A Wnt pathway inhibitor compound

Abstract

The present invention provides a compound of formula (I) having excellent Wnt pathway inhibitory activity or a pharmaceutically acceptable salt, isotope derivative, stereoisomer thereof. The present invention also provides a method for preparing the compound and its use in preventing and / or treating cancer, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.

Description

[0001] This application claims priority to a Chinese patent application filed with the State Intellectual Property Office of China on January 29, 2022, with application number 202210114025.9 and invention name “A Wnt pathway inhibitor compound”, all contents of which are incorporated by reference into this application. Technical Field

[0002] The present invention relates to a heterocyclic compound, in particular to a highly active Wnt pathway inhibitor and application thereof. Background Art

[0003] The Wnt / β-catenin signal transduction pathway is a conserved pathway in biological evolution. In normal somatic cells, β-catenin only functions as a cytoskeletal protein to form a complex with E-cadherin at the cell membrane to maintain the adhesion of homotypic cells 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, and GSK3β, thereby initiating the ubiquitin system to degrade β-catenin via the proteasome pathway, maintaining β-catenin in the cytoplasm at a low level. When cells are stimulated by Wnt signals, Wnt proteins bind to the specific receptor Frizzled protein on the cell membrane. The activated Frizzled receptor recruits intracellular Dishevelled protein, inhibits the degradation activity of the β-catenin degradation complex formed by GSK3β and other proteins, and stabilizes the free β-catenin protein in the cytoplasm. After β-catenin stably accumulated in the cytoplasm enters the cell nucleus, it binds to the LEF / TCF transcription factor family and initiates the transcription of downstream target genes (such as c-myc, c-jun, Cyclin D1, etc.). Overactivation of the Wnt / β-catenin signaling pathway is closely related to the occurrence of various cancers (including colon cancer, gastric cancer, breast cancer, etc.). For example, abnormal activation of the Wnt classical signaling pathway and nuclear accumulation of β-catenin protein are widely present in colorectal cancer, and the proliferation of cancers such as colon cancer can be inhibited by inhibiting the activity of the Wnt signaling pathway. APC mutations exist in more than 85% of colorectal cancers. The mutated APC blocks the phosphorylation and degradation of β-catenin, inducing the occurrence of colorectal cancer. In addition, Axin mutations and β-catenin mutations can also cause intracellular aggregation of β-catenin and activate the Wnt / β-catenin pathway.

[0004] 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 inhibitor compounds in the prior art. Therefore, the study of effective Wnt pathway inhibitor compounds is a need in the prior art. Summary of the invention

[0005] The inventors have unexpectedly discovered through research that the compound of formula (I) of the present invention or its pharmaceutically acceptable salt, isotope derivative, stereoisomer is an effective Wnt pathway inhibitor with excellent Wnt pathway inhibitory effects. n t pathway inhibitory activity.

[0006] Based on the above findings, in one aspect, the present invention provides a compound having a structure of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof:

[0007]

[0008] Wherein, R1 and R2 each independently represent hydrogen, (C1-C6) alkyl, halogenated (C1-C6) alkyl, (C3-C8) cycloalkyl, halogenated (C3-C8) cycloalkyl, 4-8 membered heterocycloalkyl, halogenated 4-8 membered heterocycloalkyl, -(C1-C6) alkylene, OR a , -halogenated (C1-C6) alkylene OR a 、-(C1-C6)alkylene SR a , -halogenated (C1-C6)alkylene SR a , or R1, R2 together with the carbon atom to which they are attached form a 3-8 membered ring, which may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O and S;

[0009] R3 represents (C1-C6) alkyl, halogenated (C1-C6) alkyl, (C3-C8) cycloalkyl, halogenated (C3-C8) cycloalkyl, or R3 and R1 or R2 together form a 4-7 membered ring, which may optionally contain 0 or 1 heteroatom selected from O and S;

[0010] X represents CR4 or N;

[0011] R4 each independently represents hydrogen, halogen, cyano, (C1-C3) alkyl, halogenated (C1-C3) alkyl;

[0012] L means -O- or -(CR m R m ')-, where R m , R m' each independently represents hydrogen, (C1-C3) alkyl, (C3-C8) cycloalkyl, or R m , R m 'To form a 3-5 membered ring with the carbon atom to which it is attached, the ring may contain 0 or 1 heteroatom selected from O and S;

[0013] Cy represents a 5-12 membered aromatic heterocyclic ring, which optionally contains 1, 2, 3 or 4 heteroatoms, each of which is independently selected from N, O, S;

[0014] R5 represents halogen, (C1-C6) alkyl, halogenated (C1-C6) alkyl, (C3-C8) cycloalkyl, halogenated (C3-C8) cycloalkyl, -OR a 、-halogenated OR a 、-SR a ,-halogenated SR a ;

[0015] R6 represents halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C8) cycloalkyl, halo (C3-C8) cycloalkyl, (C3-C8) heterocycloalkyl, halo (C3-C8) heterocycloalkyl, (C2-C6) alkynyl, halo (C2-C6) alkynyl, -(C1-C6) alkylene, OR a , -halogenated (C1-C6) alkylene OR a 、-(C3-C8)cycloalkyleneOR a , -halogenated (C3-C8) cycloalkylene OR a 、-(C1-C6)alkylene SR a , -halogenated (C1-C6)alkylene SR a 、-(C3-C8)cycloalkylene SR a , -halogenated (C3-C8) cycloalkylene SR a , -(C1-C6)alkyleneCN, -halo(C1-C6)alkyleneCN, -(C3-C8)cycloalkyleneCN, -halo(C3-C8)cycloalkyleneCN, -(C1-C6)alkylene-NR a R a ', -halogenated (C1-C6) alkylene-NR a R a ', -(C3-C8)cycloalkylene-NR a R a ', -halogenated (C3-C8) cycloalkylene-NR a R a ′、-CN、-NO2、-OR a 、-SR a 、-NR a R a′, where R a , R a 'Can form a 3-8 membered ring together with the N atom to which they are connected, the ring can also arbitrarily have 0, 1 or 2 heteroatoms selected from N, O, S, and the ring can be a monocyclic, bicyclic, bridged or spirocyclic ring;

[0016] R7 each independently represents hydrogen, halogen, (C1-C3) alkyl, halogenated (C1-C3) alkyl;

[0017] m and n each independently represent 0, 1 or 2;

[0018] R a , R a 'Each independently represents hydrogen, (C1-C6) alkyl, halogenated (C1-C6) alkyl, (C3-C8) cycloalkyl, halogenated (C3-C8) cycloalkyl.

[0019] In particular, when R6 is attached to a carbon atom, R6 represents halogen, (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C8)cycloalkyl, halo(C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, halo(C3-C8)heterocycloalkyl, (C2-C6)alkynyl, halo(C2-C6)alkynyl, -(C1-C6)alkylene, OR a , -halogenated (C1-C6) alkylene OR a 、-(C3-C8)cycloalkyleneOR a , -halogenated (C3-C8) cycloalkylene OR a 、-(C1-C6)alkylene SR a , -halogenated (C1-C6)alkylene SR a 、-(C3-C8)cycloalkylene SR a , -halogenated (C3-C8) cycloalkylene SR a , -(C1-C6)alkyleneCN, -halo(C1-C6)alkyleneCN, -(C3-C8)cycloalkyleneCN, -halo(C3-C8)cycloalkyleneCN, -(C1-C6)alkylene-NR a R a ', -halogenated (C1-C6) alkylene-NR a R a ', -(C3-C8)cycloalkylene-NR a R a ', -halogenated (C3-C8) cycloalkylene-NR a R a ′、-CN、-NO2、-OR a 、-SR a 、-NR a R a′, where R a , R a 'Can form a 3-8 membered ring together with the N atom to which they are connected, the ring can also arbitrarily have 0, 1 or 2 heteroatoms selected from N, O and S, and the ring can be a monocyclic, bicyclic, bridged or spirocyclic ring;

[0020] When R6 is connected to the N atom, R6 represents halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C8) cycloalkyl, halo (C3-C8) cycloalkyl, (C3-C8) heterocycloalkyl, halo (C3-C8) heterocycloalkyl, (C2-C6) alkynyl, halo (C2-C6) alkynyl, -(C1-C6) alkylene, OR a , -halogenated (C1-C6) alkylene OR a 、-(C3-C8)cycloalkyleneOR a , -halogenated (C3-C8) cycloalkylene OR a 、-(C1-C6)alkylene SR a , -halogenated (C1-C6)alkylene SR a 、-(C3-C8)cycloalkylene SR a , -halogenated (C3-C8) cycloalkylene SR a .

[0021] More preferably, R6 represents halogen, (C1-C6)alkyl, halogenated (C1-C6)alkyl, (C3-C8)cycloalkyl, halogenated (C3-C8)cycloalkyl.

[0022] In one embodiment of the present invention, R1 and R2 each independently represent hydrogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C8) cycloalkyl, halo (C3-C8) cycloalkyl, -(C1-C6) alkylene, OR a 、-(C1-C6)alkylene SR a or R1, R2 together with the carbon atom to which they are attached form a 3-8 membered ring, which may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O and S.

[0023] In one embodiment of the present invention, R3 is C1-C6)alkyl or halo(C1-C6)alkyl.

[0024] In a preferred embodiment of the present invention, R3 is (C1-C6) alkyl.

[0025] 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.

[0026] In one embodiment of the invention, Cy is pyridyl, pyrimidinyl, pyrazolyl, imidazolyl or pyrrolyl.

[0027] In one embodiment of the invention, R6 and L are attached to Cy at the ortho position.

[0028] In one embodiment of the present invention, R5 is located at the meta position relative to R6, and at the meta position or para position relative to L.

[0029] In a preferred embodiment of the present invention, X is CR4.

[0030] In another preferred embodiment of the present invention, R4 is hydrogen.

[0031] In one embodiment of the present invention, the connection between Cy and R5 and R6 is as follows:

[0032]

[0033] In a preferred embodiment of the present invention, the connection between Cy and R5 and R6 is as follows:

[0034]

[0035] In one embodiment of the present invention, R6 is selected from:

[0036]

[0037] It may be optionally substituted by 0, 1, 2, 3 or 4 selected from halogen, -CN, -OR a 、-SR a and-NR a R a ′ is substituted by a substituent.

[0038] The present invention also provides a class of compounds or pharmaceutically acceptable salts, isotopic derivatives, and stereoisomers thereof, wherein the compounds have the following structure:

[0039]

[0040]

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047] 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.

[0048] In another aspect, the present invention also provides the use of the aforementioned compound or its pharmaceutically acceptable salt, isotope derivative, stereoisomer or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and / or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.

[0049] It is particularly noted that, herein, when referring to a "compound" of the structure of formula (I), it also generally encompasses stereoisomers, diastereomers, enantiomers, racemic mixtures and isotopic derivatives thereof.

[0050] It is well known to those skilled in the art that a salt, solvate, or hydrate of a compound is an alternative form of the compound, and they can all be converted into the compound under certain conditions. Therefore, it should be noted that when referring to a compound of formula (I) herein, it generally also includes its pharmaceutically acceptable salts, and further includes its solvates and hydrates.

[0051] Similarly, when a compound is referred to herein, prodrugs, metabolites, and N-oxides thereof are also generally included.

[0052] 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 are suitable for contact with tissues of humans and lower animals, without undue toxicity, irritation, allergic reactions, etc., within the scope of reasonable medical judgment, and are considered to be a reasonable benefit / risk ratio. The salts may be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting the free base or free acid with a suitable reagent, as outlined below. For example, the free base function may be reacted with a suitable acid. Examples of pharmaceutically acceptable inorganic acid addition salts are salts formed of an amino group with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or an organic acid (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, sodium alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. Representative alkali metal or alkaline earth metal salts include salts of sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts include (where appropriate) non-toxic ammonium salts, quaternary ammonium salts, and amine cations formed with counterions, for example, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0053] The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example, by dissolving the compound of the present invention in a water-miscible organic solvent (e.g., acetone, methanol, ethanol and acetonitrile), adding an excess of an organic acid or an aqueous inorganic acid solution thereto to precipitate the salt from the resulting mixture, removing the solvent and the remaining free acid therefrom, and then isolating the precipitated salt.

[0054] The precursors or metabolites of the present invention may be precursors or metabolites 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 are suitable for contact with human and lower animal tissues within the scope of reasonable medical judgment, without undue toxicity, irritation, allergic reactions, etc., and are considered to have a reasonable benefit / risk ratio and are effective for their intended use. The term "prodrug" refers to a compound that is rapidly converted in vivo to produce the parent compound of the above formula, for example, by in vivo metabolism, or N-demethylation of the compounds of the present invention.

[0055] "Solvate" as used herein means a physical association of a compound of the invention with one or more solvent molecules (whether organic or inorganic). The physical association includes hydrogen bonding. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be separated. The solvent molecules in the solvate may exist in a regular arrangement and / or a disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0056] The "stereoisomerism" described 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 (i.e. optical isomerism). Conformational isomerism refers to a stereoisomerism phenomenon in which the atoms or atomic groups of molecules have different arrangements in space due to the rotation or distortion of carbon and carbon single bonds in organic molecules with a certain configuration. Common structures include the structures of alkane and cycloalkane compounds, such as the chair conformation and boat conformation that appear in the structure of cyclohexane. "Stereoisomer" refers to when the compounds of the present invention contain one or more asymmetric centers, and thus can be used as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and single diastereoisomers. The compounds of the present invention have asymmetric centers, and each asymmetric center will produce two optical isomers. The scope of the present invention includes all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds. The compounds described in the present invention can exist in the form of tautomers, which have different hydrogen connection points due to one or more double bond displacements. For example, a ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included in the compounds of the present invention. Enantiomers, diastereomers, racemates, mesomorphs, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof of all formula (I) to formula (III) compounds are included in the scope of the present invention.

[0057] The "isotopic derivative" of the present invention refers to a molecule in which the compound is isotopically labeled. The isotopes commonly used as isotopic labels are: hydrogen isotopes, 2 H and 3 H; Carbon isotope: 11 C, 13 C and 14 C; Chlorine isotope: 35 Cl and 37 Cl; Fluorine isotope: 18 F; Iodine isotope: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotope: 15 Oh, 17 O and 18 O and sulfur isotopes 35 S. These isotope-labeled compounds can be used to study the distribution of drug molecules in tissues. 3 H and carbon 13 C, because they are easy to label and detect, they are more widely used. Some heavy isotopes, such as deuterium ( 2 H), the substitution can enhance metabolic stability, prolong half-life and thus achieve the purpose of reducing dosage and provide therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthesis techniques in the same way as non-isotope-labeled compounds.

[0058] The present invention also provides the use of the compound of the present invention in preparing a medicament for preventing and / or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.

[0059] In addition, the present invention provides a pharmaceutical composition for preventing and / or treating cancer, tumors, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, attention-related diseases or immune-mediated diseases, which comprises the compound of the present invention as an active ingredient. The pharmaceutical composition may optionally comprise a pharmaceutically acceptable carrier.

[0060] 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, which comprises administering a compound of formula (I) of the present invention or a pharmaceutically acceptable salt, isotope derivative, stereoisomer or pharmaceutical composition of the present invention to a mammal in need thereof.

[0061] 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 diseases, psoriasis, eczema, dermatitis, atopic dermatitis, pain, lung disease, lung inflammation, adult respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic inflammatory lung 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, Sjögren's syndrome, autoimmune thyroid disease, disease, urticaria (urticaria), multiple sclerosis, scleroderma, organ transplant rejection, xenotransplantation, idiopathic thrombocytopenic purpura (ITP), Parkinson's disease, Alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, allergic sinusitis, leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, acute lymphoid leukemia (ALL), chronic lymphoid leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hairy cell leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), diffuse large B-cell lymphoma and follicular lymphoma.

[0062] Representative examples of cancer 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, renal parenchymal 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, meningioma, medulloblastoma and peripheral Neuroectodermal tumor, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphoid leukemia (ALL), chronic lymphoid leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid 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, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, or plasmacytoma.

[0063] When the compound of the present invention or a pharmaceutically acceptable salt thereof is administered in combination with another anticancer agent or immune checkpoint inhibitor for treating cancer or tumor, the compound of the present invention or a pharmaceutically acceptable salt thereof may provide an enhanced anticancer effect.

[0064] Representative examples of anticancer agents for treating cancer or tumors may include, but are not limited to, cell signaling inhibitors, chlorambucil, guanfalan, 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, epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin C, ixapric acid, thiocyanate, chloramphenicol ... lon, tamoxifen, flutamide, gonadorelin analogs, megestrol acetate, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alfa, leucovorin, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danusetinib, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib tinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saricatinib, saridegib, sorafenib, sunitinib, telatinib, tivantinib, Tivozanib, tofacitinib, traguantinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, berentuzumab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, PI3K inhibitor, CSF1R inhibitor, A2A and / or A2B receptor antagonist, IDO inhibitor, anti-PD-1 antibody, anti-PD-L1 antibody, LAG3 antibody, TIM-3 antibody and anti-CTLA-4 antibody, or any combination thereof.

[0065] When the compounds of the present invention or their pharmaceutically acceptable salts are administered in combination with another therapeutic agent for treating inflammatory diseases, autoimmune diseases and immune-mediated diseases, the compounds of the present invention or their pharmaceutically acceptable salts may provide enhanced therapeutic effects.

[0066] 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, hydroprednisolone, methylhydroprednisolone, cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNFα agents (e.g., etanercept, infliximab, adalimumab, etc.), calcineurin inhibitors (e.g., tacrolimus, piguanlimus, etc.) and antihistamines (e.g., diphenhydramine, hydroxyzine, loratadine, ebastine, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one or more therapeutic agents selected therefrom may be contained in the pharmaceutical composition of the present invention.

[0067] The compound of the present invention or its pharmaceutically acceptable salt can be used as an active ingredient. The dosage of the active ingredient can be adjusted according to multiple relevant factors (such as the condition of the subject to be treated, the type of disease and severity, the rate of administration and the doctor's opinion). In some cases, an amount less than the above dosage may be suitable. If no harmful side effects are caused, an amount greater than the above dosage can be used and the amount can be administered in divided doses every day.

[0068] 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 comprises administering the compound of the present invention or the compound or pharmaceutical composition of the present invention to a mammal in need thereof.

[0069] The pharmaceutical composition of the present invention can be formulated into dosage forms for oral administration or parenteral administration (including intramuscular, intravenous and subcutaneous routes, intratumor injection) according to any of the conventional methods, such as tablets, granules, powders, capsules, syrups, emulsions, microemulsions, solutions or suspensions.

[0070] The pharmaceutical composition 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, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers and diluents.

[0071] Examples of carriers used in the pharmaceutical compositions for injection administration of the present invention may be water, saline solutions, glucose solutions, glucose-like solutions, alcohols, glycols, ethers (e.g., polyethylene glycol 400), oils, fatty acids, fatty acid esters, glycerides, surfactants, suspending agents and emulsifiers.

[0072] Other features of the invention will become apparent as the present invention proceeds through the description of exemplary embodiments, which are given to illustrate the invention and are not intended to be limiting thereof. The following examples were prepared, isolated, and characterized using the methods disclosed herein.

[0073] The compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis, and the compounds of the present invention can be synthesized using the following methods and synthetic methods known in the field of organic synthetic chemistry or by variations thereof known to those skilled in the art. 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 suitable for the transformation achieved. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule is consistent with the proposed transformation. This sometimes requires judgment to change the order of the synthesis steps or the raw materials to obtain the desired compounds of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0074] Figure 1 Effect of compound 1 on tumor volume of human colon cancer cell Colo205 xenografts in nude mice. DETAILED DESCRIPTION

[0075] the term

[0076] If not otherwise stated, the terms used in this application, including the specification and claims, are defined as follows. If not otherwise stated, conventional methods of mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology are used. In this application, if not otherwise stated, the use of "or" or "and" means "and / or".

[0077] In the specification and claims, a given chemical formula or name shall encompass all stereoisomers and optical isomers thereof and racemates in which such isomers exist. Unless otherwise indicated, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Multiple geometric isomers of C=C double bonds, C=N double bonds, ring systems, etc. may also exist in the compounds, and all such stable isomers are encompassed by the present invention. The present invention describes cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention, and they can be separated into mixtures of isomers or separated isomeric forms. The compounds of the present invention can be separated in optically active or racemic form. All methods for preparing the compounds of the present invention and the intermediates prepared therein are considered to be part of the present invention. When enantiomeric or diastereomeric products are prepared, they can be separated by conventional methods (e.g., by chromatography or fractional crystallization). Depending on the process conditions, the final product of the present invention is obtained in free (neutral) or salt form. Both the free forms and salts of these end products are within the scope of the present invention. If desired, one form of the compound may be converted into another form. A free base or acid may be converted into a salt; a salt may be converted into a free compound or another salt; a mixture of isomeric compounds of the present invention may 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 hydrogen atoms are transposed to other parts of the molecule and the chemical bonds between the atoms of the molecule are rearranged. It should be understood that all tautomeric forms that may exist are included in the present invention.

[0078] Unless otherwise defined, the definitions of substituents of the present invention are independent of each other and not related to each other. For example (listing but not exhaustive), in one aspect, for R in a substituent a (or R a '), they are independent of each other in the definitions of different substituents. Specifically, for R a (or R a ') When a definition is selected for a substituent, it does not mean that the R a (or R a ') has the same definition in other substituents. More specifically, for example (only non-exhaustive) for NR a R a ', when R a (or R a ') is selected from hydrogen, it does not mean that in -C(O)-NR a R a ', R a (or R a ') must be hydrogen. In another aspect, when more than one R is present in a substituent a (or Ra '), these R a (or R a ') are also independent of each other. For example, in the substituent -(CR a R a ')mO-(CR a R a ')n-, when m+n is greater than or equal to 2, the m+n R a (or R a ') are independent of each other and can have the same or different meanings.

[0079] Unless otherwise defined, when a substituent is noted as "optionally substituted", the substituent is selected, for example, from substituents such as alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amino (wherein the two amino substituents are selected from alkyl, aryl or arylalkyl), alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkylthio, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, Alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, aminosulfonyl such as -SO2NH2, substituted sulfonylamino, nitro, cyano, carboxyl, carbamoyl such as -CONH2, substituted carbamoyl such as -CONHalkyl, -CONHRyl, -CONHRylalkyl or in the case of having two substituents on nitrogen selected from alkyl, aryl or arylalkyl, alkoxycarbonyl, aryl, substituted aryl, guanidinyl, heterocyclic groups such as indolyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl and the like and substituted heterocyclic groups.

[0080] The term "alkyl" or "alkylene" as used herein is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, "C1-C6 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 (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). In this article, alkyl groups are preferably alkyl groups having 1 to 6, 1 to 4, and more preferably 1 to 3 carbon atoms.

[0081] The term "alkenyl" refers to a straight or branched hydrocarbon group containing one or more double bonds and generally having a length of 2 to 20 carbon atoms. For example, a "C2-C6 alkenyl" contains two to six carbon atoms. Alkenyl includes, but is not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-butene-1-yl, etc.

[0082] The term "alkynyl" refers to a straight or branched hydrocarbon group containing one or more triple bonds and typically 2 to 20 carbon atoms in length. For example, a "C2-C6 alkynyl" contains two to six carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, etc.

[0083] The term "alkoxy" or "alkyloxy" refers to -O-alkyl. "C1-C6 alkoxy" (or alkyloxy) is intended to include C1, C2, C3, C4, C5, C6 alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy) and tert-butoxy. In this article, alkoxy is preferably an alkoxy having 1 to 6, more preferably 1 to 4 carbon atoms. Similarly, "alkylthio" or "thiothio" represents an alkyl as defined above connected by a sulfur bridge with a specified number of carbon atoms; for example, methyl-S- and ethyl-S-.

[0084] The term "carbonyl" refers to an organic functional group consisting of carbon and oxygen atoms connected by a double bond (C=O).

[0085] The term "aryl", alone or as part of a larger moiety such as "aralkyl", "arylalkoxy" or "aryloxyalkyl", refers to a monocyclic, bicyclic or tricyclic ring system having a total of 5 to 12 ring members, 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, which includes but is not limited to phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl and tetrahydronaphthyl. 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 may be attached to another group at a suitable position on the cycloalkyl ring or the aromatic ring. The dotted line drawn from the ring system indicates that the bond may be attached to any suitable ring atom.

[0086] The term "cycloalkyl" refers to a monocyclic or bicyclic cyclic alkyl. The monocyclic cyclic alkyl refers to a C3-C8 cyclic alkyl, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norbornyl. Branched cycloalkyls such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". Bicyclic cyclic alkyls include cycloalkyls of bridged rings, spiro rings or condensed rings. In this article, cycloalkyl is preferably a cycloalkyl with 3 to 8, more preferably 3 to 6 carbon atoms.

[0087] The term "cycloalkenyl" refers to a monocyclic or bicyclic cyclic alkenyl. Monocyclic cyclic alkenyl refers to a C3-C8 cyclic alkenyl, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and norbornyl. Branched cycloalkenyls such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl". Bicyclic cyclic alkenyls include cyclic alkenyls of bridged rings, spiro rings or condensed rings.

[0088] "Halo" or "halogen" includes fluorine, chlorine, bromine and iodine. "Haloalkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups with a specified number of carbon atoms and 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, heptafluoropropyl and heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl" which is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups with a specified number of carbon atoms and substituted with one or more fluorine atoms. Similarly, "halocycloalkyl" is intended to include branched cycloalkyl groups with a specified number of carbon atoms and substituted with one or more halogens.

[0089] "Haloalkoxy" or "haloalkyloxy" means a haloalkyl group as defined above connected via an oxygen bridge with a specified number of carbon atoms. For example, "halo C1-C6 alkoxy" is intended to include C1, C2, C3, C4, C5, C6 haloalkoxy. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" means a haloalkyl group as defined above connected via a sulfur bridge with a specified number of carbon atoms; for example, trifluoromethyl-S- and pentafluoroethyl-S-.

[0090] The halo (C1-C6) alkylene group OR a , -halogenated (C1-C6)alkylene SR a 、-Halo (C1-C6) alkylene NR a R a ', -halogenated (C1-C6) alkylene CN, -halogenated (C3-C8) cycloalkylene OR a , -halogenated (C3-C8) cycloalkylene SR a , -halogenated (C3-C8) cycloalkylene NR a R a ', -halogenated (C3-C8) cycloalkylene CN, etc. means -(C1-C6) alkylene OR which is arbitrarily halogenated a 、-(C1-C6)alkylene SR a 、-(C1-C6)alkylene NR a R a', -(C1-C6)alkylene CN, -(C3-C8)cycloalkylene OR a 、-(C3-C8)cycloalkylene SR a 、-(C3-C8)cycloalkylene NR a R a ', -(C3-C8)cycloalkylene CN.

[0091] In this disclosure, C is used when referring to certain substituent groups. x1 -C x2 , which means that the number of carbon atoms in the substituent group can be x1 to x2. For example, C0-C8 means that the group contains 0, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C1-C8 means that the group contains 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C2-C8 means that the group contains 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C3-C8 means that the group contains 3, 4, 5, 6, 7 or 8 carbon atoms, C4-C8 means that the group contains 4, 5, 6, 7 or 8 carbon atoms, C0-C6 means that the group contains 0, 1, 2, 3, 4, 5 or 6 carbon atoms, C1-C6 means that the group contains 1, 2, 3, 4, 5 or 6 carbon atoms, C2-C6 means that the group contains 2, 3, 4, 5 or 6 carbon atoms, and C3-C6 means that the group contains 3, 4, 5 or 6 carbon atoms.

[0092] In the present disclosure, when referring to cyclic groups (such as aryl, heteroaryl, cycloalkyl and heterocycloalkyl), the expression "x1-x2 membered ring" is used, which means that the number of ring atoms of the group can be x1 to x2. 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 thereof can be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; the 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 thereof can be 3, 4, 5 or 6; the 3-8 membered ring means that the cyclic group can be a 3-, 4-, 5-, 6-, 7- or 8-membered ring, and the number of ring atoms thereof can be 3, 4, 5, 6, 7 or 8; the 3-9 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 thereof can be 3, 4, 5, 6, 7, 8 or 9; 4-7 membered ring means that the cyclic group can be a 4, 5, 6 or 7 membered ring, and the number of its ring atoms can be 4, 5, 6 or 7; 5-8 membered ring means that the cyclic group can be a 5, 6, 7 or 8 membered ring, and the number of its ring atoms can be 5, 6, 7 or 8; 5-12 membered ring means that the cyclic group can be a 5, 6, 7, 8, 9, 10, 11 or 12 membered ring, and the number of its ring atoms can be 5, 6, 7, 8, 9, 10, 11 or 12; 6-12 membered ring means that the cyclic group can be a 6, 7, 8, 9, 10, 11 or 12 membered ring, and the number of its ring atoms can be 6, 7, 8, 9, 10, 11 or 12. The ring atoms can 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, such as heteroatoms selected from N, O and S.

[0093] In the present disclosure, one or more halogens may each independently be selected from fluorine, chlorine, bromine and iodine.

[0094] The term "heteroaryl" means a stable, designated number of monocyclic or polycyclic aromatic groups containing heteroatoms, preferably 3, 4, 5, 6, or 7-membered aromatic monocyclic or aromatic bicyclic or 7, 8, 9, 10, 11, 12-membered aromatic polycyclic heterocyclic rings, which are completely unsaturated or partially unsaturated, and which contain carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; and include any of the following polycyclic groups, wherein any heterocyclic ring defined above is fused to a benzene ring. The heteroaryl herein is preferably a 5 to 12-membered heteroaryl. Nitrogen and sulfur heteroatoms may be optionally oxidized. The nitrogen atom is substituted or unsubstituted (i.e., N or NR, wherein R is H or, if defined, another substituent). The heterocycle may be connected to its side group at any heteroatom or carbon atom that results in a stable structure. If the resulting compound is stable, the heterocyclic group described herein may be substituted on a carbon or nitrogen atom. The nitrogen in the heterocycle may be optionally quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not greater than 1. When the term "heterocycle" is used, it is intended to include heteroaryl.Examples of aromatic hetero groups include, but are not limited to, acridinyl, azetidinyl, azinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridinyl, indolenyl, dihydroindole , indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinyl, perylene, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiol, phenoxazinyl , phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidinonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolyl, 4H-quinolizinyl, quinoxalinyl, quinuclidine, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl 1,2,3,4-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, 5,6,7,8-tetrahydro-quinolyl, 2,3-dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl.The term "heteroaryl" may also include biaryl structures formed by the "aryl" defined above and a monocyclic "heteroaryl", such as but not limited to "-phenylbipyridyl-", "-phenylbipyrimidyl-", "-pyridylbiphenyl-", "-pyridylbipyrimidyl-", "-pyrimidylbiphenyl-"; the present invention also includes fused ring and spiro compounds containing, for example, the above-mentioned heterocycles.

[0095] The term "heterocycloalkyl" as used herein refers to a monocyclic heterocycloalkyl system, or a bicyclic heterocycloalkyl system, and also includes spiro heterocyclic or bridged heterocycloalkyl. In the present invention, a monocyclic heterocycloalkyl refers to a 3-8 membered saturated or unsaturated but non-aromatic cyclic alkyl system containing at least one heteroatom selected from O, N, S and P. A bicyclic heterocycloalkyl system refers to a heterocycloalkyl fused to a phenyl, or a cycloalkyl, or a cycloalkenyl, or a heterocycloalkyl, or a heteroaryl to form a bicyclic system.

[0096] The term "bridged cycloalkyl" used herein refers to a polycyclic compound that shares two or more carbon atoms. It can be divided into bicyclic bridged hydrocarbons and polycyclic bridged hydrocarbons. The former is composed of two alicyclic rings sharing two or more carbon atoms; the latter is a bridged hydrocarbon composed of three or more rings.

[0097] The term "spirocycloalkyl" as used herein refers to a polycyclic hydrocarbon group in which the single rings share a carbon atom (called a spiro atom).

[0098] The term "bridged heterocyclic group" as used herein refers to a polycyclic compound that shares two or more atoms, and the ring contains at least one heteroatom selected from O, N and S. It can be divided into bicyclic bridged heterocyclic rings and polycyclic bridged heterocyclic rings.

[0099] The term "heterospirocyclic group" as used herein refers to a polycyclic hydrocarbon group in which single rings share a carbon atom (called a spiro atom), and the ring contains at least one heteroatom selected from O, N and S atoms.

[0100] The term "substituted" as used herein means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that normal valence is maintained and the substitution results in a stable compound. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0101] In the case of nitrogen atoms (e.g., amines) present on the compounds of the invention, these nitrogen atoms can be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to obtain other compounds of the invention. Thus, the nitrogen atoms shown and claimed are considered to encompass both the shown nitrogen and its N-oxide to obtain the derivatives of the invention.

[0102] When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at 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, and at each occurrence R is independently selected from the definition of R. Furthermore, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0103] The term "patient" as used herein refers to an organism treated by the method of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., mice, apes, monkeys, horses, cows, pigs, dogs, cats, etc.) and most preferably refer to humans.

[0104] The term "effective amount" as used herein means the amount of a drug or medicament (i.e., a compound of the present invention) that will cause a biological or medical response of a tissue, system, animal, or human being, such as that sought by a researcher or clinician. In addition, the term "therapeutically effective amount" means an amount that results in improved treatment, cure, prevention, or alleviation of a disease, condition, or side effect, or reduces the rate of progression of a disease or condition, compared to a corresponding subject that has not received the above amount. An effective amount can be given in one or more administrations, applications, or doses and is not intended to be limited by a specific formulation or route of administration. The term also includes an effective amount that enhances normal physiological function within its scope.

[0105] As used herein, the term "treat," ...

[0106] The term "pharmaceutically acceptable" is used herein to refer to those compounds, substances, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response and / or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0107] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutical substance, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium, calcium or zinc stearate or stearic acid) or solvent encapsulating substance, which is involved in 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 injurious to the patient.

[0108] The term "pharmaceutical composition" means a composition comprising a compound of the present invention and at least one other pharmaceutical carrier. "Pharmaceutical carrier" refers to a medium generally accepted in the art for delivering 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 nature of the mode of administration and dosage form.

[0109] Specific pharmaceutical and medical terms

[0110] The term "acceptable," as used herein, means that a formulation component or active ingredient has no undue deleterious effect on health and well-being for the general purpose of treatment.

[0111] The term "cancer", as used herein, refers to an abnormal growth of cells that cannot be controlled and can metastasize (spread) under certain conditions. This type of cancer includes, but is not limited to, solid tumors (such as bladder, intestine, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (such as thyroid), prostate, skin (melanoma) or blood tumors (such as non-leukemic leukemia).

[0112] The term "combination administration" or its like, as used herein, refers to the administration of several selected therapeutic agents to one patient, in the same or different administration routes and at the same or different times.

[0113] The term "enhance" or "enhancing", as used herein, refers to the ability to increase or prolong the effectiveness or duration of a desired result. Therefore, in terms of enhancing the therapeutic effect of a drug, the term "enhancing" refers to the ability of a drug to increase or prolong the effectiveness or duration in a system. "Efficacy value" as used herein refers to the ability to maximize the enhancement of another therapeutic drug in an ideal system.

[0114] The term "immune disease" refers to a disease or condition that is caused by an adverse or harmful response to endogenous or exogenous antigens. The result is usually cellular dysfunction, or the resulting damage and malfunction of, or destruction of, organs or tissues that may produce immune symptoms.

[0115] The terms "kit" and "product package" are synonymous.

[0116] The term "subject" or "patient" includes mammals and non-mammals. Mammals include, but are not limited to, mammals: humans, non-human primates such as gorillas, apes and monkeys; agricultural animals such as cattle, horses, goats, sheep, pigs; livestock such as rabbits and dogs; experimental animals include rodents such as rats, mice and guinea pigs. Non-mammalian animals include, but are not limited to, birds, fish, etc. In a preferred aspect, the selected mammal is a human.

[0117] The terms "treat," "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 symptom, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing a disease or symptom to regress; alleviating complications caused by a disease or symptom, or preventing and / or treating signs caused by a disease or symptom.

[0118] As used herein, a compound or pharmaceutical composition, after administration, can improve a disease, symptom or condition, especially improve its severity, delay the onset, slow the progression of the disease, or reduce the duration of the disease. Whether fixed or temporary administration, continuous or intermittent administration, can be attributed to or related to the administration.

[0119] Route of administration

[0120] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, auricular, nasal, and topical administration. In addition, parenteral administration, by way of example only, includes intramuscular, subcutaneous, intravenous, intramedullary, ventricular, intraperitoneal, intralymphatic, and intranasal injections.

[0121] On the one hand, the administration of the compounds described herein is local rather than systemic. In a specific embodiment, the long-acting formulation is administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. In addition, in another embodiment, the drug is administered by a targeted drug delivery system. For example, a liposome wrapped by an organ-specific antibody. In this embodiment, the liposome is selectively directed to a specific organ and absorbed.

[0122] Example

[0123] General process

[0124] When the preparation route is not included, the raw materials and reagents used in the present invention are all known products, which can be synthesized according to methods known in the art, or can be obtained by purchasing commercial products. The commercial reagents used do not need to be further purified.

[0125] Room temperature refers to 20-30°C.

[0126] Unless otherwise specified in the reaction examples, the reactions were carried out under a nitrogen atmosphere, which means that the reaction flask was connected to a nitrogen balloon of about 1 L.

[0127] The hydrogenation reaction is usually carried out by evacuating the vacuum and filling with hydrogen, and the operation is repeated three times. The hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon of about 1L.

[0128] Microwave reaction use Initiator + microwave reactor.

[0129] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). -6 The units of (ppm) are given. NMR measurements were performed using (Bruker Ascend TM The NMR spectrometer was 500 (model 500), and the solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS). The following abbreviations are used for the multiplicity of NMR signals: s = singlet, brs = broad, d = doublet, t = triplet, m = multiplet. Coupling constants are listed as J values ​​and measured in Hz.

[0130] The LC-MS was determined using a Thermo liquid mass spectrometer (UltiMate 3000+MSQ PLUS). The HPLC was determined using a Thermo high pressure liquid chromatograph (UltiMate 3000). The reversed phase preparative chromatography was performed using a Thermo (UltiMate 3000) reversed phase preparative chromatograph. The rapid column chromatography was performed using an Agilent (FS-9200T) automatic column machine, and the silica gel prepacked column was performed using a Santai Pre-packed column. The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0131] The synthetic methods of some intermediates in the present invention are as follows:

[0132] Intermediate 1

[0133]

[0134] Intermediate 1 was prepared by the following steps:

[0135]

[0136] Step 1: Dissolve compound Int-1a (5.0 g, 28.09 mmol), Int-1b (5.61 g, 36.51 mmol) and sodium bicarbonate (7.08 g, 84.26 mmol) in ethanol (50 mL) and water (5 mL), and heat the reaction solution under reflux overnight. After the reaction is completed by LCMS monitoring, cool to room temperature, filter, wash the filter cake with water, and then dry to obtain an off-white solid Int-1 (5.0 g, yield 78%). ESI-MS (m / z): 227.4 [M+H] + .

[0137] Intermediate 2

[0138]

[0139] Intermediate 2 was prepared by the following steps:

[0140]

[0141] Step 1: Add sodium hydrogen (1.59 g, 39.64 mmol, content 60%) to a two-necked flask filled with anhydrous tetrahydrofuran (10 mL), place in an ice-water bath, dissolve compound Int-2a (5.0 g, 26.43 mmol) in anhydrous tetrahydrofuran (30 mL), and slowly add it dropwise to the reaction solution. After 30 minutes, deuterated iodomethane (4.02 g, 27.75 mmol) was added dropwise, and after the addition was completed, the temperature was slowly raised to room temperature and stirred overnight. After the reaction was completed by LCMS monitoring, it was cooled to 0°C, and a 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 a yellow oil Int-2b (5.0 g, yield 91%). ESI-MS (m / z): 207.2 [M+H] + .

[0142] Step 2: Int-2b (5.0 g, 24.24 mmol) was dissolved in methanol (50 mL), placed in an ice-water bath, and thionyl chloride (8.65 g, 72.73 mmol) was slowly added dropwise. After the addition was completed, the temperature was raised to room temperature, and then raised to 60°C for overnight reaction. After the reaction was completed by LCMS monitoring, the reaction solution was concentrated to obtain a yellow oil Int-2c (3.0 g, yield 79%). ESI-MS (m / z): 157.2 [M+H] + .

[0143] Step 3: Compound Int-1a (2.0 g, 11.23 mmol), Int-2c (3.17 g, 20.22 mmol) and sodium bicarbonate (2.83 g, 33.70 mmol) were dissolved in ethanol (20 mL) and water (2 mL), and the reaction solution was refluxed overnight. After the reaction was completed by LCMS monitoring, it was cooled to room temperature, filtered, the filter cake was washed with water, and then dried to obtain an off-white solid Int-2 (1.4 g, yield 54%). ESI-MS (m / z): 230.3 [M+H] + .

[0144] Intermediate 3

[0145]

[0146] Intermediate 3 was prepared by the following steps:

[0147]

[0148] Step 1: Dissolve compound Int-3a (10.17 g, 55.26 mmol) in ethanol (50 mL), add hydrazine salt Int-3b (5.0 g, 46.05 mmol) at room temperature, and reflux overnight. After the reaction is completed by LCMS monitoring, ethanol is removed by distillation under reduced pressure, and then water and ethyl acetate are added for extraction. The organic phases are combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phases are concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain a white solid Int-3c (4.0 g, yield 45%). ESI-MS (m / z): 193.2 [M+H] + .

[0149] Step 2: Add compound Int-3c (1.0 g, 5.20 mmol), Int-3d (669 mg, 5.73 mmol) and cesium carbonate (2.55 g, 7.81 mmol) to N, N-dimethylformamide (10 mL), react at 80 ° C for 5 hours, and monitor the reaction completion by LCMS. Remove N, N-dimethylformamide by distillation under reduced pressure, then add water and ethyl acetate for extraction, combine the organic phases and wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate the organic phase under reduced pressure to obtain a brown solid Int-3e (1.1 g, yield 71%). ESI-MS (m / z): 295.2 [M+H] + .

[0150] Step 3: Dissolve compound Int-3e (1.1 g, 3.74 mmol) in methanol (10 mL), add ammonia water (1 mL) and Raney nickel (3 mL suspension) to the reaction system in sequence, replace hydrogen with a hydrogen balloon and react for 16 hours under a hydrogen atmosphere at room temperature, and monitor the reaction by LCMS. The reaction solution was diluted with methanol, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol = 9: 1) to obtain a brown oily liquid Int-3 (700 mg, yield 62%). ESI-MS (m / z): 299.3 [M+H] + .

[0151] Intermediate 4

[0152]

[0153] Intermediate 4 was prepared by the following steps:

[0154]

[0155] Step 1: Dissolve compound Int-3a (1.0 g, 5.43 mmol) in ethanol (20 mL), add hydrazine salt Int-4a (979 mg, 6.52 mmol) at room temperature, and reflux overnight. After the reaction is completed by LCMS monitoring, remove ethanol by distillation under reduced pressure, add water and ethyl acetate for extraction, combine the organic phases and wash with saturated brine, dry over anhydrous sodium sulfate, concentrate the organic phase under reduced pressure and purify by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain a white solid Int-4b (909 mg, yield 93%). ESI-MS (m / z): 181.4 [M+H] + .

[0156] Step 2: Add compound Int-4b (606 mg, 3.36 mmol), Int-3d (411 mg, 3.36 mmol) and cesium carbonate (2.19 g, 6.73 mmol) to N, N-dimethylformamide (16 mL), react at 80 ° C for 5 hours, and monitor the reaction completion by LCMS. Remove N, N-dimethylformamide by distillation under reduced pressure, then add water and ethyl acetate for extraction, combine the organic phases and wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate the organic phase under reduced pressure to obtain a brown solid Int-4c (897 mg, yield 94%). ESI-MS (m / z): 283.3 [M+H] + .

[0157] 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 hydrogen with a hydrogen balloon and react for 3 hours under a hydrogen atmosphere at room temperature, and monitor the reaction by LCMS. The reaction solution was diluted with methanol, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol = 9: 1) to obtain a brown oily liquid Int-4 (412 mg, yield 45%). ESI-MS (m / z): 328.3 [M+CH3CN+H] + .

[0158] Intermediate 5b

[0159]

[0160] Intermediate 5b was prepared by the following steps:

[0161]

[0162] Step 1: Step 2: Add compound Int-5a (3.0 g, 19.73 mmol), Int-3d (2.41 g, 19.73 mmol) and cesium carbonate (12.85 g, 39.45 mmol) to acetonitrile (30 mL), stir at room temperature for 16 hours, and monitor the reaction completion by LCMS. Remove acetonitrile by distillation under reduced pressure, extract with water and ethyl acetate to the residue, combine the organic phases and wash with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate. The residue is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain a white solid Int-5b (2.17 g, yield 43%). ESI-MS (m / z): 255.2 [M+H] + .

[0163] Intermediate 6

[0164]

[0165] Intermediate 6 was prepared by the following steps:

[0166]

[0167] Step 1: Add sodium hydroxide (153 mg, 4.0 mmol, content 60%) to a two-necked flask filled with anhydrous tetrahydrofuran (5 mL), place in an ice-water bath, dissolve compound Int-2a (500 mg, 2.09 mmol) in anhydrous tetrahydrofuran (10 mL), and slowly drop it into the reaction solution. After 30 minutes, iodomethane (593 mg, 4.18 mmol) was added dropwise, and after the addition was completed, the temperature was slowly raised to room temperature and stirred overnight. After the reaction was completed by LCMS monitoring, it was cooled to 0 ° C, and a saturated aqueous solution of ammonium chloride was slowly added dropwise to quench the reaction, extracted with ethyl acetate, and the organic phase was dried to obtain a yellow solid Int-6b (500 mg, yield 94%). ESI-MS (m / z): 252.2 [MH] - .

[0168] Step 2: Int-6b (500 mg, 1.97 mmol) was dissolved in methanol (50 mL), placed in an ice-water bath, and thionyl chloride (704 mg, 5.92 mmol) was slowly added dropwise. After the addition was completed, the temperature was raised to room temperature, and then raised to 60°C to react overnight. After the reaction was completed by LCMS monitoring, the reaction solution was concentrated to obtain a 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).

[0169] Step 3: Dissolve compound Int-1a (250 mg, 1.40 mmol), Int-6c (343 mg, 1.69 mmol) and sodium bicarbonate (353 mg, 4.21 mmol) in ethanol (20 mL) and water (2 mL), and reflux the reaction solution overnight. After the reaction is completed by LCMS monitoring, cool to room temperature, filter, wash the filter cake with water, and then dry to obtain an off-white solid Int-6 (170 mg, yield 43%). ESI-MS (m / z): 277.2 [M+H] + .

[0170] Intermediate 7

[0171]

[0172] Intermediate 7 was prepared by the following steps:

[0173]

[0174] Step 1: Add compound Int-5b (400 mg, 1.57 mmol) and cesium carbonate (1.03 g, 3.15 mmol) to N, N-dimethylformamide (8 mL), and then add 1,1-difluoro-2-iodoethane (0.56 mL, 6.28 mmol) dropwise to the reaction solution. 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, and ethyl acetate was extracted. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phases were concentrated under reduced pressure to obtain a mixture of Int-7a and Int-7a'. ESI-MS (m / z): 319.1 [M+H] + .

[0175] Step 2: The product of the first step was dissolved in methanol (50 mL), and aqueous ammonia (5 mL) and Raney nickel suspension (5 mL) were added to the reaction system in sequence. The hydrogen was replaced by a hydrogen balloon and reacted for 2 hours under a hydrogen atmosphere at room temperature. The reaction was monitored by LCMS to be complete. 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 = 20: 1) to obtain a brown oily liquid Int-7 (145 mg, two-step yield 29%). ESI-MS (m / z): 323.3 [M+H] + .

[0176] Intermediate 8

[0177]

[0178] Intermediate 8 was prepared by the following steps:

[0179]

[0180] Step 1: Add compound Int-8a (2.0 g, 12.26 mmol) and Na2CO3 (2.6 g, 24.52 mmol) to water (60 mL), stir to dissolve, add iodine (3.11 g, 12.26 mmol) to the reaction solution, and stir at room temperature for 3 hours. LCMS monitors the disappearance of the raw material, adjust the pH of the reaction solution to 5-6 with dilute hydrochloric acid, and extract with ethyl acetate. Combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate, and chromatograph the residue on a silica gel column (ethyl acetate / petroleum ether = 0-30% gradient elution) to obtain a white solid Int-8b (1.5 g, yield 42%). ESI-MS (m / z): 290.2 [M+H] + .

[0181] Step 2: Dissolve compound Int-8b (0.5 g, 1.73 mmol) and benzyl bromide (337 mg, 1.98 mmol) in DMF (5 mL), add K2CO3 (364 mg, 2.64 mmol), stir at 50°C for 2 hours, and monitor the completion of translation by LCMS. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on a silica gel column (ethyl acetate / petroleum ether = 0-15% gradient elution) to obtain a white solid Int-8c (0.5 g, yield 76%). ESI-MS (m / z): 380.2 [M+H] + .

[0182] Step 3: Add compound Int-8c (500 mg, 1.32 mmol), cyclopropylboronic acid (566 mg, 6.59 mmol), tricyclohexylphosphine (74 mg, 263 umol), palladium acetate (29 mg, 131 umol), potassium phosphate (559 mg, 2.63 mmol) to dioxane (30 mL) and water (3 mL). After the reaction system is replaced with nitrogen, it is stirred at 90 ° C for 17 hours under nitrogen atmosphere protection. LCMS monitors the reaction to be complete. The reaction solution is concentrated and the residue is purified by silica gel column chromatography (ethyl acetate / petroleum ether=0-15% gradient elution) to obtain a white solid Int-8d (250 mg, yield 64%). ESI-MS (m / z): 294.3 [M+H] + .

[0183] Step 4: Dissolve compound Int-8d (250 mg, 0.85 mmol) in dichloromethane (20 mL), cool to -78 ° C, add BBr3 (0.25 mL) dropwise, keep the reaction mixture at -78 ° C and stir for 1 hour, then add water to quench, and warm to room temperature. Extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate. The residue is chromatographed on a silica gel column (ethyl acetate / petroleum ether = 0-15% gradient elution) to obtain a white solid Int-8e (172 mg, yield 100%). ESI-MS (m / z): 204.5 [M+H] + .

[0184] Step 5: Add compound Int-8e (172 mg, 0.85 mmol), Int-3d (144 mg, 1.18 mmol), Cs2CO3 (0.64 g, 2.0 mmol) to DMF (5 mL), stir at 20°C for 17 hours, and monitor the reaction until complete by LCMS. Add the reaction solution to water (100 mL), stir for 30 minutes, and filter to obtain yellow solid Int-8f (170 mg, yield 65%). ESI-MS (m / z): 306.2 [M+H] + .

[0185] Step 6: Add compound Int-8f (90 mg, 295 umol) and Raney nickel (0.5 mL, aqueous suspension) to methanol (5 mL), add ammonia water (0.1 ml), replace hydrogen in the reaction system and stir at room temperature for 2 hours under a hydrogen atmosphere. LCMS monitors the reaction to be complete. The reaction solution is filtered with diatomaceous earth, and the filtrate is concentrated to obtain a yellow solid Int-8 (85 mg), which is directly used in the next step without purification. ESI-MS (m / z): 310.3 [M+H] + .

[0186] Intermediate 9

[0187]

[0188] Intermediate 9 was prepared by the following steps:

[0189]

[0190] Step 1: Dissolve compound Int-3a (1.84 g, 10 mmol) in ethanol (20 mL), add hydrazine salt Int-9a (1.25 g, 10 mmol) at room temperature, and reflux overnight. After the reaction is completed by LCMS monitoring, remove ethanol by distillation under reduced pressure, add water and ethyl acetate for extraction, combine the organic phases and wash with saturated brine, dry over anhydrous sodium sulfate, concentrate the organic phase under reduced pressure and purify by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain a white solid Int-9b (2.0 g, yield 97%). ESI-MS (m / z): 209.4 [M+H] + .

[0191] Step 2: Dissolve compound Int-9b (2.0 g, 9.61 mmol) and compound Int-3d (1.17 g, 9.61 mmol) in N, N-dimethylformamide (10 ml), and add cesium carbonate (6.26 g, 19.21 mmol). The reaction was stirred at room temperature for 4 hours. LCMS monitored the completion of the reaction. The reaction solution was diluted with water, the obtained suspension was filtered, and the filter cake was dried by a reduced pressure rotary evaporator to obtain a brown solid compound Int-9c (1.78 g, yield 59%). ESI-MS (m / z): 311.1 [M+H] + .

[0192] Step 3: Dissolve compound Int-9c (1.78 g, 5.74 mmol) in methanol (20 mL) and ammonia water (1 mL), and add Raney Nickel (0.5 mL, water suspension). After replacing hydrogen in the reaction system, stir at room temperature for 12 hours. The reaction solution is filtered through diatomaceous earth and the filtrate is concentrated. The residue is purified by silica gel column chromatography (dichloromethane / methanol=10 / 1) to obtain a colorless oily liquid Int-9 (1.3 g, yield 72%). ESI-MS (m / z): 315.3 [M+H] + .

[0193] Intermediate 10

[0194]

[0195] Intermediate 10 is prepared by the following steps:

[0196]

[0197] Step 1: Under nitrogen atmosphere, compound Int-5b (500 mg, 1.97 mmol) and cesium carbonate (1.28 g, 3.93 mmol) were added to N, N-dimethylformamide (10 mL), and then 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.58 mL, 3.93 mmol) was added dropwise to the reaction solution. After the reaction solution was stirred at room temperature for 16 hours, LCMS monitored the completion of the reaction, and water was added to quench the reaction. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phases were concentrated under reduced pressure to obtain a mixture of compounds Int-10a and Int-10a'. ESI-MS (m / z): 328.5 [M+H] + .

[0198] Step 2: The product of the first step was dissolved in methanol (60 mL), and aqueous ammonia (6 mL) and Raney nickel suspension (6 mL) were added to the reaction system in sequence. The hydrogen was replaced by a hydrogen balloon and reacted for 2 hours under a hydrogen atmosphere and room temperature. The reaction was completed by LCMS monitoring. 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 = 20: 1) to obtain a brown oily liquid Int-10 (287 mg, two-step yield 43%). ESI-MS (m / z): 382.3 [M+CH3CN+H] + .

[0199] Intermediate 11

[0200]

[0201] Intermediate 11 was prepared by the following steps:

[0202]

[0203] Step 1: Add compound Int-5b (400 mg, 1.57 mmol) and cesium carbonate (1.03 g, 3.15 mmol) to N, N-dimethylformamide (8 mL), and then add 1-fluoro-2-iodoethane (548 mg, 3.15 mmol) dropwise to the reaction solution. After the reaction solution was stirred at room temperature for 16 hours, LCMS monitored the completion of the reaction, and water was added to quench the reaction. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phases were concentrated under reduced pressure to obtain a mixture of compounds Int-11a and Int-11a'. ESI-MS (m / z): 301.2 [M+H] + .

[0204] Step 2: The product of the first step was dissolved in methanol (50 mL), and aqueous ammonia (5 mL) and Raney nickel suspension (5 mL) were added to the reaction system in sequence. The hydrogen was replaced by a hydrogen balloon and reacted for 2 hours under a hydrogen atmosphere at room temperature. The reaction was monitored by LCMS to be complete. 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 = 20: 1) to obtain a brown oily liquid Int-11 (228 mg, two-step yield 48%). ESI-MS (m / z): 305.1 [M+H] + .

[0205] Intermediate 12

[0206]

[0207] Intermediate 12 was prepared by the following steps:

[0208]

[0209] Step 1: Dissolve compound Int-3d (120 mg, 0.1 mmol) and compound Int-12a (200 mg, 0.1 mmol) in N, N-dimethylformamide (5 mL) and add cesium carbonate (383 mg, 1.2 mmol). The reaction was stirred at room temperature for 4 hours. LCMS monitored the complete reaction of the raw materials. Water was added to dilute the reaction solution, the obtained suspension was filtered, and the filter cake was dried under reduced pressure to obtain a white solid Int-12b (265 mg, yield 88%). ESI-MS (m / z): 307.1 [M+H] + .

[0210] 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 cuprous iodide (373 mg, 2 mmol). The reaction was stirred at 130 ° C for 13 hours. LCMS monitored the complete reaction of the raw materials. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and 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] + .

[0211] Step 3: Dissolve compound Int-12c (140 mg, 0.48 mmol) in methanol (9 mL) and ammonia water (1 mL), add Raney Nickel (1 mL, water suspension), replace hydrogen in the reaction system 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 = 10 / 1) to obtain a colorless oily liquid Int-12 (80 mg, yield 57%). ESI-MS (m / z): 300.2 [M+H] + .

[0212] Intermediate 13

[0213]

[0214] Intermediate 13 was prepared by the following steps:

[0215]

[0216] Step 1: Add compound Int-13a (700 mg, 3.54 mmol), Int-3d (433 mg, 3.54 mmol) and cesium carbonate (2.31 g, 7.09 mmol) to N, N-dimethylformamide (10 mL), react at 50°C for 16 hours, and monitor the reaction completion by LCMS. Remove N, N-dimethylformamide by distillation under reduced pressure, then add water and ethyl acetate for extraction, combine the organic phases and wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate the organic phase under reduced pressure to obtain Int-13b (711 mg, yield 67%) as a white solid.

[0217] Step 2: Dissolve compound Int-13b (355 mg, 1.18 mmol) in methanol (35 mL), add ammonia water (3.5 mL) () and Raney nickel (3.5 mL suspension) to the reaction system in sequence, replace hydrogen with a hydrogen balloon and react for 3 hours under a hydrogen atmosphere and room temperature. LCMS monitors the completion of the reaction. The reaction solution is diluted with methanol, filtered, and the filtrate is concentrated and purified by silica gel column chromatography (dichloromethane: methanol = 9: 1) to obtain a brown oily liquid Int-13 (199 mg, yield 55%). ESI-MS (m / z): 304.2 [M+H] + .

[0218] Intermediate 14

[0219]

[0220] Intermediate 14 was prepared by the following steps:

[0221]

[0222] 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 overnight. After the reaction is completed by LCMS monitoring, remove ethanol by distillation under reduced pressure, add water and ethyl acetate for extraction, combine the organic phases and wash with saturated brine, dry over anhydrous sodium sulfate, concentrate the organic phase under reduced pressure and purify by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain yellow solid Int-14b (300 mg, yield 67%). ESI-MS (m / z): 219.2 [M+H] + .

[0223] Step 2: Add compound Int-14b (300 mg, 1.38 mmol), Int-3d (184 mg, 1.51 mmol) and cesium carbonate (672 mg, 2.06 mmol) to acetonitrile (5 mL), react at 80 ° C for 5 hours, and monitor the reaction completion by LCMS. Remove acetonitrile by distillation under reduced pressure, then add water and ethyl acetate for extraction, combine the organic phases and wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate the organic phase under reduced pressure to obtain a brown solid Int-14c (250 mg, yield 56%). ESI-MS (m / z): 321.2 [M+H] + .

[0224] 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 hydrogen with a hydrogen balloon and react for 16 hours under a hydrogen atmosphere at room temperature, and monitor the reaction by LCMS. The reaction solution was diluted with methanol, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol = 9: 1) to obtain a brown oily liquid Int-14 (150 mg, yield 59%). ESI-MS (m / z): 325.3 [M+H] + .

[0225] Intermediate 15

[0226]

[0227] Intermediate 15 was prepared by the following steps:

[0228]

[0229] Step 1: Add compound Int-15a (500 mg, 4.23 mmol), N-bromosuccinimide (829 mg, 4.66 mmol) and azobisisobutyronitrile (209 mg, 1.27 mmol) to 1,2-dichloroethane (10 mL). The reaction was stirred for 16 hours under a nitrogen atmosphere at 85 ° C. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain a yellow oily liquid Int-15b (244 mg, yield 29%).

[0230] Step 2: Compound Int-15c (200 mg, 0.98 mmol), Int-15b (290 mg, 1.47 mmol) and cesium carbonate (639 mg, 1.96 mmol) were added to N, N-dimethylformamide (6 mL). The reaction solution was stirred at room temperature for 16 hours. After the reaction was completed by LCMS monitoring, 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 and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain a white solid Int-15d (213 mg, yield 68%).

[0231] Step 3: Dissolve compound Int-15d (213 mg, 0.67 mmol) in methanol (22 mL), add ammonia (2.2 mL) and Raney nickel (2.2 mL, water suspension) to the reaction system in sequence, replace hydrogen with a hydrogen balloon and react for 16 hours under a hydrogen atmosphere at room temperature, and monitor the reaction by LCMS. The reaction solution is diluted with methanol, filtered, and the filtrate is concentrated to obtain the crude product Int-15. ESI-MS (m / z): 325.2 [M+H] + .

[0232] Intermediate 16

[0233]

[0234] Intermediate 16 was prepared by the following steps:

[0235]

[0236] Step 1: Compound Int-16a (1.00 g, 11.89 mmol), Int-16b (3.38 g, 23.78 mmol) and sodium ethoxide (1.62 g, 23.78 mmol) were added to dimethyl sulfoxide (10 mL) in sequence. The reaction solution was stirred at 60 ° C for 16 hours. After the reaction was completed, 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 the crude product Int-16c.

[0237] Step 2: Add compound Int-16c (1.94 g), hydrazine hydrate (673 mg, 10.75 mmol, 80%) and acetic acid (5 mL) to methanol (35 mL), and reflux the reaction solution under nitrogen atmosphere for 16 hours. After the reaction is completed, the solvent is removed by distillation under reduced pressure, and then water is added to dilute and sodium carbonate (solid) is added to pH 9, extracted with ethyl acetate, the organic phases are combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase is concentrated under reduced pressure to obtain a brown solid Int-16d (1.73 g, two-step yield 82%). ESI-MS (m / z): 177.5 [M+H] + .

[0238] Step 3: Compound Int-16d (200 mg, 1.14 mmol), Int-15b (336 mg, 1.70 mmol) and potassium carbonate (314 mg, 2.27 mmol) were added to acetonitrile (10 mL). The reaction solution was stirred at 80°C for 16 hours. After the reaction was completed by LCMS monitoring, 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 phases were concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain oily liquid Int-16e (250 mg, yield 75%) and oily liquid Int-16e' (80 mg, yield 24%). ESI-MS (m / z): 293.2 [M+H] + .

[0239] Step 4: Dissolve compound Int-16e (228 mg, 0.78 mmol) in methanol (23 mL), add ammonia (2.3 mL) and Raney nickel (2.3 mL, water suspension) to the reaction system in sequence, replace hydrogen with a hydrogen balloon and react for 3 hours under a hydrogen atmosphere at room temperature, and monitor the reaction by LCMS. The reaction solution is diluted with methanol, filtered, and the filtrate is concentrated to obtain the crude product Int-16. ESI-MS (m / z): 297.3 [M+H] + .

[0240] Intermediate 17

[0241]

[0242] Intermediate 17 was prepared by the following steps:

[0243]

[0244] Step 1: Dissolve compound Int-16e' (80 mg, 0.27 mmol) in methanol (8 mL), add ammonia (0.8 mL) and Raney nickel (0.8 mL, water suspension) to the reaction system in sequence, replace hydrogen with a hydrogen balloon and react for 3 hours under a hydrogen atmosphere at room temperature. LCMS monitors the completion of the reaction. The reaction solution is diluted with methanol, filtered, and the filtrate is concentrated to obtain the crude product Int-17. ESI-MS (m / z): 297.2 [M+H] + .

[0245] Intermediate 18

[0246]

[0247] Intermediate 18 was prepared by the following steps:

[0248]

[0249] Step 1: Dissolve compound Int-18a (2.03 g, 10 mmol) in anhydrous dimethyl sulfoxide (10 mL), add potassium hydroxide (1.68 g, 30 mmol) and deuterated iodomethane (2.17 g, 15 mmol). The reaction solution was stirred at room temperature for 12 hours. LCMS detected that the reaction was complete. The reaction solution was quenched with water, 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 a crude product of compound Int-18b (2.3 g). ESI-MS (m / z): 238.3 [M+H] + .

[0250] Step 2: Dissolve compound Int-18b (2.3 g, 10 mmol) in dioxane hydrochloride solution (5 mL, 4 M). The reaction solution was stirred at room temperature for 1 hour. LCMS detected the end of the reaction. The reaction solution was concentrated, and the residue was adjusted to a weakly alkaline pH with a saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the organic phases were combined and washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product of compound Int-18c (1.3 g).

[0251] Step 3: Dissolve compound Int-18c (450 mg, 3 mmol) and Int-18d (539 mg, 3 mmol) in tetrahydrofuran (3 mL), and add N,N-diisopropylethylamine (1 g, 7.78 mmol). The reaction solution was stirred at room temperature for 4 hours. LCMS detected that the reaction was complete. 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 residual liquid 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] + .

[0252] 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. Then, aqueous hydrochloric acid solution (2 mL, 4 M) was added. The reaction solution continued to stir at room temperature for 8 hours. LCMS detected that the reaction was complete. The reaction solution was adjusted to pH 9 with ammonia methanol solution, diluted with water, extracted with dichloromethane, the organic phases were combined and washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residual liquid was purified by silica gel column chromatography (dichloromethane / methanol=20 / 1) to obtain compound Int-18 (230 mg, yield 60%). ESI-MS (m / z): 244.4 [M+H] + .

[0253] The synthesis method of the embodiment compounds of the present invention is as follows:

[0254] Example 1

[0255] (S)-2-(((6-((1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxy)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

[0256]

[0257] Example 1 was prepared by the following steps:

[0258]

[0259] Step 1: Dissolve compound Int-1 (1.0 g, 4.41 mmol) and compound Int-3 (1.71 g, 5.74 mmol) in n-butanol (6 mL), add p-toluenesulfonic acid monohydrate (83 mg, 0.44 mmol), and stir the reaction solution at 160°C for 4 hours under microwave conditions. After the reaction solution is cooled to room temperature, the reaction solution is concentrated under reduced pressure, and the residue is 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) δ9.83 (s, 1H), 8.16 (d, J=2.4Hz, 1H), 7.91 (dd, J=8.5, 2.4H z, 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).

[0260] Example 2

[0261] (S)-2-(((6-((1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxy)pyridin-3-yl)methyl)amino)-4,7-dimethyl-8-(methyl-d3)-7,8-dihydropteridin-6(5H)-one

[0262]

[0263] Example 2 was prepared by the following steps:

[0264]

[0265] Step 1: Dissolve compound Int-2 (50 mg, 0.22 mmol) and compound Int-3 (84 mg, 0.28 mmol) in n-butanol (2 mL), add p-toluenesulfonic acid monohydrate (4 mg, 0.02 mmol), and stir the reaction solution at 160°C for 3 hours under microwave conditions. After the reaction solution is cooled to room temperature, the reaction solution is concentrated under reduced pressure, and the residue is purified by reverse preparative HPLC to obtain a white solid 2 (36 mg, yield 34%). ESI-MS (m / z): 492.2 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.86 (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).

[0266] Example 3

[0267] (S)-2-(((6-((1-(ethyl-d5)-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxy)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

[0268]

[0269] Example 3'

[0270] (S)-2-(((6-((1-(ethyl-d5)-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

[0271]

[0272] Examples 3 and 3' were prepared by the following steps:

[0273]

[0274] Step 1: Dissolve compound Int-5b (500 mg, 1.97 mmol) in N, N-dimethylformamide (10 mL), then add cesium carbonate (1.28 g, 3.93 mmol) and deuterated iodoethane (633 mg, 3.93 mmol). The reaction solution was stirred at room temperature for 4 hours. LCMS monitored the completion of the reaction. The reaction solution was diluted with a saturated sodium chloride aqueous solution and extracted with ethyl acetate. The organic phase was washed with a 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] + .

[0275] Step 2: The products 3a and 3a' obtained in the previous step were dissolved in methanol (15 mL) and ammonia water (1 mL), and RaneyNickel (1 mL, aqueous suspension) was added. 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 = 5 / 1) to obtain a colorless oily liquid 3b (186 mg, yield 33%), ESI-MS (m / z): 292.2 [M+H] + ; and colorless oily liquid 3b' (182 mg, yield 32%), ESI-MS (m / z): 292.2 [M+H] + .

[0276] Step 3: Compound 3b (60 mg, 0.21 mmol) was dissolved in n-butanol (3 mL), and compound Int-1 (31 mg, 0.14 mmol) and p-toluenesulfonic acid monohydrate (3 mg, 0.02 mmol) were added. 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 3 (29 mg, yield 29%). ESI-MS (m / z): 482.1 [M+H] + ; 1 H NMR (500MHz, DMSO) δ9.84 (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=5.8 Hz, 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).

[0277] Step 4: Starting from compound 3b' (60 mg, 0.21 mmol), a white solid 3' (20 mg, yield 18%) was obtained using a method similar to step 3. ESI-MS (m / z): 482.2 [M+H] + ; 1 H NMR (500MHz, DMSO) δ9.83 (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=5.8 Hz, 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).

[0278] Example 4

[0279] (S)-2-(((6-((1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxy)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

[0280]

[0281] Embodiment 4 '

[0282] (S)-2-(((6-((1-isopropyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

[0283]

[0284] Examples 4 and 4' were prepared by the following steps:

[0285]

[0286] Step 1: Dissolve compound Int-5b (200 mg, 0.79 mmol) in N, N-dimethylformamide (5 mL), then add cesium carbonate (513 mg, 1.57 mmol) and 2-iodopropane (268 mg, 1.57 mmol). The reaction solution was stirred at room temperature for 4 hours. LCMS monitored the completion of the reaction. The reaction solution was diluted with a saturated sodium chloride aqueous solution and extracted with ethyl acetate. The organic phase was washed with a 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] + .

[0287] Step 2: The products 4a and 4a' obtained in the previous step were dissolved in methanol (9 mL) and ammonia water (1 mL), and RaneyNickel (0.5 mL, aqueous suspension) was added. 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 = 5 / 1) to obtain a colorless oily liquid 4b (62 mg, yield 26%), ESI-MS (m / z): 301.3 [M+H] + and colorless oily liquid 4b' (60 mg, yield 25%), ESI-MS (m / z): 301.3 [M+H] + .

[0288] Step 3: Compound 4b (62 mg, 0.21 mmol) was dissolved in n-butanol (3 mL), and compound Int-1 (31 mg, 0.14 mmol) and p-toluenesulfonic acid monohydrate (3 mg, 0.02 mmol) were added. 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 4 (13 mg, yield 13%). ESI-MS (m / z): 491.2 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.83 (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).

[0289] Step 4: Starting from compound 4b' (60 mg, 0.21 mmol), a white solid 4' (5 mg, yield 5%) can be obtained using a method similar to step 3. ESI-MS (m / z): 491.1 [M+H] + ; 1H NMR (500MHz, DMSO-d6) δ9.85 (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=1 3.0, 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=6.8Hz, 3H).

[0290] Example 5

[0291] (S)-2-(((6-((1-(tert-butyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxy)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

[0292]

[0293] Example 5 was prepared by the following steps:

[0294]

[0295] Step 1: Dissolve compound Int-9 (100 mg, 0.32 mmol) and compound Int-1 (48 mg, 0.21 mmol) in n-butanol (3 mL), add p-toluenesulfonic acid monohydrate (6 mg, 0.03 mmol), and stir the reaction solution at 160°C for 3 hours under microwave conditions. After the reaction solution is cooled to room temperature, the reaction solution is concentrated under reduced pressure, and the residue is purified by reverse preparative HPLC to obtain a white solid 5 (20 mg, yield 13%). ESI-MS (m / z): 505.1 [M+H] + ; 1 H NMR (500MHz, DMSO) δ9.85 (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).

[0296] Example 6

[0297] (S)-2-(((6-((1-(2-fluoroethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxy)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

[0298]

[0299] Example 6 was prepared by the following steps:

[0300]

[0301] Step 1: Dissolve the intermediate Int-1 (37 mg, 0.16 mmol), the intermediate Int-11 (55 mg, 0.18 mmol) and trifluoroacetic acid (2 mg, 0.02 mmol) in n-butanol (2 mL) and react under microwave conditions at 160 ° C for 4 hours. LCMS monitoring of the reaction was completed. The reaction solution was purified by reverse phase preparative HPLC to obtain a white solid 6 (21 mg, yield 26%). ESI-MS (m / z): 495.2 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.93 (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).

[0302] Example 7

[0303] (S)-4,7,8-trimethyl-2-(((6-((1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxy)pyridin-3-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

[0304]

[0305] Example 7 was prepared by the following steps:

[0306]

[0307] Step 1: Dissolve the intermediate Int-1 (39 mg, 0.17 mmol), the intermediate Int-10 (65 mg, 0.19 mmol) and trifluoroacetic acid (2 mg, 0.02 mmol) in n-butanol (2 mL) and react under microwave conditions at 160°C for 4 hours. The reaction was completed by LCMS monitoring. The reaction solution was purified by reverse phase preparative HPLC to obtain a white solid 7 (24 mg, yield 26%). ESI-MS (m / z): 503.9 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.85 (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, 1 H), 6.71 (s, 1H), 5.21 (q, J=9.0Hz, 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).

[0308] Example 8

[0309] (S)-2-(((6-((1-(2,2-difluoroethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxy)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

[0310]

[0311] Example 8 was prepared by the following steps:

[0312]

[0313] Step 1: Dissolve the intermediate Int-1 (38 mg, 0.17 mmol), the intermediate Int-7 (60 mg, 0.19 mmol) and trifluoroacetic acid (2 mg, 0.02 mmol) in n-butanol (2 mL) and react under microwave conditions at 160 ° C for 4 hours. LCMS monitoring of the reaction was completed. The reaction solution was purified by reverse phase preparative HPLC to obtain a white solid 8 (24 mg, yield 27%). ESI-MS (m / z): 513.9 [M+H] + ; 1H NMR (500MHz, DMSO-d6) δ9.78 (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, 2 H), 3.92 (q, J=6.7Hz, 1H), 2.84 (s, 3H), 2.05 (s, 3H), 1.11 (d, J=6.8Hz, 3H).

[0314] Example 9

[0315] (S)-2-(((6-((2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

[0316]

[0317] Example 9 was prepared by the following steps:

[0318]

[0319] Step 1: Dissolve the intermediate Int-1 (34 mg, 0.15 mmol), the intermediate Int-8 (51 mg, 0.16 mmol) and trifluoroacetic acid (2 mg, 0.02 mmol) in n-butanol (2 mL) and react under microwave conditions at 160 ° C for 4 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse phase preparative HPLC to obtain a white solid 9 (16 mg, yield 21%). ESI-MS (m / z): 500.0 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.82 (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).

[0320] Example 10

[0321] (S)-2-(((6-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,7-dimethyl-8-(methyl-d3)-7,8-dihydropteridin-6(5H)-one

[0322]

[0323] Example 10 was prepared by the following steps:

[0324]

[0325] Step 1: Dissolve intermediate Int-2 (50 mg, 0.22 mmol), intermediate Int-13 (85 mg, 0.28 mmol) and p-toluenesulfonic acid monohydrate (4 mg, 0.02 mmol) in n-butanol (2 mL) and react under microwave at 160 ° C for 3 hours. LCMS monitoring reaction 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) δ9.86 (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).

[0326] Embodiment 11

[0327] (S)-2-(((6-((2-methoxy-6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

[0328]

[0329] Example 11 was prepared by the following steps:

[0330]

[0331] Step 1: Dissolve compound Int-12 (100 mg, 0.34 mmol) and compound Int-1 (75 mg, 0.34 mmol) in n-butanol (3 mL), add p-toluenesulfonic acid monohydrate (6 mg, 0.03 mmol), and stir the reaction solution at 160°C for 3 hours under microwave conditions. After the reaction solution is cooled to room temperature, the reaction solution is concentrated under reduced pressure, and the residue is purified by reverse preparative HPLC to obtain a white solid 11 (80 mg, yield 48%). ESI-MS (m / z): 490.2 [M+H] + ; 1 H NMR (500MHz, DMSO) δ9.81 (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=8.4 Hz, 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).

[0332] Example 12

[0333] (S)-2-(((6-((1-(bicyclo[1.1.1]pentan-1-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxy)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

[0334]

[0335] Example 12 was prepared by the following steps:

[0336]

[0337] Step 1: Dissolve compound Int-1 (50 mg, 0.22 mmol) and compound Int-14 (93 mg, 0.29 mmol) in n-butanol (2 mL), add p-toluenesulfonic acid monohydrate (4 mg, 0.02 mmol), and stir the reaction solution at 160°C for 3 hours under microwave conditions. After the reaction solution is cooled to room temperature, the reaction solution is concentrated under reduced pressure, and the residue is purified by reverse preparative HPLC to obtain a white solid 12 (36 mg, yield 30%). ESI-MS (m / z): 515.2 [M+H] + ; 1H NMR (500MHz, DMSO-d6) δ9.82 (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).

[0338] Embodiment 13

[0339] (S)-2-(((6-((3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl)methyl)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

[0340]

[0341] Example 13 was prepared by the following steps:

[0342]

[0343] Step 1: Dissolve the intermediate Int-1 (40 mg, 0.18 mmol), the intermediate Int-15 (69 mg, 0.21 mmol) and trifluoroacetic acid (2 mg, 0.02 mmol) in n-butanol (2 mL) and react under microwave conditions at 160 ° C for 3 hours. LCMS monitoring of the reaction was completed. The reaction solution was purified by reverse phase preparative HPLC to obtain a white solid 13 (37 mg, yield 41%). ESI-MS (m / z): 515.2 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.81 (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).

[0344] Embodiment 14

[0345] (S)-2-(((6-((1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxy)pyridin-3-yl)methyl)amino)-4-methyl-6a,7,8,9-tetrahydropyrrolo[2,1-h]pteridin-6(5H)-one

[0346]

[0347] Example 14 was prepared by the following steps:

[0348]

[0349] Step 1: Compound Int-1a (500 mg, 2.81 mmol) and compound 14a (602 mg, 3.65 mmol) were dissolved in ethanol (20 mL) and water (2 mL), followed by the addition of sodium bicarbonate (707 mg, 8.34 mmol), 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] + .

[0350] Step 2: Compound 14b (42 mg, 0.17 mmol) and compound Int-3 (68 mg, 0.23 mmol) were dissolved in n-butanol (2 mL), p-toluenesulfonic acid monohydrate (3 mg, 0.01 mmol) was added, and 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 14 (15 mg, yield 17%). ESI-MS (m / z): 501.3 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.69 (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, 6.2H z, 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, 3 H), 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).

[0351] Embodiment 15

[0352] (S)-4,7,8-trimethyl-2-(((6-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyridin-3-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

[0353]

[0354] Example 15 was prepared by the following steps:

[0355]

[0356] Step 1: Ethyl formate (3.17 g, 42.73 mmol) and solid sodium ethoxide (3.49 g, 50.50 mmol) were added to dry tetrahydrofuran (140 mL) in sequence. Compound 15a (7 g, 38.85 mmol) was added at 5-10°C, and the reaction solution was heated to 50°C and stirred for 2 hours. The disappearance of the raw material was monitored by HPLC. Tetrahydrofuran was evaporated under reduced pressure to obtain a yellow oil 15b, which was used directly in the next step.

[0357] Step 2: Add 150 ml of anhydrous ethanol to the oily substance 15b obtained in the previous step, stir at room temperature to dissolve, add trifluoroacetamidine (4.35 g, 33.01 mmol, purity 85%) dropwise, keep stirring at 30°C for 5 hours, then raise the temperature to 80°C and continue stirring for 2 hours, and monitor the disappearance of the raw material by HPLC. After the reaction solution is cooled, about 100 ml of ethanol is evaporated under reduced pressure, and the remaining residue is added to 300 ml of ice water, and the pH is adjusted to 3 with concentrated hydrochloric acid, stirred for 0.5 hours, filtered, and the filter cake is dried to obtain a yellow solid compound 15c (4.37 g, yield 41%, purity 99%). ESI-MS (m / z): 271.4 [M+H] + .

[0358] Step 3: Compound 15c (4.0 g, 14.80 mmol) was added to 60 ml of acetonitrile, and phosphorus oxychloride (6.81 g, 44.41 mmol) was added dropwise. After the addition was complete, the mixture was stirred for 10 minutes, heated to 80°C, and stirred for 2 hours. The conversion of the raw material was monitored by HPLC. The 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 to obtain a yellow solid 15d (3.9 g, yield 86%, purity 95%).

[0359] Step 4: Compound 15d (2.0 g, 6.93 mmol), trimethylcyclotriboroxane (2.61 g, 20.79 mmol), palladium acetate (155 mg, 0.69 mol), potassium phosphate (2.94 g, 13.86 mmol) were added to 1,4-dioxane (150 mL) in sequence, and water (15 mL) was added. Under nitrogen protection, the mixture was stirred at 90°C for 17 hours. HPLC monitored the complete conversion of the raw materials and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 9) to obtain a white solid 15e (1.86 g, yield 50%, purity 99%). ESI-MS (m / z): 269.1 [M+H] + .

[0360] Step 5: Compound 15e (1.0 g, 3.73 mmol) was added to 20 mL of methanol, and 10% palladium on carbon (100 mg) was added. The reaction system was replaced with hydrogen and stirred overnight at room temperature. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain compound 15f (630 mg, yield 92%, purity 97%). ESI-MS (m / z): 177.1 [MH] - .

[0361] Step 6: Compound 15f (0.5 g, 2.81 mmol), Cs2CO3 (1.83 g, 5.61 mmol), Int-3d (514 mg, 4.21 mmol) were added to N, N-dimethylformamide (10 mL) in sequence, stirred at 20°C overnight, and the raw materials disappeared after HPLC monitoring. The reaction solution was added to 50 ml of ice water, stirred for 0.5 hours, and filtered to obtain a yellow solid 15 g (510 mg, yield 64%, purity 99%). ESI-MS (m / z): 281.3 [M+H] + .

[0362] Step 7: Compound 15g (100 mg, 0.36 mmol) was dissolved in methanol (5 mL), added to aqueous ammonia (0.2 mL), added RaneyNickel (0.5 mL, aqueous suspension), and the reaction system was replaced with hydrogen and stirred at room temperature 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] + .

[0363] Step 8: Compound 15h (95 mg, 0.33 mmol) was dissolved in n-butanol (3 mL), and compound Int-1 (79 mg, 0.35 mmol) and p-toluenesulfonic acid monohydrate (3 mg, 0.02 mmol) were added. The reaction solution was stirred at 160°C for 3 hours under microwave conditions. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by reverse preparative HPLC to obtain a white solid 15 (31 mg, yield 21%, purity 99%). ESI-MS (m / z): 475.2 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.82 (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, 1 H), 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).

[0364] Example 16

[0365] (S)-2-(((6-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

[0366]

[0367] Example 16 was prepared by the following steps:

[0368]

[0369] Intermediate Int-1 (40 mg, 0.18 mmol), intermediate Int-16 (63 mg, 0.21 mmol) and trifluoroacetic acid (2 mg, 0.02 mmol) were dissolved in n-butanol (2 mL) and reacted under microwave conditions at 160 ° C for 3 hours. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse phase preparative HPLC to obtain a white solid 16 (33 mg, yield 38%). ESI-MS (m / z): 487.3 [M+H] + ; 1H NMR (500MHz, DMSO-d6) δ9.81 (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).

[0370] Embodiment 17

[0371] (S)-2-(((6-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

[0372]

[0373] Example 17 was prepared by the following steps:

[0374]

[0375] 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 reacted under microwave conditions at 160°C for 3 hours. The reaction was monitored by LCMS. The reaction solution was purified by reverse phase preparative HPLC to obtain a white solid 17 (15 mg, yield 20%). ESI-MS (m / z): 487.2 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.96 (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).

[0376] Embodiment 18

[0377] 2′-(((6-((1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxy)pyridin-3-yl)methyl)amino)-4′-methyl-8′-(methyl-d3)-5′,8′-dihydro-6′H-spiro[cyclopropane-1,7′-pteridine]-6′-one

[0378]

[0379] Example 18 was prepared by the following steps:

[0380]

[0381] Step 1: Dissolve compound 18a (1.01 g, 5 mmol) and potassium hydroxide (842 mg, 15 mmol) in anhydrous dimethyl sulfoxide (10 mL), and then add deuterated iodomethane (1.59 g, 11 mmol) dropwise to the reaction solution. The reaction solution was stirred at room temperature for 8 hours. LCMS monitored the end of the reaction. 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 a crude product of compound 18b (1.0 g, yield 84%). ESI-MS (m / z): 236.3 [M+H] + .

[0382] Step 2: Compound 18b (1.0 g) was dissolved in dioxane hydrochloride solution (4 M, 10 mL). The reaction mixture was stirred at room temperature for 4 hours. LCMS monitored the completion of the reaction. The reaction mixture was concentrated under reduced pressure to obtain a crude product of compound 18c (720 mg). ESI-MS (m / z): 136.1 [M+H] + .

[0383] Step 3: Dissolve compound 18c (720 mg) and compound 18d (872 mg, 4.19 mmol) in tetrahydrofuran (10 mL), add N, N-diisopropylamine (1.62 g, 12.57 mmol). The reaction solution was stirred at room temperature for 8 hours. LCMS monitored the completion of the reaction. The reaction solution was diluted with water, filtered, 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] + .

[0384] 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 that the raw material reaction was complete. Add dioxane hydrochloride solution (4 M, 1.25 mL) to the reaction solution. The reaction solution continued to stir at room temperature for 8 hours. Add ammonia methanol solution dropwise to the reaction solution, adjust the pH of the reaction solution to 10, concentrate the reaction solution under reduced pressure, and purify the residue 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] + .

[0385] Step 5: Int-3 (35 mg, 0.12 mmol) and compound 18e (28 mg, 0.12 mmol) were dissolved in n-butanol (3 mL), p-toluenesulfonic acid monohydrate (2 mg, 0.01 mmol) was added, and 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 18 (10 mg, yield 17%). ESI-MS (m / z): 504.3 [M+H] + ; 1 H NMR (500MHz, DMSO) δ8.14 (d, J=2.1Hz, 1H), 7.89 (dd, J=8.4, 2.3Hz, 1H), 7.2 0 (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).

[0386] Embodiment 19

[0387] (S)-2-(((6-((1-(3,3-difluorocyclobutyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxy)pyridin-3-yl)methyl)amino)-4,7-dimethyl-8-(methyl-d3)-7,8-dihydropteridin-6(5H)-one

[0388]

[0389] Example 19

[0390] (S)-2-(((6-((1-(3,3-difluorocyclobutyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,7-dimethyl-8-(methyl-d3)-7,8-dihydropteridin-6(5H)-one

[0391]

[0392] Examples 19 and 19' were prepared by the following steps:

[0393]

[0394] Step 1: In an ice bath, trifluoromethanesulfonic anhydride (1.25 g, 4.44 mmol) was added to a dichloromethane solution (10 mL) of compound 19a (400 mg, 3.70 mmol) and 4-dimethylaminopyridine (543 mg, 4.44 mmol). After reacting at room temperature for 16 hours, a saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phases were concentrated under reduced pressure to obtain a crude product of compound 19b, which was directly used in the next step.

[0395] 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 dropwise add crude compound 19b (284 mg) to the reaction solution. After the reaction solution was stirred at room temperature for 16 hours, the reaction was completed after LCMS monitoring, and water was added to quench the reaction. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phases were concentrated under reduced pressure to obtain a mixture of 19c and 19c' (170 mg, 84%). ESI-MS (m / z): 345.2 [M+H] + .

[0396] Step 3: The mixture of 19c and 19c' (283 mg, 0.82 mmol) was dissolved in methanol (30 mL), and aqueous ammonia (3 mL) and Raney nickel (3 mL, aqueous suspension) were added to the reaction system in sequence. The hydrogen was replaced by a hydrogen balloon and reacted under a hydrogen atmosphere at room temperature for 2 hours. The reaction was monitored by LCMS to complete. 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 for the next step. ESI-MS (m / z): 349.3 [M+H] + .

[0397] Step 4: Int-2 (80 mg, 0.35 mmol), a mixture of 19d and 19d' (146 mg, crude product) and p-toluenesulfonic acid monohydrate (4 mg, 0.03 mmol) were dissolved in n-butanol (2 mL) and reacted under microwave conditions at 160°C for 3 hours. The reaction was monitored by LCMS. The reaction solution was purified by reverse phase preparative HPLC to obtain white solids 19 (28 mg, yield 15%) and 19' (17 mg, yield 9%), respectively.

[0398] Example 19: ESI-MS (m / z): 542.3 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.82 (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=6.9Hz, 3H).

[0399] Example 19': ESI-MS (m / z): 542.2 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.82 (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).

[0400] Embodiment 20

[0401] (S)-2-(((6-((1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxy)pyridin-3-yl)methyl)amino)-7-(2,2-difluoroethyl)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

[0402]

[0403] Example 20 was prepared by the following steps:

[0404]

[0405] Step 1: Dissolve compound Int-6 (50 mg, 0.18 mmol) and compound Int-3 (70 mg, 0.23 mmol) in n-butanol (6 mL), add p-toluenesulfonic acid monohydrate (3 mg, 18 umol), and stir the reaction solution at 160°C for 3 hours under microwave conditions. After the reaction solution is cooled to room temperature, the reaction solution is concentrated under reduced pressure, and the residue is 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) δ8.16 (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).

[0406] Embodiment 21

[0407] (S)-2-(((6-((4-cyclopropyl-2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

[0408]

[0409] Example 21 was prepared by the following steps:

[0410]

[0411] Step 1: Compound 15d (550 mg, 1.91 mmol), cyclopropylboronic acid (818 mg, 9.53 mmol), palladium acetate (42 mg, 0.19 mmol), tricyclohexylphosphine (106 mg, 0.38 mmol) and potassium phosphate (1.21 g, 5.72 mmol) were added to a mixed solution of 1,4-dioxane (50 mL) and water (5 mL). After the reaction system was replaced with nitrogen, the mixture was reacted at 110° C. under a nitrogen atmosphere for 16 hours. The reaction was monitored by LCMS. The solvent 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 and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain a white solid 21a (530 mg, yield 94%). ESI-MS (m / z): 295.3 [M+H] + .

[0412] Step 2: Compound 21a (530 mg, 1.80 mmol) was dissolved in methanol (10 mL), palladium carbon (10%, 21 mg) was added to the reaction system, hydrogen was replaced by a hydrogen balloon and reacted for 16 hours under a hydrogen atmosphere at room temperature, and the reaction was completed by LCMS monitoring. The reaction solution was diluted with methanol, filtered, and the filtrate was concentrated to obtain a brown oily liquid 21b (330 mg, yield 89%). ESI-MS (m / z): 203.3 [MH] - .

[0413] Step 3: Compound 21b (330 mg, 1.62 mmol), Int-3d (236 mg, 1.94 mmol) and cesium carbonate (1.05 g, 3.23 mmol) were added to acetonitrile (10 mL) and reacted at room temperature for 16 hours. The reaction was monitored by LCMS. The 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 and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain a white solid 21c (450 mg, yield 90%). ESI-MS (m / z): 307.1 [M+H] + .

[0414] Step 4: Compound 21c (350 mg, 1.14 mmol) was dissolved in methanol (20 mL), and aqueous ammonia (3.5 mL) and Raney nickel (3.5 mL, aqueous suspension) were added to the reaction system in sequence. The hydrogen was replaced by a hydrogen balloon and reacted for 16 hours under a hydrogen atmosphere at room temperature. The reaction was monitored by LCMS. The reaction solution was diluted with methanol, filtered with diatomaceous earth, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol = 9: 1) to obtain a yellow oily liquid 21d (300 mg, yield 84%). ESI-MS (m / z): 311.2 [M+H] + .

[0415] Step 5: Compound Int-1 (50 mg, 0.22 mmol) and compound 21d (82.13 mg, 0.26 mmol) were dissolved in n-butanol (2 mL), p-toluenesulfonic acid monohydrate (4.19 mg, 22 umol) was added, and 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 21 (48.18 mg, yield 43%). ESI-MS (m / z): 501.3 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.87 (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, 1 H), 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).

[0416] Embodiment 22

[0417] 2-(((6-((1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxy)pyridin-3-yl)methyl)amino)-4,7,7-trimethyl-8-(methyl-d3)-7,8-dihydropteridin-6(5H)-one

[0418]

[0419] Example 22 was prepared by the following steps:

[0420]

[0421] Step 1: Dissolve compound Int-18 (50 mg, 0.17 mmol) and compound Int-3 (40.85 mg, 0.17 mmol) in n-butanol (2 mL), add p-toluenesulfonic acid monohydrate (2.89 mg, 17 umol), and stir the reaction solution at 160°C for 3 hours under microwave conditions. After the reaction solution is cooled to room temperature, the reaction solution is concentrated under reduced pressure, and the residue is purified by reverse preparative HPLC to obtain a white solid 22 (20 mg, yield 23%). ESI-MS (m / z): 506.3 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.85 (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).

[0422] Embodiment 23

[0423] (S)-2-(((6-((4-ethyl-2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

[0424]

[0425] Example 23 was prepared by the following steps:

[0426]

[0427] Step 1: Compound 15d (2.0 g, 6.93 mmol), vinylboronic acid pinacol ester (3.20 g, 20.79 mmol), palladium acetate (155 mg, 0.69 mol), potassium phosphate (2.94 g, 13.86 mmol) were added to 1,4-dioxane (150 mL) in sequence, and water (15 mL) was added. Under nitrogen protection, the mixture was stirred at 90°C for 17 hours. HPLC monitored the complete conversion of the raw materials and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 9) to obtain a white solid 23a (1.18 g, yield 60%, purity 61%). ESI-MS (m / z): 281.1 [M+H] + .

[0428] Step 2: Compound 23a (1.0 g, 3.73 mmol) was added to 20 ml of methanol, palladium carbon (10%, 100 mg) was added, the reaction system was replaced with hydrogen and stirred overnight at room temperature, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain compound 23b (677 mg, yield 94%, purity 97%). ESI-MS (m / z): 191.3 [MH] - .

[0429] Step 3: Compound 23b (0.5 g, 2.81 mmol), Cs2CO3 (1.83 g, 5.61 mmol), Int-3d (514 mg, 4.21 mmol) were added to N, N-dimethylformamide (10 mL) in sequence, stirred at 20°C overnight, and the raw materials disappeared after HPLC monitoring. The reaction solution was added to 50 ml of ice water, stirred for 0.5 hours, and filtered to obtain a yellow solid 23c (530 mg, yield 64%, purity 99%). ESI-MS (m / z): 294.3 [M+H] + .

[0430] Step 4: Compound 23c (100 mg, 0.36 mmol) was dissolved in methanol (5 mL), added to aqueous ammonia (0.2 mL), added Raney Nickel (0.5 mL, aqueous suspension), and the reaction system was replaced with hydrogen and stirred at room temperature 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] + .

[0431] Step 5: Compound Int-1 (79.74 mg, 0.35 mmol) and compound 23d (104.93 mg, 0.35 mmol) were dissolved in n-butanol (2 mL), p-toluenesulfonic acid monohydrate (6.68 mg, 0.35 umol) was added, and 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 23 (33 mg, yield 19%). ESI-MS (m / z): 489.3 [M+H] + ; 1H NMR (500MHz, DMSO-d6) δ9.85 (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).

[0432] Embodiment 24

[0433] (S)-2-(((6-((4-ethyl-2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyridin-3-yl)methyl)amino)-4,7-dimethyl-8-(methyl-d3)-7,8-dihydropteridin-6(5H)-one

[0434]

[0435] Int-2 was used to replace Int-1 in the fifth step of Example 23, and a similar method and reaction steps were used 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 = 2.4Hz, 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).

[0436] Embodiment 25

[0437] (S)-2-(((6-((2-(difluoromethyl)-6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,7-dimethyl-8-(methyl-d3)-7,8-dihydropteridin-6(5H)-one

[0438]

[0439] Example 25 was prepared by the following steps:

[0440]

[0441] Step 1: Dissolve compound Int-8c (930 mg, 2.45 mmol) in tetrahydrofuran (10 mL), and slowly add n-butyl lithium (1.5 mL, 2M in hexane) to the solution at -78 ° C. The reaction solution 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 detected that the reaction was complete. Add saturated ammonium chloride aqueous solution to quench the reaction, extract with dichloromethane, combine the organic phases and wash with saturated sodium chloride aqueous solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residual liquid was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 3) to obtain compound 25a (281 mg, yield 41%). ESI-MS (m / z): 282.2 [M+H] + .

[0442] Step 2: Compound 25a (230 mg, 0.82 mmol) was dissolved in dichloromethane (5 mL), and diethylaminosulfur trifluoride (264 mg, 1.64 mmol) was slowly added dropwise to the solution at 0°C, and the reaction was stirred for 2 hours at 0°C. LCMS detected that the reaction was complete. Saturated sodium bicarbonate aqueous solution was added to quench the reaction, and dichloromethane was extracted. 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 a crude product of compound 25b (247 mg). ESI-MS (m / z): 304.1 [M+H] + .

[0443] Step 3: Compound 25b (247 mg, crude product) was dissolved in dichloromethane (5 mL), and boron tribromide (308 mg, 1.23 mmol) was slowly added dropwise to the solution at -78°C, and the reaction was stirred at -78°C for 30 minutes. LCMS detected that the reaction was complete. Saturated sodium bicarbonate aqueous solution was added to quench the reaction, washed with dichloromethane, and the aqueous phase was adjusted to pH 2 with hydrochloric acid aqueous solution (4 M), extracted with dichloromethane, and 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 compound 25c (82 mg, two-step reaction yield 47%). ESI-MS (m / z): 212.3 [MH] + .

[0444] Step 4: Compound 25c (82 mg, 0.39 mmol) and compound Int-2 (47 mg, 0.39 mmol) were dissolved in N,N-dimethylformamide (3 mL), cesium carbonate (251 mg, 0.77 mmol) was added, and the reaction solution was stirred at 50 ° C for 12 hours. LCMS detected that the reaction was complete. The reaction solution was diluted with water and filtered under reduced pressure to obtain compound 25d (98 mg, yield 80%).

[0445] Step 5: Compound 25d (98 mg, 0.32 mmol) was dissolved in methanol (3 mL) and ammonia water (0.5 mL), and Raney Nickel (0.5 mL, aqueous suspension) was added. The reaction system was replaced with hydrogen and stirred at room temperature for 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 a colorless oily liquid compound 25e (40 mg, yield 40%). ESI-MS (m / z): 320.2 [M+H] + .

[0446] Step 6: Compound 25e (20 mg, 0.06 mmol) and Int-2 (15 mg, 0.06 mmol) were dissolved in n-butanol (3 mL), p-toluenesulfonic acid monohydrate (2 mg, 0.01 mmol) was added, and 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 Prep-HPLC to obtain white solid compound 25 (7 mg, yield 22%). ESI-MS (m / z): 513.2 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.89 (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).

[0447] Embodiment 26

[0448] (S)-2-(((6-((2,6-bis(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

[0449]

[0450] Example 26 was prepared by the following steps:

[0451]

[0452] Step 1: Compound 26a (1.0 g, 4.65 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), cooled to -78 °C under nitrogen protection, and n-butyl lithium (3.05 mL, 4.88 mmol) was slowly added dropwise. After one hour, triisopropyl borate (0.79 mL, 6.97 mmol) was added dropwise. After two hours, the reaction was completed by LCMS monitoring. Water was slowly added dropwise to quench the reaction. When the system was heated to 0 °C, sodium hydroxide aqueous solution (4 M, 3.49 mL, 13.95 mmol) and hydrogen peroxide (1 mL) were added dropwise, and the reaction was carried out at room temperature for 16 hours. The reaction solution was acidified with hydrochloric acid (2 M), extracted three times with dichloromethane, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain a yellow solid mixture 26b and 26b' (400 mg, yield 37%). MS (m / z): 230.5 [MH] - .

[0453] Step 2: Compounds 26b and 26b' (400 mg, 1.73 mmol), Int-3d (232.48 mg, 1.90 mmol) and N, N-diisopropylethylamine (671.1 mg, 5.19 mmol) were added to acetonitrile (10 mL) and reacted at 120°C for 4 hours. The reaction was completed after monitoring by LCMS. The 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 and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain a yellow solid 26c (180 mg, yield 31%). ESI-MS (m / z): 334.4 [M+H] + .

[0454] Step 3: Compound 26c (180 mg, 0.54 mmol) was dissolved in methanol (30 mL), and aqueous ammonia (5 mL) and Raney nickel (3.5 mL, aqueous suspension) were added to the reaction system in sequence. The hydrogen was replaced by a hydrogen balloon and reacted for 3 hours under a hydrogen atmosphere at room temperature. The reaction was monitored by LCMS to complete. The reaction solution was diluted with methanol, filtered, and the filtrate was concentrated to obtain a brown oily liquid 26d (150 mg, yield 82%). ESI-MS (m / z): 338.5 [M+H] + .

[0455] Step 4: Compound 26d (74.39 mg, 0.22 mmol) was dissolved in n-butanol (2 mL), and compound Int-1 (50 mg, 0.22 mmol) and p-toluenesulfonic acid monohydrate (4.19 mg, 22 umol) were added. The reaction solution was stirred at 160°C for 3 hours under microwave conditions. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by reverse phase preparative HPLC to obtain a white solid 26 (38.57 mg, yield 33%). ESI-MS (m / z): 528.5 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.83 (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).

[0456] Embodiment 27

[0457] (S)-3-((5-(((4,7-dimethyl-8-(methyl-d3)-6-carbonyl-5,6,7,8-tetrahydropteridin-2-yl)amino)methyl)pyridin-2-yl)oxy)-6-(trifluoromethyl)pyridine cyanide

[0458]

[0459] Example 27 was prepared by the following steps:

[0460]

[0461] Step 1: Add di-tert-butyl carbonic anhydride (1.75 g, 8.02 mmol) dropwise to a dichloromethane (40 mL) solution of Int-13 (2.03 g, 6.68 mmol) and triethylamine (1.39 mL, 10.02 mmol) under ice-water bath conditions. After stirring the reaction solution 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 by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain a white solid 27a (1.95 g, yield 72%). ESI-MS (m / z): 403.9 [M+H] + .

[0462] Step 2: Compound 27a (300 mg, 0.74 mmol), zinc cyanide (174 mg, 1.49 mmol), tetrakistriphenylphosphine palladium (172 mg, 0.15 mol) and N,N-dimethylformamide (10 mL) were added to a round-bottom flask. The reaction solution was stirred at 120°C under nitrogen protection for 24 hours, and the reaction was completed by LCMS monitoring. The solvent 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 and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain a white solid 27b (177 mg, yield 60%). ESI-MS (m / z): 395.3 [M+H] + .

[0463] Step 3: Trifluoroacetic acid (0.5 mL) was added dropwise to a dichloromethane (6 mL) solution of compound 27b. After the reaction solution was stirred at room temperature for 5 hours, the reaction was completed by LCMS monitoring. The reaction solution was concentrated by vacuum distillation, and sodium hydroxide aqueous solution was added to pH 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 a crude product 27c. ESI-MS (m / z): 295.3 [M+H] + .

[0464] Step 4: Compound Int-2 (45 mg, 0.20 mmol) was dissolved in n-butanol (3 mL), and compound 27c (64 mg, 0.22 mmol) and p-toluenesulfonic acid monohydrate (8 mg, 44 umol) were added. The reaction solution was stirred at 160 ° C for 3 hours under microwave conditions. LCMS monitored the completion of the reaction. The reaction solution was purified by reverse phase preparative HPLC to obtain a white solid 27 (16 mg, yield 8%). ESI-MS (m / z): 499.0 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.92 (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).

[0465] Embodiment 28

[0466] (S)-2-((4-cyclopropyl-2-(trifluoromethyl)pyrimidin-5-yl)oxy)-5-(((4,7,8-trimethyl-6-carbonyl-5,6,7,8-tetrahydropteridin-2-yl)amino)methyl)nicotinenitrile

[0467]

[0468] Example 28 was prepared by the following steps:

[0469]

[0470] Step 1: Add 21b (400 mg, 1.96 mmol), 28a (639 mg, 2.94 mmol), DIPEA (759 mg, 5.88 mmol) to DMF (5 mL), stir at 120°C for 2 hours, add 50 mL of ethyl acetate and 50 mL of water respectively, filter with diatomaceous earth, separate the liquids, and perform silica gel column chromatography (petroleum ether: ethyl acetate = 7: 1) on the residual liquid to obtain 28b (483 mg, yield 64%). ESI-MS (m / z): 385.1 [M+H] + .

[0471] Step 2: Add 28b (400 mg, 1.04 mmol), n-butyldi(1-adamantyl)phosphine (37 mg, 103 umol), 28c (492 mg, 2.08 mmol), TBAF (56 mg, 259 umol), palladium acetate (23 mg, 103 umol), cesium carbonate (1.02 g, 3.12 mmol), and water (1 mL) to n-butanol (7 mL), and stir at 110°C for 17 hours under nitrogen protection. LCMS showed that the raw material was completely converted, and 50 mL of ethyl acetate and 50 mL of water were added respectively, filtered through 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] + .

[0472] Step 3: Compound 28d (273 mg, 627 umol) was added to dichloromethane (3 ml), trifluoroacetic acid (1 ml) was added, and the mixture was stirred at room temperature for 2 hours. LCMS showed that the raw material was completely converted, and the mixture was distilled under reduced pressure. 10 ml of ethyl acetate and 10 ml of saturated sodium bicarbonate aqueous solution were added to the residue in turn, and 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] + .

[0473] Step 4: Add compound 28e, Int-1 (79 mg, 351 umol) obtained in the previous step and p-toluenesulfonic acid (6 mg, 35 umol) to n-butanol (2 mL) and stir at 160°C for 3 hours in a microwave oven. LCMS showed that the starting material disappeared. The reaction solution was purified by reverse phase preparative HPLC to obtain a white solid 28 (20 mg, two-step reaction yield 6%). ESI-MS (m / z): 526.3 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.87 (s, 1H), 8.95 (s, 1H), 8.43 (d, J = 2.4Hz, 1H), 8.36 (d, J = 2.3Hz, 1H), 7.03 (t, J = 6.3 Hz, 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).

[0474] Embodiment 29

[0475] (S)-4,7,8-trimethyl-2-(((6-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

[0476]

[0477] Substitute 4-methyl-6-(trifluoromethyl)pyridin-3-ol for 15f in the sixth step of Example 15, and use the subsequent similar methods and reaction steps to obtain compound 29. ESI-MS (m / z): 474.3 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.82 (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).

[0478] Embodiment 30

[0479] (S)-2-(((6-((1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxy)pyridin-3-yl)methyl)amino)-7-(methoxymethyl)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

[0480]

[0481] Example 30 was prepared by the following steps:

[0482]

[0483] Step 1: Dissolve compound 30a (1.10 g, 5 mmol) in anhydrous tetrahydrofuran (10 mL), cool the solution to 0 ° C, and slowly add sodium hydride (478 mg, 60% dispersion in mineral oil) to the reaction solution under a nitrogen atmosphere. The reaction solution was stirred at 0 ° C for 10 minutes. Then iodomethane (1.42 g, 10 mmol) was added dropwise to the reaction solution. The reaction solution slowly warmed to room temperature and continued to stir for 2 hours. LCMS detected that the reaction was complete. Add saturated ammonium chloride aqueous solution to quench the reaction, extract with ethyl acetate, combine the organic phases and wash with saturated sodium chloride aqueous solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain compound 30b (1.17 g, crude product). ESI-MS (m / z): 234.4 [M+H] + .

[0484] Step 2: Compound 30b (1.17 g) was dissolved in methanol (10 mL), and thionyl chloride (1.19 g, 10 mmol) was slowly added dropwise to the reaction solution at room temperature, and then the reaction solution was heated to 70°C and stirred at this temperature for 2 hours. LCMS detected that the reaction was complete. 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).

[0485] Step 3: Compound 30c (918 mg, crude product) and compound 18d (1.04 g, 5 mmol) were dissolved in tetrahydrofuran (10 mL), and N, N-diisopropylethylamine (1.94 g, 15 mmol) was added. The reaction was stirred at room temperature for 8 hours. LCMS detected that the reaction was complete. Water was added to quench the reaction, extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride aqueous 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) to obtain compound 30d (1.27 g, three-step reaction yield 84%). ESI-MS (m / z): 319.3 [M+H] + .

[0486] Step 4: Compound 30d (320 mg, 1 mmol) and compound Int-3 (300 mg, 1 mmol) were dissolved in N, N-dimethylformamide (5 mL), and N, N-diisopropylethylamine (390 mg, 3 mmol) was added. The reaction was stirred at room temperature for 4 hours. LCMS detected that the reaction was complete. Water was added to quench the reaction, extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride aqueous 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) to obtain compound 30e (430 mg, yield 74%). ESI-MS (m / z): 581.3 [M+H] + .

[0487] Step 5: Compound 30e (430 mg, 0.74 mmol) was dissolved in methanol (5 mL), 10% palladium on carbon (394 mg) was added, and the reaction system was stirred at room temperature for 6 hours after replacing hydrogen. LCMS detected that the reaction was complete. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain white solid compound 30 (15 mg, yield 4%). ESI-MS (m / z): 519.2 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.89 (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).

[0488] Embodiment 31

[0489] (S)-2-(((6-((1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxy)pyridin-3-yl)methyl)amino)-7-(hydroxymethyl)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

[0490]

[0491] Example 31 was prepared by the following steps:

[0492]

[0493] Step 1: Dissolve compound 30 (10 mg, 0.02 mmol) in dichloromethane (2 mL), slowly add boron tribromide (10 mg, 0.04 mmol) to the reaction solution at -78 ° C. The reaction was continued to stir at -78 ° C for 30 minutes. LCMS detected that the reaction was complete. Add saturated sodium bicarbonate aqueous solution to quench the reaction, extract with dichloromethane, combine the organic phases and wash with saturated sodium chloride aqueous solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue was purified by Prep-HPLC to obtain white solid compound 31 (8 mg, yield 80%). ESI-MS (m / z): 505.3 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.85 (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).

[0494] Embodiment 32

[0495] 4,7,7-Trimethyl-8-(methyl-d3)-2-(((6-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyridin-3-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

[0496]

[0497] Int-18 was used to replace Int-1 in the eighth step of Example 15, and compound 32 was obtained using subsequent similar methods and reaction steps. ESI-MS (m / z): 492.3 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.82 (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).

[0498] Embodiment 33

[0499] 4′-methyl-8′-(methyl-d3)-2′-(((6-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyridin-3-yl)methyl)amino)-5′,8′-dihydro-6′H-spiro[cyclopropane-1,7′-pteridine]-6′-one

[0500]

[0501] Compound 15g was used to replace Int-3 in the fifth step of Example 18, and compound 33 was obtained using subsequent similar methods and reaction steps. ESI-MS (m / z): 490.4 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.89 (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).

[0502] Embodiment 34

[0503] (S)-2-(6-(trifluoromethyl)-3-((5-(((4,7,8-trimethyl-6-carbonyl-5,6,7,8-tetrahydropteridin-2-yl)amino)methyl)pyridin-2-yl)oxy)pyridin-2-yl)acetonitrile

[0504]

[0505] Example 34 was prepared by the following steps:

[0506]

[0507] Step 1: Compound 27a (675 mg, 1.67 mmol), vinylboronic acid pinacol ester (1.29 g, 8.36 mmol), tetrakistriphenylphosphine palladium (194 mg, 0.17 mol), sodium carbonate (354 mg, 3.34 mmol), water (3 mL) and 1,4-dioxane (17 mL) were added to a round-bottom flask. The reaction solution was stirred at 120° C. under nitrogen protection for 16 hours, and the reaction was completed after LCMS monitoring. The solvent 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 and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain a white solid 34a (609 mg, yield 92%). ESI-MS (m / z): 396.4 [M+H] + .

[0508] Step 2: Sodium periodate (907 mg, 4.24 mmol) was added to a mixed solution of 34a (559 mg, 1.41 mmol) in tetrahydrofuran (12 mL) and water (3 mL). After the reaction solution was stirred at room temperature for one minute, potassium osmate (41 mg, 0.14 mmol) was added thereto. After the reaction solution was stirred at 40°C for 2 hours, LCMS monitored the completion 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 a crude product 34b. ESI-MS (m / z): 398.3 [M+H] + .

[0509] Step 3: Sodium borohydride (80 mg, 2.12 mmol) was added to a methanol (15 mL) solution of the crude product 34b under ice-water bath conditions. The reaction solution was stirred for two hours at this temperature. After the reaction was completed, 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) to obtain a white solid 34c (359 mg, two-step yield 64%). ESI-MS (m / z): 400.3 [M+H] + .

[0510] Step 4: Dichlorothionyl (0.13 mL, 1.80 mmol) was added dropwise to a solution of 34c (359 mg, 0.90 mmol) in dichloromethane (14 mL). The reaction mixture was stirred at room temperature for 2 hours, and the reaction was completed after LCMS monitoring. The reaction mixture was concentrated by vacuum distillation to obtain the crude product 34d. ESI-MS (m / z): 418.2 [M+H] + .

[0511] Step 5: Trimethylsilyl cyanide (178 mg, 1.80 mmol) was added dropwise to a solution of cesium fluoride (119 mg, 1.80 mmol) in acetonitrile (8 mL) at 10°C. After the reaction solution was stirred for 30 minutes, cesium carbonate (586 mg, 1.80 mmol) and the crude product 34d were added thereto. The reaction solution was heated to 40°C and stirred at this temperature for 16 hours. After the reaction was completed, 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 the crude product 34e. ESI-MS (m / z): 409.3 [M+H] + .

[0512] Step 6: Trifluoroacetic acid (2 mL) was added dropwise to a dichloromethane (8 mL) solution of the crude product 34e. After the reaction solution was stirred at room temperature for 1.5 hours, the reaction was completed by LCMS monitoring. The reaction solution was concentrated by vacuum distillation, and a sodium hydroxide aqueous solution was added to a pH of 8. The mixture was extracted with ethyl acetate, and the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain the crude product 34f. ESI-MS (m / z): 309.3 [M+H] + .

[0513] Step 7: Compound Int-1 (50 mg, 0.22 mmol) was dissolved in n-butanol (2 mL), and compound 34f (82 mg, crude product) and p-toluenesulfonic acid monohydrate (8 mg, 44 umol) were added. The reaction solution was stirred at 160°C for 3 hours under microwave conditions. The reaction was completed by LCMS monitoring. The reaction solution was purified by reverse phase preparative HPLC to obtain a white solid 34 (20 mg, four-step reaction yield 4%). ESI-MS (m / z): 499.0 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.83 (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).

[0514] Embodiment 35

[0515] (S)-2-(((6-((2-fluoro-6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

[0516]

[0517] Example 35 was prepared by the following steps:

[0518]

[0519] Step 1: Dissolve compound 35a (300 mg, 1.82 mmol) in anhydrous tetrahydrofuran (5 mL), cool to -78 ° C under nitrogen protection, slowly add n-butyl lithium (1.19 mL, 1.91 mmol), start to add triisopropyl borate (0.63 mL, 2.73 mmol) after one hour, and monitor the reaction by LCMS after two hours. Slowly add water to quench the reaction, and when the system is heated to 0 ° C, start to add sodium hydroxide aqueous solution (4M, 1.36 mL, 5.45 mmol) and hydrogen peroxide (1 mL), and react at room temperature for 16 hours. The reaction solution is acidified with hydrochloric acid (2 M), extracted three times with dichloromethane, concentrated, and the residue is purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain a yellow solid 35b (280 mg, yield 85%). MS (m / z): 180.5 [MH] - .

[0520] Step 2: Compound 35b (280 mg, 1.55 mmol), Int-3d (226 mg, 1.86 mmol) and cesium carbonate (1.01 g, 3.09 mmol) were added to acetonitrile (10 mL) and reacted at room temperature for 16 hours. The reaction was monitored by LCMS. The acetonitrile was removed by distillation 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 purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain a yellow oily liquid 35c (270 mg, yield 61%). ESI-MS (m / z): 284.4 [M+H] + .

[0521] Step 3: Compound 35c (270 mg, 0.95 mmol) was dissolved in methanol (30 mL), and aqueous ammonia (3.5 mL) and Raney nickel (3.5 mL, aqueous suspension) were added to the reaction system in sequence. The hydrogen was replaced by a hydrogen balloon and reacted for 3 hours under a hydrogen atmosphere at room temperature. The reaction was monitored by LCMS. The reaction solution was diluted with methanol, filtered, and the filtrate was concentrated to obtain a brown oily liquid 35d (270 mg, yield 98%). ESI-MS (m / z): 271.5 [M+H] + .

[0522] Step 4: Compound 35d (82.36 mg, 0.29 mmol) was dissolved in n-butanol (2 mL), compound Int-1 (50 mg, 0.22 mmol) and p-toluenesulfonic acid monohydrate (4.19 mg, 22 umol) were added, and the reaction solution was stirred at 160°C for 3 hours under microwave conditions. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by reverse phase preparative HPLC to obtain a white solid 35 (1.07 mg, yield 1%). ESI-MS (m / z): 478.5 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ9.80 (s, 1H), 8.25 (s, 0H), 8.18 (t, J = 8.7Hz, 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).

[0523] Embodiment 36

[0524] (S)-2-(((6-((6-chloro-2-cyclopropylpyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

[0525]

[0526] Example 36 was prepared by the following steps:

[0527]

[0528] Step 1: Add compound 36a (1.0 g, 3.91 mmol), Int-3d (478 mg, 3.91 mmol) and cesium carbonate (2.55 g, 7.83 mmol) to acetonitrile (20 mL), react at 50°C for 16 hours, and monitor the reaction completion by LCMS. Remove acetonitrile by distillation under reduced pressure, then add water and ethyl acetate for extraction, combine the organic phases and wash with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate the organic phase to obtain a white solid 36b (1.38 g, yield 98%). ESI-MS (m / z): 258.2 [M+H] + .

[0529] Step 2: Compound 36b (300 mg, 0.84 mmol), cyclopropylboronic acid (108 mg, 1.26 mmol), palladium acetate (19 mg, 84 umol), tricyclohexylphosphine (47 mg, 0.17 mmol) and potassium phosphate (534 mg, 2.52 mmol), water (2 mL) and toluene (10 mL) were added to a round-bottom flask. The reaction solution was stirred at 80 ° C under nitrogen protection for 16 hours, and the reaction was completed after LCMS monitoring. The solvent 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 and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4: 1) to obtain a white solid 36c (76 mg, yield 33%). ESI-MS (m / z): 272.4 [M+H] + .

[0530] Step 3: Compound 36c (76 mg, 0.28 mmol) was dissolved in methanol (8 mL), and aqueous ammonia (0.8 mL) and Raney nickel (0.8 mL, aqueous suspension) were added to the reaction system in sequence. The hydrogen was replaced by a hydrogen balloon and reacted for 3 hours under a hydrogen atmosphere at room temperature. The reaction was monitored by LCMS to complete. The reaction solution was diluted with methanol, filtered, and the filtrate was concentrated to obtain a brown oily liquid 36d. ESI-MS (m / z): 276.4 [M+H] + .

[0531] Step 4: Compound 36d (51 mg) obtained in the previous step was dissolved in n-butanol (2 mL), and compound Int-1 (45 mg, 0.19 mmol) and p-toluenesulfonic acid monohydrate (7 mg, 37 umol) were added. The reaction solution was stirred at 160°C for 3 hours under microwave conditions. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by reverse phase preparative HPLC to obtain a white solid 36 (10 mg, two-step reaction yield 7%). ESI-MS (m / z): 466.3 [M+H] + ; 1H NMR (500MHz, DMSO-d6) δ9.82 (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).

[0532] According to the synthetic routes and intermediate synthesis methods described in the above examples, the following examples can be obtained.

[0533]

[0534]

[0535]

[0536]

[0537] Comparative Example 1

[0538] (S)-4,7,8-trimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

[0539]

[0540] 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) δ9.81 (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).

[0541] Comparative Example 2

[0542] (S)-2-(((6-(4-fluorophenoxy)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

[0543]

[0544] 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] + ; 1H NMR (500MHz, DMSO-d6) δ9.80 (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).

[0545] Wnt pathway inhibitor biological screening and results

[0546] Experimental Example 1: Construction of Colo205-LUC-TCF / LEF-M1 reporter cell line

[0547] 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 a luciferase reporter plasmid (Promega) driven by TCF / LEF transcription factors by lipo3000 liposome transfection during the exponential growth phase of the cells. This plasmid carries a resistance gene and can be screened for resistance. The transfection was carried out in a 10 cm culture dish using a conventional complete medium without resistance. After 2 days, the medium with resistance was replaced and culture continued. After that, the resistance medium was replaced every 2 days, and the suspended cells were discarded. The original medium was centrifuged to remove cells and debris and retained as an adaptive medium. When the cells filled the culture dish, the cells were digested, counted, and subcultured in a 96-well plate so that the average number of cells in each well was 1.5 / well. The adaptation medium was used during subculture. The remaining cells were frozen. After subculture, the cells were cultured for 4 hours to allow the cells to adhere to the wall, and then the number of cells in each well was observed under a microscope. The wells with only one cell in each well are marked, which are monoclonal wells. Then culture normally, change the culture medium every 2 days, and observe. In the early stage, the wells where monoclonal cells continue to grow are marked twice and can be replaced with normal resistant culture medium. When a monoclonal well fills the wells of the 96-well plate, it is digested and subcultured to a 24-well culture plate. After the 24-well plate is full, it is subcultured to a 96-well plate and a 6-well plate. There are at least 6 wells of cells in the 96-well plate, of which 3 wells are added with known Wnt inhibitors, and the other 3 wells are not treated. After 24 hours, the fluorescence detection reagent is added to the 96-well plate cells to detect the fluorescence intensity. Select the cell line that has fluorescence expression when not treated and the fluorescence light is reduced after inhibition, and further culture. The Colo205-LUC-TCF / LEF-M1 cell line is one of the cell lines screened above. Its growth curve, cell morphology, and cell growth status are similar to those of the original Colo205 cells. The ratio of its fluorescent signal with and without inhibitor treatment is the largest among all cell lines, and the ratio can reach 4-5 times when inhibited at 4 hours, which is completely suitable for the subsequent screening of Wnt inhibitors.

[0548] Experimental Example 2: Detection of the inhibitory ability of compounds on Colo205-LUC-TCF / LEF-M1 reporter cell line

[0549] The Colo205-LUC-TCF / LEF-M1 cell line is a reporter cell stably transfected with the pGL4.49-LUC2-TCF / LEF vector. Its β-catenin Wnt pathway is continuously activated. After the addition of the inhibitor, the Wnt pathway is inhibited, and the expression level of firefly luciferase regulated by the TCF / LEF cis-element on the vector decreases. After the subsequent addition of the detection substrate, the detected light signal decreases accordingly, thereby detecting the inhibitory effect of the compound.

[0550] Add 100uL of the compound with a maximum concentration of 20uM to each well of a 96-well cell culture plate, and dilute the compound concentration by 3 times. Then inoculate 10,000 colo205 cells stably transfected with the reporter gene and 100uL of culture medium into each well, and make corresponding positive and negative control wells at the same time. Place the cells in a 5% CO2 cell culture incubator and culture at 37°C for 4h. After 4 hours, remove the culture medium, add 100uL of a reagent (Promega) containing the corresponding firefly luciferase substrate to each well, and measure the activity of the luciferase reporter gene. Use SpectraMax to read the luminescence intensity in full wavelength mode. The light signal intensity of cells treated only with DMSO is the positive control, and the light signal intensity of the cell-free well is the negative control. Calculate the concentration of ICS0 for each compound. The Colo 205 reporter gene detection data are summarized in Table 1.

[0551] Table 1. IC50 values ​​of compounds for inhibition of Colo205-LUC-TCF / LEF reporter gene

[0552]

[0553] Experimental Example 3: Proliferation inhibition test of compounds on Wnt mutant cell lines (Colo205, H929, HepG2 and DU4475) and non-Wnt mutant cell lines (RKO)

[0554] The cell lines used in the experiment are Colo205, H929, HepG2 and DU4475 cell lines in which the Wnt pathway is continuously activated and whose proliferation is Wnt pathway-dependent; and the RKO cell line in which the Wnt pathway is not activated under normal circumstances and whose proliferation is not dependent on the Wnt pathway is used as a control cell line to determine that the inhibitory effect of the compounds of the present invention on Wnt-dependent proliferation is not caused by other non-specific toxicity.

[0555] Colo205, H929, DU4475, HepG2 and RKO cell lines cultured in their respective culture media were treated during the logarithmic growth phase, and the cells were collected and prepared into a uniform cell suspension of known concentration, and then the cell suspension was added to a 96-well cell culture plate so that each well contained 1000-4000 cells. Place in a 5% CO2 cell culture incubator and culture at 37°C for 20-24 hours. On the second day, a completely dissolved, 3-fold gradient dilution of the compound was added to each cell culture well so that the final maximum concentration in the cell culture well was 10uM, and the culture was continued for 96 hours. This experiment uses Promega's cell activity detection test for detection. The more cells proliferate, the stronger the final signal intensity. The detection instrument is SpectraMax, full wavelength mode. The wells with only DMSO added were used as positive control wells, and the wells without cells were used as negative control wells. The IC50 value of each compound for the proliferation inhibition of cells with sustained Wnt activation or proliferation dependence, as well as the IC50 value for the proliferation inhibition of cells with inactivated Wnt or proliferation-independent Wnt were calculated to evaluate the inhibitory effect of the compound on the Wnt pathway and the toxic effect on normal cells (Table 2).

[0556] Table 2. IC50 values ​​of compounds for inhibition of proliferation of Wnt mutant cell lines

[0557]

[0558]

[0559] ND = Not Tested

[0560] The above results show that the compounds of the present invention have significant inhibitory activity against mutant cell lines Colo205, DU4475, NCI-H929 and HepG2, but have basically no significant inhibitory activity against Hela and RKO cell lines, which indicates that the compounds of the present invention have significant Wnt-dependent proliferation inhibitory effect.

[0561] Experimental Example 4: Tumor growth inhibition test of compound 1 on Colo205 mouse Xenograft model

[0562] In this study, the in vivo antitumor activity of control example 1 and compound 1 was evaluated using a BALB / c nude mouse xenograft tumor model of human colon cancer cell Colo205.

[0563] Female BALB / c nude mice were subcutaneously inoculated with human colon cancer cells Colo205 to establish a Colo205 BALB / c nude mouse transplant tumor model. After the tumor grew to an average tumor volume of about 80 mm3, the tumor-bearing mice were randomly divided into three groups according to the tumor volume: a solvent-treated control group, a 3 mg / kg compound 1 group, and a 10 mg / kg control example 1 group. Compound 1 and control example 1 were orally administered once a day for a 14-day administration cycle. The tumor volume was measured every other day. The body weight and tumor volume were measured on Day 14 (Table 3 and Figure 1 ).

[0564] Table 3

[0565]

[0566] ***: Compared with the Vehicle negative control group, P < 0.001.

Claims

1. A compound or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein the compound has the following structure:

2. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, and optionally a pharmaceutically acceptable carrier.

3. Use of the compound according to claim 1 or its pharmaceutically acceptable salt, isotopic derivative, stereoisomer or the pharmaceutical composition according to claim 2 in the preparation of a medicament for preventing and / or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.

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