TW202334157A - Wnt pathway inhibitor compound - Google Patents

Abstract

The present invention provides a compound represented by formula I with excellent Wnt pathway inhibitory activity or a pharmaceutically acceptable salt, an isotope derivative and a stereoisomer thereof. The present invention further provides a method for preparing the compound, and use thereof for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.

Description

A Wnt pathway inhibitor compound

The present invention relates to a heterocyclic compound, specifically to a highly active Wnt pathway inhibitor and its use.

The present invention claims the priority of the Chinese patent application submitted to the National Intellectual Property Administration of China on January 29, 2022, with the application number 202210114025.9 and the invention name "A Wnt pathway inhibitor compound", the entire content of which is incorporated by reference. in the present invention.

The Wnt/β-catenin signal transduction pathway is a pathway conserved in biological evolution. In normal somatic cells, β-catenin only functions as a cytoskeletal protein that forms a complex with E-cadherin at the cell membrane to maintain the adhesion of cells of the same type and prevent cell movement. When the Wnt signaling pathway is not activated, β-catenin in the cytoplasm is phosphorylated and forms a β-catenin degradation complex with APC, Axin, GSK3β, etc., thereby initiating the ubiquitin system to degrade β-catenin through the proteasome pathway, causing β-catenin in the cytoplasm is maintained at a low level. When cells are stimulated by Wnt signals, the Wnt protein binds to the specific receptor Frizzled protein on the cell membrane. After activation, the Frizzled receptor recruits the 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. β-catenin stably accumulated 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 associated with the development of various cancers (including colon cancer, gastric cancer, breast cancer, etc.) closely related to life. For example, abnormal initiation of the Wnt classic signaling pathway and nuclear accumulation of β-catenin protein are widely seen in colorectal cancer. Inhibiting the activity of the Wnt signaling pathway can inhibit the proliferation of cancers such as colon cancer. APC mutations exist in more than 85% of colorectal cancers. The mutated APC blocks the phosphorylation and degradation of β-catenin and induces the occurrence of colorectal cancer. In addition, Axin mutations and β-catenin self-mutation can also cause 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 currently a lack of satisfactory and effective Wnt pathway inhibitors in the existing technology. compound. Therefore, research on effective Wnt pathway inhibitor compounds is a need in the existing technology.

After research, the inventor unexpectedly found that the compound of formula (I) of the present invention or its pharmaceutically acceptable salt, isotope derivative, and stereoisomer is an effective Wnt pathway inhibitor and has excellent Wnt pathway inhibitory activity. .

Based on the above findings, in one aspect, the present invention provides a compound having the structure of formula (I) or a pharmaceutically acceptable salt, isotope derivative, or stereoisomer thereof:

Among them, R ₁ and R ₂ each independently represent hydrogen, (C ₁ -C ₆ ) alkyl, halo (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, halo (C ₃ -C ₈ )cycloalkyl, 4-8 membered heterocycloalkyl, halogenated 4-8 membered heterocycloalkyl, -(C ₁ -C ₆ )alkylene OR _a , -halogenated (C ₁ - C ₆ )alkylene OR _a , -(C ₁ -C ₆ )alkylene SR _a , -halogenated (C ₁ -C ₆ )alkylene SR _a , or R ₁ , R ₂ and those connected to them The carbon atoms together form a 3-8 membered ring, which may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O and S;

R ₃ represents (C ₁ -C ₆ ) alkyl, halogenated (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, halogenated (C ₃ -C ₈ ) cycloalkyl, or R ₃ and R ₁ or R ₂ together form a 4-7 membered ring, which may optionally contain 0 or 1 heteroatoms selected from O and S;

X represents CR ₄ or N;

R ₄ each independently represents hydrogen, halogen, cyano group, (C ₁ -C ₃ ) alkyl group, or halogenated (C ₁ -C ₃ ) alkyl group;

L represents -O- or -(CR _m R _m ')-, where R _m and R _m ' each independently represent hydrogen, (C ₁ -C ₃ ) alkyl, (C ₃ -C ₈ ) cycloalkyl , or R _m , R _m ' and the carbon atoms connected to them form a 3-5 membered ring, which ring may contain 0 or 1 heteroatom selected from O and S;

Cy represents a 5-12 membered aromatic heterocycle, which optionally contains 1, 2, 3 or 4 heteroatoms, each of which is independently selected from N, O, S;

R ₅ represents halogen, (C ₁ -C ₆ )alkyl, halogenated (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ ) cycloalkyl, halogenated (C ₃ -C ₈ ) cycloalkyl , -OR _a , -halogenated OR _a , -SR _a , -halogenated SR _a ;

R ₆ represents halogen, (C ₁ -C ₆ )alkyl, halogenated (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ ) cycloalkyl, halogenated (C ₃ -C ₈ ) cycloalkyl , (C ₃ -C ₈ ) heterocycloalkyl, halogenated (C ₃ -C ₈ ) heterocycloalkyl, (C ₂ -C ₆ ) alkynyl, halogenated (C ₂ -C ₆ ) alkynyl, - (C ₁ -C ₆ )alkylene OR _a , -halogenated (C ₁ -C ₆ )alkylene OR _a , -(C ₃ -C ₈ )cycloalkylene OR _a , -halogenated (C ₃ -C ₈ )cycloalkylene OR _a , -(C ₁ -C ₆ )alkylene SR _a , -halogenated (C ₁ -C ₆ )alkylene SR _a , -(C ₃ -C ₈ )ylene Cycloalkyl SR _a , -halogenated (C ₃ -C ₈ )cycloalkylene SR _a , -(C ₁ -C ₆ )alkylene CN, -halogenated (C ₁ -C ₆ )alkylene CN , -(C ₃ -C ₈ ) cycloalkylene CN, -halogenated (C ₃ -C ₈ ) cycloalkylene CN, - (C ₁ -C ₆ ) alkylene - NR _a R _a ', - Halogenated (C ₁ -C ₆ )alkylene-NR _a R _a ', -(C ₃ -C ₈ )cycloalkylene -NR _a R _a ', -halogenated (C ₃ -C ₈ )cycloalkylene Alkyl -NR _a R _a ', -CN, -NO ₂ , -OR _a , -SR _a , -NR _a R _a ', where R _a and R _a ' can form 3-8 together with the N atoms they are connected to. A membered ring, the ring may optionally have 0, 1 or 2 heteroatoms selected from N, O, S, and the ring may be a single ring, a bicyclic ring, a bridged ring or a spiro ring;

R ₇ each independently represents hydrogen, halogen, (C ₁ -C ₃ ) alkyl, or halogenated (C ₁ -C ₃ ) alkyl;

m and n each independently represent 0, 1 or 2;

R _a and R _a ' each independently represent hydrogen, (C ₁ -C ₆ ) alkyl group, halogenated (C ₁ -C ₆ ) alkyl group, (C ₃ -C ₈ ) cycloalkyl group, halogenated (C ₃ -C ₈ )cycloalkyl.

In particular, when R ₆ is attached to a carbon atom, R ₆ represents halogen, (C ₁ -C ₆ )alkyl, halogenated (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, Halogenated (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₈ ) heterocycloalkyl, halogenated (C ₃ -C ₈ ) heterocycloalkyl, (C ₂ -C ₆ ) alkynyl, halo Substituted (C ₂ -C ₆ ) alkynyl, -(C ₁ -C ₆ ) alkylene OR _a , -halogenated (C ₁ -C ₆ ) alkylene OR _a , -(C ₃ -C ₈ ) substituent Cycloalkyl OR _a , -halogenated (C ₃ -C ₈ )cycloalkylene OR _a , -(C ₁ -C ₆ )alkylene SR _a , -halogenated (C ₁ -C ₆ )alkylene SR _a , -(C ₃ -C ₈ )cycloalkylene SR _a , -halogenated (C ₃ -C ₈ )cycloalkylene SR _a , -(C ₁ -C ₆ )alkylene CN, -halo Substituted (C ₁ -C ₆ ) alkylene CN, -(C ₃ -C ₈ ) cycloalkylene CN, -halogenated (C ₃ -C ₈ ) cycloalkylene CN, -(C ₁ -C ₆ )Alkylene-NR _a R _a ', -halo(C ₁ -C ₆ )alkylene-NR _a R _a ', -(C ₃ -C ₈ )cycloalkylene-NR _a R _a ', -Halo(C ₃ -C ₈ )cycloalkylene-NR _a R _a ', -CN, -NO ₂ , -OR _a , -SR _a , -NR _a R a ', where R _a , R _{a '} They can form a 3-8 membered ring together with the N atoms they are connected to. The ring can also have 0, 1 or 2 heteroatoms selected from N, O and S. The ring can be a single ring, a bicyclic ring, or a bridge. ring or spiro ring;

When R ₆ is connected to the N atom, R ₆ represents halogen, (C ₁ -C ₆ ) alkyl, halo (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, halo ( C ₃ -C ₈ )cycloalkyl, (C ₃ -C ₈ )heterocycloalkyl, halo(C ₃ -C ₈ )heterocycloalkyl, (C ₂ -C ₆ )alkynyl, halo(C ₂ -C ₆ )alkynyl, -(C ₁ -C ₆ )alkylene OR _a , -halo(C ₁ -C ₆ )alkylene OR _a , -(C ₃ -C ₈ )cycloalkylene OR _a , -halogenated (C ₃ -C ₈ ) cycloalkylene OR _a , -(C ₁ -C ₆ )alkylene SR _a , -halogenated (C ₁ -C ₆ )alkylene SR _a , -(C ₃ -C ₈ )cycloalkylene SR _a , -halogenated (C ₃ -C ₈ )cycloalkylene SR _a .

More preferably, R ₆ represents halogen, (C ₁ -C ₆ )alkyl, halogenated (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ ) cycloalkyl, halogenated (C ₃ -C ₈ )cycloalkyl.

In one embodiment of the present invention, R ₁ and R ₂ each independently represent hydrogen, (C ₁ -C ₆ ) alkyl, halo (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl group, halogenated (C ₃ -C ₈ ) cycloalkyl, -(C ₁ -C ₆ ) alkylene OR _a , -(C ₁ -C ₆ ) alkylene SR _a ; or R ₁ , R ₂ and Together with the carbon atoms to which they are attached, they form a 3-8 membered ring, which may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O and S.

In one embodiment of the invention, R ₃ is C ₁ -C ₆ )alkyl or halo(C ₁ -C ₆ )alkyl.

In a preferred embodiment of the invention, R ₃ is (C ₁ -C ₆ )alkyl.

In one embodiment of the present invention, Cy is a 5-6 membered monocyclic aromatic heterocycle, or Cy is a 9-10 membered bicyclic aromatic heterocycle.

In one embodiment of the invention, Cy is pyridyl, pyrimidinyl, pyrazolyl, imidazolyl or pyrrolyl.

In one embodiment of the invention, R ₆ and L are attached to the ortho position of Cy.

In one embodiment of the invention, R ₅ is located in the meta position of R ₆ and is located in the meta or para position of L.

In a preferred embodiment of the invention, X is CR ₄ .

In another preferred embodiment of the invention, _R4 is hydrogen.

In one embodiment of the present invention, the connection between Cy and R ₅ and R ₆ is as follows:

In a preferred embodiment of the present invention, the connection between Cy and R ₅ and R ₆ is as follows:

In one embodiment of the invention, _R6 is selected from:

It may optionally be substituted by 0, 1, 2, 3 or 4 substituents selected from halogen, -CN, -OR _a , -SR _a and -NR _a R _a '.

The invention also provides a class of compounds or pharmaceutically acceptable salts, isotope derivatives, and stereoisomers thereof, wherein the compounds have the following structures:

In another aspect, the present invention also provides a pharmaceutical composition comprising the aforementioned compound or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, and optionally a pharmaceutically acceptable carrier.

In another aspect, the present invention also provides the aforementioned compounds or their pharmaceutically acceptable salts, isotope derivatives, stereoisomers or aforementioned pharmaceutical compositions for use in the prevention and/or treatment of cancer, tumors, and inflammatory diseases. , use in medicines for autoimmune diseases or immune-mediated diseases.

It is particularly noted that in this article, when referring to the "compound" of the formula (I), it generally also covers its stereoisomers, diastereomers, enantiomers, and racemic mixtures. and isotope derivatives.

It is well known to those skilled in the art that salts, solvates, water Compounds are alternative forms of compounds, and they can all be converted into the compounds under certain conditions. Therefore, special attention should be paid to the fact that when referring to the compound of formula (I) in this article, it generally also includes its Pharmaceutically acceptable salts, and thus also solvates and hydrates thereof, are included.

Similarly, reference herein to a compound generally includes its prodrugs, metabolites and nitrogen oxides.

Pharmaceutically acceptable salts of the present invention may be formed using, for example, the following inorganic or organic acids: "Pharmaceutically acceptable salts" refer to salts that, within the scope of reasonable medical judgment, are suitable for use in contact with humans and lower and other animal tissues without undue toxicity, irritation, allergic reactions, etc., which can be called a reasonable benefit/risk ratio. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base or free acid with a suitable reagent, as summarized below. For example, the free base functionality can be reacted with a suitable acid. Examples of pharmaceutically acceptable inorganic acid addition salts are amines with inorganic acids (for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or organic acids (for example, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid), or by using other methods in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, sodium alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor Sulfonate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate salt, gluconate, hernisulfate, enanthate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, Maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamateate, pectate, Persulfate, 3-phenylpropionate, phosphate, bitter salt, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonic acid Salt, undecanoate, valerate, etc. Representative alkali metal or alkaline earth metal salts include salts of sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, where appropriate, nontoxic ammonium salts, quaternary ammonium salts, and ammonium cations formed with counterions, e.g., halides, hydroxides, carboxylates, Sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.

The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example, by dissolving the compounds of the present invention in water-miscible organic solvents (such as acetone, methanol, ethanol, and acetonitrile), and adding an excess of organic acid or inorganic acid thereto. The aqueous acid is used to precipitate the salt 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 those known in the art, as long as the precursors or metabolites are converted 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 reasonable medical judgment, are suitable for contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., Demonstrates a reasonable benefit/risk ratio and is effective for its intended use. The term "prodrug" refers to a compound that is rapidly converted in vivo to produce the parent compound of the formula above, for example by metabolism in the body, or N-demethylation of a compound of the invention.

"Solvate" as used herein means a physical association of a compound of the invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain circumstances, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, solvates will be able to be separated. The solvent molecules in a solvate 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 isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methoxides, and isopropoxides. Solvation methods are well known in the art.

The "stereoisomerism" mentioned in the present invention is divided into conformational isomerism and configurational isomerism. Configurational isomerism can also be divided into cis-trans isomerism and optical isomerism (ie, optical isomerism). Conformational isomerism refers to having A stereoisomerism phenomenon in which organic molecules of a certain configuration are arranged differently in space due to the rotation or distortion of carbon and carbon single bonds. Common structures include alkanes and cycloalkanes, such as Chair and boat conformations occurring in the structure of cyclohexane. "Stereoisomers" means when a compound of the present invention contains one or more different Center of symmetry, 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 will produce two optical isomers. The scope of the present invention includes all possible optical isomers and diastereoisomer mixtures and pure or partially pure compounds. . The compounds described in this invention may exist as tautomeric forms, which have different points of attachment of hydrogens through the 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 invention. Enantiomers, diastereomers, racemates, meso, cis-trans isomers, tautomers, and geometric isomers of all compounds of formula (I) to formula (III) , epimers and their mixtures, etc., are all included in the scope of the present invention.

An "isotopic derivative" of the present invention refers to a molecule in which the compound is isotopically labeled. The isotopes commonly used as isotope labels 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 isotopically labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. In particular, deuterium ³ H and carbon ¹³ C are more widely used because they are easy to label and detect. The substitution of certain heavy isotopes, such as deuterium ( ^2H ), can enhance metabolic stability, extend half-life, thereby reducing dosage and providing therapeutic advantages. Isotopically labeled compounds generally start from labeled starting materials and are synthesized using known synthetic techniques as for non-isotopically labeled compounds.

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

Furthermore, the present invention provides pharmaceutical compositions for the prevention and/or treatment of cancer, tumors, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, attention-related diseases or immune-mediated diseases, comprising the present invention compound as the active ingredient. The pharmaceutical composition may optionally include a pharmaceutically acceptable carrier.

In addition, the present invention provides a method for preventing and/or treating cancer, tumors, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, attention-related diseases or immune-mediated diseases, comprising administering to a patient in need thereof The compound of the formula (I) of the present invention or its pharmaceutically acceptable salt, isotope derivative, stereoisomer or pharmaceutical composition of the present invention is administered to the mammal.

Representative examples of inflammatory diseases, autoimmune diseases, and immune-mediated diseases may include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis , other arthritic conditions, lupus, systemic lupus erythematosus (SLE), skin-related disorders, psoriasis, eczema, dermatitis, atopic dermatitis, pain, lung disease, lung inflammation, adult respiratory distress syndrome (ARDS) ), pulmonary sarcoidosis, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease (COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart 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 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 lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), hairy cell leukemia, He Jie King's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), diffuse large B-cell lymphoma, and follicular lymphoma.

Representative examples of cancers or tumors 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, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, Papillary thyroid cancer, kidney cancer, kidney disease Cancer, ovarian cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, brain tumors such as glioblastoma, astrocytoma , meningiomas, medulloblastomas and peripheral neuroectodermal tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL) , acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), adult T-cell leukemia 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, fat Sarcoma, fibrosarcoma, Ewing's sarcoma, or plasmacytoma.

The compounds of the present invention, or pharmaceutically acceptable salts thereof, may provide enhanced anticancer effects when administered in combination with additional anticancer agents or immune checkpoint inhibitors used to treat cancer or tumors. .

Representative examples of anti-cancer agents for treating 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 Bicin, epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifen, flutamide, gonadorelin analogs, Megestrol, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alpha, calcium leucovorin, sirolimus, sirolimus lipid, everolimus, afatin alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, czotinib, dabrafenib , dacomitinib, danusetid, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, Lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motisanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafen Rigosertib, rucaparib, rosolitinib, sacatinib, saridegib, sorafenib, sunitinib, tilatinib, tivantinib, tivozanib, tofacitinib, trametinib, Vandetanib, veliparib, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, belemtuzumab, vedotin, catumaxomab, cetuximab monoclonal antibody, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab Lizumab, PI3K inhibitors, CSF1R inhibitors, A2A and/or A2B receptor antagonists, IDO inhibitors, anti-PD-1 antibodies, anti-PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies and anti-CTLA-4 Antibodies, or any combination thereof.

The compounds of the present invention, or pharmaceutically acceptable salts thereof, may provide enhanced therapeutic effect.

Representative examples of therapeutic agents for treating inflammatory diseases, autoimmune diseases, and immune-mediated diseases may include, but are not limited to, steroidal drugs (e.g., prednisone, prednisone, methylprednisone pine, cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNFα agents (e.g., etanercept, infliximab, adalivir monoclonal antibodies, etc.), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus, etc.) and antihistamines (e.g., diphenhydramine, hydroxyzine, loratadine, ebas cetirizine, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one or more therapeutic agents selected therefrom may be included in the pharmaceutical composition of the present invention.

The compounds of the present invention or pharmaceutically acceptable salts thereof can be administered as active ingredients. The dosage 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 physician opinion. In some cases, amounts less than the above dosages may be appropriate. Amounts greater than the above dosages may be used if they do not cause deleterious side effects and may be administered in divided doses per day.

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 method includes providing A compound of the invention or a compound or pharmaceutical composition of the invention is administered to a mammal.

The pharmaceutical composition of the present invention can be formulated into a dosage form 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 a carrier such as: cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, hard Magnesium fatty acid, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers and diluents.

Examples of the carrier used in the pharmaceutical composition for injection administration of the present invention may be water, saline solution, glucose solution, glucose-like solution, alcohol, glycol, ether (eg, 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 describing the 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 field of organic synthesis. They can be synthesized using the following methods as well as synthetic methods known in the field of organic synthetic chemistry or through variations thereof known to those skilled in the art. Compounds of the invention. Preferred methods include, but are not limited to, those described below. The reaction is carried out in a solvent or solvent mixture suitable for the kit materials used and for the transformations achieved. Those skilled in the art of organic synthesis will understand that the functionality present on the molecule is consistent with the proposed transformation. This sometimes requires judgment to alter the order of synthetic steps or starting materials to obtain the desired compound of the invention.

Figure 1 shows the effect of compound 1 on tumor volume of human colon cancer cell Colo205 xenograft tumors in nude mice.

Terminology

If not otherwise stated, the terms used in this application, including the description and the scope of the patent application, are defined as follows. If not otherwise stated, conventional methods of mass spectrometry, nuclear magnetic resonance, high performance liquid chromatography (HPLC), protein chemistry, biochemistry, recombinant DNA technology and pharmacology were used. In the present invention, the use of "or" or "and" means "and/or" unless stated otherwise.

In the specification and the scope of the patent application, a given chemical formula or name shall cover all its stereoisomers and optical isomers as well as the racemates in which the above-mentioned isomers exist. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) 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 compound, and all the above stable isomers are included in the present invention. This invention describes the cis- and trans- (or E- and Z-) geometric isomers of the compounds of the invention, and they can be separated into mixtures of isomers or separate isomeric forms. The compounds of the present invention can be isolated in optically active or racemic form. All methods for preparing the compounds of the invention and the intermediates prepared therein are considered to be part of the invention. When preparing enantiomeric or diastereomeric products, they can be separated by conventional methods, for example by chromatography or fractional crystallization. Depending on the process conditions, the final product of the invention is obtained in free (neutral) or salt form. Both free forms and salts of these end products are within the scope of this invention. If desired, one form of the compound can be converted into another form. The free base or acid can be converted into a salt; the salt can be converted into the free compound or another salt; and mixtures of isomeric compounds of the invention can be separated into individual isomers. The compounds of the present invention, their free forms and salts may exist in a variety of tautomeric forms in which a hydrogen atom is transposed to other parts of the molecule. It partially rearranges the chemical bonds between the atoms of the molecule. It is to be understood that all tautomeric forms which may exist are included in the present invention.

Unless otherwise defined, the definitions of the substituents of the present invention are independent and not related to each other. For example (enumeration rather than exhaustion), in one aspect, for R ^a (or R ^a' ) in the substituent, it The definitions of different substituents are independent of each other. Specifically, when one definition is chosen for R ^a (or R ^a' ) in one substituent, it does not mean that R ^a (or R ^a' ) has the same definition in other substituents. More specifically, for example (by way of non-exhaustive list) 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. On the other hand, when there is more than one ^Ra (or Ra ^' ) in a certain substituent, these ^Ra (or Ra ^' ) are also independent. For example, in the substituent -(CR ^a R ^a' ) _m -O-(CR ^a R ^a' ) _n -, when m+n is 2 or more, m+n R ^a (or R ^a' ) are independent, they can have the same or different meanings.

Unless otherwise defined, when a substituent is designated as "optionally substituted," the substituent is selected from, for example, substituents such as alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxyl, Alkoxy, oxo, alkyloxy, aryloxy, alkyloxy, amine, alkylamino, arylamine, arylalkylamino, disubstituted amine (where 2 The amino substituent is selected from the group consisting of alkyl, aryl or arylalkyl), alkylamine, arylamine, aralkylamine, substituted alkylamine, substituted aryl Amino, substituted aralkylthioamine, thio, alkylthio, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkylsulfonyl, Arylsulfonyl, arylalkylsulfonyl, aminosulfonyl such as -SO ₂ NH ₂ , substituted sulfonylamide, nitro, cyano, carboxyl, aminoformyl such as -CONH ₂ , substituted aminomethyl groups such as -CONH alkyl, -CONH aryl, -CONH arylalkyl or the case where the nitrogen has two substituents selected from alkyl, aryl or arylalkyl, Alkoxycarbonyl, aryl, substituted aryl, guanidyl, heterocyclyl, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl , pyridinyl, morpholinyl, pyridinyl, homopyridinyl, etc. and substituted heterocyclyl.

The term "alkyl" or "alkylene" as used herein is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified 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, tert-butyl), and Pentyl (e.g. n-pentyl, isopentyl, neopentyl). In this context, the alkyl group is preferably an alkyl group having 1 to 6, 1 to 4, more preferably 1 to 3 carbon atoms.

The term "alkenyl" refers to a straight or branched hydrocarbon radical containing one or more double bonds and usually 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, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.

The term "alkynyl" refers to a straight or branched hydrocarbon group containing one or more triple bonds and usually having a length of 2 to 20 carbon atoms. For example, "C ₂ -C ₆ 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.

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" means a sulfur-bridged alkyl group as defined above having the specified number of carbon atoms; for example, methyl-S- and ethyl-S-.

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

The term "aryl", alone or as part of a larger moiety such as "aralkyl", "arylalkoxy" or "aryloxyalkyl", refers to a single ring member 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 present invention, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetralin 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. The fused aryl group can be attached to another group at a suitable position on the cycloalkyl ring or aromatic ring. The dashed lines drawn from the ring system indicate that bonds can 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 in the definition of "cycloalkyl". Bicyclic cyclic alkyl groups include bridged, spiro or fused cyclic cycloalkyl groups. In this context, the cycloalkyl group is preferably a cycloalkyl group having 3 to 8, more preferably 3 to 6 carbon atoms.

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 in the definition of "cycloalkenyl". Bicyclic cyclic alkenyl groups include bridged, spiro or condensed ring cyclic alkenyl groups.

"Halo" or "halogen" includes fluorine, chlorine, bromine and iodine. "Haloalkyl" is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified 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, heptafluoroethyl Propyl and heptachloropropyl. Examples of haloalkyl groups also include "fluoroalkyl groups" which are intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more fluorine atoms. Similarly, "halogenated cycloalkyl" is intended to include branched cycloalkyl groups having the specified number of carbon atoms substituted with 1 or more halogens.

"Haloalkoxy" or "haloalkyloxy" means a haloalkyl group as defined above having the specified number of carbon atoms linked via an oxygen bridge. For example, "halo C 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" means a sulfur-bridged haloalkyl group as defined above having the specified number of carbon atoms; for example, trifluoromethyl-S- and pentafluoroethyl -S-.

As described herein, -halogenated (C ₁ -C ₆ )alkylene OR _a , -halogenated (C ₁ -C ₆ )alkylene SR _a , -halogenated (C ₁ -C ₆ )alkylene NR _a R _a ', -halogenated (C ₁ -C ₆ ) alkylene CN, -halogenated (C ₃ -C ₈ ) cycloalkylene OR _a , -halogenated (C ₃ -C ₈ ) cycloalkylene The groups SR _a , -halogenated (C ₃ -C ₈ )cycloalkylene NR _a R _a ', -halogenated (C ₃ -C ₈ )cycloalkylene CN, etc. mean -(C) that is optionally halogenated. ₁ -C ₆ )alkylene OR _a , -(C ₁ -C ₆ )alkylene SR _a , -(C ₁ -C ₆ )alkylene NR _a R _a ', -(C ₁ -C ₆ ) Alkylene CN, -(C ₃ -C ₈ )cycloalkylene OR _a , -(C ₃ -C ₈ )cycloalkylene SR _a , -(C ₃ -C ₈ )cycloalkylene NR _a R _a ', -(C ₃ -C ₈ )cycloalkylene CN.

In the context of the present invention, 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 group may be x ₁ to x ₂ . For example, C ₀ -C ₈ means that the group contains 0, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and 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 group 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 group contains 4, 5, 6, 7 or 8 carbon atoms. A group containing 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 the context of the present invention, the expression "x ₁ -x ₂ -membered ring" is used when referring to cyclic groups (such as aryl, heteroaryl, cycloalkyl and heterocycloalkyl), which means that the group The number of ring atoms may be x ₁ to x ₂ . For example, the 3-12-membered cyclic group can be a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12-membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; 3-6 membered ring means that the cyclic group can be a 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 The 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 The 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; the 5-8-membered ring means that the cyclic group can be 5, A 6-, 7- or 8-membered ring can have 5, 6, 7 or 8 ring atoms; a 5-12-membered ring means that the cyclic group can be 5, 6, 7, 8, 9, 10, 11 or A 12-membered ring, the number of ring atoms can be 5, 6, 7, 8, 9, 10, 11 or 12; a 6-12-membered ring means that the cyclic group can be 6, 7, 8, 9, 10, An 11- or 12-membered ring may have 6, 7, 8, 9, 10, 11 or 12 ring atoms. The ring atoms may be carbon atoms or heteroatoms, such as heteroatoms selected from N, O and S. When the ring is a heterocycle, the heterocycle 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 context of the present invention, one or more halogens may be each independently selected from fluorine, chlorine, bromine and iodine.

The term "heteroaryl" means a stable specified number of monocyclic or polycyclic aromatic groups containing heteroatoms, preferably 3-membered, 4-membered, 5-membered, 6-membered, or 7-membered aromatic monocyclic or aromatic bicyclic rings. Or 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, or 12-membered aromatic polycyclic heterocycles, which are completely unsaturated or partially unsaturated, and which contain carbon atoms and 1, 2, or 3 or 4 heteroatoms independently selected from N, O and S; and includes any of the following polycyclic groups in which any heterocycle as defined above is fused to a benzene ring. The heteroaryl group herein is preferably a 5 to 12-membered heteroaryl group. Nitrogen and sulfur heteroatoms may optionally be oxidized. Nitrogen atoms are substituted or unsubstituted (ie, N or NR, where R is H or another substituent, if defined). Heterocycles can be attached to their pendant groups at any heteroatom or carbon atom that results in a stable structure. If the resulting compound is stable, the heterocyclyl groups described herein may be substituted on the carbon or nitrogen atom. The nitrogen in the heterocycle may 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, S and The total number of O atoms is not greater than 1. When the term "heterocycle" is used, it is intended to include heteroaryl groups. Examples of aromatic hetero groups include, but are not limited to, acridinyl, azetidinyl, azecinyl, benzimidazolyl, benzofuryl, benzothiofuranyl, benzothienyl, benzox Azolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, terazolyl, 4aH-terazolyl, teriolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2, 3-b] Tetrahydrofuryl, furanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridyl, pseudoindolenyl, indolenyl, Indolinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoindolyl, iso Quinolyl, isothiazolyl, isothiazopyridyl, isoxazolyl, isoxazolopyridyl, methylenedioxyphenyl, morpholinyl, diazanaphthyl, octahydroisoquinoline base, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl , oxazolidinyl, oxazolyl, oxazolopyridyl, oxazolidinyl, naphthyridyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl , phenothiazinyl, phenoxathiyl, phenoxazinyl, phthalazinyl, pyridazinyl, piridinyl, piridinonyl, 4-piperidinyl, piperonyl, pteridinyl, purinyl, Pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazopyridyl, pyrazolyl, pyridazinyl, pyridoxazolyl, pyridimidazolyl, pyridothiazolyl, pyridyl , pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolinyl, 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, thianthrenyl, thiazolyl, thienyl, thiazolopyridyl, thienothiazolyl, thienoxanyl Azolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4 -Triazolyl and xanthyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolyl, 1H-indazolyl, benzo Imidazolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, 5,6,7,8-tetrahydro-quinolyl, 2,3-dihydro-benzofuryl, chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl. The term "heteroaryl" may also include a biaryl structure formed by the above-defined "aryl" and a monocyclic "heteroaryl", such as but not limited to "-phenylbipyridyl-", "- "Phenylbipyrimidinyl", "-pyridylbiphenyl", "-pyridylbipyrimidinyl-", "-pyrimidinylbiphenyl-"; wherein the present invention also includes fused rings containing, for example, the above-mentioned heterocyclic rings and Spirocyclic compounds.

As used herein, the term "heterocycloalkyl" refers to a monocyclic heterocycloalkyl system, or to a bicyclic heterocycloalkyl system, and also includes spiroheterocyclic or bridged heterocycloalkyl groups. In the present invention, a monocyclic heterocycloalkyl group refers to a 3-8 membered cyclic alkyl group that is saturated or unsaturated but not aromatic and contains at least one heteroatom selected from O, N, S and P. system. Bicyclic heterocycloalkyl system refers to a heterocycloalkyl group fused to a phenyl group, a cycloalkyl group, a cycloalkenyl group, a heterocycloalkyl group, or a heteroaryl group. Two-ring system.

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

The term "spirocycloalkyl" as used herein refers to polycyclic hydrocarbons that share one carbon atom (called a spiro atom) between single rings.

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

The term "heterospirocyclyl" used herein refers to polycyclic hydrocarbons sharing one carbon atom (called a spiro atom) between single 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 valency is maintained and that the substitution results in a stable compound. As used herein, a cyclic double bond is a double bond formed between two adjacent ring atoms (eg, C=C, C=N, or N=N).

In the case where nitrogen atoms (e.g. amines) are present on the compounds of the invention, these nitrogen atoms can be converted into N-oxides by treatment with oxidizing agents (e.g. mCPBA and/or hydrogen peroxide) to obtain other compounds of the invention. . Therefore, the nitrogen atoms shown and claimed are deemed to encompass the nitrogen atoms shown and their N-oxides to obtain the derivatives of the invention.

When any variable occurs more than once 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 substituted with 0-3 R, then the group may be optionally substituted with up to three R groups, with R on each occurrence being independently selected from the definition of R. Furthermore, combinations of substituents and/or variables are permitted only if such combinations result in stable compounds.

The term "patient" as used herein refers to an organism to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (eg, rodents, apes, monkeys, horses, cattle, pigs, dogs, cats, etc.) and most preferably refer to humans.

As used herein, the term "effective amount" means an amount of a drug or agent (i.e., a compound of the invention) that will elicit the biological or medical response in a tissue, system, animal, or human, for example, that is sought by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means an amount that results in improved treatment, cure, prevention, or alleviation of a disease, disorder, or side effect, or a reduction in the risk of a disease, disorder, or side effect as compared to a corresponding subject that does not receive such amount. or the rate at which the condition progresses. An effective amount may be administered in one or more administrations, administrations or doses and is not intended to be limited to a particular formulation or route of administration. The term also includes within its scope an amount effective to enhance normal physiological functions.

The term "treatment" as used herein includes any effect resulting in amelioration of a condition, disease, disorder, etc., such as alleviation, reduction, regulation, amelioration or elimination, or amelioration of symptoms thereof.

The term "pharmaceutically acceptable" is used herein to refer to those compounds, substances, compositions and/or dosage forms which, within the scope of reasonable medical judgment, are suitable for use in contact with human and animal tissue without excessive toxicity, irritation sexual, allergic reactions and/or other problems or complications, and proportionate to 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 which involve carrying or transporting the subject compound from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient.

The term "pharmaceutical composition" means a composition comprising a compound of the invention and at least one other pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to 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, aromatics, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the Drug mode and nature of dosage form.

Specific pharmaceutical and medical terms

The term "acceptable," as used herein, means that a formulation component or active ingredient does not have undue deleterious effects on the health of the general target of treatment.

The term "cancer", as used herein, refers to an abnormal growth of cells that is uncontrollable and, under certain conditions, capable of metastasis (spread). This type of cancer includes, but is not limited to, solid tumors (such as bladder, bowel, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovaries, pancreas or other endocrine organs (such as thyroid), prostate , skin (melanoma) or blood tumors (such as non-leukemic leukemia).

The term "coadministration" 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 and at the same or different times.

The term "enhance" or "enhancement," as used herein, means that a desired result can be increased or prolonged in potency or duration. Therefore, in terms of enhancing the therapeutic effect of a drug, the term "enhancing" refers to the ability of the drug to increase or prolong the effectiveness or duration of the drug in the system. The ability of time. As used herein, "enhancement value" refers to the ability to maximize the enhancement of another therapeutic agent in an ideal system.

The term "immune disease" refers to a disease or condition resulting from an adverse or harmful response to endogenous or exogenous antigens. The result is usually dysfunction of cells, or damage to 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, pigs; domestic animals such as rabbits and dogs; experimental animals including rodents, such as Rats, mice and guinea pigs, etc. Non-mammals include, but are not limited to, birds, fish, etc. In a preferred aspect, the selected mammal is a human.

The terms "treatment," "treatment," or "therapy" as used herein include alleviating, inhibiting, or ameliorating symptoms or conditions of a disease; inhibiting the development of complications; ameliorating or preventing underlying metabolic syndrome; inhibiting the development of a disease or symptoms, Such as controlling the development of a disease or condition; alleviating a disease or symptoms; making a disease or symptoms subside; alleviating complications caused by a disease or symptoms, or preventing and/or treating signs caused by a disease or symptoms.

As used herein, a compound or pharmaceutical composition, when administered, can ameliorate a disease, symptom or condition, especially its severity, delay its onset, slow down its progression, or reduce its duration. Circumstances that may be attributed to or related to the administration, whether fixed or temporary, 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, and ear canal administration. , nasal administration and topical administration. In addition, by way of example only, parenteral administration includes intramuscular injection, subcutaneous injection, intravenous injection, intramedullary injection, ventricular injection, intraperitoneal injection, intralymphatic injection, and intranasal injection.

In one aspect, the compounds described herein are administered topically rather than Systemic administration. In certain embodiments, long-acting formulations are 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 this specific embodiment, the liposomes are selectively targeted to specific organs and absorbed.

Example

general process

When the preparation route is not included, the raw materials and reagents used in the present invention are all known products and can be synthesized according to methods known in the art, or can be obtained by purchasing commercially available products. None of the commercially available reagents were used without further purification.

Room temperature refers to 20-30℃.

There are no special instructions in the reaction examples, and the reactions are all carried out under a nitrogen atmosphere. Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon of about 1L.

The hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated three times. The hydrogen atmosphere refers to the reaction bottle connected to a hydrogen balloon of about 1L.

Microwave reactions use Biotage ^® Initiator+ microwave reactors.

The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). NMR was measured using a (Bruker Ascend ^TM 500) nuclear magnetic instrument. The measurement solvents were deuterated dimethylsulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl ₃ ), and deuterated methanol (CD ₃ OD). Labeled tetramethylsilane (TMS). The following abbreviations are used for the multiplicity of NMR signals: s = singlet, brs = broadt, d = doublet, t = triplet, m = multiplet. Coupling constants are listed as J values, measured in Hz.

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

The synthesis methods of some intermediates in the present invention are as follows:

Intermediate 1

Intermediate 1 is prepared by the following steps:

Step 1: Dissolve compounds Int-1a (5.0g, 28.09mmol), Int-1b (5.61g, 36.51mmol) and sodium bicarbonate (7.08g, 84.26mmol) in ethanol (50mL) and water (5mL) , the reaction solution was heated to reflux overnight. After monitoring the reaction with a liquid chromatography mass spectrometer (LCMS), it was cooled to room temperature, filtered with suction, and the filter cake was washed with water and then dried to obtain off-white solid Int-1 (5.0 g, yield 78%). ESI-MS(m/z): 227.4[M+H] ⁺ .

Intermediate 2

Intermediate 2 is prepared by the following steps:

Step 1: Add sodium hydrogen (1.59g, 39.64mmol, content 60%) into a two-necked flask containing anhydrous tetrahydrofuran (10mL), place it in an ice-water bath, and dissolve compound Int-2a (5.0g, 26.43mmol) Anhydrous tetrahydrofuran (30 mL) was slowly added dropwise to the reaction solution. After 30 minutes, deuterated methyl iodide (4.02g, 27.75mmol) was added dropwise. After the dropwise addition was completed, the mixture was slowly raised to room temperature and stirred overnight. After the reaction was monitored by LCMS, it was cooled to 0°C, saturated aqueous ammonium chloride solution was slowly added dropwise to quench the reaction, extracted with ethyl acetate, and the organic phase was dried to obtain yellow oil Int-2b (5.0g, yield 91%). ESI-MS(m/z): 207.2[M+H] ⁺ .

Step 2: Dissolve Int-2b (5.0g, 24.24mmol) in methanol (50mL), place it in an ice water bath, slowly add trisene chloride (8.65g, 72.73mmol) dropwise, and raise to room temperature, and then raised to 60°C for overnight reaction. After the reaction was monitored by LCMS, the reaction solution was concentrated to obtain yellow oil Int-2c (3.0 g, yield 79%). ESI-MS(m/z): 157.2[M+H] ⁺ .

Step 3: Dissolve compounds Int-1a (2.0g, 11.23mmol), Int-2c (3.17g, 20.22mmol) and sodium bicarbonate (2.83g, 33.70mmol) in ethanol (20mL) and water (2mL) , the reaction solution was refluxed overnight. After the reaction was monitored by LCMS, it was cooled to room temperature, filtered with suction, and the filter cake was washed with water and then dried to obtain off-white solid Int-2 (1.4 g, yield 54%). ESI-MS(m/z): 230.3[M+H] ⁺ .

Intermediate 3

Intermediate 3 is prepared by the following steps:

Step 1: Dissolve compound Int-3a (10.17g, 55.26mmol) in ethanol (50mL), add hydrazine salt Int-3b (5.0g, 46.05mmol) at room temperature, and reflux the reaction overnight. After the reaction was monitored by LCMS, the ethanol was distilled off under reduced pressure, and then water and ethyl acetate were added for extraction. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure and passed through silica gel column chromatography (petroleum ether: Ethyl acetate = 5:1) was purified to obtain white solid Int-3c (4.0 g, yield 45%). ESI-MS(m/z): 193.2[M+H] ⁺ .

Step 2: Add compounds Int-3c (1.0g, 5.20mmol), Int-3d (669mg, 5.73mmol) and cesium carbonate (2.55g, 7.81mmol) to N , N -dimethylformamide (10mL ), react at 80°C for 5 hours, and monitor the end of the reaction with LCMS. N , N -dimethylformamide was distilled off under reduced pressure, and then water and ethyl acetate were added for extraction. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain a brown solid Int-3e ( 1.1g, yield 71%). ESI-MS(m/z): 295.2[M+H] ⁺ .

Step 3: Dissolve compound Int-3e (1.1g, 3.74mmol) in methanol (10mL), add ammonia water (1mL) and Raney nickel (3mL suspension) to the reaction system in sequence, replace the hydrogen gas through a hydrogen balloon and inject hydrogen into the reaction system. The reaction was carried out under atmosphere and room temperature for 16 hours, and LCMS monitored the end of the reaction. The reaction solution was diluted with methanol and suction filtered. The filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol = 9:1) to obtain brown oily liquid Int-3 (700 mg, yield 62%). ESI-MS(m/z): 299.3[M+H] ⁺ .

Intermediate 4

Intermediate 4 is prepared by the following steps:

Step 1: Dissolve compound Int-3a (1.0g, 5.43mmol) in ethanol (20mL), add hydrazine salt Int-4a (979mg, 6.52mmol) at room temperature, and reflux the reaction overnight. After the reaction was monitored by LCMS, the ethanol was distilled off under reduced pressure, and then water and ethyl acetate were added for extraction. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure and passed through silica gel column chromatography (petroleum ether: Ethyl acetate = 5:1) was purified to obtain white solid Int-4b (909 mg, yield 93%). ESI-MS(m/z): 181.4[M+H] ⁺ .

Step 2: Add compounds Int-4b (606mg, 3.36mmol), Int-3d (411mg, 3.36mmol) and cesium carbonate (2.19g, 6.73mmol) to N , N -dimethylformamide (16mL) , react at 80°C for 5 hours, and monitor the end of the reaction with LCMS. N , N -dimethylformamide was distilled off under reduced pressure, and then water and ethyl acetate were added for extraction. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain brown solid Int-4c ( 897 mg, yield 94%). ESI-MS(m/z): 283.3[M+H] ⁺ .

Step 3: Dissolve compound Int-4c (897 mg, 3.18 mmol) in methanol (30 mL), add ammonia water (3 mL) and Raney nickel (3 mL suspension) to the reaction system in sequence, replace the hydrogen gas through a hydrogen balloon and in a hydrogen atmosphere , react at room temperature for 3 hours, and monitor the end of the reaction with LCMS. The reaction solution was diluted with methanol and suction filtered. The filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol = 9:1) to obtain brown oily liquid Int-4 (412 mg, yield 45%). ESI-MS (m/z): 328.3[M+CH ₃ CN+H] ⁺ .

Intermediate 5b

Intermediate 5b is prepared by the following steps:

Step 1: Step 2: Add compounds Int-5a (3.0g, 19.73mmol), Int-3d (2.41g, 19.73mmol) and cesium carbonate (12.85g, 39.45mmol) to acetonitrile (30mL). The mixture was stirred warmly for 16 hours, and LCMS monitored the reaction to completion. Acetonitrile was distilled off under reduced pressure, and the residue was extracted with water and ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain white solid Int-5b (2.17g, yield 43%). ESI-MS(m/z): 255.2[M+H] ⁺ .

Intermediate 6

Intermediate 6 is prepared by the following steps:

Step 1: Add sodium hydrogen (153mg, 4.0mmol, content 60%) into a two-necked flask containing anhydrous tetrahydrofuran (5mL), place it in an ice-water bath, and dissolve compound Int-2a (500mg, 2.09mmol) in anhydrous Tetrahydrofuran (10 mL) was slowly added dropwise to the reaction solution. After 30 minutes, methyl iodide (593 mg, 4.18 mmol) was added dropwise. After the dropwise addition was completed, the mixture was slowly raised to room temperature and stirred overnight. After the reaction was monitored by LCMS, it was cooled to 0°C, saturated aqueous ammonium chloride solution was slowly added dropwise to quench the reaction, extracted with ethyl acetate, and the organic phase was dried to obtain yellow solid Int-6b (500 mg, yield 94%). ESI-MS(m/z): 252.2[MH] ^- .

Step 2: Dissolve Int-6b (500mg, 1.97mmol) in methanol (50mL), place it in an ice-water bath, slowly add tyrene chloride (704mg, 5.92mmol) dropwise, and raise to room temperature after the dropwise addition is completed. , and then raised to 60°C to react overnight. After the reaction was monitored by LCMS, the reaction solution was concentrated to obtain yellow oil Int-6c (300 mg, yield 60%). ¹ H NMR (500MHz, DMSO- d6 ) δ 10.45 (br s, 1H), 9.84 (br s, 1H), 6.55-6.26 (m, 1H), 4.25 (dd, J =7.8, 4.9Hz, 1H), 3.77(s,3H),2.65-2.52(m,2H).

Step 3: Dissolve compound Int-1a (250mg, 1.40mmol), Int-6c (343mg, 1.69mmol) and sodium bicarbonate (353mg, 4.21mmol) in ethanol (20mL) and water (2mL). The reaction solution Reflux overnight. After the reaction was monitored by LCMS, it was cooled to room temperature, filtered with suction, and the filter cake was washed with water and then dried to obtain off-white solid Int-6 (170 mg, yield 43%). ESI-MS(m/z): 277.2[M+H] ⁺ .

Intermediate 7

Intermediate 7 is prepared by the following steps:

Step 1: Add compound Int-5b (400mg, 1.57mmol) and cesium carbonate (1.03g, 3.15mmol) to N , N -dimethylformamide (8mL), and then add 1, 1-Difluoro-2-iodoethane (0.56 mL, 6.28 mmol). After the reaction solution was stirred at room temperature for 24 hours, LCMS monitored that only a small amount of raw materials remained in the reaction solution. Water was added to quench the reaction, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The organic phase gave a mixture of Int-7a and Int-7a' . ESI-MS(m/z): 319.1[M+H] ⁺ .

Step 2: Dissolve the product of the first step in methanol (50 mL), add ammonia water (5 mL) and Raney nickel suspension (5 mL) to the reaction system in sequence, replace the hydrogen with a hydrogen balloon and incubate in a hydrogen atmosphere at room temperature. The reaction lasted for 2 hours, and LCMS monitored the end of the reaction. The reaction solution was diluted with methanol and filtered through celite. The filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol = 20:1) to obtain brown oily liquid Int-7 (145 mg, two-step yield 29%). . ESI-MS(m/z): 323.3[M+H] ⁺ .

Intermediate 8

Intermediate 8 is prepared by the following steps:

Step 1: Add compound Int-8a (2.0g, 12.26mmol) and Na ₂ CO ₃ (2.6g, 24.52mmol) into water (60mL), stir to dissolve, and add iodine element (3.11g, 12.26mmol) into the reaction solution and stirred at room temperature for 3 hours. LCMS monitors the disappearance of raw materials, adjusts the pH of the reaction solution to 5-6 with dilute hydrochloric acid, and extracts with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was chromatographed on silica gel (gradient elution with ethyl acetate/petroleum ether = 0-30%) to obtain white solid Int-8b (1.5g, yield 42%) . ESI-MS(m/z): 290.2[M+H] ⁺ .

Step 2: Dissolve compound Int-8b (0.5g, 1.73mmol) and benzyl bromide (337mg, 1.98mmol) in DMF (5mL), add K ₂ CO ₃ (364mg, 2.64mmol), and stir at 50°C for 2 hours. , LCMS monitors the end of translation. 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 with ethyl acetate/petroleum ether = 0-15%) to obtain white solid Int-8c (0.5g, yield 76%). ESI-MS(m/z): 380.2[M+H] ⁺ .

Step 3: Combine compound Int-8c (500mg, 1.32mmol), cyclopropylboronic acid (566mg, 6.59mmol), tricyclohexylphosphine (74mg, 263umol), palladium acetate (29mg, 131umol), potassium phosphate (559mg, 2.63 mmol) was added to dioxane (30 mL) and water (3 mL). After the reaction system was replaced with nitrogen, it was stirred at 90°C for 17 hours under the protection of nitrogen atmosphere. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (gradient elution with ethyl acetate/petroleum ether = 0-15%) to obtain white solid Int-8d (250 mg, yield 64%). ESI-MS(m/z): 294.3[M+H] ⁺ .

Step 4: Dissolve compound Int-8d (250mg, 0.85mmol) in dichloromethane (20mL), cool to -78°C and add BBr ₃ (0.25mL) dropwise. The reaction solution is stirred at -78°C for 1 hour. Add water to quench and bring to room temperature. Extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate. The residue was subjected to silica gel column chromatography (gradient elution with ethyl acetate/petroleum ether = 0-15%) to obtain white solid Int-8e (172 mg, yield 100%). ESI-MS(m/z): 204.5[M+H] ⁺ .

Step 5: Add compounds Int-8e (172mg, 0.85mmol), Int-3d (144mg, 1.18mmol), Cs ₂ CO ₃ (0.64g, 2.0mmol) into DMF (5mL), and stir at 20°C for 17 hours. , LCMS monitored that the reaction was complete. The reaction solution was added to water (100 mL), stirred for 30 minutes, and filtered with suction to obtain yellow solid Int-8f (170 mg, yield 65%). ESI-MS(m/z): 306.2[M+H] ⁺ .

Step 6: Add compound Int-8f (90mg, 295umol) and Raney Nickel (0.5mL, water suspension) to methanol (5mL), add ammonia water (0.1ml), and replace hydrogen with the reaction system in a hydrogen atmosphere. Stir at room temperature for 2 hours, and LCMS monitors that the reaction is complete. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain yellow solid Int-8 (85 mg), which was directly used in the next reaction without purification. ESI-MS(m/z): 310.3[M+H] ⁺ .

Intermediate 9

Intermediate 9 is prepared by the following steps:

Step 1: Dissolve compound Int-3a (1.84g, 10mmol) in ethanol (20mL), add hydrazine salt Int-9a (1.25g, 10mmol) at room temperature, and react under reflux overnight. After the reaction was monitored by LCMS, the ethanol was distilled off under reduced pressure, and then water and ethyl acetate were added for extraction. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure and passed through silica gel column chromatography (petroleum ether: Ethyl acetate = 5:1) was purified to obtain white solid Int-9b (2.0 g, yield 97%). ESI-MS(m/z): 209.4[M+H] ⁺ .

Step 2: Dissolve compound Int-9b (2.0g, 9.61mmol) and compound Int-3d (1.17g, 9.61mmol) in N , N -dimethylformamide (10ml), add cesium carbonate (6.26 g,19.21mmol). The reaction was stirred at room temperature for 4 hours. LCMS monitored the reaction to completion. The reaction solution was diluted with water, and the resulting suspension was filtered. The filter cake was dried on a reduced-pressure rotary evaporator to obtain brown solid compound Int-9c (1.78g, yield 59%). ESI-MS(m/z): 311.1[M+H] ⁺ .

Step 3: Dissolve compound Int-9c (1.78g, 5.74mmol) in methanol (20mL) and ammonia water (1mL), and add Raney Nickel (0.5mL, water suspension). The reaction system was replaced with hydrogen and stirred at room temperature for 12 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain colorless oily liquid Int-9 (1.3 g, yield 72%). ESI-MS(m/z): 315.3[M+H] ⁺ .

Intermediate 10

Intermediate 10 was prepared by the following steps:

Step 1: Under nitrogen atmosphere, add compound Int-5b (500mg, 1.97mmol) and cesium carbonate (1.28g, 3.93mmol) to N,N-dimethylformamide (10mL), and then add to the reaction 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.58 mL, 3.93 mmol) was added dropwise. After the reaction solution was stirred at room temperature for 16 hours, LCMS monitored the end of the reaction. Water was added to quench the reaction, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain compound Int- Mixture of 10a and Int-10a' . ESI-MS(m/z): 328.5[M+H] ⁺ .

Step 2: Dissolve the product of the first step in methanol (60 mL), add ammonia water (6 mL) and Raney nickel suspension (6 mL) to the reaction system in sequence, replace the hydrogen with a hydrogen balloon and incubate in a hydrogen atmosphere at room temperature. The reaction lasted for 2 hours, and LCMS monitored the end of the reaction. The reaction solution was diluted with methanol and filtered through celite. The filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol = 20:1) to obtain brown oily liquid Int-10 (287 mg, two-step yield 43%). . ESI-MS (m/z): 382.3[M+CH ₃ CN+H] ⁺ .

Intermediate 11

Intermediate 11 was prepared by the following steps:

Step 1: Add compound Int-5b (400mg, 1.57mmol) and cesium carbonate (1.03g, 3.15mmol) to N , N -dimethylformamide (8mL), and then add 1- Fluoro-2-iodoethane (548 mg, 3.15 mmol). After the reaction solution was stirred at room temperature for 16 hours, LCMS monitored the end of the reaction. Water was added to quench the reaction, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain compound Int- Mixture of 11a and Int-11a' . ESI-MS(m/z): 301.2[M+H]+.

Step 2: Dissolve the product of the first step in methanol (50 mL), add ammonia water (5 mL) and Raney nickel suspension (5 mL) to the reaction system in sequence, replace the hydrogen with a hydrogen balloon and incubate in a hydrogen atmosphere at room temperature. The reaction lasted for 2 hours, and LCMS monitored the end of the reaction. The reaction solution was diluted with methanol and filtered through celite. The filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol = 20:1) to obtain brown oily liquid Int-11 (228 mg, two-step yield 48%). . ESI-MS(m/z): 305.1[M+H] ⁺ .

Intermediate 12

Intermediate 12 was prepared by the following steps:

Step 1: Dissolve compound Int-3d (120mg, 0.1mmol) and compound Int-12a (200mg, 0.1mmol) in N , N -dimethylformamide (5mL), add cesium carbonate (383mg, 1.2 mmol). The reaction was stirred at room temperature for 4 hours. LCMS monitored the complete reaction of raw materials. Water was added to the reaction solution to dilute it, the resulting suspension was filtered, and the filter cake was dried under reduced pressure to obtain white solid Int-12b (265 mg, yield 88%). ESI-MS(m/z): 307.1[M+H] ⁺ .

Step 2: Dissolve compound Int-12b (150 mg, 0.5 mmol) and methyl fluorosulfonyl difluoroacetate (189 mg, 0.1 mmol) in N , N -dimethylformamide (5 mL), and add iodine Cuprous oxide (373mg, 2mmol). The reaction was stirred at 130°C for 13 hours. LCMS monitored the complete reaction of raw materials. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/3) to obtain compound Int-12c (140 mg, yield 96%). ESI-MS(m/z): 296.1[M+H] ⁺ .

Step 3: Dissolve compound Int-12c (140mg, 0.48mmol) in methanol (9mL) and ammonia (1mL), add Raney Nickel (1mL, water suspension), replace hydrogen with the reaction system and stir at room temperature. 12 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain colorless oily liquid Int-12 (80 mg, yield 57%). ESI-MS(m/z): 300.2[M+H] ⁺ .

Intermediate 13

Intermediate 13 was prepared by the following steps:

Step 1: Add compounds Int-13a (700mg, 3.54mmol), Int-3d (433mg, 3.54mmol) and cesium carbonate (2.31g, 7.09mmol) to N , N -dimethylformamide (10mL) , react at 50°C for 16 hours, and monitor the end of the reaction with LCMS. N , N -dimethylformamide was distilled off under reduced pressure, and then water and ethyl acetate were added for extraction. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain a white solid Int-13b ( 711 mg, yield 67%).

Step 2: Dissolve compound Int-13b (355mg, 1.18mmol) in methanol (35mL), add ammonia (3.5mL) ( ) and Raney nickel (3.5mL suspension) to the reaction system in sequence, and replace the hydrogen gas through a hydrogen balloon The reaction was carried out under hydrogen atmosphere and room temperature for 3 hours, and LCMS monitored the completion of the reaction. The reaction solution was diluted with methanol and suction filtered. The filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol = 9:1) to obtain brown oily liquid Int-13 (199 mg, yield 55%). ESI-MS(m/z): 304.2[M+H] ⁺ .

Intermediate 14

Intermediate 14 was prepared by the following steps:

Step 1: Dissolve compound Int-3a (450.22 mg, 2.45 mmol) in ethanol (5 mL), add hydrazine salt Int-14a (200 mg, 2.04 mmol) at room temperature, and reflux the reaction overnight. After the reaction was monitored by LCMS, the ethanol was distilled off under reduced pressure, and then water and ethyl acetate were added for extraction. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure and passed through silica gel column chromatography (petroleum ether: Ethyl acetate = 5:1) was purified to obtain yellow solid Int-14b (300 mg, yield 67%). ESI-MS(m/z): 219.2[M+H] ⁺ .

Step 2: Add compounds Int-14b (300mg, 1.38mmol), Int-3d (184mg, 1.51mmol) and cesium carbonate (672mg, 2.06mmol) into acetonitrile (5mL) and react at 80°C for 5 hours. LCMS monitored the reaction to completion. Acetonitrile was removed by distillation under reduced pressure, and water and ethyl acetate were added for extraction. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain brown solid Int-14c (250 mg, yield 56%). ESI-MS(m/z): 321.2[M+H] ⁺ .

Step 3: Dissolve compound Int-14c (250 mg, 0.78 mmol) in methanol (5 mL), add ammonia water (1 mL) and Raney nickel (3 mL suspension) to the reaction system in sequence, replace the hydrogen gas through a hydrogen balloon and in a hydrogen atmosphere , react at room temperature for 16 hours, and LCMS monitors the end of the reaction. The reaction solution was diluted with methanol and suction filtered. The filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol = 9:1) to obtain brown oily liquid Int-14 (150 mg, yield 59%). ESI-MS(m/z): 325.3[M+H] ⁺ .

Intermediate 15

Intermediate 15 was prepared by the following steps:

Step 1: Add compound Int-15a (500mg, 4.23mmol), N -bromosuccinimide (829mg, 4.66mmol) and azobisisobutyronitrile (209mg, 1.27mmol) to 1,2- in dichloroethane (10 mL). The reaction was stirred under nitrogen atmosphere at 85°C for 16 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain yellow oily liquid Int-15b (244 mg, yield 29%).

Step 2: Add compounds Int-15c (200mg, 0.98mmol), Int-15b (290mg, 1.47mmol) and cesium carbonate (639mg, 1.96mmol) to N , N -dimethylformamide (6mL) . The reaction solution was stirred at room temperature for 16 hours. After the reaction was monitored by LCMS, water was added to quench the reaction, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure and passed through silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) was purified to obtain white solid Int-15d (213 mg, yield 68%).

Step 3: Dissolve compound Int-15d (213mg, 0.67mmol) in methanol (22mL), add ammonia water (2.2mL) and Raney nickel (2.2mL, water suspension) to the reaction system in sequence, and replace it with a hydrogen balloon Hydrogen was added and reacted for 16 hours in a hydrogen atmosphere and room temperature, and LCMS monitored the end of the reaction. The reaction solution was diluted with methanol, filtered with suction, and the filtrate was concentrated to obtain crude product Int-15 . ESI-MS(m/z): 325.2[M+H] ⁺ .

Intermediate 16

Intermediate 16 was prepared by the following steps:

Step 1: Add compounds Int-16a (1.00g, 11.89mmol), Int-16b (3.38g, 23.78mmol) and sodium ethoxide (1.62g, 23.78mmol) to dimethylsulfoxide (10mL) in sequence. The reaction solution was stirred at 60°C for 16 hours. After the reaction, 6N hydrochloric acid was added to quench the reaction, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain crude product Int-16c .

Step 2: Add compound Int-16c (1.94g), hydrazine hydrate (673mg, 10.75mmol, 80%) and acetic acid (5mL) to methanol (35mL), and the reaction solution is refluxed under nitrogen atmosphere for 16 hours. After the reaction was monitored by LCMS, the solvent was evaporated under reduced pressure, then diluted with water and sodium carbonate (solid) was added until the pH was 9, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The organic phase gave Int-16d as a brown solid (1.73g, two-step yield 82%). ESI-MS(m/z): 177.5[M+H] ⁺ .

Step 3: Add compounds Int-16d (200mg, 1.14mmol), Int-15b (336mg, 1.70mmol) and potassium carbonate (314mg, 2.27mmol) to acetonitrile (10mL). The reaction solution was stirred at 80°C for 16 hours. After the reaction was monitored by LCMS, water was added to quench the reaction, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure and passed through silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) Purified to obtain oily liquid Int-16e (250mg, yield 75%) and oily liquid Int-16e' (80mg, yield 24%). ESI-MS(m/z): 293.2[M+H] ⁺ .

Step 4: Dissolve compound Int-16e (228 mg, 0.78 mmol) in methanol (23 mL), add ammonia water (2.3 mL) and Raney nickel (2.3 mL, water suspension) to the reaction system in sequence, and replace with a hydrogen balloon. Hydrogen was added and reacted for 3 hours in a hydrogen atmosphere and room temperature, and LCMS monitored the completion of the reaction. The reaction solution was diluted with methanol, filtered with suction, and the filtrate was concentrated to obtain crude product Int-16 . ESI-MS(m/z): 297.3[M+H] ⁺ .

Intermediate 17

Intermediate 17 was prepared by the following steps:

Step 1: Dissolve compound Int-16e' (80mg, 0.27mmol) in methanol (8mL), add ammonia water (0.8mL) and Raney nickel (0.8mL, water suspension) to the reaction system in sequence, and pass the hydrogen balloon through The hydrogen gas was replaced and the reaction was carried out in a hydrogen atmosphere and room temperature for 3 hours, and LCMS monitored the completion of the reaction. The reaction solution was diluted with methanol, filtered with suction, and the filtrate was concentrated to obtain crude product Int-17 . ESI-MS(m/z): 297.2[M+H] ⁺ .

Intermediate 18

Intermediate 18 was prepared by the following steps:

Step 1: Dissolve compound Int-18a (2.03g, 10mmol) in anhydrous dimethylstyrene (10mL), add potassium hydroxide (1.68g, 30mmol) and deuterated methyl iodide (2.17g, 15mmol). The reaction solution was stirred at room temperature for 12 hours. LCMS detects the end of the reaction. The reaction solution was quenched with water and extracted with dichloromethane. The organic phases were combined and washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product of compound Int-18b (2.3g). ESI-MS(m/z): 238.3[M+H] ⁺ .

Step 2: Dissolve compound Int-18b (2.3g, 10mmol) in dioxane hydrochloride solution (5mL, 4M). The reaction solution was stirred at room temperature for 1 hour. LCMS detects the end of the reaction. The reaction solution was concentrated, and the pH of the residue was adjusted to weak alkalinity with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, the organic phases were combined and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound Int-18c (1.3 g) crude product.

Step 3: Dissolve compounds Int-18c (450mg, 3mmol) and Int-18d (539mg, 3mmol) in tetrahydrofuran (3mL), and add N , N -diisopropylethylamine (1g, 7.78mmol). The reaction solution was stirred at room temperature for 4 hours. LCMS detects the end of the reaction. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain Compound Int-18e (459 mg, yield 58%). ESI-MS(m/z): 309.3[M+H] ⁺ .

Step 4: Dissolve compound Int-18e (400 mg, 1.30 mmol) in methanol (5 mL), add potassium carbonate (269 mg, 1.94 mmol), and then add sodium dithionite (677 mg, 3.89 mmol). The reaction solution was stirred at room temperature for 30 minutes. Aqueous hydrochloric acid (2 mL, 4M) was then added. The reaction solution was continued to stir at room temperature for 8 hours. LCMS detects the end of the reaction. The reaction solution was adjusted to pH 9 with ammonia-methanol solution, diluted with water, and extracted with methylene chloride. The organic phases were combined and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residual liquid was subjected to silica gel column chromatography (methylene chloride). /methanol=20/1) was purified to obtain compound Int-18 (230 mg, yield 60%). ESI-MS(m/z): 244.4[M+H] ⁺ .

The synthesis method of the example compounds in the present invention is as follows:

Example 1

(S)-2-(((6-((1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)pyridin-3-yl)methyl)amine methyl)-4,7,8-trimethyl-7,8-dihydropterin-6(5H)-one

Example 1 is prepared by the following steps:

Step 1: Dissolve compound Int-1 (1.0g, 4.41mmol) and compound Int-3 (1.71g, 5.74mmol) in n-butanol (6mL), add p-toluenesulfonic acid monohydrate (83mg, 0.44 mmol), the reaction solution was stirred at 160°C for 4 hours under microwave conditions. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was directly purified by reverse preparative HPLC to obtain a white solid 1 (987 mg, yield 45%). ESI-MS (m/z): 489.2[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 9.83 (s, 1H), 8.16 (d, J =2.4Hz, 1H), 7.91 (dd , J =8.5,2.4Hz,1H),7.20(d, J =8.4Hz,1H),6.99(t, J =6.2Hz,1H),6.53(s,1H),4.37(qt, J =11.5, 6.4Hz,2H),3.99(q, J =6.8Hz,1H),3.50-3.41(m,1H),2.91(s,3H),2.12(s,3H),1.18(d, J =6.8Hz, 3H), 1.03 (dt, J =7.5, 4.6Hz, 2H), 0.92 (dt, J =7.3, 3.8Hz, 2H).

Example 2

(S)-2-(((6-((1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)pyridin-3-yl)methyl)amine methyl)-4,7-dimethyl-8-(methyl-d3)-7,8-dihydropterin-6(5H)-one

Example 2 is prepared by the following steps:

Step 1: Dissolve compound Int-2 (50mg, 0.22mmol) and compound Int-3 (84mg, 0.28mmol) in n-butanol (2mL), add p-toluenesulfonic acid monohydrate (4mg, 0.02mmol) , the reaction solution was stirred at 160°C for 3 hours under microwave conditions. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by reverse preparative HPLC to obtain white solid 2 (36 mg, yield 34%). ESI-MS (m/z): 492.2[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO-d6) δ 9.86 (s, 1H), 8.16 (d, J =2.3Hz, 1H), 7.91 (dd , J =8.4,2.4Hz,1H),7.21(d, J =8.4Hz,1H),7.03(t, J =6.0Hz,1H),6.55(s,1H),4.46-4.29(m,2H) ,3.99(q, J =6.8Hz,1H),3.46(tt, J =7.4,3.8Hz,1H),2.11(s,3H),1.17(d, J =6.8Hz,3H),1.02(p, J =4.7,4.2Hz,2H),0.92(dt, J =7.2,3.5Hz,2H).

Example 3

(S)-2-(((6-((1-(ethyl-d5)-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)pyridin-3-yl)methyl (base)amino)-4,7,8-trimethyl-7,8-dihydropterin-6(5H)-one

Example 3’

(S)-2-(((6-((1-(ethyl-d5)-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxo)pyridin-3-yl)methyl (base)amino)-4,7,8-trimethyl-7,8-dihydropterin-6(5H)-one

Examples 3 and 3’ were prepared by the following steps:

Step 1: Dissolve compound Int-5b (500mg, 1.97mmol) in N , N -dimethylformamide (10mL), then add cesium carbonate (1.28g, 3.93mmol) and deuterated ethyl iodide ( 633 mg, 3.93 mmol). The reaction solution was stirred at room temperature for 4 hours. LCMS monitored the reaction to completion. The reaction solution was diluted with saturated sodium chloride aqueous solution, and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a mixture of compounds 3a and 3a' . ESI-MS(m/z): 288.9[M+H] ⁺ .

Step 2: Dissolve the products 3a and 3a' obtained in the previous step in methanol (15 mL) and ammonia water (1 mL), add Raney Nickel (1 mL, water suspension), replace the reaction system with hydrogen, and stir at room temperature for 12 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=5/1) to obtain colorless oily liquid 3b (186 mg, yield 33%), ESI-MS (m/z): 292.2 [M+H] ⁺ ; and colorless oily liquid 3b' (182mg, yield 32%), ESI-MS (m/z): 292.2[M+H] ⁺ .

Step 3: Dissolve compound 3b (60mg, 0.21mmol) in n-butanol (3mL), add compound Int-1 (31mg, 0.14mmol) and p-toluenesulfonic acid monohydrate (3mg, 0.02mmol), The reaction solution was stirred at 160°C for 3 hours under microwave conditions. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by reverse preparative HPLC to obtain white solid 3 (29 mg, yield 29%). ESI-MS (m/z): 482.1[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO) δ 9.84 (s, 1H), 8.15 (d, J =2.1Hz, 1H), 7.90 (dd, J =8.4,2.3Hz,1H),7.19(d, J =8.4Hz,1H),7.01(t, J =5.8Hz,1H),6.53(s,1H),4.36(qd, J =15.2,6.3Hz ,2H),3.99(q, J =6.8Hz,1H),2.90(s,3H),2.11(s,3H),1.17(d, J =6.8Hz,3H).

Step 4: Starting from compound 3b' (60 mg, 0.21 mmo), use a method similar to the third step to obtain white solid 3' (20 mg, yield 18%). ESI-MS (m/z): 482.2[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO) δ 9.83 (s, 1H), 8.12 (d, J =2.1Hz, 1H), 7.82 (dd, J =8.4,2.3Hz,1H),7.04(d, J =8.4Hz,1H),6.97(t, J =5.8Hz,1H),6.68(s,1H),4.34(qd, J =15.2,6.4Hz ,2H),3.99(q, J =6.8Hz,1H),2.91(s,3H),2.11(s,3H),1.17(d, J =6.8Hz,3H).

Example 4

(S)-2-(((6-((1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)pyridin-3-yl)methyl)amine methyl)-4,7,8-trimethyl-7,8-dihydropterin-6(5H)-one

Example 4’

(S)-2-(((6-((1-isopropyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxo) Pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropterin-6(5H)-one

Examples 4 and 4' were prepared by the following steps:

Step 1: Dissolve compound Int-5b (200mg, 0.79mmol) in N , N -dimethylformamide (5mL), then add cesium carbonate (513mg, 1.57mmol) and 2-iodopropane (268mg ,1.57mmol). The reaction solution was stirred at room temperature for 4 hours. LCMS monitored the reaction to completion. The reaction solution was diluted with saturated sodium chloride aqueous solution, and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a mixture of compounds 4a and 4a' . ESI-MS(m/z): 297.2[M+H] ⁺ .

Step 2: Dissolve the products 4a and 4a' obtained in the previous step in methanol (9mL) and ammonia (1mL), add Raney Nickel (0.5mL, water suspension), replace the reaction system with hydrogen and stir at room temperature. 12 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=5/1) to obtain colorless oily liquid 4b (62 mg, yield 26%), ESI-MS (m/z): 301.3 [M+H] ⁺ ; and colorless oily liquid 4b' (60mg, yield 25%), ESI-MS (m/z): 301.3[M+H] ⁺ .

Step 3: Dissolve compound 4b (62mg, 0.21mmol) in n-butanol (3mL), add compound Int-1 (31mg, 0.14mmol) and p-toluenesulfonic acid monohydrate (3mg, 0.02mmol), and react The solution was stirred under microwave conditions at 160°C for 3 hours. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by reverse preparative HPLC to obtain white solid 4 (13 mg, yield 13%). ESI-MS (m/z): 491.2[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO-d6) δ 9.83 (s, 1H), 8.15 (d, J =2.2Hz, 1H), 7.90 (dd , J =8.4,2.4Hz,1H),7.19(d, J =8.4Hz,1H),7.03-6.97(m,1H),6.50(s,1H),4.49(dt, J =13.3,6.6Hz, 1H),4.41-4.31(m,2H),3.99(q, J =6.8Hz,1H),2.90(s,3H),2.11(s,3H),1.35(d, J =6.6Hz,6H), 1.17(d, J =6.8Hz,3H).

Step 4: Starting from compound 4b' (60 mg, 0.21 mmo), a white solid 4' (5 mg, yield 5%) can be obtained using a method similar to the third step. ESI-MS (m/z): 491.1[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 9.85 (s, 1H), 8.13 (d, J =2.2Hz, 1H), 7.83 (dd , J =8.4,2.4Hz,1H),7.02(t, J =8.9Hz,2H),6.65(s,1H),4.55(dt, J =13.0,6.4Hz,1H),4.35(qd, J = 15.2,6.4Hz,2H),3.99(q, J =6.7Hz,1H),2.91(s,3H),2.11(s,3H),1.46-1.39(m,6H),1.17(d, J =6.8 Hz,3H).

Example 5

(S)-2-(((6-((1-(tert-butyl))-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)pyridin-3-yl)methyl (base)amino)-4,7,8-trimethyl-7,8-dihydropterin-6(5H)-one

Example 5 is prepared by the following steps:

Step 1: Dissolve compound Int-9 (100mg, 0.32mmol) and compound Int-1 (48mg, 0.21mmol) in n-butanol (3mL), add p-toluenesulfonic acid monohydrate (6mg, 0.03mmol) , the reaction solution was stirred at 160°C for 3 hours under microwave conditions. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by reverse preparative HPLC to obtain white solid 5 (20 mg, yield 13%). ESI-MS (m/z): 505.1[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO) δ 9.85 (s, 1H), 8.18 (d, J =1.8Hz, 1H), 7.89 (dd, J =8.4,2.1Hz,1H),7.19(d, J =8.4Hz,1H),7.02(t, J =4.7Hz,1H),6.49(s,1H),4.37(qd, J =15.3,6.3Hz ,2H),3.99(q, J =6.7Hz,1H),2.90(s,3H),2.11(s,3H),1.54(s,9H),1.17(d, J =6.8Hz,3H).

Example 6

(S)-2-(((6-((1-(2-fluoroethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)pyridin-3-yl) Methyl)amino)-4,7,8-trimethyl-7,8-dihydropterin-6(5H)-one

Example 6 is prepared by the following steps:

Step 1: Dissolve intermediate Int-1 (37mg, 0.16mmol), intermediate Int-11 (55mg, 0.18mmol) and trifluoroacetic acid (2mg, 0.02mmol) in n-butanol (2mL), and microwave React at 160°C for 4 hours. LCMS monitored the reaction to completion. The reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 6 (21 mg, yield 26%). ESI-MS (m/z): 495.2[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d ₆ ) δ 9.93 (s, 1H), 8.18 (d, J =2.3Hz, 1H), 7.91 ( dd, J =8.4,2.4Hz,1H),7.20(d, J =8.4Hz,1H),6.60(s,1H),4.74(dt, J =47.1,4.7Hz,2H),4.46-4.33(m ,4H),4.03(q, J =6.8Hz,1H),2.93(s,3H),2.13(s,3H),1.20(d, J =6.8Hz,3H).

Example 7

(S)-4,7,8-trimethyl-2-(((6-((1-(2,2,2-trifluoroethyl))-3-(trifluoromethyl)-1H-pyra Azol-5-yl)oxo)pyridin-3-yl)methyl)amino)-7,8-dihydropterin-6(5H)-one

Example 7 is prepared by the following steps:

Step 1: Dissolve intermediate Int-1 (39mg, 0.17mmol), intermediate Int-10 (65mg, 0.19mmol) and trifluoroacetic acid (2mg, 0.02mmol) in n-butanol (2mL), and microwave React at 160°C for 4 hours. LCMS monitored the reaction to completion. The reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 7 (24 mg, yield 26%). ESI-MS (m/z): 503.9[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d ₆ ) δ 9.85 (s, 1H), 8.19 (d, J =2.4Hz, 1H), 7.92 ( dd, J =8.4,2.4Hz,1H),7.22(d, J =8.4Hz,1H),7.03(t, J =6.4Hz,1H),6.71(s,1H),5.21(q, J =9.0 Hz,2H),4.50-4.30(m,2H),3.99(q, J =6.8Hz,1H),2.91(s,3H),2.12(s,3H),1.17(d, J =6.8Hz,3H ).

Example 8

(S)-2-(((6-((1-(2,2-difluoroethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)pyridine-3 -(yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropterin-6(5H)-one

Example 8 was prepared by the following steps:

Step 1: Dissolve intermediate Int-1 (38mg, 0.17mmol), intermediate Int-7 (60mg, 0.19mmol) and trifluoroacetic acid (2mg, 0.02mmol) in n-butanol (2mL), microwave React at 160°C for 4 hours. LCMS monitored the reaction to completion. The reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 8 (24 mg, yield 27%). ESI-MS (m/z): 513.9[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d ₆ ) δ 9.78 (s, 1H), 8.11 (d, J =2.3Hz, 1H), 7.84 ( dd, J =8.4,2.3Hz,1H),7.13(d, J =8.4Hz,1H),6.96(t, J =6.3Hz,1H),6.59(s,1H),6.33(tt, J =54.3 ,3.6Hz,1H),4.56(td, J =15.2,3.5Hz,2H),4.40-4.23(m,2H),3.92(q, J =6.7Hz,1H),2.84(s,3H),2.05 (s,3H),1.11(d, J =6.8Hz,3H).

Example 9

(S)-2-(((6-((2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)oxo)pyridin-3-yl)methyl)amino)-4 ,7,8-trimethyl-7,8-dihydropterin-6(5H)-one

Example 9 is prepared by the following steps:

Step 1: Dissolve intermediate Int-1 (34mg, 0.15mmol), intermediate Int-8 (51mg, 0.16mmol) and trifluoroacetic acid (2mg, 0.02mmol) in n-butanol (2mL), and microwave React at 160°C for 4 hours. LCMS monitored the reaction to completion. The reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 9 (16 mg, yield 21%). ESI-MS (m/z): 500.0[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d ₆ ) δ 9.82 (s, 1H), 8.08 (d, J = 2.3Hz, 1H), 7.88 ( dd, J =8.4,2.4Hz,1H),7.75-7.64(m,2H),7.17(d, J =8.4Hz,1H),6.97(t, J =6.3Hz,1H),4.44-4.27(m ,2H),3.99(q, J =6.8Hz,1H),2.91(s,3H),2.23-2.16(m,1H),2.12(s,3H),1.18(d, J =6.8Hz,3H) ,0.98-0.90(m,4H).

Example 10

(S)-2-(((6-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)oxo)pyridin-3-yl)methyl)amino)-4,7 -Dimethyl-8-(methyl-d3)-7,8-dihydropterin-6(5H)-one

Example 10 was prepared by the following steps:

Step 1: Dissolve intermediate Int-2 (50mg, 0.22mmol), intermediate Int-13 (85mg, 0.28mmol) and p-toluenesulfonic acid monohydrate (4mg, 0.02mmol) in n-butanol (2mL) in the microwave at 160°C for 3 hours. LCMS monitored the reaction to completion. The reaction solution was purified by reverse-phase preparative HPLC to obtain a white solid 10 (23 mg, yield 21%). ESI-MS (m/z): 499.2[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 9.86 (s, 1H), 8.14-8.01 (m, 3H), 7.91 (dd, J = 8.5,2.4Hz,1H),7.23(d, J =8.4Hz,1H),7.02(t, J =6.2Hz,1H),4.35(qd, J =15.2,6.3Hz,2H),3.99(q, J =6.8Hz,1H),2.12(s,3H),1.17(d, J =6.9Hz,3H).

Example 11

(S)-2-(((6-((2-methoxy-6-(trifluoromethyl)pyridin-3-yl)oxo)pyridin-3-yl)methyl)amino)-4 ,7,8-trimethyl-7,8-dihydropterin-6(5H)-one

Example 11 was prepared by the following steps:

Step 1: Dissolve compound Int-12 (100mg, 0.34mmol) and compound Int-1 (75mg, 0.34mmol) in n-butanol (3mL), add p-toluenesulfonic acid monohydrate (6mg, 0.03mmol) , the reaction solution was stirred at 160°C for 3 hours under microwave conditions. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by reverse preparative HPLC to obtain white solid 11 (80 mg, yield 48%). ESI-MS (m/z): 490.2[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO) δ 9.81 (s, 1H), 8.01 (d, J =1.9Hz, 1H), 7.83 (dd, J =8.4,2.3Hz,1H),7.77(d, J =7.9Hz,1H),7.55(d, J =7.9Hz,1H),7.08(d, J =8.4Hz,1H),6.94(t, J =5.7Hz,1H),4.33(qd, J =15.1,6.3Hz,2H),3.98(q, J =6.8Hz,1H),3.83(s,3H),2.90(s,3H),2.11(s ,3H),1.17(d, J =6.8Hz,3H).

Example 12

(S)-2-(((6-((1-(bicyclo[1.1.1]pentan-1-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxy Generation)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropterin-6(5H)-one

Example 12 was prepared by the following steps:

Step 1: Dissolve compound Int-1 (50mg, 0.22mmol) and compound Int-14 (93mg, 0.29mmol) in n-butanol (2mL), add p-toluenesulfonic acid monohydrate (4mg, 0.02mmol) , the reaction solution was stirred at 160°C for 3 hours under microwave conditions. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by reverse preparative HPLC to obtain white solid 12 (36 mg, yield 30%). ESI-MS (m/z): 515.2[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 9.82 (s, 1H), 8.15 (d, J =2.4Hz, 1H), 7.90 (dd , J =8.5,2.4Hz,1H),7.18(d, J =8.4Hz,1H),7.00(t, J =6.2Hz,1H),6.58(s,1H),4.52-4.31(m,2H) ,3.99(q, J =6.8Hz,1H),2.91(s,3H),2.55(s,1H),2.16(s,6H),2.11(s,3H),1.17(d, J =6.8Hz, 3H).

Example 13

(S)-2-(((6-((3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)methyl)pyridin-3-yl)methyl)amino)- 4,7,8-Trimethyl-7,8-dihydropterin-6(5H)-one

Example 13 was prepared by the following steps:

Step 1: Dissolve intermediate Int-1 (40mg, 0.18mmol), intermediate Int-15 (69mg, 0.21mmol) and trifluoroacetic acid (2mg, 0.02mmol) in n-butanol (2mL), microwave React at 160°C for 3 hours. LCMS monitored the reaction to completion. The reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 13 (37 mg, yield 41%). ESI-MS (m/z): 515.2[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d ₆ ) δ 9.81 (s, 1H), 8.43 (d, J = 2.2Hz, 1H), 7.74 ( dd, J =8.0,2.2Hz,1H),7.62(s,1H),7.18(d, J =8.0Hz,1H),7.09-6.92(m,1H),5.67(s,2H),4.46-4.31 (m,2H),3.98(q, J =6.8Hz,1H),2.87(s,3H),2.10(s,3H),1.16(d, J =6.9Hz,3H).

Example 14

(S)-2-(((6-((1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)pyridin-3-yl)methyl)amine methyl)-4-methyl-6a,7,8,9-tetrahydropyrrolo[2,1-h]pteridin-6(5H)-one

Example 14 was prepared by the following steps:

Step 1: Dissolve compound Int-1a (500mg, 2.81mmol) and compound 14a (602mg, 3.65mmol) in ethanol (20mL) and water (2mL), then add sodium bicarbonate (707mg, 8.34mmol), and The temperature of the reaction solution was raised to 80°C and stirred for 16 hours. After the reaction solution was cooled to room temperature, water (12 mL) was added to the reaction solution, and after filtration, an off-white solid 14b (385 mg, yield 57%) was obtained. ESI-MS (m/z): 239.4 [M+H] ⁺ .

Step 2: Dissolve compound 14b (42mg, 0.17mmol) and compound Int-3 (68mg, 0.23mmol) in n-butanol (2mL), add p-toluenesulfonic acid monohydrate (3mg, 0.01mmol), and react The solution was stirred under microwave conditions at 160°C for 3 hours. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by reverse preparative HPLC to obtain a white solid 14 (15 mg, yield 17%). ESI-MS (m/z): 501.3[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 9.69 (s, 1H), 8.09 (d, J = 2.4Hz, 1H), 7.83 (dd ,J=8.4,2.4Hz,1H),7.12(d,J=8.4Hz,1H),6.92(t,J=6.3Hz,1H),6.46(s,1H),4.39-4.22(m,2H) ,3.90(dd,J=9.1,6.2Hz,1H),3.47(dt,J=11.1,7.5Hz,1H),3.40(tt,J=7.5,3.8Hz,1H),2.19-2.08(m,1H ),2.04(s,3H),1.84(tq,J=14.0,5.9,5.3Hz,3H),0.96(p,J=4.8,4.3Hz,2H),0.86(dt,J=7.3,3.6Hz, 2H).

Example 15

(S)-4,7,8-Trimethyl-2-(((6-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)oxo)pyridin-3-yl) )Methyl)amino)-7,8-dihydropterin-6(5H)-one

Example 15 was prepared by the following steps:

Step 1: Add ethyl formate (3.17g, 42.73mmol) and solid sodium ethoxide (3.49g, 50.50mmol) to dry tetrahydrofuran (140mL) in sequence. After adding compound 15a (7g, 38.85mmol) at a temperature of 5-10°C, the reaction solution was heated to 50°C and stirred for 2 hours. HPLC monitored the disappearance of the raw materials. Tetrahydrofuran was evaporated under reduced pressure to obtain yellow oil 15b , which was used directly in the next step.

Step 2: Add 150 ml of absolute ethanol to the oily substance 15b 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. , then raise the temperature to 80°C and continue stirring for 2 hours. HPLC monitors the disappearance of the raw materials. After the reaction solution cooled down, about 100 ml of ethanol was evaporated under reduced pressure. The remaining residue was added to 300 ml of ice water, and the pH was adjusted to 3 with concentrated hydrochloric acid. Stir for 0.5 hours, filter with suction, and dry the filter cake to obtain yellow solid compound 15c (4.37 g, yield 41%, purity 99%). ESI-MS(m/z): 271.4[M+H] ⁺ .

Step 3: Add compound 15c (4.0g, 14.80mmol) to 60ml acetonitrile, add phosphorus oxychloride (6.81g, 44.41mmol) dropwise, stir for 10 minutes after the dropwise addition, raise the temperature to 80°C, and keep stirring for 2 hour, HPLC monitored that the raw material conversion was complete. Acetonitrile was removed under reduced pressure, and the residual liquid was added to 200 mL of ice water, stirred for 0.5 hours, and filtered with suction to obtain yellow solid 15d (3.9 g, yield 86%, purity 95%).

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

Step 5: Add compound 15e (1.0g, 3.73mmol) to 20mL methanol, add 10% palladium on carbon (100mg), replace hydrogen with the reaction system and stir at room temperature overnight. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain compound 15f (630 mg, yield 92%, purity 97%). ESI-MS(m/z): 177.1[MH] ^- .

Step 6: Add compound 15f (0.5g, 2.81mmol), Cs ₂ CO ₃ (1.83g, 5.61mmol), Int-3d (514mg, 4.21mmol) to N,N-dimethylformamide ( 10 mL), stir overnight at 20°C, and HPLC monitors the disappearance of the raw materials. Add the reaction solution to 50 ml of ice water, stir for 0.5 hours, and filter with suction to obtain 15 g of yellow solid (510 mg, yield 64%, purity 99%). ESI-MS(m/z): 281.3[M+H] ⁺ .

Step 7: Dissolve 15g of compound (100mg, 0.36mmol) in methanol (5mL), add ammonia water (0.2mL), add Raney Nickel (0.5mL, water suspension), and replace the reaction system with hydrogen at room temperature. Stir for 2 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain compound 15h (95 mg, yield 93%, purity 90%), ESI-MS (m/z): 284.9 [M+H] ⁺ .

Step 8: Dissolve compound 15h (95 mg, 0.33 mmol) in n-butanol (3 mL), add compound Int-1 (79 mg, 0.35 mmol) and p-toluenesulfonic acid monohydrate (3 mg, 0.02 mmol), and react. The solution was stirred under microwave conditions at 160°C for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by reverse preparative HPLC to obtain white solid 15 (31 mg, yield 21%, purity 99%). ESI-MS (m/z): 475.2[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 9.82 (s, 1H), 8.86 (s, 1H), 8.07 (d, J =2.4Hz ,1H),7.91(dd, J =8.4,2.4Hz,1H),7.23(d, J =8.4Hz,1H),6.98(s,1H),4.45-4.25(m,2H),3.99(q, J =6.8Hz,1H),2.91(s,3H),2.42(s,3H),2.11(s,3H),1.18(d, J =6.9Hz,3H).

Example 16

(S)-2-(((6-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)pyridin-3-yl)methyl)amine methyl)-4,7,8-trimethyl-7,8-dihydropterin-6(5H)-one

Example 16 was prepared by the following steps:

Intermediate Int-1 (40mg, 0.18mmol), intermediate Int-16 (63mg, 0.21mmol) and trifluoroacetic acid (2mg, 0.02mmol) were dissolved in n-butanol (2mL) and microwaved at 160°C. React for 3 hours. LCMS monitored the reaction to completion. The reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 16 (33 mg, yield 38%). ESI-MS (m/z): 487.3[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d ₆ ) δ 9.81 (s, 1H), 8.48 (d, J =2.1Hz, 1H), 7.71 ( dd, J =8.0,2.3Hz,1H),7.02(d, J =8.1Hz,1H),6.98(t, J =6.4Hz,1H),6.42(s,1H),5.54(s,2H), 4.43-4.31(m,2H),3.98(q, J =6.8Hz,1H),2.89(s,3H),2.10(s,3H),1.96-1.89(m,1H),1.17(d, J = 6.8Hz,3H),0.92-0.84(m,2H),0.70-0.63(m,2H).

Example 17

(S)-2-(((6-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)pyridin-3-yl)methyl)amine methyl)-4,7,8-trimethyl-7,8-dihydropterin-6(5H)-one

Example 17 was prepared by the following steps:

Intermediate Int-1 (35 mg, 0.15 mmol), intermediate Int-17 (50 mg, 0.17 mmol) and trifluoroacetic acid (2 mg, 0.02 mmol) were dissolved in n-butanol (2 mL) and microwaved at 160°C. React for 3 hours. LCMS monitored the reaction to completion. The reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 17 (15 mg, yield 20%). ESI-MS (m/z): 487.2[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d ₆ ) δ 9.96 (s, 1H), 8.46 (s, 1H), 7.70 (dd, J =8.2 ,2.2Hz,1H),6.90(d, J =8.0Hz,1H),6.67(s,1H),5.41(s,2H),4.39(s,2H),4.15-3.91(m,1H),2.91 (s,3H),2.13(s,3H),1.96-1.87(m,1H),1.20(d, J =6.8Hz,3H),0.92-0.83(m,2H),0.72-0.63(m,2H ).

Example 18

2'-(((6-((1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)pyridin-3-yl)methyl)amino)- 4'-Methyl-8'-(methyl-d3)-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridin]-6'-one

Example 18 was prepared by the following steps:

Step 1: Dissolve compound 18a (1.01g, 5mmol) and potassium hydroxide (842mg, 15mmol) in anhydrous dimethylsulfoxide (10mL), and then add deuterated methyl iodide (1.59g, 11mmol) dropwise to in the reaction solution. The reaction solution was stirred at room temperature for 8 hours. LCMS monitored the reaction to completion. The reaction solution was diluted with water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product of compound 18b (1.0 g, yield 84%). ESI-MS(m/z): 236.3[M+H] ⁺ .

Step 2: Dissolve compound 18b (1.0g) in dioxane hydrochloride solution (4M, 10mL). The reaction solution was stirred at room temperature for 4 hours. LCMS monitored the reaction to completion. The reaction solution was concentrated under reduced pressure to obtain a crude product of compound 18c (720 mg). ESI-MS(m/z): 136.1[M+H] ⁺ .

Step 3: Dissolve compound 18c (720mg) and compound 18d (872mg, 4.19mmol) in tetrahydrofuran (10mL), and add N , N -diisopropylpropylamine (1.62g, 12.57mmol). The reaction solution was stirred at room temperature for 8 hours. LCMS monitored the reaction to completion. The reaction solution was diluted with water, filtered, and the filter cake was washed with water and dried to obtain an off-white solid 18d (993 mg, two-step reaction yield 77%). ESI-MS(m/z): 307.2[M+H] ⁺ .

Step 4: Dissolve compound 18d (306 mg, 1 mmol) and potassium carbonate (207 mg, 1.5 mmol) in methanol (10 mL). Dissolve sodium dithionite (871 mg, 5 mmol) in water and add dropwise to the reaction solution. The reaction solution was stirred at room temperature for 15 minutes. LCMS monitored the complete reaction of raw materials. Dioxane hydrochloride solution (4M, 1.25mL) was added to the reaction solution. The reaction solution was continued to stir at room temperature for 8 hours. Ammonia methanol solution was added dropwise to the reaction solution, the pH of the reaction solution was adjusted to 10, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain compound 18e (30 mg, yield 13%). ESI-MS(m/z): 242.3[M+H] ⁺ .

Step 5: Dissolve Int-3 (35mg, 0.12mmol) and compound 18e (28mg, 0.12mmol) in n-butanol (3mL), add p-toluenesulfonic acid monohydrate (2mg, 0.01mmol), and the reaction solution Stir at 160°C for 3 hours under microwave conditions. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by reverse preparative HPLC to obtain a white solid 18 (10 mg, yield 17%). ESI-MS (m/z): 504.3[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO) δ 8.14 (d, J =2.1Hz, 1H), 7.89 (dd, J =8.4, 2.3Hz, 1H ),7.20(d, J =8.4Hz,1H),7.06-6.98(m,1H),6.54(s,1H),4.36(d, J =6.2Hz,2H),3.46(ddd, J =11.4, 7.5,3.9Hz,1H),2.11(s,3H),1.27(dd, J =7.5,5.1Hz,2H),1.11(dd, J =7.5,5.1Hz,2H),1.06-0.99(m,2H ),0.91(dt, J =7.7,5.3Hz,2H).

Example 19

(S)-2-(((6-((1-(3,3-difluorocyclobutyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)pyridine- 3-yl)methyl)amino)-4,7-dimethyl-8-(methyl-d3)-7,8-dihydropterin-6(5H)-one

Example 19’

(S)-2-(((6-((1-(3,3-difluorocyclobutyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxo)pyridine- 3-yl)methyl)amino)-4,7-dimethyl-8-(methyl-d3)-7,8-dihydropterin-6(5H)-one

Examples 19 and 19' were prepared by the following steps:

Step 1: Add trifluoromethanesulfonic anhydride (1.25g, 4.44mmol) to compound 19a (400mg, 3.70mmol) and 4-dimethylaminopyridine (543mg, 4.44mmol) dichloride under ice bath conditions. Methane solution (10 mL). After reacting at room temperature for 16 hours, add saturated aqueous ammonium chloride solution to quench the reaction, extract with dichloromethane, combine the organic phases and wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate the organic phase under reduced pressure to obtain the crude product of compound 19b . , used directly for the next reaction.

Step 2: Dissolve compound Int-5b (150 mg, 0.59 mmol) and cesium carbonate (385 mg, 1.18 mmol) in N , N -dimethylformamide (5 mL), and then add crude compound 19b dropwise to the reaction solution (284mg). After the reaction solution was stirred at room temperature for 16 hours, LCMS monitored the end of the reaction. Water was added to quench the reaction, and extraction was performed with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain 19c and 19c . ' mixture (170mg, 84%). ESI-MS(m/z): 345.2[M+H] ⁺ .

Step 3: Dissolve the mixture of 19c and 19c' (283 mg, 0.82 mmol) in methanol (30 mL), add ammonia water (3 mL) and Raney nickel (3 mL, water suspension) to the reaction system in sequence, and pass the hydrogen balloon through The hydrogen gas was replaced and the reaction was carried out in a hydrogen atmosphere and room temperature for 2 hours, and LCMS monitored the completion of the reaction. The reaction solution was diluted with methanol, filtered through diatomaceous earth, and the filtrate was concentrated to obtain a mixture of 19d and 19d' , which was directly used in the next reaction. ESI-MS(m/z): 349.3[M+H] ⁺ .

Step 4: Dissolve Int-2 (80 mg, 0.35 mmol), the mixture of 19d and 19d' (146 mg, crude product) and p-toluenesulfonic acid monohydrate (4 mg, 0.03 mmol) in n-butanol (2 mL). React under microwave conditions at 160°C for 3 hours. LCMS monitored the reaction to completion. The reaction solution was purified by reverse-phase preparative HPLC, and white solids 19 (28 mg, yield 15%) and 19' (17 mg, yield 9%) were obtained respectively.

Example 19: ESI-MS (m/z): 542.3[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d ₆ ) δ 9.82 (s, 1H), 8.14 (d, J = 2.3Hz, 1H ),7.91(dd, J =8.4,2.4Hz,1H),7.21(d, J =8.4Hz,1H),6.99(t, J =6.2Hz,1H),6.62(s,1H), 4.97-4.79 (m,1H),4.48-4.29(m,2H),3.99(q, J =6.8Hz,1H),3.20-3.03(m,4H),2.11(s,3H),1.17(d, J =6.9 Hz,3H).

Example 19': ESI-MS (m/z): 542.2[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d ₆ ) δ 9.82 (s, 1H), 8.13 (d, J =2.4Hz, 1H),7.84(dd, J =8.4,2.4Hz,1H),7.08(d, J =8.4Hz,1H),6.96(t, J =6.3Hz,1H),6.81(s,1H),5.00- 4.86(m,1H),4.47-4.28(m,2H),3.99(q, J =6.8Hz,1H),3.28-3.11(m,4H),2.12(s,3H),1.18(d, J = 6.8Hz,3H).

Example 20

(S)-2-(((6-((1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)pyridin-3-yl)methyl)amine methyl)-7-(2,2-difluoroethyl)-4,8-dimethyl-7,8-dihydropterin-6(5H)-one

Example 20 was prepared by the following steps:

Step 1: Dissolve compound Int-6 (50mg, 0.18mmol) and compound Int-3 (70mg, 0.23mmol) in n-butanol (6mL), add p-toluenesulfonic acid monohydrate (3mg, 18umol), The reaction solution was stirred at 160°C for 3 hours under microwave conditions. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by reverse preparative HPLC to obtain a white solid 20 (3.9 mg, yield 4%). ESI-MS (m/z): 539.3[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 8.16 (d, J =2.3Hz, 1H), 7.91 (dd, J =8.4, 2.5Hz ,1H),7.20(d, J =8.4Hz,1H),7.06(s,1H),6.54(s,1H),6.21-5.90(m,1H),4.42-4.29(m,2H),4.26- 4.17(m,1H),3.51-3.46(m,1H),2.96(s,3H),2.32-2.21(m,2H),2.13(s,3H),1.06-1.01(m,2H),0.96- 0.91(m,2H).

Example 21

(S)-2-(((6-((4-cyclopropyl-2-(trifluoromethyl)pyrimidin-5-yl)oxo)pyridin-3-yl)methyl)amino)-4 ,7,8-trimethyl-7,8-dihydropterin-6(5H)-one

Example 21 was prepared by the following steps:

Step 1: Combine compound 15d (550mg, 1.91mmol), cyclopropylboronic acid (818mg, 9.53mmol), palladium acetate (42mg, 0.19mmol), tricyclohexylphosphine (106mg, 0.38mmol) and potassium phosphate (1.21g , 5.72 mmol) was added to the mixed solution of 1,4-dioxane (50 mL) and water (5 mL). After the reaction system was replaced with nitrogen, the reaction was carried out at 110°C for 16 hours under a nitrogen atmosphere. LCMS monitored the end of the reaction. The solvent was distilled off under reduced pressure, and then water and ethyl acetate were added for extraction. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated and passed through silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) Purification gave 21a as a white solid (530 mg, yield 94%). ESI-MS(m/z): 295.3[M+H] ⁺ .

Step 2: Dissolve compound 21a (530 mg, 1.80 mmol) in methanol (10 mL), add palladium carbon (10%, 21 mg) to the reaction system, replace the hydrogen with a hydrogen balloon, and react for 16 hours in a hydrogen atmosphere at room temperature. , LCMS monitors the end of the reaction. The reaction solution was diluted with methanol and filtered with suction. The filtrate was concentrated to obtain brown oily liquid 21b (330 mg, yield 89%). ESI-MS(m/z): 203.3[MH] ^- .

Step 3: Add compound 21b (330mg, 1.62mmol), Int-3d (236mg, 1.94mmol) and cesium carbonate (1.05g, 3.23mmol) into acetonitrile (10mL), react at room temperature for 16 hours, LCMS Monitor the end of the reaction. Acetonitrile was distilled off under reduced pressure, and then water and ethyl acetate were added for extraction. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated and passed through silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) Purification gave 21c as a white solid (450 mg, yield 90%). ESI-MS(m/z): 307.1[M+H] ⁺ .

Step 4: Dissolve compound 21c (350mg, 1.14mmol) in methanol (20mL), add ammonia water (3.5mL) and Raney nickel (3.5mL, water suspension) to the reaction system in sequence, replace the hydrogen gas through a hydrogen balloon and The reaction was carried out under hydrogen atmosphere and room temperature for 16 hours, and LCMS monitored the completion of the reaction. The reaction solution was diluted with methanol, filtered through diatomaceous earth, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol = 9:1) to obtain yellow oily liquid 21d (300 mg, yield 84%). ESI-MS(m/z): 311.2[M+H] ⁺ .

Step 5: Dissolve compound Int-1 (50mg, 0.22mmol) and compound 21d (82.13mg, 0.26mmol) in n-butanol (2mL), add p-toluenesulfonic acid monohydrate (4.19mg, 22umol), The reaction solution was stirred at 160°C for 3 hours under microwave conditions. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by reverse preparative HPLC to obtain white solid 21 (48.18 mg, yield 43%). ESI-MS (m/z): 501.3[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 9.87 (s, 1H), 8.78 (s, 1H), 8.08 (d, J =2.3Hz ,1H),7.91(dd, J =8.5,2.4Hz,1H),7.26(d, J =8.4Hz,1H),7.04(d, J =6.5Hz,1H),4.35(qd, J =15.1, 6.3Hz,2H),4.00(q, J =6.8Hz,1H),2.91(s,3H),2.27-2.17(m,1H),2.12(s,3H),1.17(d, J =6.8Hz, 3H),1.15-1.07(m,4H).

Example 22

2-(((6-((1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)pyridin-3-yl)methyl)amino)-4 ,7,7-trimethyl-8-(methyl-d3)-7,8-dihydropterin-6(5H)-one

Example 22 was prepared by the following steps:

Step 1: Dissolve compound Int-18 (50mg, 0.17mmol) and compound Int-3 (40.85mg, 0.17mmol) in n-butanol (2mL), add p-toluenesulfonic acid monohydrate (2.89mg, 17umol ), the reaction solution was stirred at 160°C for 3 hours under microwave conditions. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by reverse preparative HPLC to obtain white solid 22 (20 mg, yield 23%). ESI-MS (m/z): 506.3[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 9.85 (s, 1H), 8.15 (d, J =2.0Hz, 1H), 7.90 (dd , J =8.4,2.3Hz,1H),7.20(d, J =8.4Hz,1H),7.08-6.98(m,1H),6.55(s,1H),4.37(d, J =6.2Hz,2H) ,3.49-3.44(m,1H),2.12(s,3H),1.31(s,6H),1.06-1.00(m,2H),0.91(td, J =7.2,5.1Hz,2H).

Example 23

(S)-2-(((6-((4-ethyl-2-(trifluoromethyl)pyrimidin-5-yl)oxo)pyridin-3-yl)methyl)amino)-4, 7,8-Trimethyl-7,8-dihydropterin-6(5H)-one

Example 23 was prepared by the following steps:

Step 1: Add compound 15d (2.0g, 6.93mmol), vinyl borate pinacol ester (3.20g, 20.79mmol), palladium acetate (155mg, 0.69mol), and potassium phosphate (2.94g, 13.86mmol) in sequence. To 1,4-dioxane (150 mL), add water (15 mL), insulate and stir at 90°C for 17 hours under nitrogen protection, HPLC monitors the complete conversion of the raw material, and the filtrate is concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/9) to obtain white solid 23a (1.18 g, yield 60%, purity 61%). ESI-MS(m/z): 281.1[M+H] ⁺ .

Step 2: Add compound 23a (1.0g, 3.73mmol) to 20ml of methanol, add palladium carbon (10%, 100mg), replace the reaction system with hydrogen and stir at room temperature overnight, filter the reaction solution through diatomaceous earth, and filter the filtrate Concentration gave compound 23b (677 mg, yield 94%, purity 97%). ESI-MS(m/z): 191.3[MH] ^- .

Step 3: Add compound 23b (0.5g, 2.81mmol), Cs ₂ CO ₃ (1.83g, 5.61mmol), Int-3d (514mg, 4.21mmol) to N , N -dimethylformamide ( 10 mL), stir at 20°C overnight, and monitor the disappearance of raw materials by HPLC. The reaction solution was added to 50 ml of ice water, stirred for 0.5 hours, and filtered with suction to obtain yellow solid 23c (530 mg, yield 64%, purity 99%). ESI-MS(m/z): 294.3[M+H] ⁺ .

Step 4: Dissolve compound 23c (100 mg, 0.36 mmol) in methanol (5 mL), add ammonia water (0.2 mL), add Raney Nickel (0.5 mL, water suspension), and replace the reaction system with hydrogen at room temperature. Stir for 2 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain compound 23d (97 mg, yield 93%, purity 90%), ESI-MS (m/z): 298.5 [M+H] ⁺ .

Step 5: Dissolve compound Int-1 (79.74mg, 0.35mmol) and compound 23d (104.93mg, 0.35mmol) in n-butanol (2mL), add p-toluenesulfonic acid monohydrate (6.68mg, 0.35umol) ), the reaction solution was stirred at 160°C for 3 hours under microwave conditions. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by reverse preparative HPLC to obtain white solid 23 (33 mg, yield 19%). ESI-MS (m/z): 489.3[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 9.85 (s, 1H), 8.87 (s, 1H), 8.07 (s, 1H), 7.91 (d, J =8.1Hz,1H),7.24(d, J =8.4Hz,1H),7.01(s,1H),4.35(s,2H),4.08-3.91(m,1H),2.90(s, 3H),2.82-2.68(m,2H),2.11(s,3H),1.32-0.96(m,6H).

Example 24

(S)-2-(((6-((4-ethyl-2-(trifluoromethyl)pyrimidin-5-yl)oxo)pyridin-3-yl)methyl)amino)-4, 7-Dimethyl-8-(methyl-d3)-7,8-dihydropterin-6(5H)-one

Replace Int-1 in the fifth step in Example 23 with Int-2 , and use similar methods and reaction steps to obtain compound 24 . ESI-MS (m/z): 492.3[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ9.82 (s, 1H), 8.87 (s, 1H), 8.08 (d, J =2.4 Hz,1H),7.92(dd, J =8.5,2.4Hz,1H),7.24(d, J =8.4Hz,1H),7.02-6.95(m,1H),4.36(dd, J =8.7,6.3Hz ,2H),4.00(t, J =6.8Hz,1H),2.76(q, J =7.5Hz,2H),2.12(s,3H),1.20-1.16(m,6H).

Example 25

(S)-2-(((6-((2-(difluoromethyl)-6-(trifluoromethyl)pyridin-3-yl)oxo)pyridin-3-yl)methyl)amine )-4,7-dimethyl-8-(methyl-d3)-7,8-dihydropterin-6(5H)-one

Example 25 was prepared by the following steps:

Step 1: Dissolve compound Int-8c (930 mg, 2.45 mmol) in tetrahydrofuran (10 mL), and slowly add n-butyllithium (1.5 mL, 2 M in hexane) into the solution dropwise at -78°C. The reaction solution was continued to stir at -78°C for 10 minutes. Then N , N -dimethylformamide (359 mg, 4.91 mmol) was slowly added dropwise to the reaction solution, and the reaction solution was stirred at -78°C for 1 hour. LCMS detects the end of the reaction. Add saturated aqueous ammonium chloride solution to quench the reaction, extract with dichloromethane, combine the organic phases and wash with saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and pass the residual liquid through silica gel column chromatography (petroleum ether/ethyl acetate = 10/3) Purified compound 25a (281 mg, yield 41%). ESI-MS(m/z): 282.2[M+H] ⁺ .

Step 2: Dissolve compound 25a (230mg, 0.82mmol) in dichloromethane (5mL), slowly add diethylamine sulfur trifluoride (264mg, 1.64mmol) into the solution dropwise at 0°C, and react. Stirring was continued at 0°C for 2 hours. LCMS detects the end of the reaction. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane. The organic phases were combined and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product of compound 25b (247 mg). ESI-MS(m/z): 304.1[M+H] ⁺ .

Step 3: Dissolve compound 25b (247mg, crude product) in dichloromethane (5mL), slowly add boron tribromide (308mg, 1.23mmol) dropwise into the solution at -78°C, and react at -78°C Continue stirring for 30 minutes. LCMS detects the end of the reaction. Add saturated sodium bicarbonate aqueous solution to quench the reaction, wash with dichloromethane, adjust the pH of the aqueous phase to 2 with hydrochloric acid aqueous solution (4M), extract with dichloromethane, combine the organic phases and wash with saturated sodium chloride aqueous solution, dry over anhydrous sodium sulfate, and reduce Concentrate under pressure to obtain compound 25c (82 mg, two-step reaction yield 47%). ESI-MS(m/z): 212.3[MH] ⁺ .

Step 4: Dissolve compound 25c (82mg, 0.39mmol) and compound Int-2 (47mg, 0.39mmol) in N , N -dimethylformamide (3mL), and add cesium carbonate (251mg, 0.77mmol) , the reaction solution was stirred at 50°C for 12 hours. LCMS detects the end of the reaction. The reaction solution was diluted with water and filtered under reduced pressure to obtain compound 25d (98 mg, yield 80%).

Step 5: Dissolve compound 25d (98mg, 0.32mmol) in methanol (3mL) and ammonia (0.5mL), add Raney Nickel (0.5mL, water suspension), replace hydrogen with the reaction system and stir at room temperature. After 12 hours, LC-MS monitored that the reaction was complete. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain colorless oily liquid compound 25e (40 mg, yield 40%). ESI-MS(m/z): 320.2[M+H] ⁺ .

Step 6: Dissolve compound 25e (20mg, 0.06mmol) and Int-2 (15mg, 0.06mmol) in n-butanol (3mL), add p-toluenesulfonic acid monohydrate (2mg, 0.01mmol), and the reaction solution Stir at 160°C for 3 hours under microwave conditions. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain compound 25 (7 mg, yield 22%) as a white solid. ESI-MS (m/z): 513.2[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d 6) δ 9.89 (s, 1H), 8.16 (d, J =8.7Hz, 1H), 8.12 ( d, J =1.5Hz,1H),8.06(d, J =8.9Hz,1H),7.94-7.88(m,1H),7.23(d, J =8.4Hz,1H),7.22-7.18(m,1H ),6.58(s,1H),4.41-4.33(m,2H),4.03-3.98(m,1H),2.12(s,3H),1.18(d, J =5.8Hz,3H).

Example 26

(S)-2-(((6-((2,6-bis(trifluoromethyl)pyridin-3-yl)oxo)pyridin-3-yl)methyl)amino)-4,7, 8-Trimethyl-7,8-dihydropterin-6(5H)-one

Example 26 was prepared by the following steps:

Step 1: Dissolve compound 26a (1.0g, 4.65mmol) in anhydrous tetrahydrofuran (20mL), cool to -78°C under nitrogen protection, and start slowly adding n-butyllithium (3.05mL, 4.88mmol) dropwise. After an hour, the dropwise addition of triisopropyl borate (0.79 mL, 6.97 mmol) was started, and LCMS monitored the end of the reaction two hours later. Water was slowly added dropwise to quench the reaction. When the system warmed to 0°C, sodium hydroxide aqueous solution (4M, 3.49mL, 13.95mmol) and hydrogen peroxide (1mL) were added dropwise, and the reaction was carried out at room temperature for 16 hours. The reaction solution was acidified with hydrochloric acid (2M), extracted three times with dichloromethane, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 10:1) to obtain yellow solid mixtures 26b and 26b' (400 mg, yield 37%). MS(m/z): 230.5[MH] ^- .

Step 2: Add compounds 26b and 26b' (400mg, 1.73mmol), Int-3d (232.48mg, 1.90mmol) and N,N-diisopropylethylamine (671.1mg, 5.19mmol) to acetonitrile (10mL ), react at 120°C for 4 hours, and monitor the end of the reaction with LCMS. Acetonitrile was distilled off under reduced pressure, and then water and ethyl acetate were added for extraction. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated and passed through silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) Purification gave 26c as a yellow solid (180 mg, yield 31%). ESI-MS(m/z): 334.4[M+H] ⁺ .

Step 3: Dissolve compound 26c (180 mg, 0.54 mmol) in methanol (30 mL), add ammonia water (5 mL) and Raney nickel (3.5 mL, water suspension) to the reaction system in sequence, replace the hydrogen gas through a hydrogen balloon and place it in the The reaction was carried out under hydrogen atmosphere and room temperature for 3 hours, and LCMS monitored the completion of the reaction. The reaction solution was diluted with methanol, filtered with suction, and the filtrate was concentrated to obtain brown oily liquid 26d (150 mg, yield 82%). ESI-MS(m/z): 338.5[M+H] ⁺ .

Step 4: Dissolve compound 26d (74.39mg, 0.22mmol) in n-butanol (2mL), add compound Int-1 (50mg, 0.22mmol) and p-toluenesulfonic acid monohydrate (4.19mg, 22umol), The reaction solution was stirred at 160°C for 3 hours under microwave conditions. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by reverse-phase preparative HPLC to obtain white solid 26 (38.57 mg, yield 33%). ESI-MS (m/z): 528.5[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d 6) δ 9.83 (s, 1H), 8.31 (d, J =8.7Hz, 1H), 8.21 ( d, J =8.7Hz,1H),8.13(d, J =2.4Hz,1H),7.93(dd, J =8.4,2.4Hz,1H),7.25(d, J =8.4Hz,1H),7.01( t, J =6.3Hz,1H),4.49-4.30(m,2H),4.00(q, J =6.8Hz,1H),2.92(s,3H),2.13(s,3H),1.19(d, J =6.8Hz,3H).

Example 27

(S)-3-((5-(((4,7-dimethyl-8-(methyl-d3)-6-carbonyl-5,6,7,8-tetrahydropterin-2-yl )amino)methyl)pyridin-2-yl)oxo)-6-(trifluoromethyl)cyanopyridine

Example 27 was prepared by the following steps:

Step 1: Under ice-water bath conditions, add di-tert-butyl carbonic anhydride (1.75g, 8.02mmol) dropwise to the dichloride solution of Int-13 (2.03g, 6.68mmol) and triethylamine (1.39mL, 10.02mmol). Methane (40 mL) solution. After the reaction solution was stirred at room temperature for 16 hours, water was added to quench the reaction. Extract with dichloromethane, combine the organic phases and wash with saturated brine, dry over anhydrous sodium sulfate, concentrate the organic phase and purify through silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain white solid 27a (1.95g, collected rate 72%). ESI-MS(m/z): 403.9[M+H] ⁺ .

Step 2: Combine compound 27a (300 mg, 0.74 mmol), zinc cyanide (174 mg, 1.49 mmol), tetrakis triphenylphosphine palladium (172 mg, 0.15 mol) and N , N -dimethylformamide (10 mL) Add to round bottom flask. After the reaction solution was stirred at 120°C under nitrogen protection for 24 hours, LCMS monitored the end of the reaction. The solvent was evaporated under reduced pressure, and water and ethyl acetate were added for extraction. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1). A white solid 27b was obtained (177 mg, yield 60%). ESI-MS(m/z): 395.3[M +H] ⁺ .

Step 3: Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of compound 27b in dichloromethane (6 mL). After the reaction solution was stirred at room temperature for 5 hours, LCMS monitored the completion of the reaction. The reaction solution was concentrated by distillation under reduced pressure, and aqueous sodium hydroxide solution was added until the pH was 8. The mixture was extracted with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain crude product 27c . ESI-MS(m/z): 295.3[M+H] ⁺ .

Step 4: Dissolve compound Int-2 (45mg, 0.20mmol) in n-butanol (3mL), add compound 27c (64mg, 0.22mmol) and p-toluenesulfonic acid monohydrate (8mg, 44umol), the reaction solution Stir at 160°C for 3 hours under microwave conditions. LCMS monitored the reaction to completion. The reaction solution was purified by reverse-phase preparative HPLC to obtain 27 as a white solid (16 mg, yield 8%). ESI-MS (m/z): 499.0[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6) δ 9.92 (s, 1H), 8.25 (d, J =8.9Hz, 1H), 8.15 (d , J =8.8Hz,1H),8.11(d, J =2.4Hz,1H),7.91(dd, J =8.4,2.4Hz,1H),7.27(d, J =8.4Hz,1H),4.43-4.32 (m,2H),4.06-3.96(m,1H),2.08(s,3H),1.16(d, J =7.0Hz,3H).

Example 28

(S)-2-((4-cyclopropyl-2-(trifluoromethyl)pyrimidin-5-yl)oxo)-5-(((4,7,8-trimethyl-6-carbonyl -5,6,7,8-tetrahydropterin-2-yl)amino)methyl)nicotine nitrile

Example 28 was prepared by the following steps:

Step 1: Add 21b (400mg, 1.96mmol), 28a (639mg, 2.94mmol), DIPEA (759mg, 5.88mmol) into DMF (5mL), stir at 120°C for 2 hours, and add 50mL of ethyl acetate respectively. Ester, 50 mL of water, diatomaceous earth suction filtration, liquid separation, and the residue was silica gel column chromatographed (petroleum ether: ethyl acetate = 7:1) to obtain 28b (483 mg, yield 64%). ESI-MS(m/z): 385.1[M+H] ⁺ .

Step 2: Combine 28b (400mg, 1.04mmol), n-butylbis(1-adamantyl)phosphine (37mg, 103umol), 28c (492mg, 2.08mmol), TBAF (56mg, 259umol), palladium acetate (23mg , 103umol), cesium carbonate (1.02g, 3.12mmol), and water (1mL) were added to n-butanol (7mL), and stirred at 110°C for 17 hours under nitrogen protection. LCMS showed that the raw material was completely converted. 50 mL of ethyl acetate and 50 mL of water were added, filtered with diatomaceous earth, extracted and separated, and the organic phase was concentrated. The residue was subjected to silica gel column chromatography with petroleum ether: ethyl acetate = 1:2 to obtain 28d (273 mg, yield 60%). ESI-MS(m/z): 436.1[M+H] ⁺ .

Step 3: Add compound 28d (273 mg, 627umol) to dichloromethane (3 ml), add trifluoroacetic acid (1 ml), and stir at room temperature for 2 hours. LCMS showed that the raw material was completely converted and distilled under reduced pressure. 10 ml of ethyl acetate and 10 ml of saturated sodium bicarbonate aqueous solution were added to the residue in sequence. The liquids were separated. The organic phase was washed with water, dried over sodium sulfate, and concentrated to obtain a brown oil, which was used directly in the next step. ESI-MS(m/z): 336.0[M+H] ⁺ .

Step 4: Add compound 28e , Int-1 (79 mg, 351umol) and p-toluenesulfonic acid (6mg, 35umol) obtained in the previous step into n-butanol (2mL), and stir under microwave at 160°C for 3 hours. LCMS showed disappearance of starting material. The reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 28 (20 mg, two-step reaction yield 6%). ESI-MS (m/z): 526.3[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 9.87 (s, 1H), 8.95 (s, 1H), 8.43 (d, J =2.4Hz ,1H),8.36(d, J =2.3Hz,1H),7.03(t, J =6.3Hz,1H),4.42-4.34(m,2H),4.03-3.97(m,1H),2.91(s, 3H),2.28-2.23(m,1H),2.11(s,3H),1.19-1.11(m,7H).

Example 29

(S)-4,7,8-Trimethyl-2-(((6-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)oxo)pyridin-3-yl) )Methyl)amino)-7,8-dihydropterin-6(5H)-one

Substitute 4-methyl-6-(trifluoromethyl)pyridin-3-ol for 15f in the sixth step in Example 15, and use subsequent similar methods and reaction steps to obtain compound 29 . ESI-MS (m/z): 474.3[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 9.82 (s, 1H), 8.48 (s, 1H), 8.04 (d, J =2.3Hz ,1H),7.96(s,1H),7.87(dd, J =8.4,2.4Hz,1H),7.16(d, J =8.3Hz,1H),6.98(t, J =6.2Hz,1H),4.44 -4.26(m,2H),3.99(q, J =6.8Hz,1H),2.91(s,3H),2.21(s,3H),2.11(s,3H),1.17(d,J=6.8Hz, 3H).

Example 30

(S)-2-(((6-((1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)pyridin-3-yl)methyl)amine methyl)-7-(methoxymethyl)-4,8-dimethyl-7,8-dihydropterin-6(5H)-one

Example 30 was prepared by the following steps:

Step 1: Dissolve compound 30a (1.10g, 5mmol) in anhydrous tetrahydrofuran (10mL), cool the solution to 0°C, and slowly add sodium hydride (478mg, 60% dispersion in mineral oil) to the reaction solution under a nitrogen atmosphere middle. The reaction solution was stirred at 0°C for 10 minutes. Then, methyl iodide (1.42g, 10mmol) was added dropwise to the reaction solution. The reaction solution slowly warmed to room temperature and continued stirring for 2 hours. LCMS detects the end of the reaction. The reaction was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phases were combined and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 30b (1.17g, crude product). ESI-MS(m/z): 234.4[M+H] ⁺ .

Step 2: Dissolve compound 30b (1.17g) in methanol (10 mL), slowly add triturous dichloride (1.19g, 10 mmol) into the reaction solution at room temperature, then heat the reaction solution to 70°C and Continue stirring at this temperature for 2 hours. LCMS detects the end of the reaction. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure to obtain compound 30c (918 mg, crude product).

Step 3: Dissolve compound 30c (918mg, crude product) and compound 18d (1.04g, 5mmol) in tetrahydrofuran (10mL), and add N , N -diisopropylethylamine (1.94g, 15mmol). The reaction was stirred at room temperature for 8 hours. LCMS detects the end of the reaction. The reaction was quenched by adding water, extracted with ethyl acetate, the organic phases were combined and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1). Compound 30d (1.27g, three-step reaction yield 84%) was obtained. ESI-MS(m/z): 319.3[M+H] ⁺ .

Step 4: Dissolve compound 30d (320mg, 1mmol) and compound Int-3 (300mg, 1mmol) in N , N -dimethylformamide (5mL), add N , N -diisopropylethylamine (390mg, 3mmol). The reaction was stirred at room temperature for 4 hours. LCMS detects the end of the reaction. The reaction was quenched by adding water, extracted with ethyl acetate, the organic phases were combined and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1). Compound 30e (430 mg, yield 74%) was obtained. ESI-MS(m/z): 581.3[M+H] ⁺ .

Step 5: Dissolve compound 30e (430 mg, 0.74 mmol) in methanol (5 mL), add 10% palladium on carbon (394 mg), replace hydrogen with the reaction system, and stir at room temperature for 6 hours. LCMS detects the end of the reaction. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC to obtain compound 30 as a white solid (15 mg, yield 4%). ESI-MS (m/z): 519.2[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 9.89 (s, 1H), 8.16 (s, 1H), 7.91 (d, J =8.2Hz ,1H),7.19(d, J =8.4Hz,1H),6.91(t, J =5.4Hz,1H),6.53(s,1H),4.42-4.29(m,2H),4.14(s,1H) ,3.66-3.55(m,2H),3.50-3.42(m,1H),3.15(s,3H),2.95(s,3H),2.08(s,3H),1.06-0.99(m,2H),0.95 -0.88(m,2H).

Example 31

(S)-2-(((6-((1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxo)pyridin-3-yl)methyl)amine methyl)-7-(hydroxymethyl)-4,8-dimethyl-7,8-dihydropterin-6(5H)-one

Example 31 was prepared by the following steps:

Step 1: Dissolve compound 30 (10 mg, 0.02 mmol) in dichloromethane (2 mL), and slowly add boron tribromide (10 mg, 0.04 mmol) dropwise to the reaction solution at -78°C. The reaction was continued with stirring at -78°C for 30 minutes. LCMS detects the end of the reaction. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, the organic phases were combined and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by Prep-HPLC to obtain compound 31 as a white solid (8 mg, Yield 80%). ESI-MS (m/z): 505.3[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 9.85 (s, 1H), 8.16 (s, 1H), 7.91 (d, J =8.4Hz ,1H),7.19(d, J =8.4Hz,1H),6.86(t, J =6.1Hz,1H),6.54(s,1H),4.98(t, J =5.2Hz,1H),4.35-4.29 (m,2H),3.96(s,1H),3.76-3.61(m,2H),3.51-3.43(m,1H),2.96(s,3H),2.07(s,3H),1.12-0.99(m ,2H),0.98-0.88(m,2H).

Example 32

4,7,7-Trimethyl-8-(methyl-d3)-2-(((6-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)oxo) Pyridin-3-yl)methyl)amino)-7,8-dihydropterin-6(5H)-one

Replace Int-1 in the eighth step in Example 15 with Int-18 , and use subsequent similar methods and reaction steps to obtain compound 32 . ESI-MS (m/z): 492.3[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 9.82 (s, 1H), 8.86 (s, 1H), 8.07 (s, 1H), 7.91 (dd, J =8.4,1.9Hz,1H),7.23(d, J =8.4Hz,1H),6.99(t, J =5.9Hz,1H),4.36(d, J =6.1Hz,2H),2.42 (s,3H),2.13(s,3H),1.31(s,6H).

Example 33

4'-Methyl-8'-(methyl-d3)-2'-(((6-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)oxo)pyridine- 3-yl)methyl)amino)-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridin]-6'-one

Compound 15g was used to replace Int-3 in the fifth step in Example 18, and subsequent similar methods and reaction steps were used to obtain compound 33 . ESI-MS (m/z): 490.4[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 9.89 (s, 1H), 8.86 (s, 1H), 8.06 (s, 1H), 7.90 (d, J =8.4Hz,1H),7.22(d, J =8.4Hz,1H),6.99(t, J =5.9Hz,1H),4.35(d, J =6.2Hz,2H),2.42(s ,3H),2.11(s,3H),1.31-1.27(m,2H),1.15-1.08(m,2H).

Example 34

(S)-2-(6-(trifluoromethyl)-3-((5-(((4,7,8-trimethyl-6-carbonyl-5,6,7,8-tetrahydropteranyl) Din-2-yl)amino)methyl)pyridin-2-yl)oxo)pyridin-2-yl)acetonitrile

Example 34 was prepared by the following steps:

Step 1: Combine compound 27a (675mg, 1.67mmol), vinylboronic acid pinacol ester (1.29g, 8.36mmol), tetrakis triphenylphosphine palladium (194mg, 0.17mol), sodium carbonate (354mg, 3.34mmol) , water (3 mL) and 1,4-dioxane (17 mL) were added to the round bottom flask. After the reaction solution was stirred at 120°C under nitrogen protection for 16 hours, LCMS monitored the end of the reaction. The solvent was evaporated under reduced pressure, and water and ethyl acetate were added for extraction. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1). A white solid 34a was obtained (609 mg, yield 92%). ESI-MS(m/z): 396.4[M+H] ⁺ .

Step 2: Add sodium periodate (907 mg, 4.24 mmol) to a mixed solution of 34a (559 mg, 1.41 mmol) in tetrahydrofuran (12 mL) and water (3 mL). The reaction solution was stirred at room temperature for one minute. To this was added potassium osmate (41 mg, 0.14 mmol). After the reaction solution was stirred at 40°C for 2 hours, LCMS monitored the end of the reaction. Water and ethyl acetate were added for extraction, the organic phases were combined and washed with sodium thiosulfate aqueous solution and saturated brine in sequence, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain crude product 34b . ESI-MS(m/z): 398.3[M+H] ⁺ .

Step 3: Add sodium borohydride (80 mg, 2.12 mmol) to the methanol (15 mL) solution of crude product 34b under ice-water bath conditions. The reaction solution was continued to stir at this temperature for two hours. After monitoring the reaction with LCMS, water and ethyl acetate were added for extraction. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1). A white solid 34c was obtained (359 mg, two-step yield 64%). ESI-MS(m/z): 400.3[M+H] ⁺ .

Step 4: Add triturous dichloride (0.13 mL, 1.80 mmol) dropwise to a solution of 34c (359 mg, 0.90 mmol) in dichloromethane (14 mL). After the reaction solution was stirred at room temperature for 2 hours, LCMS monitored the completion of the reaction. The reaction solution was concentrated by distillation under reduced pressure to obtain crude product 34d . ESI-MS(m/z): 418.2[M+H] ⁺ .

Step 5: Add trimethylsilyl cyanide (178 mg, 1.80 mmol) dropwise to the solution of cesium fluoride (119 mg, 1.80 mmol) in acetonitrile (8 mL) at 10°C. After the reaction liquid was stirred for 30 minutes, cesium carbonate (586 mg, 1.80 mmol) and the above-mentioned crude product 34d were added to it. The reaction liquid was heated to 40°C and stirred at this temperature for 16 hours. After the reaction was monitored by LCMS, water and ethyl acetate were added for extraction. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain crude product 34e . ESI-MS(m/z): 409.3[M+H] ⁺ .

Step 6: Add trifluoroacetic acid (2 mL) dropwise to the solution of the above crude product 34e in dichloromethane (8 mL). After the reaction solution was stirred at room temperature for 1.5 hours, LCMS monitored the completion of the reaction. The reaction solution was concentrated by distillation under reduced pressure, and aqueous sodium hydroxide solution was added until the pH was 8. The mixture was extracted with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain crude product 34f . ESI-MS(m/z): 309.3[M+H] ⁺ .

Step 7: Dissolve compound Int-1 (50mg, 0.22mmol) in n-butanol (2mL), add compound 34f (82mg, crude product) and p-toluenesulfonic acid monohydrate (8mg, 44umol), and the reaction solution is Under microwave conditions, stir at 160°C for 3 hours. LCMS monitored the reaction to completion. The reaction solution was purified by reverse-phase preparative HPLC to obtain white solid 34 (20 mg, four-step reaction yield 4%). ESI-MS (m/z): 499.0[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d ₆ ) δ 9.83 (s, 1H), 8.11 (d, J = 2.3Hz, 1H), 8.02- 7.84(m,3H),7.18(d, J =8.4Hz,1H),7.10-6.91(m,1H),4.42-4.30(m,2H),4.27(s,2H),3.98(q, J = 6.8Hz,1H),2.90(s,3H),2.10(s,3H),1.17(d, J =6.8Hz,3H).

Example 35

(S)-2-(((6-((2-Fluoro-6-(trifluoromethyl)pyridin-3-yl)oxo)pyridin-3-yl)methyl)amino)-4,7 ,8-trimethyl-7,8-dihydropterin-6(5H)-one

Example 35 was prepared by the following steps:

Step 1: Dissolve compound 35a (300mg, 1.82mmol) in anhydrous tetrahydrofuran (5mL), cool to -78°C under nitrogen protection, and start slowly adding n-butyllithium (1.19mL, 1.91mmol) dropwise for one hour. After that, triisopropyl borate (0.63 mL, 2.73 mmol) was added dropwise, and LCMS monitored the end of the reaction two hours later. Water was slowly added dropwise to quench the reaction. When the system warmed to 0°C, sodium hydroxide aqueous solution (4M, 1.36mL, 5.45mmol) and hydrogen peroxide (1mL) were added dropwise, and the reaction was carried out at room temperature for 16 hours. The reaction solution was acidified with hydrochloric acid (2M), extracted three times with dichloromethane, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 10:1) to obtain yellow solid 35b (280 mg, yield 85%). MS(m/z): 180.5[MH] ^- .

Step 2: Add compound 35b (280mg, 1.55mmol), Int-3d (226mg, 1.86mmol) and cesium carbonate (1.01g, 3.09mmol) into acetonitrile (10mL), react at room temperature for 16 hours, LCMS Monitor the end of the reaction. Acetonitrile was distilled off under reduced pressure, and then water and ethyl acetate were added for extraction. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated and passed through silica gel column chromatography (petroleum ether: ethyl acetate = 5:1). Purification yielded yellow oily liquid 35c (270 mg, yield 61%). ESI-MS(m/z): 284.4[M+H] ⁺ .

Step 3: Dissolve compound 35c (270mg, 0.95mmol) in methanol (30mL), add ammonia water (3.5mL) and Raney nickel (3.5mL, water suspension) to the reaction system in sequence, replace the hydrogen gas through a hydrogen balloon and The reaction was carried out under hydrogen atmosphere and room temperature for 3 hours, and LCMS monitored the completion of the reaction. The reaction solution was diluted with methanol, filtered with suction, and the filtrate was concentrated to obtain a brown oily liquid 35d (270 mg, yield 98%). ESI-MS(m/z): 271.5[M+H] ⁺ .

Step 4: Dissolve compound 35d (82.36mg, 0.29mmol) in n-butanol (2mL), add compound Int-1 (50mg, 0.22mmol) and p-toluenesulfonic acid monohydrate (4.19mg, 22umol), The reaction solution was stirred at 160°C for 3 hours under microwave conditions. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by reverse-phase preparative HPLC to obtain white solid 35 (1.07 mg, yield 1%). ESI-MS (m/z): 478.5[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d 6)δ 9.80 (s, 1H), 8.25 (s, 0H), 8.18 (t, J =8.7 Hz,1H),8.06(s,1H),7.98(d, J =8.1Hz,1H),7.89(dd, J =8.3,2.2Hz,1H),7.20(d, J =8.5Hz,1H), 6.97(d, J =6.8Hz,1H),4.35(qd,J=15.2,6.4Hz,2H),3.98(q, J =6.8Hz,1H),2.90(s,3H),2.11(s,3H ),1.17(d, J =6.7Hz,3H).

Example 36

(S)-2-(((6-((6-chloro-2-cyclopropylpyridin-3-yl)oxo)pyridin-3-yl)methyl)amino)-4,7,8- Trimethyl-7,8-dihydropterin-6(5H)-one

Example 36 was prepared by the following steps:

Step 1: Add compound 36a (1.0g, 3.91mmol), Int-3d (478mg, 3.91mmol) and cesium carbonate (2.55g, 7.83mmol) to acetonitrile (20mL) and react at 50°C for 16 hours. LCMS monitored the reaction to completion. Acetonitrile was removed by distillation under reduced pressure, and water and ethyl acetate were added for extraction. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was filtered and concentrated to obtain white solid 36b (1.38 g, yield 98%). ESI-MS(m/z): 258.2[M+H] ⁺ .

Step 2: Combine compound 36b (300mg, 0.84mmol), cyclopropylboronic acid (108mg, 1.26mmol), palladium acetate (19mg, 84umol), tricyclohexylphosphine (47mg, 0.17mmol) and potassium phosphate (534mg, 2.52 mmol), water (2 mL) and toluene (10 mL) were added to the round bottom flask. After the reaction solution was stirred at 80°C under nitrogen protection for 16 hours, LCMS monitored the end of the reaction. The solvent was evaporated under reduced pressure, and water and ethyl acetate were added for extraction. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1). A white solid 36c was obtained (76 mg, yield 33%). ESI-MS(m/z): 272.4[M+H] ⁺ .

Step 3: Dissolve compound 36c (76 mg, 0.28 mmol) in methanol (8 mL), add ammonia water (0.8 mL) and Raney nickel (0.8 mL, water suspension) to the reaction system in sequence, replace the hydrogen gas through a hydrogen balloon and The reaction was carried out under hydrogen atmosphere and room temperature for 3 hours, and LCMS monitored the completion of the reaction. The reaction solution was diluted with methanol, filtered with suction, and the filtrate was concentrated to obtain a brown oily liquid 36d . ESI-MS(m/z): 276.4[M+H] ⁺ .

Step 4: Dissolve compound 36d (51mg) obtained in the previous step in n-butanol (2mL), add compound Int-1 (45mg, 0.19mmol) and p-toluenesulfonic acid monohydrate (7mg, 37umol), and react. The solution was stirred under microwave conditions at 160°C for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by reverse-phase preparative HPLC to obtain white solid 36 (10 mg, two-step reaction yield 7%). ESI-MS (m/z): 466.3[M+H] ⁺ ; 1H NMR (500MHz, DMSO-d6) δ 9.82 (s, 1H), 8.05 (d, J =2.3Hz, 1H), 7.83 (dd, J =8.5,2.4Hz,1H),7.53(d, J =8.4Hz,1H),7.26(d, J =8.4Hz,1H),7.09(d, J =8.4Hz,1H),7.01-6.90( m,1H),4.40-4.25(m,2H),3.98(q, J =6.8Hz,1H),2.90(s,3H),2.10(s,3H),2.05(p, J =6.4Hz,1H ),1.16(d, J =6.8Hz,3H),0.93-0.85(m,4H).

According to the synthetic routes and synthetic methods of intermediates described in the above examples, the following examples can be obtained.

Comparative example 1

(S)-4,7,8-trimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl) Methyl)amino)-7,8-dihydropterin-6(5H)-one

Comparative Example 1 was obtained by referring to the synthesis method of compound 136 described in patent WO2019209757. ESI-MS (m/z): 447.2[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 9.81 (s, 1H), 8.63 (s, 1H), 7.88 (d, J =8.1Hz ,1H),7.84(d, J =8.3Hz,1H),7.76(s,1H),7.43(d, J =1.3Hz,1H),6.61-6.56(m,1H),5.45(s,2H) ,4.28-4.20(m,2H),3.99(q, J =6.8Hz,1H),2.93(s,3H),2.13(s,3H),1.18(d, J =6.9Hz,3H).

Comparative example 2

(S)-2-(((6-(4-fluorophenoxy)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridine -6(5H)-ketone

Comparative Example 2 was obtained by referring to the synthesis method of compound 54 described in patent WO2019209757. ESI-MS (m/z): 409.8[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO- d6 ) δ 9.80 (s, 1H), 8.07 (d, J =2.3Hz, 1H), 7.79 (dd , J =8.6,2.3Hz,1H),7.28-7.18(m,2H),7.18-7.08(m,2H),7.01-6.88(m,2H),4.44-4.26(m,2H),3.98(q , J =6.9Hz,1H),2.91(s,3H),2.11(s,3H),1.17(d, J =6.7Hz,3H).

Wnt pathway inhibitor biological screening and results

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

The Colo205 cell line (Cell Bank of the Chinese Academy of Sciences, Cat # TCHu102) was purchased from the Cell Bank of the Chinese Academy of Sciences. After amplification and subculture, the cells were transfected with TCF/LEF transcription factors using the lipo3000 lipofectamine transfection method during the exponential growth phase of the cells. Driver luciferase reporter plasmid (Promega). This plasmid contains a resistance gene and can be used for resistance screening. Transfections were performed in 10 cm dishes using conventional complete medium without resistance. After 2 days, replace the medium with resistance and continue culturing. 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 adaptive medium. When the cells fill the culture dish, digest the cells, count them, and passage them in a 96-well plate so that the number of cells contained in each well is an average of 1.5 cells/well. Use adaptation medium during passage. The remaining cells were cryopreserved. After passage, incubate 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 are labeled and are monoclonal wells. Then culture normally, replace the culture medium every 2 days, and observe. In the early stage, monoclonal cells have wells where they can continue to grow. They are marked twice and can be replaced with normal resistant medium. When a single clone well fills the wells of the 96-well plate, digest and passage it into a 24-well culture plate. After the 24-well plate is full, pass it into a 96-well plate and a 6-well plate. The 96-well plate Cells were cultured in at least 6 wells, of which 3 wells were added with known Wnt inhibitors, and the other 3 wells were left untreated. After 24 hours, fluorescent detection reagent was added to the cells in the 96-well plate to detect the fluorescence intensity. Select cell lines that have fluorescent expression when not treated and whose fluorescent light is reduced after inhibition for further culture. The Colo205-LUC-TCF/LEF-M1 cell line is one of the above-selected cell lines. Its growth curve, cell morphology, and cell growth status are similar to those of the original Colo205 cells, and its fluorescent signals are treated with and without inhibitors. The ratio is relatively large among all cell lines, and the ratio can reach 4-5 times when inhibited at 4 hours, which is completely suitable for the screening of Wnt inhibitors in the later stage.

Test Example 2: Compound report on Colo205-LUC-TCF/LEF-M1 Testing of Inhibitory Capacity on Cell Lines

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

Add 100uL of a compound with a maximum concentration of 20uM to each well of a 96-well cell culture plate, and make a 3-fold gradient dilution of the compound concentration. Then, 10,000 colo205 cells stably transfected with the reporter gene and 100uL medium were inoculated into each well, and corresponding positive and negative control wells were made. Place the cells into a 5% CO2 cell incubator and incubate at 37°C for 4 hours. After 4 hours, remove the culture medium and add 100uL of reagent (Promega) containing the corresponding firefly luciferase substrate to each well to measure luciferin. Enzyme reporter gene activity. Luminescence intensity was 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. The IC50 concentration of each compound was calculated. Colo 205 reporter gene detection data are summarized in Table 1.

Table 1. IC ₅₀ values of compounds for inhibiting Colo205-LUC-TCF/LEF reporter gene

Test Example 3: Proliferation inhibitory test of compounds on Wnt mutant cell lines (Colo205, H929, HepG2 and DU4475) and non-Wnt mutant cell lines (RKO)

The cell lines used in the experiment are Colo205, H929, HepG2 and DU4475 cell lines, which continuously activate the Wnt pathway, and their proliferation is Wnt pathway-dependent; while under normal circumstances, the Wnt pathway does not activate, and the proliferation is independent of the Wnt pathway RKO. The cell line is used as a control cell line to determine the inhibitory effects of the compounds of the present invention on Wnt-dependent proliferation. The production effects are not due to other non-specific toxicities.

The Colo205, H929, DU4475, HepG2 and RKO cell lines cultured in their respective culture media were treated during the logarithmic growth phase. The cells were collected and prepared into a uniform cell suspension of known concentration, and then added to a 96-well cell culture plate. Cell suspension to contain 1000-4000 cells per well. Place in a 5% CO2 cell culture incubator and incubate at 37°C for 20-24 hours. The next day, add the completely dissolved compound in a 3-fold gradient dilution to each cell culture well so that the final maximum concentration in the cell culture well is 10 uM, and continue culturing for 96 hours. This test uses Promega's cell viability detection test. The more cells proliferate, the stronger the final signal intensity will be. The detection instrument is SpectraMax, full wavelength mode. The wells with only DMSO added were used as positive control wells, and the wells with no cells seeded were used as negative control wells. The IC50 values of each compound for inhibiting the proliferation of Wnt-continuously initiated or proliferation-dependent cells were calculated, as well as the IC50 values for Wnt-uninitiated or proliferation-independent cells. The IC50 value of cell proliferation inhibition was used to evaluate the compound's inhibitory effect on the Wnt pathway and its toxic effect on normal cells (Table 2).

Table 2. IC ₅₀ values of compounds inhibiting the proliferation of Wnt curve cell lines

The above results show that the compound of the present invention has significant inhibitory activity against mutant cell lines Colo205, DU4475, NCI-H929 and HepG2, but has basically no significant inhibitory activity against Hela and RKO cell lines, which indicates that the compound of the present invention has significant Wnt dependence. proliferation inhibitory effect.

Test Example 4: Tumor Growth Inhibition Test of Compound 1 on Colo205 Mouse Xenograft Model

In this study, the BALB/c Nude nude mouse transplanted tumor model of human colon cancer cell Colo205 was used to evaluate the in vivo anti-tumor activity of Control Example 1 and Compound 1.

Female BALB/c Nude nude mice were subcutaneously inoculated with human colon cancer cell Colo205 to establish a Colo205 BALB/c Nude nude mouse transplanted tumor model. After the tumors grew to an average tumor volume of about 80 mm ³ , the tumor-bearing mice were randomly divided into three groups according to the tumor volume: solvent-treated control group, 3 mg/kg compound group 1, and 10 mg/kg control group 1. Compound 1 and Comparative Example 1 were administered orally once a day for a 14-day administration period. Tumor volume was measured every other day. Body weight and tumor volume were measured on Day 14 (Table 3 and Figure 1).

table 3

Claims (18)

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

It is characterized by: R ₁ and R ₂ each independently represent hydrogen, (C ₁ -C ₆ )alkyl, halogenated (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, halogenated (C ₃ - C ₈ ) cycloalkyl, 4-8 membered heterocycloalkyl, halogenated 4-8 membered heterocycloalkyl, -(C ₁ -C ₆ )alkylene OR _a , -halogenated (C ₁ -C ₆ )alkylene OR _a , -(C ₁ -C ₆ )alkylene SR _a , -halogenated (C ₁ -C ₆ )alkylene SR _a , or R ₁ , R ₂ and the carbon atoms connected to them Together they form a 3-8 membered ring which may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O and S; R ₃ represents (C ₁ -C ₆ ) alkyl, halogenated (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, halogenated (C ₃ -C ₈ ) cycloalkyl, or R ₃ and R ₁ or R ₂ together form a 4-7 membered ring, which may optionally contain 0 or 1 heteroatoms selected from O and S; X represents CR ₄ or N; R ₄ each independently represents hydrogen, halogen, cyano group, (C ₁ -C ₃ ) alkyl group, or halogenated (C ₁ -C ₃ ) alkyl group; L represents -O- or -(CR _m R _m ')-, where R _m and R _m ' each independently represent hydrogen, (C ₁ - C ₃ ) alkyl, (C ₃ - C ₈ ) cycloalkyl , or R _m , R _m ' and the carbon atoms connected to them form a 3-5 membered ring, which ring may contain 0 or 1 heteroatom selected from O and S; Cy represents a 5-12 membered aromatic heterocycle, which optionally contains 1, 2, 3 or 4 heteroatoms, each of which is independently selected from the group consisting of N, O and S; R ₅ represents halogen, (C ₁ -C ₆ )alkyl, halogenated (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ ) cycloalkyl, halogenated (C ₃ -C ₈ ) cycloalkyl , -OR _a , -halogenated OR _a , -SR _a , -halogenated SR _a ; R ₆ represents halogen, (C ₁ -C ₆ )alkyl, halogenated (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ ) cycloalkyl, halogenated (C ₃ -C ₈ ) cycloalkyl , (C ₃ -C ₈ ) heterocycloalkyl, halogenated (C ₃ -C ₈ ) heterocycloalkyl, (C ₂ -C ₆ ) alkynyl, halogenated (C ₂ -C ₆ ) alkynyl, - (C ₁ -C ₆ )alkylene OR _a , -halogenated (C ₁ -C ₆ )alkylene OR _a , -(C ₃ -C ₈ )cycloalkylene OR _a , -halogenated (C ₃ -C ₈ )cycloalkylene OR _a , -(C ₁ -C ₆ )alkylene SR _a , -halogenated (C ₁ -C ₆ )alkylene SR _a , -(C ₃ -C ₈ )ylene Cycloalkyl SR _a , -halogenated (C ₃ -C ₈ )cycloalkylene SR _a , -(C ₁ -C ₆ )alkylene CN, -halogenated (C ₁ -C ₆ )alkylene CN , -(C ₃ -C ₈ )cycloalkylene CN, -halogenated (C ₃ -C ₈ )cycloalkylene CN, -(C ₁ -C ₆ )alkylene -NR _a R _a ', - Halogenated (C ₁ -C ₆ )alkylene-NR _a R _a ', -(C ₃ -C ₈ )cycloalkylene -NR _a R _a ', -halogenated (C ₃ -C ₈ )cycloalkylene Alkyl -NR _a R _a ', -CN, -NO ₂ , -OR _a , -SR _a , -NR _a R _a ', where R _a and R _a ' can form 3-8 together with the N atoms they are connected to. A membered ring, the ring may optionally have 0, 1 or 2 heteroatoms selected from N, O and S, and the ring may be a single ring, a bicyclic ring, a bridged ring or a spiro ring; R ₇ each independently represents hydrogen, halogen, (C ₁ -C ₃ ) alkyl, or halogenated (C ₁ -C ₃ ) alkyl; m and n each independently represent 0, 1 or 2; R _a and R _a ' each independently represent hydrogen, (C ₁ -C ₆ ) alkyl group, halogenated (C ₁ -C ₆ ) alkyl group, (C ₃ -C ₈ ) cycloalkyl group, halogenated (C ₃ -C ₈ )cycloalkyl. The compound having the structure of formula (I) or its pharmaceutically acceptable salt, isotope derivative, or stereoisomer as described in claim 1, wherein, When R ₆ is attached to a carbon atom, R ₆ represents halogen, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, halo( C ₃ -C ₈ )cycloalkyl, (C ₃ -C ₈ )heterocycloalkyl, halo(C ₃ -C ₈ )heterocycloalkyl, (C ₂ -C ₆ )alkynyl, halo(C ₂ -C ₆ )alkynyl, -(C ₁ -C ₆ )alkylene OR _a , -halo(C ₁ -C ₆ )alkylene OR _a , -(C ₃ -C ₈ )cycloalkylene OR _a , -halogenated (C ₃ -C ₈ ) cycloalkylene OR _a , -(C ₁ -C ₆ )alkylene SR _a , -halogenated (C ₁ -C ₆ )alkylene SR _a , -(C ₃ -C ₈ )cycloalkylene SR _a , -halogenated (C ₃ -C ₈ )cycloalkylene SR _a , -(C ₁ -C ₆ )alkylene CN, -halogenated (C ₁ -C ₆ )alkylene CN, -(C ₃ -C ₈ )cycloalkylene CN, -halogenated (C ₃ -C ₈ )cycloalkylene CN, -(C ₁ -C ₆ )alkylene Base -NR _a R _a ', -halogenated (C ₁ -C ₆ ) alkylene -NR _a R _a ', -(C ₃ -C ₈ ) cycloalkylene -NR _a R _a ', -halogenated (C ₃ -C ₈ ) cycloalkylene -NR _a R _a ', -CN, -NO ₂ , -OR _a , -SR _a , -NR _a R _a ', where R _a and R _a ' can be combined with them The connected N atoms together form a 3-8 membered ring. The ring may optionally have 0, 1 or 2 heteroatoms selected from N, O and S. The ring may be a single ring, a bicyclic ring, a bridged ring or a spiro ring. ring; When R ₆ is connected to the N atom, R ₆ represents halogen, (C ₁ -C ₆ ) alkyl, halo (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, halo ( C ₃ -C ₈ )cycloalkyl, (C ₃ -C ₈ )heterocycloalkyl, halo(C ₃ -C ₈ )heterocycloalkyl, (C ₂ -C ₆ )alkynyl, halo(C ₂ -C ₆ )alkynyl, -(C ₁ -C ₆ )alkylene OR _a , -halo(C ₁ -C ₆ )alkylene OR _a , -(C ₃ -C ₈ )cycloalkylene OR _a , -halogenated (C ₃ -C ₈ ) cycloalkylene OR _a , -(C ₁ -C ₆ )alkylene SR _a , -halogenated (C ₁ -C ₆ )alkylene SR _a , -(C ₃ -C ₈ )cycloalkylene SR _a , -halogenated (C ₃ -C ₈ )cycloalkylene SR _a . The compound having the structure of formula (I) or its pharmaceutically acceptable salt, isotope derivative, or stereoisomer as described in any of the preceding claims, wherein R ₆ represents halogen, (C ₁ -C ₆ ) alkane group, halo(C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, halo(C ₃ -C ₈ )cycloalkyl. The compound having the structure of formula (I) or its pharmaceutically acceptable salt, isotope derivative, or stereoisomer as described in any of the preceding claims, wherein R ₁ and R ₂ each independently represent hydrogen, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, halo(C ₃ -C ₈ )cycloalkyl, -(C ₁ -C ₆ ) Alkylene OR _a , -(C ₁ -C ₆ ) alkylene SR _a ; or R ₁ and R ₂ together with the carbon atoms connected to them form a 3-8 membered ring, and the ring can optionally Contains 0, 1, 2 or 3 heteroatoms selected from N, O and S. The compound having the structure of formula (I) as described in any of the preceding claims, or its pharmaceutically acceptable salt, isotope derivative, or stereoisomer, wherein R ₃ is (C ₁ -C ₆ ) alkyl or Halogenated (C ₁ -C ₆ )alkyl. The compound having the structure of formula (I) as described in any of the preceding claims, or its pharmaceutically acceptable salt, isotope derivative, or stereoisomer, wherein R ₃ is a (C ₁ -C ₆ ) alkyl group. The compound having the structure of formula (I) or its pharmaceutically acceptable salt, isotope derivative, or stereoisomer as described in any of the preceding claims, wherein Cy is a 5-6 membered monocyclic aromatic heterocycle, or Cy is a 9-10 membered bicyclic aromatic heterocycle. The compound having the structure of formula (I) or its pharmaceutically acceptable salt, isotope derivative, or stereoisomer as described in any of the preceding claims, wherein Cy is pyridyl, pyrimidinyl, pyrazolyl, imidazole base or pyrrolyl group. The compound having the structure of formula (I) as described in any of the preceding claims, or its pharmaceutically acceptable salt, isotope derivative, or stereoisomer, wherein R ₆ and L are connected to the ortho position of Cy. The compound having the structure of formula (I) or its pharmaceutically acceptable salt, isotope derivative, or stereoisomer as described in any of the preceding claims, wherein R ₅ is located at the meta position of R ₆ and is located at the meta position of L Metaposition or counterposition. The compound having the structure of formula (I) as described in any of the preceding claims, or its pharmaceutically acceptable salt, isotope derivative, or stereoisomer, wherein X is CR ₄ . The compound having the structure of formula (I) as described in any of the preceding claims, or its pharmaceutically acceptable salt, isotope derivative, or stereoisomer, wherein R ₄ is hydrogen. The compound having the structure of formula (I) or its pharmaceutically acceptable salt, isotope derivative, or stereoisomer as described in any of the preceding claims, wherein the connection between Cy and R ₅ and R ₆ is as follows:

The compound having the structure of formula (I) or its pharmaceutically acceptable salt, isotope derivative, or stereoisomer as described in any of the preceding claims, wherein the connection between Cy and R ₅ and R ₆ is as follows:

The compound having the structure of formula (I) or its pharmaceutically acceptable salt, isotope derivative, or stereoisomer as described in any of the preceding claims, wherein R ₆ is selected from:

It may optionally be substituted by 0, 1, 2, 3 or 4 substituents selected from halogen, -CN, -OR _a , -SR _a and -NR _a R _a '. A compound or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein the compound has the following structure:

. A pharmaceutical composition comprising the compound described in any of the preceding claims or a pharmaceutically acceptable salt, isotope derivative, stereoisomer thereof, and optionally a pharmaceutically acceptable carrier. The compound described in any one of claims 1 to 16 or its pharmaceutically acceptable salt, isotope derivative, stereoisomer or the pharmaceutical composition described in claim 17 is used for the prevention and/or treatment of cancer. , tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.

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