose of reducing the dose and provide therapeutic advantages. Isotopically labeled compounds are generally synthesized starting from labeled starting materials and carried out in the same manner as non-isotopically labeled compounds using known synthetic techniques.

The present invention also provides the use of the compound of the present invention in the preparation of medicaments for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.

In addition, the present invention provides a pharmaceutical composition for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease, which comprises the present invention compounds as active ingredients. The pharmaceutical composition may optionally comprise a pharmaceutically acceptable carrier.

In addition, the present invention provides a method for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease, which comprises Mammals are administered compounds of the invention.

Representative examples of inflammatory, autoimmune, and immune-mediated diseases may include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis , Other Arthritis Conditions, Lupus, Systemic Lupus Erythematosus (SLE), Skin Related Disorders, Psoriasis, Eczema, Dermatitis, Atopic Dermatitis, Pain, Lung Disease, Lung Inflammation, Adult Respiratory Distress Acute respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease (Chronic Obstruction Pulmonary Disease, COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart disease Failure, myocardial ischemia-reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjogren's syndrome, autoimmune thyroid disease, urticaria (rubella), multiple sclerosis , scleroderma, organ transplant rejection, xenotransplantation, Idiopathic thrombocytopenic purpura (Idiopathic thrombocytopenic purpura, ITP), Parkinson's disease, Alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, allergic sinusitis, Leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia , AML), Chronic Myeloid Leukemia (CML), Hairy Cell Leukemia, Hodgkin's Disease, Non-Hodgkin's Lymphoma, Multiple Myeloma, Myelodysplastic Syndromes (MDS), Myeloproliferative neoplasm (Myeloproliferative Neoplasm, MPN), diffuse large B-cell lymphoma and follicular lymphoma.

Representative examples of cancer or tumor may include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neuroblastoma, rectal cancer , colon cancer, familial adenomatous polyposis carcinoma, hereditary nonpolyposis colorectal cancer, esophagus cancer, lip cancer, larynx cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid cancer, Papillary thyroid cancer, renal cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine body cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, brain tumors such as Glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumor, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphoblastic leukemia (ALL ), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (Diffuse Large B-cell Lymphoma, DLBCL) , hepatocellular carcinoma, gallbladder cancer, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma , craniopharyngioma, osteosarcoma, chondrosarcoma, sarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, or plasmacytoma.

When the compound of the present invention or a pharmaceutically acceptable salt thereof is administered in combination with another anticancer agent or immune checkpoint inhibitor for the treatment of cancer or tumors, the compound of the present invention or a pharmaceutically acceptable salt thereof can provide enhanced anticancer effects .

Representative examples of anticancer agents useful in the treatment of cancer or tumors may include, but are not limited to, cell signaling inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan , carmustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, Gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin Bixin, epirubicin, daunomycin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifen, flutamide, gonadorelin analogs, Megestrol, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alpha, leucovorin, sirolimus, sirolimus ester, everolimus, alfatinib Ni, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, britinib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib , dacomitinib, danucitinib, dasatinib, multivitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, Lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motsanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, Quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tiratinib, tivantinib, tivozanib, tofacitinib, Trametinib, vandetanib, veliparib, vemurafenib, vimodegib, volasertib, alemtuzumab, bevacizumab, berentuzumab vedotin, catumaxumab Antibodies, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumumab Monoclonal antibody, trastuzumab, PI3K inhibitor, CSF1R inhibitor, A2A and/or A2B receptor antagonist Antibody, IDO inhibitor, anti-PD-1 antibody, anti-PD-L1 antibody, LAG3 antibody, TIM-3 antibody and anti-CTLA-4 antibody, or any combination thereof.

Compounds of the present invention, or pharmaceutically acceptable salts thereof, provide enhanced therapeutic effect.

Representative examples of therapeutic agents useful in the treatment of inflammatory, autoimmune, and immune-mediated diseases can include, but are not limited to, steroidal drugs (e.g., prednisone, prednisone, prednisone, methylphenidate, Cortisone, cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNFα agents (eg, etanercept, infliximab, adalib monoclonal antibody, etc.), calcineurin inhibitors (eg, tacrolimus, pimecrolimus, etc.), and antihistamines (eg, diphenhydramine, hydroxyzine, loratadine, ebazan Tin, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one or more therapeutic agents selected from them can be included in the pharmaceutical composition of the present invention.

The compound of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally as an active ingredient, and its effective amount ranges from 0.1 to 2,000 mg/kg body weight/day in the case of mammals including humans (about 70 kg body weight), Preferably 1 to 1,000 mg/kg body weight/day, and administered in single or 4 divided doses per day, or with or without a scheduled time. The dose of the active ingredient may be adjusted according to a number of relevant factors such as the condition of the subject to be treated, the type and severity of the disease, the rate of administration and the opinion of the physician. In some cases, amounts less than the above dosages may be appropriate. Amounts greater than the above doses may be used if no deleterious side effects are caused and such amounts may be administered in divided doses daily.

In addition, the present invention also provides a method for preventing and/or treating tumors, cancers, viral infections, organ transplant rejection, neurodegenerative diseases, attention-related diseases or autoimmune diseases, which includes A mammal is administered a compound of the invention or a pharmaceutical composition of the invention.

The pharmaceutical composition of the present invention can be formulated into dosage forms for oral administration or parenteral administration (including intramuscular, intravenous and subcutaneous routes, intratumoral injection) according to any of conventional methods, such as tablets, granules, powders , capsules, syrups, emulsions, microemulsions, solutions or suspensions.

Pharmaceutical compositions of the present invention for oral administration can be prepared by mixing the active ingredient with carriers such as cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, stearic acid, Magnesium stearate, calcium stearate, gelatin, talc, surfactant, suspending agent, emulsifier and diluent.

Examples of carriers employed in the pharmaceutical composition for injection administration of the present invention can be water, saline solution, glucose solution, glucose-like solution (glucose-like solution), alcohol, glycol, ether (for example, polyethylene glycol 400 ), oils, fatty acids, fatty acid esters, glycerides, surfactants, suspending agents and emulsifiers.

Other features of the invention will become apparent in the course of the description of exemplary embodiments of the invention which are given to illustrate the invention and are not intended to be limiting thereof, the following examples were prepared using the methods disclosed in the invention , separation and characterization.

The compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis and can be synthesized using the methods described below as well as synthetic methods known in the art of synthetic organic chemistry or by variations thereof known to those skilled in the art Compounds of the invention. Preferred methods include, but are not limited to, those described below. Reactions are performed in solvents or solvent mixtures appropriate to the kit materials used and to the transformations effected. Those skilled in the art of organic synthesis will appreciate that the functionality present on the molecule is consistent with the proposed transitions. This sometimes requires judgment to alter the order of synthetic steps or starting materials to obtain the desired compound of the invention.

the term

Unless otherwise stated, the terms used in the application of the present invention, including the specification and scope of claims, are defined as follows. If not stated otherwise, conventional methods of mass spectrometry, nuclear magnetic resonance, High Performance Liquid Chromatography (HPLC), protein chemistry, biochemistry, recombinant deoxyribonucleic acid (DNA) techniques and pharmacology were used. In this application, the use of "or" or "and" means "and/or" if not stated otherwise.

In the specification and claims, a given chemical formula or name shall cover all stereoisomers and optical isomers thereof and racemates in which the above-mentioned isomers exist. Unless otherwise indicated, all chiral (enantiomers and diastereoisomers) and racemic forms are within the scope of the invention. Various geometric isomers of C=C double bonds, C=N double bonds, ring systems, etc. may also exist in the compounds, and all the above stable isomers are encompassed in the present invention. The present invention describes cis- and trans- (or E- and Z-) geometric isomers of the compounds of the invention and which may be isolated as a mixture of isomers or as separated isomeric forms. The compounds of the invention may be isolated in optically active or racemic forms. All methods used to prepare the compounds of the invention and intermediates prepared therein are considered part of the invention. When preparing enantiomeric or diastereomeric products, they may be separated by customary methods, for example by chromatography or fractional crystallization. Depending on the process conditions, the end products of the invention are obtained in free (neutral) or salt form. The free forms and salts of these end products are within the scope of the present invention. A compound can be converted from one form to another, if desired. A free base or acid can be converted into a salt; a salt can be converted into the free compound or another salt; a mixture of isomeric compounds of the invention can be separated into the individual isomers. The compounds of the invention, their free forms and salts, may exist in various tautomeric forms in which the hydrogen atoms are transposed to other parts of the molecule and thus the chemical bonds between the atoms of the molecule are rearranged. It is to be understood that all tautomeric forms which may exist are included within the present invention.

Unless otherwise defined, the definitions of substituents in the present invention are independent and not interrelated, for example (listed but not exhaustive), in one aspect, for R ^a (or R ^a ') in the substituent, its are independent of each other in the definitions of the different substituents. Specifically, when one definition is selected for R ^a (or R ^a ') in one substituent, it does not mean that the R ^a (or R ^a ') has the same definition in other substituents. More specifically, for example (but not exhaustively) for NR ^a R ^a ', when the definition of R ^a (or R ^a ') is selected from hydrogen, it does not mean that in -C(O)-NR In ^a R ^a ', R ^a (or R ^a ') must be hydrogen. In another aspect, when there is more than one R ^a (or R ^a ') in a certain substituent, these R ^a (or R ^a ') are also independently independent. For example, in the substituent -(CR ^a R ^a' ) _m -O-(CR ^a R ^a' ) _n -, in the case where m+n is greater than or equal to 2, the m+n R ^a (or R ^a ') are independent, and they may have the same or different meanings.

Unless otherwise defined, when a substituent is noted as "optionally substituted", the substituent is selected from, for example, the following substituents, such as alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxy, Alkoxy, oxo, alkacyl, aryloxy, alkyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amino (wherein 2 amino substituents are selected from selected from alkyl, aryl or arylalkyl), alkylamino, arylamino, aralkanylamino, substituted alkanylamino, substituted arylamino, substituted aralkanylamino, Thio, alkylthio, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl radical, aminosulfonyl such as -SO ₂ NH ₂ , substituted sulfonylamino, nitro, cyano, carboxyl, carbamoyl such as -CONH ₂ , substituted carbamoyl such as -CONHalkyl, -CONH Aryl, -CONH arylalkyl or the case of nitrogen with two substituents selected from alkyl, aryl or arylalkyl, alkoxycarbonyl, aryl, substituted aryl, guanidino, Heterocyclic groups such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazine and substituted heterocyclic groups.

The term "alkyl" or "alkylene" as used herein is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms. For example, "C ₁ -C ₆ alkyl" means an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl, t-butyl), and Pentyl (eg n-pentyl, isopentyl, neopentyl). Herein, the alkyl group is preferably an alkyl group having 1 to 6, more preferably 1 to 4 carbon atoms.

The term "alkenyl" denotes a straight or branched chain hydrocarbon group containing one or more double bonds and generally having a length of 2 to 20 carbon atoms. For example, "C2-C6 alkenyl" contains two to six carbon atoms. Alkenyl groups include, but are not limited to, eg vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. In this context, alkenyl is preferably C ₂ -C ₆ alkenyl.

The term "alkynyl" denotes a straight or branched chain hydrocarbon group containing one or more triple bonds and generally having a length of 2 to 20 carbon atoms. For example, " _C2 - _C6 alkynyl" contains two to six carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, and the like. In this context, alkynyl is preferably C ₂ -C ₆ alkynyl.

The term "alkoxy" or "alkyloxy" refers to -O-alkyl. "C ₁ -C ₆ alkoxy" (or alkyloxy) is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy), and tert-butoxy. Herein, the alkoxy group is preferably an alkoxy group having 1 to 6, more preferably 1 to 4 carbon atoms. Similarly, "alkylthio" or "thiothio" denotes an alkyl group as defined above having the indicated number of carbon atoms attached through a sulfur bridge; eg methyl-S- and ethyl-S-.

The term "carbonyl" refers to an organic functional group (C=O) consisting of two atoms, carbon and oxygen, joined by a double bond.

The term "aryl", alone or as part of a larger moiety such as "aralkyl", "arylalkoxy" or "aryloxyalkyl", refers to a single group having a total of 5 to 12 ring members Cyclic, bicyclic or tricyclic ring systems, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. In certain embodiments of the invention, "aryl" refers to an aromatic ring system which includes, but is not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthalene base. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring, non-limiting examples of which include benzyl, phenethyl, and the like. A fused aryl group can be attached to another group at a suitable position on the cycloalkyl ring or aromatic ring. Dashed lines drawn from ring systems indicate that bonds may be attached to any suitable ring atom.

The term "cycloalkyl" refers to a monocyclic or bicyclic cyclic alkyl group. Monocyclic cyclic alkyl refers to C ₃ -C ₈ cyclic alkyl, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norbornyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included within the definition of "cycloalkyl". Bicyclic cyclic alkyl groups include bridged, spiro or fused cycloalkyl groups. In this context, cycloalkyl is preferably C ₃ -C ₆ cycloalkyl.

The term "cycloalkenyl" refers to a monocyclic or bicyclic cyclic alkenyl group. Monocyclic cyclic alkenyl refers to C ₃ -C ₈ cyclic alkenyl, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and norbornenyl. Branched cycloalkenyl groups such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included within the definition of "cycloalkenyl". Bicyclic cyclic alkenyl groups include bridged, spiro, or fused cyclic alkenyl groups.

"Halo" or "halogen" includes fluoro, chloro, bromo and iodo. "Haloalkyl" is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoro Propyl and Heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl" intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and substituted with 1 or more fluorine atoms.

"Haloalkoxy" or "haloalkyloxy" means a haloalkyl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge. For example, "haloC ₁ -C ₆ alkoxy" is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ haloalkoxy. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" denotes a haloalkyl group as defined above having the indicated number of carbon atoms attached through a sulfur bridge; for example trifluoromethyl-S- and pentafluoroethyl -S-.

In the present disclosure, the expression C _x1 -C _x2 is used when referring to some substituent groups, which means that the number of carbon atoms in the substituent groups may be x1 to x2. For example, C ₀ -C ₈ means that the group contains 0, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C ₁ -C ₈ means that the group contains 1, 2, 3 , 4, 5, 6, 7 or 8 carbon atoms, C ₂ -C ₈ means that the group contains 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C ₃ -C ₈ means that the The group contains 3, 4, 5, 6, 7 or 8 carbon atoms, C ₄ -C ₈ means that the group contains 4, 5, 6, 7 or 8 carbon atoms, C ₀ -C ₆ means that the The group contains 0, 1, 2, 3, 4, 5 or 6 carbon atoms, C ₁ -C ₆ means that the group contains 1, 2, 3, 4, 5 or 6 carbon atoms, C ₂ -C ₆ means that the group contains 2, 3, 4, 5 or 6 carbon atoms, and C ₃ -C ₆ means that the group contains 3, 4, 5 or 6 carbon atoms.

In this disclosure, the expression "x1-x2 membered ring" is used when referring to cyclic groups (such as aryl, heteroaryl, cycloalkyl, and heterocycloalkyl), which means that the ring atoms of the group The number can be x1 to x2. For example, the 3-12 membered cyclic group may be a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered ring, and the number of ring atoms may be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; 3-6-membered ring means that the cyclic group can be 3, 4, 5 or 6-membered ring, and the number of ring atoms can be 3, 4, 5 or 6 ; 3-8 membered ring means that the cyclic group can be 3, 4, 5, 6, 7 or 8-membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7 or 8; 3-9 A membered ring means that the cyclic group can be a 3, 4, 5, 6, 7, 8 or 9-membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7, 8 or 9; 4-7 A membered ring means that the cyclic group can be a 4, 5, 6 or 7-membered ring, and the number of ring atoms can be 4, 5, 6 or 7; a 5-8-membered ring means that the cyclic group can be 5, 6, 7 or 8-membered ring, the number of ring atoms can be 5, 6, 7 or 8; 5-12 membered ring means that the ring group can be 5, 6, 7, 8, 9, 10, 11 or 12-membered ring, the number of ring atoms can be 5, 6, 7, 8, 9, 10, 11 or 12; 6-12 membered ring means that the ring group can be 6, 7, 8, 9, 10, 11- or 12-membered rings may have 6, 7, 8, 9, 10, 11 or 12 ring atoms. The ring atoms may be carbon atoms or heteroatoms, for example selected from N, O and S. When the ring is heterocyclic, the heterocyclic ring may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more ring heteroatoms, for example selected from N, O and S of heteroatoms.

In the present disclosure, the one or more halogens may each be independently selected from fluorine, chlorine, bromine and iodine.

The term "heteroaryl" means a stable 3-membered, 4-membered, 5-membered, 6-membered, or 7-membered aromatic monocyclic or aromatic bicyclic ring or 7-, 8-, 9-, 10-, 11-, 12-membered An aromatic polycyclic heterocycle which is fully unsaturated or partially unsaturated and which contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; and includes Any of the following polycyclic groups in which any heterocyclic ring as defined above is fused to a benzene ring. Nitrogen and sulfur heteroatoms can be optionally oxidized. The nitrogen atom is substituted or unsubstituted (ie N or NR, where R is H or another substituent if defined). A heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclyl groups described herein may be substituted on carbon or nitrogen atoms if the resulting compound is stable. The nitrogen in the heterocycle can optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not greater than one. When the term "heterocycle" is used, it is intended to include heteroaryl. Examples of heteroaryl groups include, but are not limited to, acridinyl, azetidinyl, aziocinyl, benzimidazolyl, benzofuryl, benzothiofuranyl, benzothienyl, benzooxa Azolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-oxazolyl, oxalinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2, 3-b] Tetrahydrofuryl, furyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridyl, indolenyl, indolinyl, Indolazinyl, indolyl, 3H-indolyl, isatinoyl (isatinoyl), isobenzofuryl, isochromanyl, isoindazolyl, isodihydroindolyl, isoindolyl, iso Quinolinyl, isothiazolyl, isothiazolopyridyl, isoxazolyl, isoxazolopyridyl, methylenedioxyphenyl, morpholinyl, diazanaphthyl, octahydroisoquinoline oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl , oxazolidinyl, oxazolyl, oxazolopyridyl, oxazolidinyl, diazaphenyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl , phenothiazine Base, phenoxathiyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidinonyl, 4-piperidinyl, piperonyl, pteridinyl, purinyl, pyranyl, Pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridyl, pyrazolyl, pyridazinyl, pyridoxazolyl, pyridimidazolyl, pyridothiazolyl, pyridyl, pyrimidinyl, Pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinazinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, Tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydroquinolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl , 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthryl, thiazolyl, thienyl, thiazolopyridyl, thienothiazolyl, thienooxazolyl, thiophene Imidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl And xanthenyl, quinolinyl, isoquinolyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl, 1 ,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro- Benzofuryl, chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl. The term "heteroaryl" may also include biaryl structures formed by the above-defined "aryl" and a monocyclic "heteroaryl", such as but not limited to "-phenylbipyridyl-", "- "Phenyl bipyrimidyl", "-pyridyl biphenyl", "-pyridyl bipyrimidyl-", "-pyrimidyl biphenyl-"; wherein the present invention also includes condensed rings containing, for example, the above-mentioned heterocycles and Spiro compound.

As used herein, the term "heterocycloalkyl" refers to a monocyclic heterocycloalkyl system, or a bicyclic heterocycloalkyl system, and also includes spiroheterocycle or bridged heterocycloalkyl. Monocyclic heterocycloalkyl refers to a 3-8 membered, saturated or unsaturated but non-aromatic cyclic alkyl system containing at least one heteroatom selected from O, N, S and P. The bicyclic heterocycloalkyl system refers to a heterocycloalkyl fused to a phenyl group, or a cycloalkyl group, or a cycloalkenyl group, or a heterocycloalkyl group, or a heteroaryl group formed two-ring system.

The term "bridged cycloalkyl" as used herein refers to polycyclic compounds sharing two or more carbon atoms. Can be divided into bicyclic bridged ring hydrocarbons and polycyclic bridged ring hydrocarbons. The former is composed of two alicyclic rings sharing more than two carbon atoms; the latter is a bridged ring hydrocarbon composed of more than three rings.

The term "spirocycloalkyl" as used herein refers to polycyclic hydrocarbons in which monocyclic rings share one carbon atom (called a spiro atom).

The term "bridged ring heterogroup" as used herein refers to a polycyclic compound sharing two or more carbon atoms, and the ring contains at least one heteroatom selected from O, N and S atoms. It can be divided into bicyclic bridged heterocycles and polycyclic bridged heterocycles.

The term "heterospirocyclyl" used herein refers to a polycyclic hydrocarbon that shares one carbon atom (called a spiro atom) between monocyclic rings, and the ring contains at least one heteroatom selected from O, N and S atoms.

The term "substituted" as used herein means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that normal valences are maintained and that the substitution results in a stable compound. A ring double bond, as used herein, is a double bond formed between two adjacent ring atoms (eg, C=C, C=N or N=N).

Where nitrogen atoms (e.g. amines) are present on compounds of the invention, these nitrogen atoms can be converted to N-oxides by treatment with oxidizing agents (e.g. mCPBA and/or hydrogen peroxide) to obtain other compounds of the invention . Accordingly, both shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxides to obtain the derivatives of the present invention.

When any variable occurs more than one time in any composition or formula of a compound, its definition on each occurrence is independent of its definition on every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R, then said group may be optionally substituted with up to three R groups, and R at each occurrence is independently selected from the definition of R. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term "patient" as used herein refers to an organism being treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (eg, murine, ape, monkey, equine, bovine, porcine, canine, feline, etc.) and most preferably refer to humans.

As used herein, the term "effective amount" means the amount of a drug or agent (ie, a compound of the invention) that will elicit the biological or medical response sought by, eg, a researcher or clinician in a tissue, system, animal or human. Furthermore, the term "therapeutically effective amount" means such Amount: An amount that results in improved treatment, cure, prevention or alleviation of a disease, disorder or side effect, or reduced rate of progression in a disease or disorder, compared to a corresponding subject not receiving the above amount. An effective amount may be given in one or more administrations, applications or doses and is not intended to be limited by a particular formulation or route of administration. The term also includes within its scope amounts effective to enhance normal physiological function.

As used herein, the term "treating" includes any effect that results in amelioration of a condition, disease, disorder, etc., such as alleviation, reduction, regulation, amelioration or elimination, or amelioration of the symptoms thereof.

The term "pharmaceutically acceptable" is used herein to refer to those compounds, substances, compositions and/or dosage forms: within the scope of sound medical judgment, they are suitable for use in contact with human and animal tissues without excessive toxicity, irritation sex, allergic reactions, and/or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutical substance, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g. lubricant, talc, magnesium stearate, , calcium stearate, or zinc stearate, or stearic acid) or solvent-encapsulated substances involved in the carrying or transport of a subject compound from one organ or body part to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

The term "pharmaceutical composition" means a composition comprising a compound of the present invention together with at least one other pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" means a medium generally accepted in the art for the delivery of biologically active agents to animals, particularly mammals, including (i.e.) adjuvants, excipients or vehicles, such as diluents, preservatives , fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the given The mode of administration and the nature of the dosage form.

Certain pharmaceutical and medical terms

The term "acceptable", as used herein, means that a formulation ingredient or active ingredient does not have an undue adverse effect on health for the general purpose of treatment.

The term "cancer", as used herein, refers to an uncontrollable abnormal growth of cells, And can transfer (spread) under certain conditions. Cancers of this type include, but are not limited to, solid tumors (eg, bladder, bowel, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (eg, thyroid), prostate , skin (melanoma), or blood cancer (such as non-leukemic leukemia).

The term "administration in combination" or similar terms, as used herein, refers to the administration of several selected therapeutic agents to a patient, in the same or different modes of administration at the same or different times.

The term "enhancing" or "capable of enhancing", as used herein, means that a desired result is capable of being increased or prolonged, either in potency or duration. Thus, in relation to enhancing the therapeutic effect of a drug, the term "capable of potentiating" refers to the ability of the drug to increase or prolong its potency or duration in the system. As used herein, "potency value" refers to the ability to maximize the enhancement of another therapeutic drug in an ideal system.

The term "immune disease" refers to a disease or condition of an adverse or deleterious reaction to an endogenous or exogenous antigen. The result is usually dysfunction of the cells, or destruction thereof and dysfunction, or destruction of organs or tissues that may produce immune symptoms.

The terms "kit" and "product packaging" are synonymous.

The term "subject" or "patient" includes mammals and non-mammals. Mammals include, but are not limited to, mammals: humans, non-human primates such as orangutans, apes, and monkeys; agricultural animals such as cattle, horses, goats, sheep, and pigs; domestic animals such as rabbits and dogs; experimental animals include rodents, such as Rats, mice and guinea pigs etc. Non-mammalian animals include, but are not limited to, birds, fish, and the like. In a preferred aspect, the selected mammal is a human.

The term "treatment", "course of treatment" or "therapy" as used herein includes alleviating, suppressing or ameliorating the symptoms or conditions of a disease; inhibiting the development of complications; ameliorating or preventing the underlying metabolic syndrome; inhibiting the development of diseases or symptoms, Such as controlling the development of a disease or condition; alleviating a disease or a symptom; causing a disease or a symptom to regress; alleviating a complication caused by a disease or a symptom, or preventing and/or treating a sign caused by a disease or a symptom.

As used herein, a certain compound or pharmaceutical composition, after administration, can make a certain disease Improvement in disease, symptoms or condition, especially improvement in severity, delay in onset, slowing of disease progression, or reduction in duration of disease. Circumstances that may be attributable to or related to the administration, whether fixed or episodic, continuous or intermittent.

Route of administration

Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, ear canal , nasal administration and topical administration. In addition, by way of example only, parenteral administration includes intramuscular injection, subcutaneous injection, intravenous injection, intramedullary injection, intraventricular injection, intraperitoneal injection, intralymphatic injection, and intranasal injection.

In one aspect, the compounds described herein are administered locally rather than systemically. In certain embodiments, the depot formulation is administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in another specific embodiment, the drug is administered via a targeted drug delivery system. For example, liposomes coated with organ-specific antibodies. In such embodiments, the liposomes are selectively directed to and taken up by specific organs.

Pharmaceutical Composition and Dosage

The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of the present invention formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents, and optionally one or more of the above-mentioned other therapeutic agent. The compounds of the invention may be administered for any of the above uses by any suitable means, e.g. orally, such as tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried sublingual; buccal; parenteral, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions nasally, including to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally, such as in the form of a suppository; or by intratumoral injection. They can be administered alone, but are usually used based on the chosen route of administration Drug carriers selected by appropriate routes and standard pharmaceutical practice.

Pharmaceutical carriers are formulated according to a number of factors within the purview of those skilled in the art. These factors include, but are not limited to: the type and nature of the active agent being formulated; the subject to whom the composition containing the active agent is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutical carriers include aqueous and non-aqueous liquid media and various solid and semisolid pharmaceutical carriers.

The above-mentioned carrier may include many different ingredients and additives in addition to the active agent, and the above-mentioned other ingredients are included in the formulation for various reasons known to those skilled in the art, such as stabilizers, binders, and the like. A description of suitable pharmaceutical carriers and the factors involved in carrier selection can be found in several readily available sources, such as Allen L.V.Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012 ), Pharmaceutical Press.

Dosage regimens for the compounds of this invention will of course vary depending on known factors such as the pharmacodynamic properties of the particular agent and its mode and route of administration; the recipient's species, age, sex, health, medical condition and Weight; nature and extent of symptoms; type of concomitant therapy; frequency of treatment; route of administration, patient's renal and hepatic function, and desired effects. As a general guide, the daily oral dosage of each active ingredient should be from about 0.001 mg/day to about 10-5000 mg/day, preferably from about 0.01 mg/day to about 1000 mg/day, and most preferably From about 0.1 mg/day to about 250 mg/day. The most preferred dose intravenously will be about 0.01 mg/kg/minute to about 10 mg/kg/minute during a constant rate infusion. The compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily.

The compounds are usually formulated with a suitable pharmaceutical diluent, excipient or carrier (herein collectively referred to as drug carriers) in the form of mixtures for administration.

Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 mg to about 2000 mg of active Sexual ingredients/dosage unit. In these pharmaceutical compositions, the active ingredient will generally be present in an amount of about 0.1-95% by weight, based on the total weight of the composition.

A typical capsule for oral administration contains at least one compound of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture was passed through a 60 mesh screen and packed into size 1 gelatin capsules.

A typical injectable formulation can be prepared by aseptically placing at least one compound of the present invention (250 mg) in a vial, lyophilizing in a sterile manner and sealing. For use, the vial contents are mixed with 2 mL of normal saline to produce an injectable formulation.

Included within the scope of the present invention are pharmaceutical compositions comprising (alone or in combination with a pharmaceutical carrier) a therapeutically effective amount of at least one compound of the present invention as an active ingredient. Optionally, compounds of the invention may be used alone, in combination with other compounds of the invention, or in combination with one or more other therapeutic agents (eg, anticancer agents or other pharmaceutically active substances).

Irrespective of the chosen route of administration, the compounds of the invention (which may be used in suitably hydrated form) and/or the pharmaceutical compositions of the invention are formulated into pharmaceutical dosage forms by conventional methods known to those skilled in the art .

Actual dosage levels of the active ingredient in the pharmaceutical compositions of the present invention can be varied to obtain an amount of active ingredient effective to achieve the desired therapeutic response, composition and mode of administration for a particular patient without being toxic to the patient.

The selected dosage level will depend on a variety of factors, including the activity of the particular compound of the invention employed, or its ester, salt or amide; the route of administration; the time of administration; the rate of excretion of the particular compound employed; the rate and extent of absorption; Duration of treatment; other drugs, compounds and/or substances used in combination with the particular compound employed; age, sex, weight, condition, general health and prior medical history of the patient being treated, among other factors well known in the medical art.

A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, a physician or veterinarian may start a compound of the invention used in a pharmaceutical composition at a lower level than is necessary to achieve a desired therapeutic effect. The test of drugs, and gradually increase the dose until the desired effect is achieved. In general, a suitable daily dose of a compound of the invention will be that amount of the compound at the lowest dose effective to produce a therapeutic effect. Such effective dosage will generally depend on the factors mentioned above. Typically, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention to patients range from about 0.01 to about 50 mg/kg body weight/day. If desired, an effective daily dose of the active compound may be administered in two, three, four, five, six or more sub-doses at appropriate intervals throughout the day, optionally in unit dosage form. In certain aspects of the invention, the administration is once daily.

Although the compounds of the present invention may be administered alone, it is preferred to administer the compounds in the form of pharmaceutical formulations (compositions).

Kit/Product Packaging

Kits/product packaging are also described herein for use in the treatment of the above indications. These kits may consist of transporters, packs, or container boxes that may be divided into compartments to accommodate one or more containers, such as vials, test tubes, and the like, each containing the method a single component in . Suitable containers include bottles, vials, syringes, test tubes and the like. Containers are made of acceptable materials such as glass or plastic.

For example, a container may contain one or more compounds described herein, either as a pharmaceutical compound or in admixture with other ingredients described herein. The container can have a sterile outlet (eg, the container can be an IV bag or bottle, the stopper of which can be pierced by a hypodermic needle). Such a kit may contain a compound, together with instructions for use, labels or instructions for the methods described herein.

A typical kit may include one or more containers, each containing one or more materials (e.g., reagents, which may also be concentrated stock solutions, and/or devices) to accommodate commercial promotion and user requirements for the compound. . These materials include but are not limited to buffers, diluents, filters, needles, syringes, transporters, bags, containers, bottles and and/or test tubes with a list of contents and/or instructions for use, the inner packaging also with instructions. Instructions for the entire set are to be included.

Labels can be displayed on or closely associated with the container. The appearance of the label on the container means that the label letters, numbers or other features are pasted, molded, or engraved on the container; the label can also appear in the container box or shipping box containing various containers, such as in the product insert. A label may be used to indicate a specific therapeutic use of the contents. The label may also bear instructions for use of the contents, such as described in the methods above.

All features described in this specification (including any stated claims, abstracts and drawings), and/or all steps involved in any method or process, may exist in any combination, unless certain features or steps are mutually exclusive in the same combination.

The above-mentioned features mentioned in the present invention, or the features mentioned in the embodiments can be combined arbitrarily. All the features disclosed in the specification of this case can be used in combination with any combination, and each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equivalent or similar purpose. Therefore, unless otherwise stated, the disclosed features are only general examples of equivalent or similar features.

Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. For the experimental methods without specific conditions indicated in the following examples, usually follow the conventional conditions or the conditions suggested by the manufacturer. All percentages, ratios, ratios, or parts are by weight unless otherwise indicated.

The unit of weight volume percentage in the present invention is well known to those skilled in the art, for example, it refers to the weight (g) of solute in 100 ml of solution. Unless otherwise defined, all professional and scientific terms used herein have the same meanings as are familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the method of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

Example

general process

When the preparation route is not included, the raw materials and reagents used in the present invention are known products, which can be synthesized according to methods known in the art, or can be obtained by purchasing commercially available products. All commercially available reagents were used without further purification.

Room temperature means 20-30°C.

There is no special description in the reaction examples, and the reactions are all carried out under a nitrogen atmosphere. The nitrogen atmosphere refers to a nitrogen balloon of about 1 L connected to the reaction flask.

The hydrogenation reaction is usually vacuumized and filled with hydrogen, and the operation is repeated 3 times. The hydrogen atmosphere means that the reaction bottle is connected with a hydrogen balloon of about 1L.

Microwave reaction using Biotage ^® Initiator+ Microwave Reactor.

The structure of the compound of the present invention is determined by nuclear magnetic resonance (Nuclear Magnetic Resonance, NMR) and mass spectrometry (Mass Spectrometry, MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). The determination of NMR is to use (Bruker Ascend ^TM 500 type) NMR instrument, and the determination solvent is deuterated dimethyl sulfide (DMSO-d 6 ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), internal Labeled as Tetramethylsilane (TMS). The following abbreviations are used for the multiplicity of NMR signals: s = singlet, brs = broad, d = doublet, t = triplet, m = multiplet. Coupling constants are listed as J values, measured in Hz.

The determination of LC-MS used Thermo liquid mass spectrometer (UltiMate 3000+MSQ PLUS). For HPLC measurement, a Thermo high pressure liquid chromatograph (UltiMate 3000) was used. Reverse-phase preparative chromatography Thermo (UltiMate 3000) reverse-phase preparative chromatography was used. The flash column chromatography uses Agel (FS-9200T) automatic column passing machine, and the silica gel prepacked column uses Santai SEPAFLASH® prepacked column. Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin-layer chromatography silica gel plates, and the specifications of thin-layer chromatography separation and purification products are 0.4mm~0.5mm.

Example 1

(S)-4,5-Dimethyl-2-((trans-3-(3,4,5-trifluorophenoxy)cyclobutyl)amino)-4,5,9,10-tetrahydro -6H,8H-Pyrido[3,2,1-de]pteridin-6-one

Compound 1 was prepared by the following steps:

The first step: cis-3-BOC-aminocyclobutanol 1a (250mg, 1.34mmol), methanesulfonic anhydride (465mg, 2.67mmol) and N,N-diisopropylethylamine (517mg, 4.01mmol ) was dissolved in dichloromethane (2 mL), and stirred overnight at room temperature. Thin layer chromatography (Thin layer chromatography, TLC) monitored the end of the reaction, the reaction solution was diluted with dichloromethane, washed with water and saturated brine successively, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow solid 1b (300 mg, yield 84%). ¹ H NMR (500MHz, DMSO- d6 )δ7.23(d, J =8.3Hz, 1H), 4.69-4.64(m, 1H), 3.63-3.60(m, 1H), 3.13(s, 3H), 2.70 -2.62(m,2H),2.16-2.09(m,2H),1.37(s,9H).

Second step: Dissolve compound 1b (300mg, 1.13mmol), compound 1c (251mg, 1.70mmol) and cesium carbonate (737mg, 2.26mmol) in N,N-dimethylformamide (2mL) at 80 Stir overnight at °C. Liquid chromatography-tandem mass spectrometry (LCMS) monitored the end of the reaction, the reaction solution was diluted with ethyl acetate, washed with water and saturated brine in turn, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was Purification by silica gel column chromatography (dichloromethane/methanol=20/1) gave white solid 1d (280 mg, yield 78%). ESI-MS (m/z): 318.6 [M+H] ⁺ .

Step 3: Compound 1d (280mg, 882umol) was dissolved in dichloromethane (2mL), 1,4-dioxane hydrochloride solution (4M, 1.10mL) was added dropwise, and stirred overnight at room temperature. LCMS monitored the completion of the reaction, and the reaction solution was concentrated to obtain a white solid 1e (170 mg, yield 75%). ESI-MS (m/z): 218.4 [M+H] ⁺ .

The fourth step: 2,4-dichloropyrido[3,2-d]pyrimidine 1f (1.7g, 8.50mmol) and (S)-2-(methylamino)propionic acid methyl ester hydrochloride 1g ( 1.70 g, 11.05 mmol) was dissolved in tetrahydrofuran (40 mL), triethylamine (2.58 g, 25.50 mmol, 3.53 mL) was added, and stirred overnight at room temperature. The completion of the reaction was monitored by LCMS, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography to obtain a yellow oil 1h (1.1 g, yield 46%). ESI-MS (m/z): 281.2 [M+H] ⁺ .

Step 5: Dissolve compound 1h (1.1g, 3.92mmol) in tetrahydrofuran (20mL), add aqueous hydrochloric acid (6N, 0.65mL) and platinum dioxide (88mg, 0.39mmol), and replace the hydrogen gas with a hydrogen balloon in the reaction system, Stir at room temperature under hydrogen balloon pressure for 48 hours, and monitor the completion of the reaction by LCMS. The reaction solution was diluted with methanol, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain white solid 1i (900 mg, yield 90%). ESI-MS (m/z): 253.2 [M+H] ⁺ .

Step 6: Dissolve compound 1i (50mg, 197umol), compound 1e (65mg, 257umol) and p-toluenesulfonic acid monohydrate (3.7mg, 19umol) in n-butanol (2mL), microwave at 160°C React for 2 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 1 (13 mg, yield 15%). ESI-MS (m/z): 434.3[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 6.90-6.82 (m, 3H), 4.86-4.81 (m, 1H), 4.42-4.36 ( m,1H),4.12(q, J =6.8Hz,1H),4,05-4.00(m,1H),3.30-3.24(m,1H),2.94(s,3H),2.55-2.52(m, 2H),2.48-2.38(m,2H),2.36-2.28(m,2H),1.97-1.88(m,1H),1.85-1.76(m,1H),1.23(d, J =6.8Hz,3H) .

Example 2

(S)-4,5-Dimethyl-2-((trans-3-((6-(trifluoromethyl)pyridin-3-yl)oxo)cyclobutyl)amino)-4,5, 9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

Compound 2 was prepared by the following steps:

The first step: Dissolve compound 1b (500mg, 1.88mmol), compound 2a (461mg, 2.83mmol) and cesium carbonate (1.23g, 3.77mmol) in N,N-dimethylformamide (2mL), in Stir overnight at 80°C. LCMS monitored the completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water and saturated brine successively, the organic phase was dried over anhydrous sodium sulfate, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=20/ 1) A white solid 2b (500 mg, yield 79%) was obtained. ESI-MS (m/z): 333.3 [M+H] ⁺ .

Step 2: Compound 2b (500mg, 1.50mmol) was dissolved in dichloromethane (2mL), 1,4-dioxane hydrochloride solution (4M, 1.88mL) was added dropwise, and stirred overnight at room temperature. LCMS monitored the completion of the reaction, and the reaction solution was concentrated to obtain a white solid 2c (300 mg, yield 74%). ESI-MS (m/z): 233.5 [M+H] ⁺ .

Step 3: Dissolve compound 1i (50mg, 197umol), compound 2c (68mg, 256umol) and p-toluenesulfonic acid monohydrate (3.7mg, 19umol) in n-butanol (2mL), and microwave at 160°C React for 2 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 2 (10.1 mg, yield 11%). ESI-MS (m/z): 449.2[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 8.38(d, J =2.8Hz, 1H), 7.83(d, J =8.7Hz, 1H ),7.46(dd, J =8.7,2.9 Hz,1H),6.91(d, J =6.9Hz,1H),5.05-5.00(m,1H),4.46-4.42(m,1H),4.12(q, J =6.9Hz,1H),4.03-3.99(m,2H),3.28-3.25(m,1H),2.95(s,3H),2.50-2.38(m,4H),1.97-1.87(m,1H) , 1.84-1.77 (m, 1H), 1.23 (d, J =6.7Hz, 3H).

Example 3

(R)-4,6-Dimethyl-N-(trans-3-(3,4,5-trifluorophenoxy)cyclobutyl)-5,6-dihydro-4H-pyrrolo[3 ,2,1-De]pteridin-2-amine

Compound 3 was prepared by the following steps:

The first step: Compound 3a (500mg, 2.66mmol), compound 3b (946mg, 3.99mmol), potassium carbonate (1.47g, 10.64mmol) and 18-crown-6 (351mg, 1.33mmol) were dissolved in 1,4- Dioxane (10 mL) was stirred overnight at 80°C. LCMS monitored the completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water and saturated brine in turn, the organic phase was dried over anhydrous sodium sulfate, concentrated by filtration, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/ 1) A yellow solid 3c (600 mg, yield 65%) was obtained. ESI-MS (m/z): 345.3 [M+H] ⁺ .

Step 2: Compound 3c (600mg, 1.74mmol) was dissolved in dichloromethane (2mL), 1,4-dioxane hydrochloride solution (4M, 2.17mL) was added dropwise, and stirred overnight at room temperature. The completion of the reaction was monitored by LCMS, and the reaction solution was concentrated to obtain a white solid 3d (400 mg, yield 81%). ESI-MS (m/z): 245.3 [M+H] ⁺ .

Step 3: Dissolve compound 3d (400mg, 1.63mmol) and N,N-diisopropylethylamine (632mg, 4.90mmol) in 1,4-dioxane (5mL) at 100°C Stir overnight. LCMS monitored the completion of the reaction, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain a yellow solid 3e (150 mg, yield 44%). ESI-MS (m/z): 209.4 [M+H] ⁺ .

Step 4: Dissolve compound 3e (150mg, 718umol), methyl iodide (153mg, 1.08mmol) and cesium carbonate (468mg, 1.44mmol) in N,N-dimethylformamide (2mL) at 80°C Stirring overnight. LCMS monitored the completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water and saturated brine in turn, the organic phase was dried over anhydrous sodium sulfate, concentrated by filtration, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1 ) afforded 3f (100 mg, yield 62%) as a yellow solid. ESI-MS (m/z): 223.4 [M+H] ⁺ .

Step 5: Dissolve compound 3f (30mg, 134umol), compound 1e (68mg, 256umol) and trifluoroacetic acid (1.5mg, 13umol) in n-butanol (2mL) and react under microwave conditions at 160°C for 2 hours . LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain a white solid 3 (6.8 mg, yield 12%). ESI-MS (m/z): 404.2[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 8.19 (s, 1H), 7.30 (d, J =2.8Hz, 1H), 6.92-6.82 (m,2H),6.04(d, J =2.8Hz,1H),4.93-4.81(m,1H),4.46-4.41(m,1H),4.37-4.24(m,1H),3.64(dd, J =12.4,3.9Hz,1H),3.35-3.30(m,1H),3.05(s,3H),2.48-2.42(m,2H),2.38-2.33(m,2H),1.42(d, J =6.4 Hz, 3H).

Example 4

(R)-4,6-Dimethyl-N-(trans-3-((6-(trifluoromethyl)pyridin-3-yl)oxo)cyclobutyl)-5,6-dihydro- 4H-Pyrrolo[3,2,1-de]pteridin-2-amine

Compound 4 was prepared by the following steps:

Step 1: Dissolve compound 3f (30mg, 134umol), compound 2b (40mg, 175umol) and trifluoroacetic acid (1.5mg, 13umol) in n-butanol (2mL) and react under microwave conditions at 160°C for 2 hours . LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain 4 (9.3 mg, yield 16%) as a white solid. ESI-MS (m/z): 419.5[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO- d6 ) δ 8.39(d, J =2.8Hz, 1H), 8.20(s, 1H), 7.84(d , J =8.7Hz,1H),7.47(dd, J =8.7,2.9Hz,1H),7.30(d, J =2.8Hz,1H),6.69(br s,1H),6.04(d, J =2.8 Hz,1H),5.08-5.02(m,1H),4.53-4.45(m,1H),4.35-4.25(m,1H),3.64(dd, J =12.3,3.9Hz,2H),3.05(s, 3H), 2.50-2.40(m, 4H), 1.42(d, J =6.4Hz, 3H).

Example 5

(S)-4,6-Dimethyl-N-(trans-3-((6-(trifluoromethyl)pyridin-3-yl)oxo)cyclobutyl)-5,6-dihydro- 4H-Pyrrolo[3,2,1-de]pteridin-2-amine

Compound 5 was prepared by the following steps:

The first step: Dissolve compound 3a (792mg, 4.21mmol), compound 5a (1g, 4.21mmol), potassium carbonate (2.33g, 16.86mmol) and 18-crown-6 (557mg, 2.11mmol) in 1,4- Dioxane (10 mL) was stirred overnight at 80°C. LCMS monitored the completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water and saturated brine in turn, the organic phase was dried over anhydrous sodium sulfate, concentrated by filtration, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/ 1) A yellow solid 5b (1 g, yield 68%) was obtained. ESI-MS (m/z): 345.3 [M+H] ⁺ .

Step 2: Dissolve compound 5b (1.0g, 2.90mmol) in dichloromethane (10mL), add 1,4-dioxane hydrochloride solution (4M, 3.62mL) dropwise, and stir overnight at room temperature . LCMS monitored the completion of the reaction, and the reaction solution was concentrated to obtain a white solid 5c (700 mg, yield 98%). ESI-MS (m/z): 245.4 [M+H] ⁺ .

Step 3: Dissolve compound 5c (700mg, 2.86mmol) and N,N-diisopropylethylamine (1.11g, 8.57mmol, 1.49mL) in 1,4-dioxane (10mL), and Stir overnight at 100°C. The completion of the reaction was monitored by LCMS, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain a yellow solid 5d (250 mg, yield 41%). ESI-MS (m/z): 209.4 [M+H] ⁺ .

Step 4: Dissolve compound 5d (250mg, 1.20mmol), methyl iodide (153mg, 1.08mmol) and cesium carbonate (468mg, 1.44mmol) in N,N-dimethylformamide (2mL) at 80 Stir overnight at °C. LCMS monitored the completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water and saturated brine in turn, the organic phase was dried over anhydrous sodium sulfate, concentrated by filtration, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1 ) gave yellow solid 5e (150 mg, yield 56%). ESI-MS (m/z): 223.4 [M+H] ⁺ .

Step 5: Dissolve compound 5e (30mg, 134umol), compound 2b (47mg, 175umol) and trifluoroacetic acid (1.5mg, 13umol) in n-butanol (2mL) and react under microwave conditions at 160°C for 2 hours . LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain a white solid 5 (9.2 mg, yield 16%). ESI-MS (m/z): 419.4[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO- d6 ) δ 8.39(d, J =2.8Hz, 1H), 8.22(s, 1H), 7.84(d , J =8.7Hz,1H),7.47(dd, J =8.7,2.8Hz,1H),7.30(d, J =2.8Hz,1H),6.74(br s,1H),6.04(d, J =2.8 Hz, 1H),5.10-4.99(m,1H),4.51-4.45(m,1H),4.31-4.25(m,1H),3.64(d, J =8.5Hz,1H),3.34-3.27(m, 1H), 3.05(s, 3H), 2.49-2.39(m, 4H), 1.42(d, J =6.4Hz, 3H).

Example 6

(S)-4,6-Dimethyl-N-(trans-3-(3,4,5-trifluorophenoxy)cyclobutyl)-5,6-dihydro-4H-pyrrolo[3 ,2,1-De]pteridin-2-amine

Compound 6 was prepared by the following steps:

Step 1: Dissolve compound 5e (30mg, 134umol), compound 1e (44mg, 175umol) and trifluoroacetic acid (1.5mg, 13umol) in n-butanol (2mL) and react under microwave conditions at 160°C for 2 hours . LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain a white solid 6 (17.84 mg, yield 32%). ESI-MS (m/z): 404.2[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO- d6 ) δ 8.22 (s, 1H), 7.31 (d, J =2.8Hz, 1H), 6.91-6.84 (m,2H),6.05(d, J =2.8Hz,1H),4.94-4.80(m,1H),4.45-4.40(m,1H),4.31-4.25(m,1H),3.68-3.63(m ,1H), 3.31(dd, J =12.4,8.2Hz,1H),3.05(s,3H),2.47-2.29(m,4H),1.42(d, J =6.4Hz,3H).

Example 7

(S)-4,5-Dimethyl-2-((cis-3-((6-(trifluoromethyl)pyridin-3-yl)amino)cyclobutyl)amino)-4,5,9 ,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

Compound 7 was prepared by the following steps:

The first step: 5-bromo-2-trifluoromethylpyridine 7a (452mg, 2.00mmol), cis-3-amino-1-cyclobutylcarbamate tert-butyl ester 7b (372mg, 2.00mmol), Pd2 (dba)3 (91.5mg, 0.10mmol), Xantphos (115.6mg, 0.20mmol) and cesium carbonate (1.3g, 4.00mmol) were dissolved in dioxane (10mL), stirred overnight at 100°C under nitrogen protection. The end of the reaction was monitored by TLC, the reaction solution was cooled to room temperature, filtered, the filter cake was washed twice with dichloromethane, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to obtain a white solid 7c (580 mg, 87% yield). ESI-MS (m/z): 332.3 [M+H] ⁺ .

Step 2: Dissolve compound 7c (100 mg, 0.3 mmol) in methanol (5 mL), add hydrogen chloride-dioxane solution (4M, 0.75 mL, 3 mmol) dropwise at room temperature, and stir at room temperature for 2 hours. The completion of the reaction was monitored by TLC, and the reaction solution was spin-dried to obtain a white solid 7d (80 mg, yield 99%). ESI-MS (m/z): 232.4 [M+H] ⁺ .

Step 3: Dissolve compound 1i (76mg, 0.30umol), compound 7d (80mg, 0.30mol) and p-toluenesulfonic acid monohydrate (5.7mg, 0.03mol) in n-butanol (3mL) and heat in microwave at 160°C Under the conditions of reaction for 2 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain a white solid 7 (45 mg, yield 33%). ESI-MS(m/z): 448.5[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO- d ₆ )δ 8.01(d, J =2.7Hz,1H),7.51(d, J =8.7Hz, 1H),6.98-6.90(m,2H),6.81(d, J =7.5Hz,1H),4.19-3.97(m,3H),3.58(q, J =7.4Hz,1H),3.32-3.21(m ,1H),2.96(s,3H),2.83-2.70(m,2H),2.55-2.52(m,2H),1.98-1.88(m,1H),1.86-1.73(m,3H),1.23(d , J =6.8Hz,3H).

Example 8

(S)-4,5-Dimethyl-2-((trans-3-((6-(trifluoromethyl)pyridin-3-yl)amino)cyclobutyl)amino)-4,5,9 ,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

Substitute tert-butyl (trans-3-aminocyclobutyl)carbamate for 7b in the first step in Example 7, and use similar methods and reaction steps to obtain compound 8 . ESI-MS(m/z): 448.5[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO- d ₆ )δ 7.98(d, J =2.7Hz,1H), 7.53(d, J =8.6Hz, 1H),7.08(d, J =5.5Hz,1H),6.92-6.80(m,2H),4.44(q, J =7.3Hz,1H),4.12(q, J =6.7Hz,1H),4.07- 3.98(m,1H),3.96-3.86(m,1H),3.32-3.22(m,1H),2.95(s,3H),2.42-2.28(m,2H),2.25-2.14(m,2H), 1.97-1.87(m, 1H), 1.85-1.72(m, 1H), 1.23(d, J =6.8Hz, 3H).

Example 9

(S)-4,5-Dimethyl-2-((trans-3-((6-(trifluoromethyl)pyridin-3-yl)amino)cyclopentyl)amino)-4,5,9 ,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

Substituting tert-butyl N-[trans-3-aminocyclopentyl]carbamate for 7b in the first step in Example 7, and using a similar method and reaction steps, compound 9 was obtained. ESI-MS(m/z): 462.4[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ )δ 8.04(d, J =2.7Hz,1H),7.51(d, J =8.7Hz, 1H),6.98(dd, J =8.7,2.8Hz,1H),6.74(d, J =6.6Hz,1H),6.56(d, J =7.6Hz,1H),4.29(q, J =6.9Hz, 1H),4.11(q, J =6.7Hz,1H),4.03(dt, J =13.0,4.7Hz,1H),3.92(q, J =6.4Hz,1H),3.30-3.22(m,1H), 2.93(s,3H),2.53(d, J =5.0Hz,2H),2.19-2.02(m,2H),1.91(p, J =6.9Hz,2H),1.80(dt, J =12.7,6.7Hz ,2H), 1.58-1.41(m,2H), 1.23(d, J =6.8Hz,3H).

Example 10

(S)-4,5-Dimethyl-2-((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)azetidin-3-yl)amino)-4, 5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

Compound 10 was prepared by the following steps:

The first step: Dissolve compound 1i (200mg, 79lumol) and compound 10a (451mg, 1.58mmol) in 10mL dioxane, add Pd ₂ dba ₃ (72mg, 79umol), S-Phos (65mg, 158umol) and Sodium tert-butoxide (228mg, 2.37mmol) was overnight at 100°C under the protection of nitrogen, and the reaction of the starting material was complete as monitored by LCMS. The reaction solution was concentrated, and the residue was purified by preparative thin-layer chromatography (dichloromethane/methanol=20/1) to obtain compound 10b (90 mg, yield 29%), a yellow oil. ESI-MS (m/z): 389.5 [M+H] ⁺ .

The second step: compound 10b (90mg, 232umol) was dissolved in 10mL of dichloromethane, trifluoroacetic acid (1mL) was added, stirred at room temperature for 4 hours, LCMS monitored the complete reaction of raw materials, and the reaction solution was concentrated to obtain compound 10c (90mg), The yellow oil was directly used in the next reaction. ESI-MS (m/z): 289.4 [M+H] ⁺ .

Step 3: Compounds 10c (90mg) and 10d (53mg, 269umol) were dissolved in 10mL of acetonitrile, potassium carbonate (93mg, 673umol) was added, and reacted at 60°C for 4 hours. LCMS monitored the complete reaction of the raw materials. The reaction solution was concentrated, and the residue was purified by reverse preparative HPLC to obtain compound 10 (10 mg, yield 10.3%) as a white solid. ESI-MS (m/z): 448.5[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 8.66(s, 1H), 7.96(d, J =8.0Hz, 1H), 7.85(d ,J=8.0Hz,1H),6.89(d, J =6.9Hz,1H),4.40(q, J =7.0Hz,1H),4.12(q, J =6.8Hz,1H),4.01(dt, J =13.0,4.9Hz,1H),3.72(s,2H),3.59(t, J =6.8Hz,2H),3.30-3.23(m,1H),2.95(d, J =8.0Hz,5H),2.52 (s,2H),1.92(d, J =14.5Hz,1H),1.80(d, J =3.9Hz,1H),1.23(d, J =6.7Hz,3H).

Example 11

(S)-4,5-Dimethyl-2-(((1s,3R)-3-(((6-(trifluoromethyl)pyridin-3-yl)oxo)methyl)cyclobutyl )amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

Compound 11 was prepared by the following steps:

The first step: cis-3-hydroxymethylcyclobutylcarbamate tert-butyl ester 11a (150mg, 0.745mmol), methanesulfonic anhydride (259mg, 1.49mmol) and N,N-diisopropylethylamine (385mg, 2.98mmol) was dissolved in dichloromethane (5mL) and stirred overnight at room temperature. The completion of the reaction was monitored by TLC. The reaction solution was diluted with dichloromethane, washed with water and saturated brine successively, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow solid 11b (204 mg, yield 98%). ¹ H NMR (500MHz, DMSO- d6 )δ 7.10(d, J =8.1Hz, 1H), 4.11(d, J =5.2Hz, 2H), 3.19(d, J =1.6Hz, 1H), 3.16(d , J =1.6Hz, 3H), 2.26(d, J =5.9Hz, 1H), 1.68(d, J =8.7Hz, 2H), 1.57-1.47(m, 2H), 1.37(s, 9H).

The second step: Dissolve compound 11b (204mg, 731umol), compound 2a (131mg, 0.8mmol) and cesium carbonate (485mg, 1.49mmol) in N,N-dimethylformamide (5mL), at 90°C Stir overnight. The end of the reaction was monitored by TLC, the reaction solution was diluted with water, extracted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated by filtration, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) A yellow solid 11c (185 mg, yield 72%) was obtained. ESI-MS (m/z): 347.2 [M+H] ⁺ .

Step 3: Compound 11c (120mg, 346umol) was dissolved in dichloromethane (5mL), and 4M dioxane hydrochloride solution (0.87mL) was added at 0°C and stirred overnight. The completion of the reaction was monitored by TLC, and the reaction was directly spin-dried to obtain a white solid 11d (85 mg, yield 99%). ESI-MS (m/z): 247.4 [M+H] ⁺ .

Step 4: Dissolve compound 11d (82mg, 336umol), compound 1i (85mg, 336umol) and p-toluenesulfonic acid monohydrate (5.7mg, 33.6umol) in n-butanol (3mL), microwave at 160°C The reaction was carried out for 3 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain a white solid 11 (25 mg, yield 16%). ESI-MS (m/z): 463.3[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 8.47(d, J =3.0Hz, 1H), 7.85(d, J =8.5Hz, 1H ),7.64(dd, J =9.0,3.0Hz,1H),6.81(br s,1H),4.32-4.23(m,1H),4.16-4.09(m,3H),4.08-4.01(m,1H) ,3.30-3.24(m,2H),2.95(s,3H),2.48-2.38(m,3H),1.97-1.88(m,1H),1.86-1.73(m,3H),1.23(d, J = 7.0Hz, 3H).

Example 12

(S)-2-(((1s,3R)-3-(((1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)methyl)ring Butyl)amino)-4,5-dimethyl-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

Compound 12 was prepared by the following steps:

Step 1: Ethyl trifluoroacetylacetate 12a (1.7g, 9.21mmol) and cyclopropylhydrazine hydrochloride 12b (1.0g, 9.21mmol) were dissolved in 20mL of ethanol and reacted overnight at 80°C. The reaction solution was concentrated, the residue was slurried with petroleum ether, and filtered to obtain compound 12c (800 mg, yield 45%) as a brown solid. ESI-MS (m/z): 193.2 [M+H] ⁺ .

Second step: Dissolve compound 11b (872mg, 3.12mmol), compound 12c (500mg, 2.61mmol) and cesium carbonate (1.70g, 5.22mmol) in N,N-dimethylformamide (20mL) at 90 Stir overnight at °C. The end of the reaction was monitored by TLC, the reaction solution was diluted with water, extracted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated by filtration, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) Yellow solid 12d (495 mg, yield 52%) was obtained. ESI-MS (m/z): 362.6 [M+H] ⁺ .

Step 3: Dissolve compound 12d (495 mg, 1.1 mmol) in dichloromethane (30 mL), add 4M dioxane hydrochloride solution (1.37 mL) at 0°C and stir overnight. The end of the reaction was monitored by TLC, and directly spin-dried to obtain a white solid 12e (231 mg, yield 80%). ESI-MS (m/z): 262.6 [M+H] ⁺ .

Step 4: Dissolve compound 12e (26mg, 95umol), compound 1i (20mg, 79umol) and p-toluenesulfonic acid monohydrate (0.4mg, 7.9umol) in n-butanol (3mL), microwave at 160°C The reaction was carried out for 3 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 12 (13 mg, yield 35%). ESI-MS (m/z): 492.4[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 6.67(br s,1H),6.17(s,1H),4.26-4.18(m,1H ),4.15-4.06(m,2H),4.05-3.97(m,1H),3.54-3.21(m,5H),2.94(s,3H),2.60-2.50(m,2H),2.47-2.35(m , 3H), 1.96-1.86(m, 1H), 1.85-1.70(m, 3H), 1.21(d, J =6.8Hz, 3H), 1.05-0.90(m, 4H).

Example 13

(S)-2-(((1s,3R)-3-(((1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)methyl)ring Butyl)amino)-5-(hydroxymethyl)-4,5-dimethyl-4,5,9,10-tetrahydro-6H,8H-pyrido [3,2,1-des]pteridin-6-one

Compound 13 was prepared by the following steps:

The first step: 2,4-dichloropyrido[3,2-d]pyrimidine 1f (4.0g, 20.0mmol) and 2-methyl-L-serine methyl ester hydrochloride 13a (4.07g, 24.0mmol ) was dissolved in dichloromethane (30 mL), N,N-diisopropylethylamine (7.75 g, 59.99 mmol, 10.45 mL) was added, and stirred overnight at room temperature. The completion of the reaction was monitored by LCMS, the reaction solution was diluted with dichloromethane, washed with water and saturated brine respectively, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a white solid 13b (5.0 g, yield 84%). ESI-MS (m/z): 297.3 [M+H] ⁺ .

The second step: Dissolve compound 13b (5.0g, 16.85mmol) in tetrahydrofuran (50mL), add aqueous hydrochloric acid (6M, 5.62mL) and platinum dioxide (382mg, 1.69mmol), and replace the hydrogen gas with a hydrogen balloon in the reaction system, Stir at room temperature under hydrogen balloon pressure for 48 hours, and monitor the completion of the reaction by LCMS. The reaction solution was diluted with methanol, filtered, and the filtrate was concentrated to give white solid 13c (4.0 g, yield 88%). ESI-MS (m/z): 269.3 [M+H] ⁺ .

The third step: Dissolve compound 13c (1.5g, 5.58mmol) and iodomethane (1.58g, 11.16mmol) in acetonitrile (5mL), add cesium carbonate (3.64g, 11.16 mmol), and the reaction mixture is heated at room temperature Stir for 48 hours. LCMS monitored the completion of the reaction. The reaction solution was diluted with ethyl acetate, filtered and washed with water and saturated brine respectively, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain yellow solid 13d (1.1 g, yield 69%). ESI-MS (m/z): 283.3 [M+H] ⁺ .

Step 4: Dissolve compound 12e (25mg, 84umol), compound 13d (20mg, 70.7umol) and p-toluenesulfonic acid monohydrate (0.4mg, 7.07umol) in n-butanol (3mL), and microwave at 160°C Under the condition of reaction for 3 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 13 (13 mg, yield 35%). ESI-MS(m/z): 522.3[M+H] ⁺ ; ¹ H NMR(500MHz,DMSO- d6 )δ 6.54(br s,1H),6.17(s,1H),5.06(t, J =5.5 Hz,1H),4.29-4.18(m,1H),4.10(d, J =4.9Hz,2H),3.76-3.67(m,2H),3.65-3.58(m,1H),3.57-3.49(m, 2H),2.97(s,3H),2.55-2.45(m,2H),2.44-2.32(m,3H),1.88-1.72(m,4H),1.33(s,3H),0.98(d, J = 7.8Hz, 4H).

Example 14

(S)-5-(hydroxymethyl)-4,5-dimethyl-2-(((1s,3R)-3-(((2-methyl-6-(trifluoromethyl)pyridine- 3-yl)oxo)methyl)cyclobutyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de] pteridin-6-one

Compound 14 was prepared by the following steps:

The first step: Compound 2a (2.0g, 12.26mmol), Na ₂ CO ₃ (2.6g, 24.52mmol) was added to water (60mL), stirred and dissolved, and iodine (3.11g, 12.26mmol) was added to the reaction solution, stirred at room temperature for 3 hours. LCMS monitored the disappearance of the raw materials, adjusted the pH of the reaction solution to 5-6 with dilute hydrochloric acid, and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated by filtration, and the residue was chromatographed on silica gel column (ethyl acetate/petroleum ether=0-30% gradient elution) to obtain white solid 14a (1.5 g, yield 42%). ESI-MS (m/z): 290.2 [M+H] ⁺ .

Step 2: Dissolve compound 14a (0.5g, 1.73mmol), benzyl bromide (337mg, 1.98mmol) in DMF (5mL), add K ₂ CO ₃ (364mg, 2.64mmol), stir at 50°C for 2 hours, LCMS Monitor translation completion. The reaction solution was diluted with water, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to silica gel column chromatography (gradient elution of ethyl acetate/petroleum ether=0-15%) to obtain 14b (0.5 g, yield 76%) as a white solid. ESI-MS (m/z): 380.2 [M+H] ⁺ .

The third step: Compound 14b (412mg, 1.09mmol), palladium acetate (24mg, 109umol), trimethylboroxane (682mg, 5.43mmol), tricyclohexylphosphine (152mg, 523umol), tripotassium phosphate (922mg, 4.35mmol), water (3mL), 1,4-dioxane (30mL) were added to a 100mL two-necked flask, and after nitrogen replacement, stirred overnight at 90°C, TLC monitored the end of the reaction, and the reaction solution was water Dilute, filter with diatomaceous earth, extract with ethyl acetate, and finally wash with saturated brine, dry the organic phase over anhydrous sodium sulfate, filter and concentrate, and the residue is purified by silica gel column chromatography (petroleum ether/ethyl acetate=10 /1) Yellow liquid 14c (198 mg, yield 68%) was obtained. ESI-MS (m/z): 268.2 [M+H]+.

Step 4: Dissolve compound 14c (198mg, 741umol) in dichloromethane (10mL), add boron tribromide (928mg, 3.71umol) dropwise at -78°C and stir for 1 hour. TLC monitors the end of the reaction. The solution was diluted with water, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain yellow liquid 14d (143 mg, obtained rate of 91%). ESI-MS (m/z): 178.4 [M+H]+.

Step 5: Dissolve compound 14d (120mg, 677umol), compound 11b (208mg, 745umol) and cesium carbonate (441mg, 1.35mmol) in N,N-dimethylformamide (5mL) at 90°C Stir overnight. The end of the reaction was monitored by TLC, the reaction solution was diluted with water, extracted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated by filtration, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain yellow solid 14e (196 mg, yield 80%). ESI-MS (m/z): 361.4 [M+H] ⁺ .

Step 6: Dissolve compound 14e (196mg, 543umol) in dichloromethane (10mL), add 4M hydrochloric acid (0.952mL) at 0°C and stir overnight. The completion of the reaction was monitored by TLC, and the reaction was directly spin-dried to obtain a white solid 14f (112 mg, yield 79%). ESI-MS (m/z): 261.3 [M+H] ⁺ .

Step 7: Dissolve compound 14f (27mg, 106umol), compound 13d (20mg, 70.7umol) and p-toluenesulfonic acid monohydrate (0.4mg, 7.07umol) in n-butanol (3mL), and microwave at 160°C Under the condition of reaction for 3 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain a white solid 14 (19 mg, yield 52%). ESI-MS (m/z): 507.3[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 7.67(d, J =8.5Hz, 1H), 7.48(d, J =8.5Hz, 1H ),6.54(br s,1H),5.06(t, J =5.5Hz,1H),4.29-4.19(m,1H),4.05(d, J =4.8Hz,2H),3.77-3.66(m,2H ),3.65-3.60(m,1H),3.58-3.53(m,1H),2.98(s,3H),2.48-2.35(m,8H),1.90-1.74(m,4H),1.33(s,3H ).

Example 15

(S)-2-(((1s,3R)-3-(((2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)oxo)methyl)cyclobutyl)amino )-5-(hydroxymethyl)-4,5-dimethyl-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de] pteridin-6-one

Compound 15 was prepared by the following steps:

The first step: Compound 14b (300mg, 0.791mmol), palladium acetate (18mg, 79umol), cyclopropylboronic acid (339mg, 3.96mmol), tricyclohexylphosphine (152mg, 523umol), tripotassium phosphate (672mg, 3.17 mmol), water (1mL), and 1,4-dioxane (10mL) were added to a 100mL two-necked flask, and after nitrogen replacement, stirred overnight at 90°C. The reaction was monitored by TLC, and the reaction solution was diluted with water and washed with silicon Filter through alginate, then extract with ethyl acetate, and finally wash with saturated brine, dry the organic phase over anhydrous sodium sulfate, filter and concentrate, and the residue is purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to obtain Yellow liquid 15a (209 mg, yield 90%). ESI-MS (m/z): 294.3 [M+H]+.

The second step: Dissolve compound 15a (209mg, 712umol) in dichloromethane (10mL), add boron tribromide (829mg, 3.56umol) dropwise at -78°C and stir for 1 hour, TLC monitors the end of the reaction, the reaction The solution was diluted with water, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain yellow liquid 15b (122 mg, obtained rate of 84%). ESI-MS (m/z): 204.4 [M+H]+.

Step 3: Dissolve compound 15b (122mg, 590umol), compound 11b (211mg, 758umol) and cesium carbonate (449mg, 1.38mmol) in N,N-dimethylformamide (5mL) at 90°C Stir overnight. The end of the reaction was monitored by TLC, the reaction solution was diluted with water, extracted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated by filtration, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) A yellow solid 15c (152 mg, yield 66%) was obtained. ESI-MS (m/z): 387.3 [M+H] ⁺ .

Step 4: Dissolve compound 15c (152mg, 393umol) in dichloromethane (10mL), add 4M hydrochloric acid (0.706mL) at 0°C and stir overnight. The completion of the reaction was monitored by TLC, and the reaction was directly spin-dried to obtain a white solid 15d (92 mg, yield 79%). ESI-MS (m/z): 287.3 [M+H] ⁺ .

Step 5: Dissolve compound 15d (46mg, 159umol), compound 13d (30mg, 106umol) and p-toluenesulfonic acid monohydrate (0.5mg, 10.6umol) in n-butanol (3mL), microwave at 160°C The reaction was carried out for 3 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain a white solid 15 (18 mg, yield 32%). ESI-MS (m/z): 533.1[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 7.56(dd, J =8.5,3.8Hz,1H), 7.45(d, J =8.5Hz ,1H),6.55(br s,1H),5.06(t,J=5.7Hz,1H),4.30-4.18(m,1H),4.06(d,J=5.1Hz,2H),3.77-3.66(m ,2H),3.65-3.59(m,1H),3.57-3.52(m,1H),2.98(s,3H),2.52-2.45(m,2H),2.44-2.35(m,3H),1.87-1.75 (m,4H), 1.33(s,3H), 1.02-0.97(m,2H), 0.95-0.89(m,2H).

Example 16

(S)-5-(methoxymethyl)-4-(methyl-d3)-2-(((1s,3R)-3-(((6-(trifluoromethyl)pyridine-3- Base) oxo) methyl) cyclobutyl) amino) -4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]phene pyridin-6-one

Compound 16 was prepared by the following steps:

The first step: 2,4-dichloropyrido[3,2-d]pyrimidine 1f (2g, 10.00mmol) and O-methyl-L-serine methyl ester hydrochloride 16a (2.45g, 15.00mmol) Dissolve in tetrahydrofuran (20 mL), add N,N-diisopropylethylamine (3.88 g, 30.00 mmol, 5.22 mL), and stir overnight at room temperature. LCMS monitored the completion of the reaction, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain yellow oil 16b (2.5 g, yield 84%). ESI-MS (m/z): 297.2 [M+H] ⁺ .

The second step: Dissolve compound 16b (2.5g, 8.43mmol) in tetrahydrofuran (30mL), add aqueous hydrochloric acid (6N, 1.40mL) and platinum dioxide (191 mg, 0.84mmol), and replace the hydrogen with a hydrogen balloon in the reaction system , stirred at room temperature under hydrogen balloon pressure for 48 hours, and LCMS monitored the completion of the reaction. The reaction solution was diluted with methanol, filtered through celite, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain gray solid 16c (2.0 g, yield 88%). ESI-MS (m/z): 269.3 [M+H] ⁺ .

Step 3: Dissolve compound 16c (200mg, 0.74mmol) and deuterated methyl iodide (215mg, 1.49mmol) in acetonitrile (5mL), add cesium carbonate (485mg, 1.49mmol), and react at 50°C for 2 Hour. LCMS monitored the completion of the reaction. The reaction solution was diluted with dichloromethane, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane/methanol=20/1) to obtain a yellow solid 16d (200 mg, yield 94%). ESI-MS (m/z): 286.3 [M+H] ⁺ .

Step 4: Dissolve compound 16d (25mg, 89umol), compound 11c (32mg, 131umol) and p-toluenesulfonic acid monohydrate (0.45mg, 8.9umol) in n-butanol (3mL), microwave at 160°C The reaction was carried out for 3 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain 16 (5 mg, yield 10%) as a white solid. ESI-MS (m/z): 496.4[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 8.43(d, J =2.7Hz, 1H), 7.82(d, J =8.7Hz, 1H ),7.59(dd, J =8.8,2.8Hz,1H),6.60(br s,1H),4.32-4.20(m,2H),4.09(d, J =5.0Hz,2H),4.03-3.94(m ,1H),3.72-3.60(m,2H),3.16(s,3H),2.52-2,46(m,2H),2.45-2.32(m,3H),1.94-1.85(m,1H),1.84 -1.69(m,3H).

Example 17

(S)-5-(hydroxymethyl)-4,5-dimethyl-2-(((1s,3R)-3-(((6-(trifluoromethyl)pyridin-3-yl)oxy Substitute)methyl)cyclobutyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridine-6- ketone

Using 6-(trifluoromethyl)pyridin-3-ol 2a to replace the raw material 14d in the fifth step in Example 14, and using a similar method and reaction steps, compound 17 was obtained. ESI-MS (m/z): 493.3[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 8.43(d, J =2.7Hz, 1H), 7.82(d, J =8.7Hz, 1H ),7.59(dd, J =8.6,2.8Hz,1H),6.53(br s,1H),5.06(t, J =5,5Hz,1H),4.29-4.18(m,1H),4.10(d, J =4.9Hz,2H),3.78-3.66(m,2H),3.65-3.58(m,1H),3.57-3.51(m,1H),2.98(s,3H),2.52-2.46(m,2H) ,2.45-2.34(m,3H),1.90-1.73(m,4H),1.33(s,3H).

Example 18

(S)-4,5-Dimethyl-2-(((1s,3R)-3-(((2-(trifluoromethyl)pyrimidin-5-yl)oxo)methyl)cyclobutyl )amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

Substitute 2-(trifluoromethyl)pyrimidin-5-ol for 2a in the first step in Example 11, and use a similar method and reaction steps to obtain compound 18 . ESI-MS (m/z): 464.3[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 8.76(s, 2H), 6.70(s, 1H), 4.28-4.17(m, 3H) ,4.11(q, J =6.8Hz,1H),4.11-4.39(m,1H),3.33(s,1H),3.30-3.22(m,2H),2.94(s,3H),2.52-2.46(m , 2H), 2.45-2.35(m, 3H), 1.95-1.86(m, 1H), 1.85-1.72(m, 3H), 1.21(d, J =6.7Hz, 3H).

Example 19

(S)-5-(Hydroxymethyl)-4,5-dimethyl-2-(((1s,3R)-3-((3,4,5-trifluorophenoxy)methyl)cyclo Butyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

Using 3,4,5-trifluorophenol 1c to replace the raw material 14d in the fifth step in Example 14, and using a similar method and reaction steps, compound 19 was obtained. ESI-MS (m/z): 478.4[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 7.10-6.95 (m, 2H), 6.48 (d, J =7.8Hz, 1H), 5.06 (br s,1H),4.24(q, J =8.0Hz,1H),3.94(d, J =5.9Hz,2H),3.81-3.70(m,2H),3.69-3.64(m,1H),3.57 (d, J =11.3Hz,1H),3.00(s,3H),2.52-2.45(m,2H),2.43-2.33(m,3H),1.90-1.80(m,2H),1.79-1.71(m ,2H), 1.35(s,3H).

Example 20

(S)-2-(((1s,3R)-3-((4-fluoro-2-(trifluoromethyl)phenoxy)methyl)cyclobutyl)amino)-5-(hydroxymethyl )-4,5-Dimethyl-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

Substituting 4-fluoro-2-(trifluoromethyl)phenol for the raw material 14d in the fifth step in Example 14, and using a similar method and reaction steps, compound 20 was obtained. ESI-MS (m/z): 510.4[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 )δ 7.60-7.50(m,2H),7.34-7.27(m,1H),6.43(br s ,1H),5.08(t, J =5.6Hz,1H),4.22(q, J =8.2Hz,1H),4.06(d, J =5.2Hz,2H),3.77-3.68(m,2H),3.67 -3.62(m,1H),3.61-3.55(m,1H),2.99(s,3H),2.51-2.45(m,2H),2.43-2.35(m,3H),1.90-1.83(m,2H) ,1.82-1.71(m,2H),1.34(s,3H).

Example 21

(S)-5-(hydroxymethyl)-4,5-dimethyl-2-(((1s,3R)-3-(((2-phenyl-6-(trifluoromethyl)pyridine- 3-yl)oxo)methyl)cyclobutyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de] pteridin-6-one

Compound 21 was prepared by the following steps:

The first step: Dissolve compound 21a (290mg, 1.46mmol), compound 11b (451mg, 1.61mmol) and cesium carbonate (191mg, 2.92mmol) in N,N-dimethylformamide (5mL), at 90°C Stirring overnight. The end of the reaction was monitored by TLC, the reaction solution was diluted with water, extracted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated by filtration, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) A yellow solid 21b (445 mg, yield 79%) was obtained. ESI-MS (m/z): 381.3 [M+H] ⁺ .

The second step: Compound 21b (158mg, 414umol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (30mg, 41.4umol), phenylboronic acid ( 101mg, 829umol), cesium carbonate (405mg, 1.24mmol), water (1mL), and dioxane (10mL) were added to a 25mL two-necked flask, and after nitrogen replacement, stirred overnight at 90°C, and TLC monitored the end of the reaction. The reaction solution was diluted with water, filtered with diatomaceous earth, extracted with ethyl acetate, and finally washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated by filtration, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate Ester=10/1) gave yellow liquid 21c (152 mg, yield 87%). ESI-MS (m/z): 423.4 [M+H] ⁺ .

Step 3: Compound 21c (78mg, 164umol) was dissolved in dichloromethane (5mL), and 4M dioxane hydrochloride solution (0.1mL) was added at 0°C and stirred overnight. The completion of the reaction was monitored by TLC, and the reaction was directly spin-dried to obtain a white solid 21d (43 mg, yield 72%). ESI-MS (m/z): 323.7 [M+H] ⁺ .

Step 4: Dissolve compound 21d (43mg, 133umol), compound 13d (25mg, 88.4umol) and p-toluenesulfonic acid monohydrate (1.31mg, 13.3umol) in n-butanol (3mL), and microwave at 160°C Under the condition of reaction for 3 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain a white solid 21 (14 mg, yield 27%). ESI-MS (m/z): 569.9[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 7.92(d, J =7.7Hz, 2H), 7.83(d, J =8.6Hz, 1H ),7.74(d, J =8.6Hz,1H),7.60-7.41(m,2H),7.44(d, J =7.2Hz,1H),6.40(br s,1H),5.06(t, J =5.6 Hz,1H),4.23(p, J =8.2Hz,1H),4.13(d, J =5.3Hz,2H),3.79-3.68(m,2H),3.66-3.61(m,1H),3.58-3.52 (m,1H), 2.98(s,3H), 2.52-2.35(m,5H), 1.90-1.72(m,4H), 1.33(s,2H).

Example 22

(S)-5-(Hydroxymethyl)-4,5-dimethyl-2-(((1s,3R)-3-(((2-(pyrrolidin-1-yl)-6-(tri Fluoromethyl)pyridin-3-yl)oxo)methyl)cyclobutyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido [3,2,1-des]pteridin-6-one

Compound 22 was prepared by the following steps:

The first step: Compound 14b (210mg, 554umol), Pd ₂ (dba) ₃ (50.7mg, 55.4umol), tetrahydropyrrole (89mg, 830umol), potassium tert-butoxide (310mg, 2.77mmol), 2-di Cyclohexaphosphino-2'-(N,N-dimethylamine)-biphenyl (65mg, 166umol) and toluene (8mL) were added to a 50mL one-necked flask, and the reaction system was replaced with nitrogen and stirred overnight at 80°C, LCMS The reaction was shown to be completely converted. The reaction solution was filtered with diatomaceous earth, extracted with ethyl acetate and water, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated by filtration, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain yellow liquid 22a (132 mg, yield 73%). ESI-MS (m/z): 323.3 [M+H]+.

The second step: Dissolve compound 22a (132mg, 409umol) in dichloromethane (10mL), add boron tribromide (474mg, 1.89umol) dropwise at -78°C and stir for 1 hour, TLC monitors the end of the reaction, the reaction The solution was diluted with water, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain yellow liquid 22b (65 mg, yield rate of 73%). ESI-MS (m/z): 233.3 [M+H]+.

Step 3: Dissolve compound 22b (65mg, 279umol) and compound 11b (86mg, 307umol) and cesium carbonate (189mg, 560umol) in N,N-dimethylformamide (5mL) and stir at 90°C overnight. The end of the reaction was monitored by TLC, the reaction solution was diluted with water, extracted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated by filtration, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) A yellow solid 22c (78 mg, yield 67%) was obtained. ESI-MS (m/z): 416.5 [M+H] ⁺ .

Step 4: Dissolve compound 22c (78mg, 187umol) in dichloromethane (5mL), add 4M dioxane hydrochloride solution (0.1mL) at 0°C and stir overnight. The completion of the reaction was monitored by TLC, and the reaction was directly spin-dried to obtain a white solid 22d (45 mg, yield 76%). ESI-MS (m/z): 316.5 [M+H] ⁺ .

Step 5: Dissolve compound 22d (40mg, 114umol), compound 13d (25mg, 88.4umol) and p-toluenesulfonic acid monohydrate (1.52mg, 8.82umol) in n-butanol (3mL), and microwave at 160°C Under the condition of reaction for 3 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain 22 (5 mg, yield 10%) as a white solid. ESI-MS (m/z): 562.4[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 7.12(d, J =7.9Hz, 1H), 6.95(d, J =7.9Hz, 1H ),6.50(br s,1H),5.07(t, J =5.4Hz,1H),4.28-4.16(m,1H),3.93(d, J =5.1Hz,2H),3.76-3.68(m,2H ),3.65-3.53(m,6H),2.98(s,3H),2.51-2.45(m,2H),2.43-2.35(m,3H),1.92-1.68(m,8H),1.33(s,3H ).

Example 23

(S)-5-(Hydroxymethyl)-4,5-dimethyl-2-(((1r,3S)-3-(3,4,5-trifluorophenoxy)cyclobutyl)amino )-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

Substitute intermediate 1e for 12e in the fourth step in Example 13, and use similar methods and reaction steps to obtain compound 23 . ESI-MS (m/z): 464.5[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 6.90-6.80 (m, 2H), 6.71 (d, J =6.9Hz, 1H), 5.07 (d, J =5.0Hz,1H),4.87-4.78(m,1H),4.45-4.33(m,1H),3.78-3.68(m,2H),3.66-3.58(m,1H),3.57-3.50 (m,1H), 2.97(s,3H), 2.52-2.37(m,4H), 2.36-2.28(m,2H), 1.90-1,75(m,2H), 1.33(s,3H).

Example 24

(S)-5-(Hydroxymethyl)-4-methyl-2-(((1r,3S)-3-(3,4,5-trifluorophenoxy)cyclobutyl)amino)-4 ,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

Compound 24 was prepared by the following steps:

Step 1: Dissolve compound 16c (500mg, 1.86mmol) and iodomethane (343mg, 2.42mmol) in acetonitrile (10mL), add cesium carbonate (1.21g, 372mmol), and react at 50°C for 2 hours. LCMS monitored the completion of the reaction. The reaction solution was diluted with dichloromethane, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane/methanol=20/1) to obtain a white solid 24a (350 mg, yield 66%). ESI-MS (m/z): 283.3 [M+H] ⁺ .

The second step: 24a (250mg, 0.88mmol) was dissolved in dichloromethane (2mL), and then boron tribromide (2.21g, 8.84mmol, 0.85mL) was added dropwise at 0°C. React for two hours. LCMS monitored the completion of the reaction. The reaction solution was carefully quenched with sodium bicarbonate solution, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by filtration, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=10/1) , to obtain white solid 24b (100 mg, yield 42%). ESI-MS (m/z): 269.3 [M+H] ⁺ .

Step 3: Dissolve compound 24b (30mg, 111umol), compound 1e (42mg, 167umol) and p-toluenesulfonic acid monohydrate (1.92mg, 11.1umol) in n-butanol (3mL), microwave at 160°C The reaction was carried out for 3 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain 24 (16 mg, yield 32%) as a white solid. ESI-MS (m/z): 450.3[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 6.91-6.79 (m, 2H), 6.76-6.69 (m, 1H), 5.01-4.95 ( m,1H),4.87-4.81(m,1H),4.45-4.33(m,1H),4.16-3.94(m,2H),3.80-3.63(m,2H),2.97(s,3H),2.51- 2.44 (m, 2H), 2.41-2.35 (m, 2H), 1.95-1.85 (m, 1H), 1.81-1.69 (m, 1H).

Example 25

(S)-4,5-Dimethyl-2-(((1r,3S)-3-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)oxo)cyclobutane Base)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

Substitute intermediate 14d for 2a in the first step in Example 2, and use similar methods and reaction steps to obtain compound 25 . ESI-MS(m/z): 463.5[M+H] ⁺ ; ¹ H NMR(500MHz, DMSO- d6 )δ7.66(d, J =8.5Hz,1H), 7.25(d, J =8.5Hz, 1H),6.88(d, J =6.8Hz,1H),4.97(br s,1H),4.50-4.36(m,1H),4.11(q, J =6.8Hz,1H),4.04-3.98(m, 1H),3.35-3.29(m,2H),2.94(s,3H),2.60-2.30(m,9H),2.00-1.88(m,1H),1.85-1.75(m,1H),1.23(d, J =6.6Hz, 3H).

Example 26

(S)-4,5-Dimethyl-2-(((1r,3S)-3-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)oxo)ring Butyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

Compound 26 was prepared by the following steps:

The first step: Ethyl formate (3.17g, 42.73mmol) and solid sodium ethoxide (3.49g, 50.50mmol) were sequentially added into dry tetrahydrofuran (140mL). After compound 26a (7 g, 38.85 mmol) was added at a temperature of 5-10° C., the reaction solution was heated to 50° C. and kept stirring for 2 hours, and the disappearance of the raw material was monitored by HPLC. Tetrahydrofuran was distilled off under reduced pressure to obtain yellow oil 26b , which was directly used in the next step.

The second step: add 150ml of absolute ethanol to the oil 26b obtained in the previous step, stir and dissolve at room temperature, add trifluoroacetamidine (4.35g, 33.01mmol, purity 85%) dropwise, and keep stirring at 30°C for 5 hours , and then the temperature was raised to 80° C. to continue stirring for 2 hours, and the disappearance of the raw material was monitored by HPLC. After the reaction solution cooled down, about 100ml of ethanol was evaporated under reduced pressure, the remaining residue was added to 300ml of ice water, the pH was adjusted to 3 with concentrated hydrochloric acid, stirred for 0.5 hours, filtered with suction, and the filter cake was dried to obtain compound 26c as a yellow solid (4.37g, yield 41%, purity 99%). ESI-MS (m/z): 271.4 [M+H] ⁺ .

Step 3: Add compound 26c (4.0g, 14.80mmol) to 60ml of acetonitrile, dropwise add phosphorus oxychloride (6.81g, 44.41mmol), stir for 10 minutes after the addition, heat up to 80°C, and keep stirring for 2 Hours, HPLC monitoring raw material conversion is complete. Acetonitrile was removed under reduced pressure, and the residue was added to 200 mL of ice water, stirred for 0.5 hours, and filtered with suction to obtain a yellow solid 26d (3.9 g, yield 86%, purity 95%).

The fourth step: compound 26d (2.0g, 6.93mmol), trimethylboroxane (2.61g, 20.79mmol), palladium acetate (155mg, 0.69mol), potassium phosphate (2.94g, 13.86mmol) in sequence Add it to 1,4-dioxane (150 mL), add water (15 mL), under nitrogen protection, keep stirring at 90° C. for 17 hours, HPLC monitors that the conversion of the raw material is complete, and the filtrate is concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/9) to obtain a white solid 26e (1.86 g, yield 50%, purity 99%). ESI-MS (m/z): 269.1 [M+H] ⁺ .

The fifth step: Dissolve compound 26e (280mg, 1.04mmol) in methanol (10mL), then add palladium carbon (13mg, 104umol), and replace the reaction system with hydrogen, react for 5 hours, TLC monitors the end of the reaction, and the reaction solution is used Celite was filtered, and the filtrate was concentrated to obtain yellow liquid 26f (170 mg, yield 91%). ESI-MS (m/z): 177.5 [MH] ^- .

Step 6: Dissolve compound 26f (120mg, 673umol) and compound 1b (268mg, 1.01mmol) and cesium carbonate (548mg, 1.68mmol) in N,N-dimethylformamide (5mL) at 90°C Stir overnight. The end of the reaction was monitored by TLC, the reaction solution was diluted with water, extracted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated by filtration, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) 26g (148mg, yield 62%) of yellow solid was obtained. ESI-MS (m/z): 348.5 [M+H] ⁺ .

Step 7: Dissolve compound 26g (148mg, 340umol) in dichloromethane (5mL), add 4M hydrochloric acid (0.4mL) at 0°C and stir overnight. The end of the reaction was monitored by TLC, and directly spin-dried to obtain a white solid 26h (84 mg, yield 86%). ESI-MS (m/z): 284.4 [M+H] ⁺ .

Step 8: Dissolve compound 26h (30mg, 118umol), compound 1i (35mg, 142umol) and p-toluenesulfonic acid monohydrate (2mg, 11.8umol) in n-butanol (3mL), and microwave at 160°C React for 3 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse-phase preparative HPLC to obtain 26 (14 mg, yield 25%) as a white solid. ESI-MS (m/z): 464.5[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ8.34 (s, 1H), 6.87 (d, J =6.9Hz, 1H), 5.19- 5.08(m,1H),4.52-4.41(m,1H),4.12(q, J =6.9Hz,1H),4.08-3.99(m,1H),3.29-3.24(m,2H),2.95(s, 3H), 2.58-2.41(m, 9H), 2.00-1.90(m, 1H), 1.86-1.73(m, 1H), 1.23(d, J =6.8Hz, 3H).

According to the synthetic route and the synthetic method of the intermediate described in the above examples, the following examples can be obtained.

Biological Screening and Results of Wnt Pathway Inhibitors

Test Example 1: Construction of Colo205-LUC-TCF/LEF-M1 reporter cell line

Colo205 cell line (Cell Bank of Chinese Academy of Sciences, Cat # TCHu102) was purchased from the Cell Bank of Chinese Academy of Sciences. After expansion and subculture, in the exponential growth phase of the cells, transfection with lipo3000 liposomes was transfected with TCF/LEF transcription factors driven luciferase reporter plasmid (Promega). The plasmid carries a resistance gene for resistance screening. Transfection was carried out in 10 cm culture dishes using conventional complete medium without resistance. After 2 days, the medium with resistance was replaced, and the culture was continued. Afterwards, the resistant medium was replaced every 2 days, and the suspended cells were discarded. The original medium was centrifuged to remove cells and debris and retained as an adaptive medium. When the cells covered the culture dish, the cells were digested, counted, and subcultured in a 96-well plate, so that the average number of cells contained in each well was 1.5 per well, and an adaptive medium was used for subculture. The remaining cells were frozen. After subculture, culture for 4 hours to allow the cells to adhere to the wall, and then observe the number of cells in each well under a microscope. Wells with only 1 cell per well were labeled as monoclonal wells. Afterwards, normal culture was performed, and the culture medium was replaced every 2 days, and observed. There are holes where the monoclonal cells continue to grow in the early stage, and they are labeled twice, and can be replaced with normal resistant medium. When the cells in the monoclonal wells are full of 96-well plates, they are digested and passaged to 24-well culture plates. After the 24-well plates are full, they are passed to one 96-well plate and one 6-well plate. The cells in the 96-well plate were subcultured to at least 6 wells, 3 wells were added with known Wnt inhibitors, and the other 3 wells were not treated. After 24 hours, the cells in the 96-well plate were added with a fluorescence detection reagent to detect the fluorescence intensity. Cell lines with fluorescent expression when not treated and decreased fluorescent light after inhibition were selected and further cultured. Colo205-LUC-TCF/LEF-M1 cell line is one of the above screened cell lines, its growth curve, cell shape, and cell growth state are similar to those of the original Colo205 cells, and the fluorescence signals of inhibitor treatment and no treatment The ratio is the largest among all cell lines, and the ratio can be inhibited by 4-5 times at 4 hours, which is completely suitable for the screening of Wnt inhibitors in the later stage.

Test Example 2: Detection of Compounds’ Inhibitory Ability to Colo205-LUC-TCF/LEF M1 Reporter Cell Line

The Colo205-LUC-TCF/LEF M1 cell line is a reporter tool cell stably transfected with the pGL4.49-LUC2-TCF/LEF vector, and its β-catenin Wnt pathway is continuously activated. The expression of firefly luciferase regulated by the TCF/LEF cis-element decreased, and after adding the detection substrate, the detection The received light signal decreases accordingly, thereby detecting the inhibitory effect of the compound.

Add 100 μL of the compound with the highest concentration of 20 μM to each well of the 96-well cell culture plate, and make a 3-fold serial dilution of the compound concentration. Then 10,000 colo205 cells stably transfected with the reporter gene and 100 μL medium were inoculated into each well, and corresponding treatments were performed simultaneously as positive and negative control wells. Place the cells in a 5% _CO2 cell culture incubator and incubate at 37°C for 4 hours. After 4 hours, remove the culture medium, add 100 μL of reagent (Promega) containing the corresponding firefly luciferase substrate to each well, and measure luciferin. Enzyme reporter gene activity. Luminescence intensities were read with SpectraMax in full wavelength mode. The light signal intensity of cells treated only with DMSO was used as a positive control, and the light signal intensity of wells without cells was used as a negative control, and the concentration of IC ₅₀ of each compound was calculated. Colo 205 reporter gene detection data are summarized in Table 1 below.

Test Example 3: Anti-proliferation test of compounds on Wnt mutant cell lines (Colo205, DU4475, NCI-H929 and HepG2) and non-Wnt mutant cell lines (Hela and RKO)

The cell lines used in the experiment are Colo205, DU4475, NCI-H929 and HepG2 cell lines whose Wnt pathway is continuously activated, and whose proliferation is Wnt pathway-dependent; under normal circumstances, the Wnt pathway is not activated, and the proliferation is not dependent on the Wnt pathway HELA and RKO cell lines were used as control cell lines, and it was judged that the inhibitory effect of the compound of the present invention on Wnt-dependent proliferation was not caused by other non-specific toxicity.

Colo205, Du4475, NCI-H929, HepG2, HELA, and RKO cell lines cultured in their respective culture media were treated during the logarithmic growth phase, and the cells were collected and prepared into a uniform cell suspension of known concentration, and then cultured in 96-well cells The cell suspension was added to the plate so that each well contained 1000 cells. Place in a 5% CO ₂ incubator and incubate at 37°C for 20-24h. On the second day, the fully dissolved, 3-fold serially diluted compound was added to each cell culture well, so that the final maximum concentration in the cell culture well was 20 μM, and the culture was continued for 96 h. In this test, Promega's cell viability detection test is used for detection. The more the cells proliferate, the stronger the final signal intensity will be. The detection instrument is SpectraMax, full wavelength mode. The wells only added with DMSO were used as positive control wells, and the wells without inoculated cells were used as negative control wells. The _IC50 values of each compound for the inhibition of proliferation of Wnt-initiated or proliferation-dependent cells, and for Wnt-uninitiated or proliferation-independent cells were calculated. The IC ₅₀ value of the inhibition of cell proliferation was used to evaluate the inhibitory effect of the compound on the Wnt pathway and the toxic effect on normal cells. The results are shown in Table 2 below.

The above results show that the compound of the present invention has significant inhibitory activity on mutant cell lines Colo205, DU4475, NCI-H929 and HepG2, but has no significant inhibitory activity on Hela and RKO cell lines, which shows that the compound of the present invention has significant and selective Sexual Wnt pathway inhibition.

Claims (20)

A compound having a structure of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, and stereoisomer thereof:

in: --- Indicates the presence or absence of a single bond; R ¹ represents C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 3-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, and said R1 Can be optionally 0, 1, 2, 3 selected from: hydrogen, halogen, OR ^a , nitro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ - C ₆ ) haloalkyl, (C ₃ -C ₆ ) cycloalkyl, halo (C ₃ -C ₆ ) cycloalkyl, 3-6 membered heterocycloalkyl, halogenated 3-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, cyano, S R ^a , halo(C ₁ -C ₆ )alkoxy, halo(C ₃ -C ₆ )cycloalkoxy, halo (C ₁ -C ₆ )alkylthio, (C ₃ -C ₆ )cycloalkyloxy, (C ₃ -C ₆ )cycloalkylthio, halo(C ₃ -C ₆ )cycloalkane Substituents of thio groups are substituted; X represents a covalent bond or -(CR ^a R ^a' ) _m -, -(CR ^a R ^a' ) _m -O-(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m -N (R ^b )-(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m -S-(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m C(O) (CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m S(O) ₂ (CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m C(O)N(R ^b )(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m S(O) ₂ N(R ^b )(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m N(R ^b )C(O)(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m N(R ^b )S(O) ₂ (CR ^a R ^a' ) _n -, -( CR ^a R ^a' ) _m OC(O)N(R ^b )(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m N(R ^b )C(O)O(CR ^a R ^{a '} ) _n -, -(CR ^a R ^a' ) _m N(R ^b )C(O)N(R ^b' )(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m N( R ^b )S(O) ₂ N(R ^b' )(CR ^a R ^a' ) _n -; Cy represents C ₃ -C ₅ cycloalkyl or 4-5 membered cycloheteroalkyl, and it can be arbitrarily replaced by 0, 1 or 2 selected from hydrogen, halogen, -OR ^a , (C ₁ -C ₆ ) alkane Substituents of radical, (C ₁ -C ₆ ) haloalkyl, (C ₃ -C ₆ ) cycloalkyl, cyano and hydroxy (C ₁ -C ₆ ) alkyl; R ² represents hydrogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) haloalkyl, (C ₃ -C ₆ ) cycloalkyl or hydroxy (C ₁ -C ₆ ) alkyl; R ³ and R ^3' each independently represent hydrogen, halogen, OR ^a , (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, hydroxy C ₁ -C ₆ alkyl or (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl; Or R ³ and R ^3' form a 3-6 membered saturated or unsaturated ring together with the carbon atom connected to it, and the ring can also optionally contain 1 or 2 heteroatoms selected from O, S and N, And the ring can be optionally substituted by 0, 1 or 2 substituents selected from halogen, hydroxyl and C ₁ -C ₆ alkyl; Or R ² , R ³ or R ² , R ^3' together form a 4-6 membered saturated or unsaturated ring with the atoms connected to it, and the ring can also optionally contain 1 or 2 members selected from O, S and N heteroatoms, and the ring can also be optionally substituted by 0, 1 or 2 substituents selected from halogen, hydroxyl and C ₁ -C ₆ alkyl; R ⁴ and R ^4' each independently represent hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, hydroxyl C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl; or R ⁴ and R ^4' together form =O; ^RT and ^RT' each independently represent hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxy C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogen, OR ^a ; or ^RT and RT ^' together form a 3-6 membered ring with the atom attached to it; Wherein, when --- represents the absence of a single bond, A represents (CR ^L R ^L' ) _p , wherein ^RL and ^RL' each independently represent hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ Haloalkyl, hydroxy C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogen, OR ^a , or ^RL and ^RL' together form a 3-6 membered ring with the carbon atom connected to it, in which Can optionally contain 0, 1 or 2 heteroatoms selected from O, S and N, and the ring can also be optionally substituted by 0, 1 or 2 substituents selected from halogen and hydroxyl; Among them, when --- indicates the presence of a single bond, A indicates CR ^H , wherein R ^H indicates hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxyl C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogen, OR ^a ; Wherein, R ^a , R ^a' , R ^b , R ^b' each independently represent hydrogen or C ₁ -C ₆ alkyl; Wherein, m, n and p represent 0, 1 or 2 each independently. The compound as described in Claim 1 or its pharmaceutically acceptable salt, isotopic derivative, stereoisomer has the following formula (II) structure:

Wherein R ¹ , R ² , R ³ , R ^3' , R ⁴ , R ^4' , X, Cy have the definitions as in Claim 1. The compound as described in Claim 1 or its pharmaceutically acceptable salt, isotopic derivative, stereoisomer has the following formula (III) structure:

Wherein R ¹ , R ² , R ³ , R ^3' , R ⁴ , R ^4' , ^RT , RT ^' , ^RL , ^RL' , X, and Cy are as defined in Claim 1. Compounds or pharmaceutically acceptable salts, isotopic derivatives, and stereoisomers thereof as claimed in any one of claims 1-3, wherein R ² represents hydrogen, C ₁ -C ₆ alkyl, hydroxyl (C ₁ -C ₆ alkyl) or C ₃ -C ₆ cycloalkyl. The compound or its pharmaceutically acceptable salt, isotopic derivative, stereoisomer as described in any one of claims 1-4, wherein, R ³ , R ^3' each independently represent hydrogen, C ₁ -C ₆ Alkyl or hydroxy (C ₁ -C ₆ alkyl). The compound or its pharmaceutically acceptable salt, isotopic derivative, stereoisomer as described in any one of claims 1-5, wherein, R ⁴ , R ^4' each independently represent hydrogen, C ₁ -C ₆ Alkyl, C ₃ -C ₆ cycloalkyl, or R ⁴ and R ^4' together form =O. Compounds or pharmaceutically acceptable salts, isotopic derivatives, and stereoisomers thereof as claimed in any one of claims 1-6, wherein Cy represents C ₃ -C ₅ cycloalkyl or 4-5 membered cycloheteroalkane base, preferably, Cy represents

The compound or its pharmaceutically acceptable salt, isotopic derivative, stereoisomer as described in any one of claims 1-7, wherein X represents a covalent bond or -(CR ^a R ^a' ) _m -, - (CR ^a R ^a' ) _m -O-(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m -N(R ^b )-(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m -S-(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m C(O)N(R ^b )(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m S(O) ₂ N(R ^b )(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m N(R ^b )C(O)(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m N(R ^b )S(O) ₂ (CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m OC(O)N(R ^b )(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m N(R ^b )C(O)O(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m N (R ^b )C(O)N(R ^b' )(CR ^a R ^a' ) _n -, -(CR ^a R ^a' ) _m N(R ^b )S(O) ₂ N(R ^b' )( CR ^a R ^a' ) _n -. The compound or its pharmaceutically acceptable salts, isotopic derivatives, and stereoisomers as described in Claim 8, wherein X represents -O-, -NR ^b -, -CR ^a R ^a' -, -OCR ^a R ^a' -, -CR ^a R ^a' O-, -C(O)-, -C(O)NR ^b -, -NR ^b C(O)-, -NR ^b -C(O)-NR ^b -, -CR ^a R ^a' -C(O)NR ^b -, -CR ^a R ^a' -NR ^b C(O)-, -S-, -NR ^b S(O) ₂ -, -SO ₂ NR ^b , -OC(O)NR ^b -, -S(O) ₂ , -C(O)NR ^b -, -C(O)CR ^a R ^a' -, -CR ^a R ^a' C(O)NR ^b -, -NR ^b C(O)CR ^a R ^a' -, -NR ^b C(O)O-; wherein R ^a , R ^a' , R ^b each independently represent hydrogen or C ₁ -C ₆ alkyl . The compound or its pharmaceutically acceptable salts, isotopic derivatives, and stereoisomers as described in Claim 9, wherein X represents -(CR ^a R ^a' ) _m -O-(CR ^a R ^a' ) _n -, preferably -O-, -OCR ^a R ^a' -, -CR ^a R ^a' O-, more preferably -O- or -O-CH ₂ -. The compound according to any one of claims 1-10, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein RT and ^{RT '} represent hydrogen. The compound according to any one of claims 1-11, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein ^RL and RL ^' represent hydrogen. The compound as described in any one of claims 1-12, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein R ^H represents hydrogen. Compounds or pharmaceutically acceptable salts, isotopic derivatives, and stereoisomers thereof as described in any one of claims 1-13, wherein R ¹ represents C substituted by 0, 1, 2, or 3 substituents ₃ -C ₆ cycloalkyl, 3-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, wherein the substituents are selected from halogen, (C ₁ -C ₆ ) alkane radical, (C ₁ -C ₆ ) haloalkyl, (C ₃ -C ₆ ) cycloalkyl, halo (C ₃ -C ₆ ) cycloalkyl, 3-6 membered heterocycloalkyl, halo 3-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl. The compound as described in Claim 14 or its pharmaceutically acceptable salt, isotope derivative, stereoisomer, wherein, R ¹ represents C ₃ -C ₆ cycloalkyl, 3-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, and said R ¹ can be optionally selected from 0, 1, 2, 3: hydrogen, halogen, (C ₁ -C ₆ ) alkyl, Substituents of (C ₁ -C ₆ ) haloalkyl, (C ₃ -C ₆ ) cycloalkyl, halo (C ₃ -C ₆ ) cycloalkyl. The compound or pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof as claimed in item 14, wherein, ^R is selected from:

The compound or its pharmaceutically acceptable salt, isotope derivative, stereoisomer as described in claim item 15, wherein, R ¹ is selected from:

A compound having the following structure:

A pharmaceutical composition, comprising the compound described in any one of claims 1-18 or a pharmaceutically acceptable salt, isotopic derivative, and stereoisomer thereof. A compound as described in any one of Claims 1-18 or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer, and the drug described in Claim 19 Use of the composition composition in the preparation of medicines for preventing and/or treating cancer, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.