A highly active Wnt pathway inhibitor compound

Abstract

The present invention provides a compound for inhibiting the activity of the Wnt pathway having the structure of formula (I) and a pharmaceutical composition comprising the compound. The present invention also provides the use of the compound in the prevention and / or treatment of cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.

Description

[0001] This application claims the priority of Chinese Patent Application No. 202011175894.X, entitled "A Compound with High Activity as a Wnt Pathway Inhibitor", filed with the Chinese Patent Office on October 28, 2020, the content of which is incorporated herein by reference in its entirety. Technical Field

[0002] The present invention relates to a heterocyclic compound, and particularly to a highly active Wnt pathway inhibitor and its uses. Background Art

[0003] The Wnt / β-catenin signal transduction pathway is a conserved pathway in biological evolution. In normal somatic cells, β-catenin only acts as a cytoskeletal protein to form a complex with E-cadherin at the cell membrane, playing a role in maintaining the adhesion of homotypic cells and preventing cell movement. When the Wnt signal pathway is not activated, β-catenin in the cytoplasm is phosphorylated and forms a β-catenin degradation complex with APC, Axin, GSK3β, etc., initiating the ubiquitin system to degrade β-catenin via the proteasome pathway, so that the β-catenin in the cytoplasm is maintained at a low level. When the cell is stimulated by Wnt signals, the Wnt protein binds to the specific receptor Frizzled protein on the cell membrane. The activated Frizzled receptor recruits the intracellular Dishevelled protein, inhibiting the degradation activity of the β-Catenin degradation complex formed by proteins such as GSK3β, and stabilizing the free β-Catenin protein in the cytoplasm. The β-Catenin protein that accumulates stably in the cytoplasm enters the nucleus and binds to the LEF / TCF transcription factor family, initiating the transcription of downstream target genes (such as c-myc, c-jun, Cyclin D1, etc.). The overactivation of the Wnt / β-catenin signal pathway is closely related to the occurrence of various cancers (including colorectal cancer, gastric cancer, breast cancer, etc.). For example, there are widespread abnormal activations of the Wnt canonical signal pathway and nuclear accumulation of β-catenin protein in colorectal cancer, and inhibiting the activity of the Wnt signal pathway can inhibit the proliferation of colorectal cancer. Mutations in APC 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, mutations in Axin and self-mutations of β-catenin can also cause intracellular aggregation of β-catenin, activating the Wnt / β-catenin pathway. Summary of the Invention

[0004] The present invention provides a compound having the structure of formula (I) for inhibiting the activity of the Wnt pathway, and pharmaceutically acceptable salts, isotope derivatives, and stereoisomers thereof:

[0005]

[0006] Wherein: --- indicates presence or absence;

[0007] R1 represents C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl, and said R1 may optionally be substituted by 0, 1, 2, or 3 substituents selected from: hydrogen, halogen, ORa, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, cyano, SR a , halo(C1-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C1-C6)alkylthio, (C3-C6)cycloalkyloxy, (C3-C6)cycloalkylthio, halo(C3-C6)cycloalkylthio;

[0008] X represents -(CR a R a’ ) m -, -(CR a R a’ ) m O(CR a R a’ ) n -, -(CR a R a’ ) m S(CR a R a’ ) n -;

[0009] Cy represents C6-C 10 aryl or 5-10 membered heteroaryl, and it may optionally be substituted by 0, 1, 2, or 3 substituents selected from: hydrogen, halogen, -ORa, (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, cyano, hydroxy(C1-C6)alkyl;

[0010] R2 represents hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C1-C6)alkyl;

[0011] R3 and R 3’ each independently represent hydrogen, halogen, OR a , (C1-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C1-C6 alkyl), (C1-C6)alkoxy(C1-C6)alkyl;

[0012] Or R3 and R 3’Together with the connected carbon atom, form a 3-6 membered saturated or unsaturated ring, which may optionally contain 1 or 2 heteroatoms selected from O, S, and N; and the ring may also be optionally substituted by 0, 1, or 2 halogens, hydroxyl groups, C1-C6 alkyl groups;

[0013] Or R2, R3, or R 2’ 、R3 together with the atom they are attached to form a 4-6 membered saturated or unsaturated ring, which may optionally contain 1 or 2 heteroatoms selected from O, S, and N; and the ring may also be optionally substituted by 0, 1, or 2 halogens, hydroxyl groups, C1-C6 alkyl groups;

[0014] R4 and R 4’ Each independently represents hydrogen, C1-C6 alkyl group, C3-C6 cycloalkyl group, hydroxy(C1-C6)alkyl group, halo(C1-C6)alkyl group, (C1-C6)alkoxy(C1-C6)alkyl group;

[0015] Or R4 and R 4’ Together form =O;

[0016] R T And R T’ Each independently represents hydrogen, C1-C6 alkyl group, halo(C1-C6)alkyl group, hydroxy C1-C6 alkyl group, C3-C6 cycloalkyl group, halogen, OR a ;

[0017] Or R T And R T’ Together with the atom they are attached to form a 3-6 membered ring;

[0018] Wherein, when --- represents non-existence, A represents (CR L R L’ ) p Where R L And R L’ Each independently represents hydrogen, C1-C6 alkyl group, halo(C1-C6)alkyl group, hydroxy(C1-C6)alkyl group, C3-C6 cycloalkyl group, halogen, OR a 、Or R L And R L’ Together with the connected carbon atom form a 3-6 membered ring, which may optionally contain 0, 1, or 2 heteroatoms selected from O, S, and N, and the ring may also be optionally substituted by 0, 1, or 2 halogens, hydroxyl groups;

[0019] Wherein, when --- represents existence, A represents CR H Where, R Hrepresents hydrogen, C1-C6 alkyl, halo(C1-C6 alkyl), hydroxy(C1-C6 alkyl), C3-C6 cycloalkyl, halogen, OR a ;

[0020] wherein, R a , R a’ each independently represents hydrogen and C1-C6 alkyl;

[0021] wherein m, n, p each independently represent 0, 1, 2.

[0022] In one embodiment, wherein X represents -O-, -CH2-, -OCH2 or -CH2CH2-.

[0023] In one embodiment, wherein Cy represents pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, imidazolyl, phenyl which is substituted by 0, 1, 2 substituents selected from (C1-C6) alkyl, (C3-C6) cycloalkyl, halo(C1-C6 alkyl), -OR a , halogen, cyano, NR a R a’ , hydroxy(C1-C6) alkyl; wherein, R a , R a’ each independently represents hydrogen and C1-C6 alkyl.

[0024] In one embodiment, wherein R1 represents (C1-C6) alkyl, (C3-C6) cycloalkyl, (C6-C 10 ) aryl, (5-10)-membered heteroaryl, which is optionally substituted by 0, 1, 2 substituents selected from halogen, OR a , (C1-C6) alkyl, halo(C1-C6 alkyl); wherein, R a represents hydrogen and C1-C6 alkyl.

[0025] In one embodiment, wherein R2 represents hydrogen or (C1-C6) alkyl.

[0026] In one embodiment, wherein R3 and R 3’ each independently represents hydrogen or (C1-C6) alkyl.

[0027] In one embodiment, wherein R4 and R 4’ together form =O.

[0028] Preferably, the compound of the present invention has the following structure:

[0029]

[0030]

[0031]

[0032]

[0033]

[0034]

[0035]

[0036]

[0037]

[0038]

[0039]

[0040]

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047] It should be noted particularly that in this article, when referring to a "compound" with a specific structural formula, it generally also encompasses its stereoisomers, diastereoisomers, enantiomers, racemic mixtures, and isotopic derivatives.

[0048] As is well known to those skilled in the art, a salt, solvate, or hydrate of a compound is an alternative form of the compound, and they can all be converted into the said compound under certain conditions. Therefore, it should be noted particularly that in this article, when referring to a compound, it generally also includes its pharmaceutically acceptable salts, and further includes its solvates and hydrates.

[0049] Similarly, in this article, when referring to a compound, it generally also includes its prodrugs, metabolites, and N-oxides.

[0050] The pharmaceutically acceptable salts of the present invention can be formed using, for example, the following inorganic or organic acids: "Pharmaceutically acceptable salts" refer to salts that, within the scope of reasonable medical judgment, are suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and afford a reasonable benefit / risk ratio. The salts can 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 functionality can be reacted with a suitable acid. In addition, when the compounds of the present invention carry an acidic moiety, suitable pharmaceutically acceptable salts can include metal salts, such as alkali metal salts (e.g., sodium or potassium salts); and alkaline earth metal salts (e.g., calcium or magnesium salts). Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by the reaction 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 salts formed by using other methods in the prior art such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, gluconates, hernisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactates, lactobionates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc. 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, e.g., halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0051] The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example, by dissolving the compounds of the present invention in a water-miscible organic solvent (e.g., acetone, methanol, ethanol, and acetonitrile), adding an aqueous solution of an excess of an organic or inorganic acid thereto such that the salt precipitates from the resulting mixture, removing the solvent and the remaining free acid therefrom, and then isolating the precipitated salt.

[0052] The precursors or metabolites described in the present invention can be precursors or metabolites known in the art, as long as the precursors or metabolites can be converted into the compounds through in vivo metabolism. For example, "prodrug" refers to those prodrugs of the compounds of the present invention, which, within the scope of reasonable medical judgment, are suitable for contacting the tissues of humans and lower animals, without undue toxicity, irritation, allergic reaction, etc., and have a reasonable benefit / risk ratio and are effective for their intended uses. The term "prodrug" refers to a compound that is rapidly converted in vivo to produce the parent compound of the above formula, for example, through in vivo metabolism or N-demethylation of the compounds of the present invention.

[0053] The "solvate" described in the present invention means the physical association of the compounds of the present invention with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonds. 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 capable of being isolated. The solvent molecules in the solvate may be present in a regular arrangement and / or a disordered arrangement. The solvate may contain a stoichiometric or non-stoichiometric amount of solvent molecules. "Solvate" encompasses solvates in the solution phase and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are known in the art.

[0054] The "stereoisomerism" described in the present invention is divided into conformational isomerism and configurational isomerism. Configurational isomerism can be further divided into cis-trans isomerism and optical isomerism (i.e., enantiomerism). Conformational isomerism refers to a stereoisomeric phenomenon in which an organic molecule with a certain configuration has different arrangements of its atoms or groups in space due to the rotation or distortion of carbon-carbon single bonds. Common examples include the structures of alkanes and cycloalkanes, such as the chair conformation and boat conformation in the structure of cyclohexane. "Stereoisomers" refer to those compounds of the present invention that contain one or more asymmetric centers and can thus exist as racemates and racemic mixtures, single enantiomers, diastereoisomeric 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 diastereoisomeric mixtures and pure or partially pure compounds. The compounds described in the present invention may exist in tautomeric forms, which have different hydrogen attachment points due to the displacement of one or more double bonds. For example, a ketone and its enol form are keto-enol tautomers. Each tautomer and its mixture are included in the compounds of the present invention. All enantiomers, diastereoisomers, racemates, meso forms, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof of the compounds of formula (I) are included within the scope of the present invention.

[0055] The "isotope derivatives" of the present invention refer to molecules in which the compounds in this patent are isotopically labeled. The isotopes commonly used for isotope labeling are: hydrogen isotopes, 2 H and 3 H; carbon isotopes: 11 C, 13 C and 14 C; chlorine isotopes: 35 Cl and 37 Cl; fluorine isotope: 18 F; iodine isotopes: 123 I and 125 I; nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotope 35 S. These isotopically labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. In particular, deuterium 3 H and carbon 13 C are more widely used because they are easy to label and convenient to detect. The substitution of certain heavy isotopes, such as deuterium ([[]] 2 H), can enhance metabolic stability, prolong the half-life, and thus achieve the purpose of reducing the dose and providing therapeutic advantages. Isotopically labeled compounds generally start from labeled starting materials and are synthesized using known synthetic techniques in the same way as non-isotopically labeled compounds.

[0056] The present invention also provides the use of the compounds of the present invention in the preparation of drugs for preventing and / or treating cancer, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.

[0057] 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 compounds of the present invention as an active ingredient.

[0058] 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 the compounds of the present invention to a mammal in need thereof.

[0059] Representative examples of inflammatory diseases, autoimmune diseases, and immune-mediated diseases can 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 diseases, pulmonary inflammation, adult respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic pulmonary inflammatory diseases, chronic obstructive pulmonary disease (COPD), cardiovascular diseases, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia-reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjogren's syndrome, autoimmune thyroid diseases, urticaria (hives), 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 lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hairy cell leukemia, Hodgkin's disease, non-Hodgkin lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), diffuse large B-cell lymphoma, and follicular lymphoma.

[0060] Representative examples of cancers or tumors can include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis carcinoma, hereditary non-polyposis 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, corpus cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral primitive neuroectodermal tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic 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 cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, or plasmacytoma.

[0061] When the compound of the present invention or a pharmaceutically acceptable salt thereof is administered in combination with another anti-cancer agent or immune checkpoint inhibitor for treating cancer or tumor, the compound of the present invention or a pharmaceutically acceptable salt thereof can provide enhanced anti-cancer effects.

[0062] Representative examples of anti-cancer agents for treating cancer or tumor may include but are not limited to cell signal transduction inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunomycin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifen, flutamide, gonadorelin analogs, megestrol acetate, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon α, calcium folinate, sirolimus, sirolimus esters, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brigatinib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danusertib, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, seracatinib, saridegib, sorafenib, sunitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, belantamab mafodotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, PI3K inhibitors, CSF1R inhibitors, A2A and / or A2B receptor antagonists, IDO inhibitors, anti-PD-1 antibodies, anti-PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies and anti-CTLA-4 antibodies or any combination thereof.

[0063] When the compound of the present invention or a pharmaceutically acceptable salt thereof is administered in combination with another therapeutic agent for treating inflammatory diseases, autoimmune diseases, and immune-mediated diseases, the compound of the present invention or a pharmaceutically acceptable salt thereof can provide enhanced therapeutic effects.

[0064] Representative examples of therapeutic agents for treating inflammatory diseases, autoimmune diseases, and immune-mediated diseases may include, but are not limited to, steroid drugs (e.g., prednisone, hydrocortisone, methylprednisolone, cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNFα agents (e.g., etanercept, infliximab, adalimumab, etc.), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus, etc.), and antihistamines (e.g., diphenhydramine, hydroxyzine, loratadine, ebastine, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one therapeutic agent selected therefrom may be included in the pharmaceutical composition of the present invention.

[0065] The compound of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally as an active ingredient, and the effective amount ranges from 0.1 to 2,000 mg / kg body weight / day, preferably 1 to 1,000 mg / kg body weight / day, in the case of mammals including humans (body weight about 70 kg), and is administered once or in 4 divided doses per day, either following or not following a predetermined schedule. The dose of the active ingredient can be adjusted according to a plurality of relevant factors (e.g., the condition of the subject to be treated, the type and severity of the disease, the rate of administration, and the doctor's opinion). In some cases, an amount less than the above dose may be appropriate. An amount greater than the above dose may be used if no harmful side effects are caused, and this amount can be administered in divided doses per day.

[0066] In addition, the present invention also provides a method for preventing and / or treating tumors, cancers, viral infections, organ transplant rejection, neurodegenerative diseases, attention-related diseases, or autoimmune diseases, which includes administering the compound of the present invention or the pharmaceutical composition of the present invention to a mammal in need thereof.

[0067] The pharmaceutical composition of the present invention can be formulated into a dosage form for oral administration or parenteral administration (including intramuscular, intravenous, and subcutaneous routes, intratumoral injection) according to any one of conventional methods, such as tablets, granules, powders, capsules, syrups, emulsions, microemulsions, solutions, or suspensions.

[0068] The pharmaceutical composition of the present invention for oral administration can be prepared by mixing the active ingredient with carriers such as cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifying agents and diluents. Examples of carriers employed in the injection compositions of the present invention are water, salt solutions, glucose solutions, glucose-like solutions, alcohols, diols, ethers (e.g., polyethylene glycol 400), oils, fatty acids, fatty acid esters, glycerol esters, surfactants, suspending agents and emulsifying agents.

[0069] In the process of describing exemplary embodiments of the present invention, other features of the present invention will become apparent. The said embodiments are given for the purpose of illustrating the present invention and are not intended to be limiting thereof. The following examples are prepared, separated and characterized using the methods disclosed in the present invention.

[0070] The compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the following methods as well as 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 reactions are carried out in solvents or solvent mixtures suitable for the kit materials used and suitable for the transformations to be achieved. Those skilled in the art of organic synthesis will understand that the functionality present on the molecule is consistent with the proposed transformation. This sometimes requires a judgment to change the order of synthetic steps or the starting materials to obtain the desired compounds of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0071] Figure 1 The effect of Compound 11 on the tumor volume of human myeloma cell NCI-H929 SCID xenograft tumors is shown. DETAILED DESCRIPTION OF THE INVENTION

[0072] TERMS

[0073] Unless otherwise specified, the terms used in the present invention application, including the specification and claims, are defined as follows. It must be noted that in the specification and the appended claims, the singular form "a" includes the plural meaning if there is no other clear indication in the text. Unless otherwise specified, conventional methods of mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology are used. In the present application, unless otherwise specified, the use of "or" or "and" means "and / or".

[0074] In the specification and claims, a given chemical formula or name shall cover all stereoisomers and optical isomers and racemates in which such isomers are present. Unless otherwise indicated, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Many geometric isomers of C═C double bonds, C═N double bonds, ring systems, etc. may also be present in the compounds, and all such stable isomers are covered by the present invention. The present invention describes the 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 separate isomer forms. The compounds of the present invention can be separated in optically active or racemic forms. 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 preparing enantiomeric or diastereomeric products, they can be separated by conventional methods (such as by chromatography or fractional crystallization). Depending on the method conditions, the end products of the present invention are obtained in free (neutral) or salt form. Both the free form and the salts of these end products are within the scope of the present invention. If desired, one form of the compound can be converted into another form. The free base or acid can be converted into a salt; the salt can be converted into the free compound or another salt; a mixture of isomeric compounds of the present invention can be separated into individual isomers. The compounds of the present invention, their free forms and salts can exist in a variety of tautomeric forms, in which a hydrogen atom is transposed to other parts of the molecule and thus 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.

[0075] Unless otherwise defined, the definitions of the substituents of the present invention are independent of each other rather than interrelated. For example, for the substituent R a (or R a ’), it is independent in the definitions of different substituents. Specifically, for R a (or R a ’), when selecting a definition in one substituent, it does not mean that this R a (or R a ’) has the same definition in other substituents. More specifically, for example (only listing non-exhaustively), for NR a R a ’, when the definition of R a (or R a ’) is selected from hydrogen, it does not mean that in -C(O)-NR a R a ’, R a (or R a ’) must be hydrogen.

[0076] Unless otherwise defined, when a substituent is labeled as "optionally substituted", the substituent is selected from, for example, the following substituents, such as alkyl, cycloalkyl, aryl, heterocyclic, halogen, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine groups (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, sulfonamino such as -SO2NH2, substituted sulfonamino, nitro, cyano, carboxy, carbamoyl such as -CONH2, substituted carbamoyl such as -CONHalkyl, -CONHaryl, -CONHarylalkyl or in the case of having two substituents selected from alkyl, aryl or arylalkyl on nitrogen, alkoxycarbonyl, aryl, substituted aryl, guanidyl, heterocyclic, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, etc. and substituted heterocyclic.

[0077] As used herein, the term "alkyl" or "alkylene" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1-C6 alkyl" represents an alkyl having 1 to 6 carbon atoms. Examples of alkyl 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).

[0078] The term "alkenyl" represents a straight-chain or branched hydrocarbon group containing one or more double bonds and usually having a length of 2 to 20 carbon atoms. For example, "C2-C6 alkenyl" contains two to six carbon atoms. Alkenyl includes, but is not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, etc.

[0079] The term "alkynyl" represents a straight-chain or branched hydrocarbon group containing one or more triple bonds and usually having a length of 2 to 20 carbon atoms. For example, "C2-C6 alkynyl" contains two to six carbon atoms. Representative alkynyl includes, but is not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, etc.

[0080] The term "alkoxy" or "alkyloxy" means -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. Similarly, "alkylthio" or "thioalkyloxy" denotes an alkyl group as defined above linked by a sulfur bridge with a specified number of carbon atoms; for example, methyl-S- and ethyl-S-.

[0081] The term "carbonyl" refers to an organic functional group (C=O) formed by the double bond connection of two atoms of carbon and oxygen.

[0082] The term "aryl", alone or as part of a larger moiety such as "aralkyl", "aralkyloxy", 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, including but 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 include benzyl, phenethyl, etc. A fused aryl may be attached to another group at a suitable position on a cycloalkyl ring or an aromatic ring. The dashed lines drawn from the ring system indicate that the bond may be attached to any suitable ring atom.

[0083] The term "cycloalkyl" refers to a monocyclic or bicyclic cyclic alkyl. Monocyclic cyclic alkyl refers to 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 alkyl includes bridged, spiro, or fused ring cycloalkyls.

[0084] The term "cycloalkenyl" refers to a monocyclic or bicyclic cyclic alkenyl. Monocyclic cyclic alkenyl refers to C3-C8 cyclic alkenyl, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and norbornenyl. Branched cycloalkenyls such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl". Bicyclic cyclic alkenyl includes bridged, spiro, or fused ring cyclic alkenyls.

[0085] "Halogenated" or "halogen" includes fluorine, chlorine, bromine, and iodine. "Halogenated alkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms and substituted with one or more halogens. Examples of halogenated alkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of halogenated alkyl also include "fluoroalkyl" which is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms and substituted with one or more fluorine atoms.

[0086] "Halogenated alkoxy" or "halogenated alkyloxy" means a halogenated alkyl as defined above connected by an oxygen bridge having a specified number of carbon atoms. For example, "halogenated C1-C6 alkoxy" is intended to include C1, C2, C3, C4, C5, C6 halogenated alkoxy. Examples of halogenated alkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "halogenated alkylthio" or "thiohalogenated alkyloxy" means a halogenated alkyl as defined above connected by a sulfur bridge having a specified number of carbon atoms; for example, trifluoromethyl-S- and pentafluoroethyl-S-.

[0087] In the present disclosure, when referring to some substituents, the expression C x1 -C x2 is used, which means that the number of carbon atoms in the substituent group can be from 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, C3-C6 means that the group contains 3, 4, 5, or 6 carbon atoms.

[0088] 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 from 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 its ring atoms 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 its ring atoms 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 its ring atoms 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 its ring atoms can be 3, 4, 5, 6, 7, 8 or 9; the 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; the 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; the 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; the 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 can contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more ring heteroatoms, such as heteroatoms selected from N, O, and S.

[0089] In the present disclosure, one or more halogens can each independently be selected from fluorine, chlorine, bromine, and iodine.

[0090] The term "heteroaryl" means a stable 3-, 4-, 5-, 6-, or 7-membered aromatic monocyclic or aromatic bicyclic or 7-, 8-, 9-, 10-, 11-, 12-membered aromatic polycyclic heterocycle that is completely unsaturated, partially unsaturated, and that contains carbon atoms and one, two, three, or four heteroatoms independently selected from N, O, and S; and includes any of the following polycyclic groups in which any of the heterocycles defined above is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The nitrogen atoms are substituted or unsubstituted (i.e., N or NR, where R is H or, if defined, another substituent). The heterocycle may be attached to its side group at any heteroatom or carbon atom that results in a stable structure. If the resulting compound is stable, the heterocyclic groups described herein may be substituted on a carbon or nitrogen atom. The nitrogen in the heterocycle may optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other. Preferably, 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 heteroaryl groups include, but are not limited to, acridinyl, azetidinyl, azoninyl, benzimidazolyl, benzofuranyl, benzothienyl, 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, dihydroindolyl, indazinyl, 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, phthalazinyl, piperazinyl, piperidinyl, piperidinone, 4-piperidinone, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridobenzimidazolyl, pyridothiazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidinone, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl, thienobenzimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, dihydroindolyl, 1H-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 2,3-dihydrobenzofuranyl, chromanyl, 1,2,3,4-tetrahydroquinoxalinyl, and 1,2,3,4-tetrahydroquinazolinyl.The term "heteroaryl" may also include biaryl structures formed by "aryl" as defined above and monocyclic "heteroaryl", such as but not limited to "-phenylbipyridyl-", "-phenylbipyrimidinyl", "-pyridylbiphenyl", "-pyridylbipyrimidinyl-", "-pyrimidinylbiphenyl-"; wherein the present invention also includes fused-ring and spiro compounds containing the above-mentioned heterocycles.

[0091] As used herein, the term "heterocycloalkyl" refers to a monocyclic heterocycloalkyl system, or a bicyclic heterocycloalkyl system, and also includes spiroheterocycles or bridged heterocycloalkyls. Monocyclic heterocycloalkyl refers to a saturated or unsaturated but non-aromatic cyclic alkyl system with 3-8 members and at least one selected from O, N, S, P. The bicyclic heterocycloalkyl system refers to a heterocycloalkyl fused to a phenyl, or a cycloalkyl, or a cycloalkenyl, or a heterocycloalkyl, or a heteroaryl.

[0092] As used herein, the term "bridged cycloalkyl" refers to a polycyclic compound sharing 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.

[0093] As used herein, the term "spirocycloalkyl" refers to a polycyclic hydrocarbon in which a single carbon atom (called a spiro atom) is shared between monocyclic rings.

[0094] As used herein, the term "bridged heterocyclic group" refers to a polycyclic compound sharing two or more carbon atoms, and at least one atom selected from O, N, S is contained in the ring. It can be divided into bicyclic bridged heterocycles and polycyclic bridged heterocycles.

[0095] As used herein, the term "heterospiro group" refers to a polycyclic hydrocarbon in which a single carbon atom (called a spiro atom) is shared between monocyclic rings, and at least one atom selected from O, N, S is contained in the ring.

[0096] As used herein, the term "substituted" means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that the normal valence is maintained and the substitution results in a stable compound. The ring double bonds used herein are double bonds formed between two adjacent ring atoms (such as C═C, C═N or N═N).

[0097] In the case where nitrogen atoms (such as amines) are present in the compounds of the present invention, these nitrogen atoms can be converted into N-oxides by treatment with an oxidizing agent (such as mCPBA and / or hydrogen peroxide) to obtain other compounds of the present invention. Therefore, the nitrogen atoms shown and claimed are considered to cover both the shown nitrogen and its N-oxides to obtain the derivatives of the present invention.

[0098] When any variable occurs more than once in any composition or formula of a compound, its definition at each occurrence is independent of its definition at each other occurrence. Thus, for example, if a group is shown to be substituted with 0 - 3 R's, the group may optionally be substituted with up to three R groups, and at each occurrence R is independently selected from the definition of R. In addition, combinations of substituents and / or variables are permitted only if the above combinations would result in a stable compound.

[0099] As used herein, the term "patient" refers to an organism that is treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (such as rats, apes / monkeys, horses, cows, pigs, dogs, cats, etc.) and most preferably refers to humans.

[0100] As used herein, the term "effective amount" means an amount of a drug or agent (i.e., a compound of the present invention) that will elicit a biological or medical response of a tissue, system, animal, or human that is sought by, for example, a researcher or clinician. In addition, the term "therapeutically effective amount" means an amount that, compared to a corresponding subject who has not received such amount, results in improved treatment, cure, prevention, or alleviation of a disease, disorder, or side effect, or reduction in the rate of progression of a disease or disorder. The effective amount may be administered in one or more administrations, applications, or dosages and is not intended to be limited to a particular formulation or route of administration. The term also includes within its scope an effective amount that enhances normal physiological functions.

[0101] As used herein, the term "treatment" includes any effect that results in the improvement of a disorder, disease, condition, etc., such as alleviation, reduction, modulation, amelioration, or elimination, or improvement of its symptoms.

[0102] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are 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 are commensurate with a reasonable benefit / risk ratio.

[0103] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (such as a lubricant, talc, magnesium stearate, calcium stearate, or zinc stearate or stearic acid) or solvent encapsulating material, which involves carrying or transporting the subject compound from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0104] 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 that is commonly accepted in the art for delivering a bioactive agent to an animal (specifically a mammal), including (i.e.) adjuvants, excipients or vehicles such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the mode of administration and the nature of the dosage form.

[0105] Specific pharmaceutical and medical terms

[0106] The term "acceptable", as used herein, means that a pharmaceutical ingredient or active ingredient does not have an excessive adverse effect on the health of the general treatment target.

[0107] The term "cancer", as used herein, refers to an abnormal growth of cells that cannot be controlled and that, under certain conditions, can metastasize (spread). This type of cancer includes, but is not limited to, solid tumors (such as those of the bladder, intestine, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (such as the thyroid), prostate, skin (melanoma) or blood tumors (such as aleukemic leukemia).

[0108] The term "co-administration" or similar terms, as used herein, refers to the administration of several selected therapeutic agents to a patient, either in the same or different modes of administration and at the same or different times.

[0109] The term "enhance" or "able to enhance", as used herein, means that the expected result can be increased or extended in terms of potency or duration. Thus, in enhancing the therapeutic effect of a drug, the term "able to enhance" means that the drug has the ability to increase or extend the potency or duration in the system. The "synergistic value" as used herein refers to the ability to maximize the enhancement of another therapeutic agent in an ideal system.

[0110] The term "immune disease" refers to a disease or condition resulting from an adverse or harmful reaction to an endogenous or exogenous antigen. The result usually causes dysfunction of cells, or destruction and resulting dysfunction thereof, or destruction of organs or tissues that may produce immune symptoms.

[0111] The terms "kit" and "product package" are synonyms.

[0112] The terms "subject" or "patient" include mammals and non-mammals. Mammals include, but are not limited to, mammals such as humans, non-human primates such as orangutans, apes, and monkeys; agricultural animals such as cows, horses, goats, sheep, pigs; domestic animals such as rabbits, dogs; experimental animals include rodents such as rats, mice, and guinea pigs, etc. Non-mammalian animals include, but are not limited to, birds, fish, etc. In a preferred embodiment, the selected mammal is a human.

[0113] The terms "treatment", "treatment process", or "therapy" as used herein include alleviating, inhibiting, or improving the symptoms or conditions of a disease; inhibiting the occurrence of complications; improving or preventing potential metabolic syndrome; inhibiting the occurrence of a disease or symptoms, such as controlling the development of a disease or condition; alleviating a disease or symptoms; reducing a disease or symptoms; causing a disease or symptoms to subside; alleviating the complications caused by a disease or symptoms, or preventing and / or treating the signs caused by a disease or symptoms.

[0114] As used herein, a certain compound or pharmaceutical composition, after administration, can improve a certain disease, symptom, or condition, especially the severity thereof, delay the onset, slow down the progression of the disease, or reduce the duration of the disease. Whether administered regularly or temporarily, continuously or intermittently, it can be attributed to or related to the situation of administration.

[0115] Route of administration

[0116] Suitable routes of administration include, but are not limited to, oral, intravenous injection, rectal, aerosol, parenteral administration, ophthalmic administration, pulmonary administration, transdermal administration, vaginal administration, otic administration, nasal administration, and topical administration. In addition, by way of example only, parenteral administration includes intramuscular injection, subcutaneous injection, intravenous injection, intramedullary injection, intracardiac injection, intraperitoneal injection, intralymphatic injection, and intranasal injection.

[0117] In one aspect, the mode of administration of the compounds described herein is local rather than systemic. In a specific embodiment, the long-acting preparation is administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. In addition, in another specific embodiment, the drug is administered through a targeted drug delivery system. For example, liposomes encapsulated by organ-specific antibodies. In such a specific embodiment, the liposomes are selectively directed to a specific organ and absorbed.

[0118] Pharmaceutical compositions and dosages

[0119] The present invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of one or more compounds of the present invention formulated with one or more pharmaceutical carriers (additives) and / or diluents, and optionally one or more of the other therapeutic agents described above. The compounds of the present invention can be administered for any of the above uses by any suitable means, for example, orally, such as tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nano-suspensions, micro-suspensions, spray-dried dispersions), syrups and emulsions; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular or intra-sternal injection or infusion techniques (for example, in the form of a sterile injectable aqueous or non-aqueous solution or suspension); nasally, including administration to the nasal mucosa, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally, such as in the form of a suppository; or by intratumoral injection. They can be administered alone, but are usually administered using a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice.

[0120] The pharmaceutical carrier is formulated according to a number of factors within the knowledge of those skilled in the art. These factors include, but are not limited to: the type and nature of the active agent being formulated; the subject to whom the composition containing the active agent is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutical carriers include aqueous and non-aqueous liquid media and various solid and semi-solid dosage forms.

[0121] The above carriers can include many different components and additives in addition to the active agent, and the other components are included in the formulation for various reasons well known to those skilled in the art, such as stabilizing the active agent, binders, etc. Descriptions of suitable pharmaceutical carriers and the factors involved in carrier selection can be found in a number of readily available sources, such as Allen L.V. Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012), Pharmaceutical Press.

[0122] Of course, the dosage regimen of the compounds of the present invention varies depending on known factors such as the pharmacodynamic properties of the specific agent and its mode and route of administration; the species, age, sex, health status, medical condition and weight of the recipient; the nature and degree of the symptoms; the types of concurrent treatments; the frequency of treatment; the route of administration, the renal and hepatic functions of the patient and the desired effect. According to general guidance, when used for a specified effect, the daily oral dose of each active ingredient should be about 0.001 mg / day to about 10 - 5000 mg / day, preferably about 0.01 mg / day to about 1000 mg / day, and most preferably about 0.1 mg / day to about 250 mg / day. During constant rate infusion, the most preferred intravenous dose should be about 0.01 mg / kg / minute to about 10 mg / kg / minute. The compounds of the present invention can be administered in a single daily dose, or the total daily dose can be administered in divided doses two, three or four times a day.

[0123] The compounds are generally administered in the form of a mixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as pharmaceutical carriers) appropriately selected in accordance with the intended form of administration (e.g., oral tablets, capsules, elixirs and syrups) and in accordance with conventional pharmaceutical practice.

[0124] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 2000 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will generally be present in an amount of about 0.1 - 95% by weight, based on the total weight of the composition.

[0125] A typical capsule for oral administration contains at least one compound of the present invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed through a 60 - mesh sieve and packaged into a size 1 gelatin capsule.

[0126] A typical injectable preparation can be prepared as follows: at least one compound of the present invention (250 mg) is placed in a vial in a sterile manner, freeze - dried in a sterile manner and sealed. For use, the contents of the vial are mixed with 2 mL of physiological saline to produce an injectable preparation.

[0127] The scope of the present invention includes pharmaceutical compositions (alone or in combination with a pharmaceutical carrier) containing a therapeutically effective amount of at least one compound of the present invention as an active ingredient. Optionally, the compounds of the present invention can be used alone, in combination with other compounds of the present invention or in combination with one or more other therapeutic agents (e.g., anticancer agents or other pharmaceutically active substances).

[0128] Regardless of the selected route of administration, the compounds of the present invention (which can be used in a suitable hydrated form) and / or the pharmaceutical compositions of the present invention are formulated into a pharmaceutical dosage form by conventional methods known to those skilled in the art.

[0129] The actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention can be varied so as to obtain an amount of the active ingredient that is effective for achieving the desired therapeutic response for a particular patient, composition, and mode of administration and is non-toxic to the patient.

[0130] The selected dosage level will depend upon a variety of factors including the activity of the specific compound or its ester, salt or amide employed in the present invention; the route of administration; the time of administration; the rate of excretion of the specific compound employed; the rate and extent of absorption; the duration of the treatment; other drugs, compounds and / or substances used in combination with the specific compound employed; and factors well known in the medical arts such as the age, sex, weight, condition, general health, and prior medical history of the patient being treated.

[0131] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the required pharmaceutical composition. For example, in order to achieve the desired therapeutic effect, the physician or veterinarian may begin with a relatively low amount of the compound of the present invention employed in the pharmaceutical composition below the level required and gradually increase the dosage until the desired effect is achieved. Generally, the appropriate daily dosage of the compound of the present invention will be the amount of the compound that is the lowest dosage effective to produce the therapeutic effect. Such effective dosage will generally depend upon the above factors. Generally, the dosage of the compound of the present invention for a patient for oral, intravenous, intraventricular, and subcutaneous administration ranges from about 0.01 to about 50 mg / kg body weight per day. If desired, the effective daily dosage of the active compound may be administered in two, three, four, five, six or more sub-doses at appropriate intervals throughout the day, optionally in unit dosage forms. In certain aspects of the present invention, administration is once daily.

[0132] While the compounds of the present invention may be administered alone, it is preferable to administer the compounds in the form of a pharmaceutical formulation (composition).

[0133] Kit / Product Package

[0134] For use in the treatment of the above-indicated indications, kits / product packages are also described herein. These kits may consist of a dispenser, a packet or a container cassette which may be divided into a plurality of cells for accommodating one or more containers such as vials, test tubes and the like, each container containing a separate ingredient of the method. Suitable containers include bottles, vials, syringes and test tubes, etc. The containers are made of acceptable materials such as glass or plastic.

[0135] For example, the container may contain one or more of the compounds described herein, which may exist in the form of a pharmaceutical ingredient or as a mixture with other ingredients described herein. The container may have a sterile outlet (for example, the container may be an intravenous infusion bag or bottle, and the stopper may be pierced by a subcutaneous syringe needle). Such a kit may carry a compound, as well as instructions, labels, or operating instructions for the methods of use described herein.

[0136] A typical kit may include one or more containers, and each container contains one or more materials (such as reagents, which can also be concentrated stock solutions, and / or instruments) to meet the needs of commercial promotion and users' use of the compound. These materials include, but are not limited to, buffers, diluents, filters, needles, syringes, delivery devices, packages, containers, bottles, and / or test tubes, accompanied by an inventory list and / or instructions for use, and the inner packaging also has instructions. All instructions in the set should be included.

[0137] The label may be displayed on the container or be closely related to the container. When the label appears on the container, it means that the letters, numbers, or other features of the label are pasted, molded, or engraved on the container; the label may also appear in the container box or shipping box containing multiple containers, such as in the product insert. A label can be used to indicate a specific therapeutic use of the contents. The label can also indicate the instructions for using the contents, such as those described in the above methods.

[0138] All features described in this specification (including any of the described claims, abstract, and drawings), and / or all steps involved in any method or process, may exist in any combination, unless some features or steps are mutually exclusive in the same combination.

[0139] The above-mentioned features of the present invention, or the features mentioned in the embodiments, can be combined arbitrarily. All features disclosed in the specification of this case can be used in combination with any composition form, and each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equivalent or similar features.

[0140] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions mentioned in the following embodiments are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, all percentages, ratios, proportions, or parts are by weight.

[0141] The unit of weight / volume percentage in the present invention is well-known to those skilled in the art. For example, it refers to the weight of the solute in 100 milliliters of solution. Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to the described content can be applied to the method of the present invention. The preferred methods and materials described herein are for illustrative purposes only.

[0142] Examples

[0143] General procedure

[0144] When the preparation route is not included, the raw materials and reagents used in the present invention are known products, which can be synthesized according to methods known in the art or obtained by purchasing commercially available products. The commercially available reagents used do not require further purification. Room temperature refers to 20 - 30 °C.

[0145] Unless otherwise specified in the reaction examples, the reactions are carried out under a nitrogen atmosphere. A nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1 L.

[0146] For the hydrogenation reaction, it is usually evacuated, filled with hydrogen, and the operation is repeated 3 times. A hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L.

[0147] The microwave reaction uses Initiator + microwave reactor.

[0148] The structure of the compounds of the present invention is determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR measurement is carried out using a (Bruker Ascend TM 500 type) nuclear magnetic resonance instrument, and the solvents for measurement are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS). The following abbreviations are used for the multiplicity of NMR signals: s = singlet, brs = broad peak, d = doublet, t = triplet, m = multiplet. The coupling constant is listed as the J value and measured in Hz.

[0149] The LC-MS measurement is carried out using a Thermo liquid chromatography - mass spectrometry instrument (UltiMate 3000 + MSQ PLUS). The HPLC measurement is carried out using a Thermo high - performance liquid chromatography instrument (UltiMate 3000). The reversed - phase preparative chromatography uses a Thermo (UltiMate 3000) reversed - phase preparative chromatography instrument. The flash column chromatography uses an Agela (FS - 9200T) automatic column - passing machine, and the pre - packed silica gel column uses 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 of products is 0.4 mm to 0.5 mm.

[0150] Example 1

[0151] (S)-4,5-Dimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0152]

[0153] Compound 1 was prepared by the following steps:

[0154]

[0155] The first step: Dissolve 6-(trifluoromethyl)-3-pyridinemethanol 1a (4.0 g, 22.58 mmol) in dichloromethane (20 mL), and dropwise add thionyl chloride (26.87 g, 225.83 mmol, 16.38 mL) under ice bath conditions. After the addition, the reaction was warmed to room temperature and stirred overnight at 55 °C. The reaction solution was concentrated to obtain a crude yellow oil 1b (4.4 g, yield 99%). ESI-MS (m / z): 196.5 [M+H] + .

[0156] The second step: Dissolve compound 1b (4.4 g, 22.48 mmol) and compound 1c (1.8 g, 18.73 mmol) in N,N-dimethylformamide (10 mL), add potassium carbonate (6.47 g, 46.83 mmol), and stir overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow solid 1d (4.5 g, yield 94%). ESI-MS (m / z): 256.4 [M+H] + .

[0157] Step 3: Dissolve compound 1d (4.5 g, 17.63 mmol) and hydroxylamine hydrochloride (1.73 g, 26.45 mmol) in ethanol (20 mL), and stir overnight at room temperature. Add zinc powder (4.58 g, 70.53 mmol) and acetic acid (50 mL) to the reaction solution, and heat to 70 °C for reaction overnight. After the reaction is completed, most of the solvent is evaporated under reduced pressure. The residue is adjusted to pH 11 - 12 with 2N sodium hydroxide, and filtered. The filtrate is extracted with dichloromethane three times. The organic phases are combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow oil 1e (3.5 g, yield 77%). ESI-MS (m / z): 257.6 [M + H] + .

[0158] Step 4: Dissolve 2,4-dichloropyrido[3,2-d]pyrimidine 1f (1.7 g, 8.50 mmol) and (S)-methyl 2-(methylamino)propionate hydrochloride 1g (1.70 g, 11.05 mmol) in tetrahydrofuran (40 mL), add triethylamine (2.58 g, 25.50 mmol, 3.53 mL), and stir overnight at room temperature. Monitor the reaction by LCMS until it is completed. Concentrate the reaction solution, and purify the residue by silica gel column chromatography to obtain a yellow oil 1h (1.1 g, yield 46%). ESI-MS (m / z): 281 [M + H] + .

[0159] Step 5: Dissolve compound 1h (1.1 g, 3.92 mmol) in tetrahydrofuran (20 mL), add hydrochloric acid aqueous solution (6N, 0.65 mL) and platinum dioxide (88 mg, 0.39 mmol). Replace the hydrogen in the reaction system with a hydrogen balloon, and stir for 48 hours under the pressure of the hydrogen balloon at room temperature. Monitor the reaction by LCMS until it is completed. Dilute the reaction solution with methanol, filter, concentrate the filtrate and purify it by silica gel column chromatography to obtain a white solid 1i (900 mg, yield 90%). ESI-MS (m / z): 253 [M + H] + .

[0160] Step 6: Disperse compound 1i (300 mg, 1.19 mmol), compound 1e (395 mg, 1.54 mmol), Pd2(dba)3 (217 mg, 0.23 mmol), t-BuONa (342 mg, 3.56 mmol) and X-Phos (113 mg, 0.23 mmol) in toluene (10 mL). After replacing the reaction system with nitrogen, heat to 100 °C for reaction for 16 hours. Monitor the reaction by LCMS until it is completed. Concentrate the reaction solution, purify the residue by silica gel column chromatography, and further purify the crude product by preparative HPLC to obtain a white solid 1 (143 mg, yield 25%). ESI-MS (m / z): 473.2 [M + H]+ ; 1 HNMR(500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.13 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.82 (dd, J = 8.0, 1.5 Hz, 1H), 7.74 (s, 1H), 7.41 (s, 1H), 6.67 (t, J = 5.5 Hz 1H), 5.43 (s, 2H), 4.28 - 4.16 (m, 2H), 4.10 (q, J = 7.0 Hz, 1H), 4.04 - 3.96 (m, 1H), 3.30 - 3.20 (m, 1H), 2.93 (s, 3H), 2.54 - 2.50 (m, 2H), 1.95 - 1.85 (m, 1H), 1.84 - 1.70 (m, 1H), 1.21 (d, J = 7.0 Hz, 3H).

[0161] Example 2

[0162] (R)-4,5-Dimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0163]

[0164] Replace 1 g of (R)-methyl 2-(methylamino)propionate hydrochloride in the fourth step of Example 1 with (S)-methyl 2-(methylamino)propionate hydrochloride, and compound 2 can be obtained by a similar method and reaction steps. ESI-MS (m / z): 473.5 [M + H] + ; 1 HNMR(500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.17 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.77 (s, 1H), 7.44 (s, 1H), 6.69 (t, J = 5.0 Hz, 1H), 5.46 (s, 2H), 4.33 - 4.18 (m, 2H), 4.12 (q, J = 7.0 Hz, 1H), 4.07 - 4.00 (m, 1H), 3.31 - 3.24 (m, 1H), 2.95 (s, 3H), 2.56 - 2.52 (m, 2H), 1.98 - 1.90 (m, 1H), 1.85 - 1.75 (m, 1H), 1.23 (d, J = 6.5 Hz, 3H).

[0165] Example 3

[0166] 6-Methyl-4-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydro-3,5,6,9a-tetraazabenzo[cd]azulen-9(6H)-one

[0167]

[0168] Compound 3 was prepared by the following steps:

[0169]

[0170] The first step: Dissolve compound 3a (5.0 g, 26.59 mmol), triethylamine (5.38 g, 53.19 mmol) and 4-dimethylaminopyridine (324 mg, 2.66 mmol) in dichloromethane (50 mL). Dropwise add di-tert-butyl dicarbonate (6.38 g, 29.25 mmol) at room temperature and stir overnight. Monitor the reaction by LCMS until completion. Concentrate the reaction solution, and purify the residue by silica gel column chromatography to obtain compound 3b (5.3 g, yield 69%). ESI-MS (m / z): 288.4 [M+H] + .

[0171] The second step: Dissolve compound 3b (1.0 g, 3.48 mmol), ethyl 3-(methylamino)propionate 3c (0.55 g, 4.2 mmol) and N,N-diisopropylethylamine (1.35 g, 10.4 mmol) in tetrahydrofuran (10 mL). Stir at 50 °C overnight. Monitor the reaction by TLC until completion. Concentrate the reaction solution, and purify the residue by silica gel column chromatography to obtain a colorless oil 3d (1.33 g, yield 100%). ESI-MS (m / z): 383.2 [M+H] + .

[0172] The third step: Dissolve compound 3d (1.3 g, 3.40 mmol) and compound 1e (1.04 g, 4.07 mmol) in n-butanol (5 mL). Add trifluoroacetic acid (0.13 mL, 1.7 mmol). Heat the reaction solution to 150 °C by microwave for 5 hours. Monitor the reaction by LCMS until completion. Concentrate the reaction solution, and purify the residue by silica gel column chromatography to obtain a mixture of brown solids 3e and 3f (0.8 g), which is directly used for the next step. ESI-MS (m / z): 503.3 [M+H] + , 531.3 [M+H] + .

[0173] Step 4: Dissolve the product from the previous step (300 mg) in tetrahydrofuran (5 mL), add 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL, 1.2 mmol), and react at 70 °C for 16 h under nitrogen protection. Monitor the reaction by LCMS until it is completed. Concentrate the reaction solution, and prepare the residue by preparative HPLC to obtain white solid 3 (4 mg). ESI-LCMS (m / z): 457.2 [M+H] + ; 1 HNMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 7.90 - 7.82 (m, 3H), 7.78 (s, 1H), 7.44 (s, 1H), 6.64 (t, J = 6.1 Hz, 1H), 6.47 (d, J = 3.7 Hz, 1H), 5.45 (s, 2H), 4.32 (d, J = 6.1 Hz, 2H), 3.68 - 3.61 (m, 2H), 3.16 (s, 3H), 3.14 - 3.09 (m, 2H).

[0174] Examples 4, 5 and 6

[0175] 6,7-Dimethyl-4-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydro-3,5,6,9a-tetraazabenzo[cd]azulen-9(6H)-one

[0176]

[0177] (R)-6,7-Dimethyl-4-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydro-3,5,6,9a-tetraazabenzo[cd]azulen-9(6H)-one

[0178]

[0179] (S)-6,7-Dimethyl-4-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydro-3,5,6,9a-tetraazabenzo[cd]azulen-9(6H)-one

[0180]

[0181] Compounds 4, 5 and 6 are prepared by the following steps:

[0182]

[0183] Step 1: Dissolve compound 3b (1.0 g, 3.5 mmol) and ethyl 3-(methylamino)butanoate 4a (0.6 g, 4.2 mmol) in tetrahydrofuran (10 mL), and add N,N-diisopropylethylamine (1.35 g, 10.4 mmol). React at 50 °C overnight, and monitor the reaction completion by TLC. Concentrate the reaction solution, and purify the residue by silica gel column chromatography to obtain yellow solid 4b (1.22 g, yield 89%). ESI-MS (m / z): 397.3 [M+H] + .

[0184] Step 2: Dissolve compound 4b (1.17 g, 2.9 mmol) in n-butanol (5 mL), add trifluoroacetic acid (0.2 mL, 2.9 mmol), and heat the system to 150 °C by microwave for 5 h. Monitor the reaction completion by LCMS. Concentrate the reaction solution, and purify the residue by silica gel column chromatography to obtain a mixture of brown solids 4c and 4d (1.1 g), which is directly used in the next step. ESI-MS (m / z): 517.2 [M+H] + , 545.5 [M+H] + .

[0185] Step 3: Dissolve the mixture of 4c and 4d (320 mg) obtained in the previous step in tetrahydrofuran (5 mL), and add 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL, 1.2 mmol). Stir at 70 °C overnight, and monitor the reaction completion by LC-MS. Concentrate the reaction solution, and purify the residue by silica gel column chromatography to obtain white solid 4 (110 mg, yield 38%). ESI-MS (m / z): 471.0 [M+H] + ; 1 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 7.88 - 7.81 (m, 3H), 7.76 (s, 1H), 7.43 (s, 1H), 6.64 (br s, 1H), 6.44 (d, J = 3.6 Hz, 1H), 5.43 (s, 2H), 4.30 (d, J = 5.9 Hz, 2H), 3.96 - 3.88 (m, 1H), 3.37 (d, J = 16.1 Hz, 1H), 3.16 (s, 3H), 3.00 (dd, J = 16.0, 6.7 Hz, 1H), 1.10 (d, J = 6.8 Hz, 3H).

[0186] Step 4: Resolve the racemic compound 4 (102 mg) using a chiral column to obtain compound 5 (P1, 50 mg) and compound 6 (P2, 40 mg).

[0187] Compound 5: Retention time on chiral column = 5.62 min (ICH column, HEP:IPA (0.1% DEA) = 60:40); ESI-MS (m / z): 471.3 [M+H] + ; 1 HNMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 7.89 - 7.83 (m, 3H), 7.78 (s, 1H), 7.44 (s, 1H), 6.64 (t, J = 6.1 Hz, 1H), 6.45 (d, J = 3.6 Hz, 1H), 5.45 (s, 2H), 4.31 (d, J = 6.0 Hz, 2H), 3.98 - 3.89 (m, 1H), 3.38 (d, J = 15.9 Hz, 1H), 3.18 (s, 3H), 3.02 (dd, J = 16.0, 6.7 Hz, 1H), 1.12 (d, J = 6.8 Hz, 3H).

[0188] Compound 6: Retention time on chiral column = 6.24 min (ICH column, HEP:IPA (0.1% DEA) = 60:40); ESI-MS (m / z): 471.3 [M+H] + ; 1 HNMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 7.89 - 7.83 (m, 3H), 7.78 (s, 1H), 7.45 (s, 1H), 6.64 (t, J = 5.7 Hz, 1H), 6.46 (d, J = 3.6 Hz, 1H), 5.45 (s, 2H), 4.32 (d, J = 6.0 Hz, 2H), 3.98 - 3.87 (m, 1H), 3.38 (d, J = 16.0 Hz, 1H), 3.18 (s, 3H), 3.02 (dd, J = 16.0, 6.7 Hz, 1H), 1.12 (d, J = 6.8 Hz, 3H).

[0189] Example 7

[0190] (S)-4,5-Dimethyl-2-(((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0191]

[0192] Compound 7 was prepared by the following steps:

[0193]

[0194] Step 1: Dissolve 1H-pyrazole-4-carbaldehyde 1c (5 g, 52.04 mmol) in N,N-dimethylformamide (20 mL), and successively add Cs2CO3 (33.91 g, 104.07 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (18.12 g, 78.05 mmol). After reacting at room temperature for 4 hours, TLC shows that the raw materials are completely converted. Dilute the reaction solution with ethyl acetate and wash it with saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter and concentrate to obtain compound 7a (8.0 g), which is directly used in the next step of the reaction.

[0195] Step 2: Dissolve the compound 7a (8.0 g) obtained in the previous step in ethanol (20 mL), add hydroxylamine hydrochloride (6.24 g, 89.83 mmol), and stir the reaction solution at room temperature overnight. Concentrate the reaction solution to obtain the crude oxime, redissolve it in acetic acid (50 mL), and add zinc powder (17.47 g, 267.18 mmol). React the reaction solution at 60 °C for 2 hours, and monitor the reaction by LC-MS until it is completely converted. Cool the reaction solution to room temperature, dilute it with ethyl acetate, and alkalize it to pH = 10 with NaOH solution (2N). Filter the mixture, and concentrate the filtrate to obtain compound 7b (4.5 g), which is directly used in the next step of the reaction.

[0196] Step 3: Disperse compound 1i (200 mg, 0.79 mmol), compound 7b (212 mg, 1.19 mmol), Pd2(dba)3 (144 mg, 0.15 mmol), t-BuONa (228 mg, 2.37 mmol) and X-Phos (75 mg, 0.15 mmol) in toluene (10 mL). After replacing the nitrogen in the reaction system, heat it to 100 °C and react for 16 hours. Monitor the end of the reaction by LCMS, concentrate the reaction solution, purify the residue by silica gel column chromatography, and further purify the obtained crude product by preparative HPLC to obtain white solid 7 (71 mg, yield 22%). ESI-MS (m / z): 396.3 [M+H] + ; 1 HNMR (500 MHz, DMSO-d6) δ 8.13 (s, 2H), 7.67 (s, 1H), 7.46 (s, 1H), 6.74 (t, J = 5.0 Hz, 1H), 5.03 (q, J = 9.0 Hz, 2H), 4.30 - 4.17 (m, 2H), 4.11 (q, J = 7.0 Hz, 1H), 4.04 - 3.96 (m, 1H), 3.29 - 3.21 (m, 1H), 2.94 (s, 3H), 2.53 - 2.50 (m, 2H), 1.96 - 1.88 (m, 1H), 1.86 - 1.75 (m, 1H), 1.21 (d, J = 7.0 Hz, 3H).

[0197] Example 8

[0198] (S)-4,5-Dimethyl-2-(((6-(trifluoromethoxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0199]

[0200] Compound 8 was prepared by the following steps:

[0201]

[0202] The first step: Compound 1i (80 mg, 0.31 mmol), 6-(trifluoromethoxy)pyridine-3-methylamine hydrochloride 8a (94 mg, 0.41 mmol), Pd2(dba)3 (57 mg, 0.063 mmol), X-Phos (30 mg, 0.063 mmol) and t-BuONa (91 mg, 0.094 mmol) were dispersed in toluene (5 mL). After the system was purged with nitrogen, it was heated to 100 °C and reacted for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was concentrated, and the residue was purified by preparative HPLC to obtain a white solid 8 (28 mg, yield 22%). ESI-MS (m / z): 409.3 [M+H] + ; 1 1H NMR (500 MHz, DMSO-d6) δ 8.31 (d, J = 2.5 Hz, 1H), 8.20 (s, 1H), 7.95 (dd, J = 8.5, 2.5 Hz, 1H), 7.24 (d, J = 8.5 Hz, 1H), 7.12 (t, J = 6.0 Hz, 1H), 4.48 - 4.36 (m, 2H), 4.12 (q, J = 7.0 Hz, 1H), 4.08 - 3.97 (m, 1H), 3.33 - 3.23 (m, 1H), 2.92 (s, 3H), 1.99 - 1.88 (m, 1H), 1.86 - 1.73 (m, 1H), 1.23 (d, J = 7.0 Hz, 3H).

[0203] Example 9

[0204] 6,7-Dimethyl-4-(((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydro-3,5,6,9a-tetraazabenzo[cd]azulen-9(6H)-one

[0205]

[0206] Compound 9 was prepared by the following steps:

[0207]

[0208] Step 1: Dissolve compound 4b (1.2 g, 3.0 mmol) and compound 7b (0.65 g, 3.63 mmol) in n-butanol (5 mL), add trifluoroacetic acid (0.2 mL, 2.9 mmol), heat the reaction solution to 150 °C by microwave for 5 hours, and monitor the completion of the reaction by LC-MS. Concentrate the reaction solution, and purify the residue by silica gel column chromatography to obtain a mixture of brown solids 9a and 9b (0.95 g), which is directly used in the next step. ESI-MS (m / z): 440.3 [M+H] + , 468.2 [M+H] + .

[0209] Step 2: Dissolve 9a and 9b (300 mg) in tetrahydrofuran (5 mL), add 1,8-diazabicyclo[5.4.0]undec-7-ene (0.20 mL, 1.4 mmol). Stir at 70 °C overnight, and monitor the completion of the reaction by LC-MS. Concentrate the reaction solution, and purify the residue by silica gel column chromatography to obtain white solid 9 (130 mg). ESI-MS (m / z): 394.3 [M+H] + ; 1 1H NMR (500 MHz, DMSO-d6) δ 7.87 (d, J = 3.7 Hz, 1H), 7.70 (s, 1H), 7.50 (s, 1H), 6.72 (br s, 1H), 6.46 (d, J = 3.6 Hz, 1H), 5.05 (q, J = 9.2 Hz, 2H), 4.33 (d, J = 6.1 Hz, 2H), 3.97 - 3.93 (m, 1H), 3.39 (d, J = 15.9 Hz, 1H), 3.20 (s, 3H), 3.02 (dd, J = 16.1, 6.7 Hz, 1H), 1.12 (d, J = 6.9 Hz, 3H).

[0210] Example 10

[0211] 6-Methyl-4-(((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydro-3,5,6,9a-tetraazabenzo[cd]azulen-9(6H)-one

[0212]

[0213] Compound 10 was prepared by the following steps:

[0214]

[0215] Step 1: Dissolve compound 3d (500 mg, 1.3 mmol) and 7b (0.28 g, 1.57 mmol) in n-butanol (4 mL), add trifluoroacetic acid (0.1 mL, 1.3 mmol), heat the reaction mixture to 150 °C by microwave for 5 h, and monitor the reaction completion by LC-MS. Concentrate the reaction mixture, and purify the residue by silica gel column chromatography to obtain a mixture of brown solids 10a and 10b (420 mg), which is directly used for the next step. ESI-MS (m / z): 426.3 [M+H] + , 454.2 [M+H] + 。

[0216] Step 2: Dissolve 10a and 10b (420 mg) in tetrahydrofuran (5 mL), add 1,8-diazabicyclo[5.4.0]undec-7-ene (0.29 mL, 2.0 mmol). Stir at 70 °C overnight and monitor the reaction completion by LC-MS. Concentrate the reaction mixture, and purify the residue by silica gel column chromatography to obtain white solid 10 (50 mg, yield of two steps: 10%). ESI-MS (m / z): 380.3 [M+H] + ; 1 HNMR (500 MHz, DMSO-d6) δ 7.87 (d, J = 3.7 Hz, 1H), 7.70 (s, 1H), 7.50 (s, 1H), 6.71 (br s, 1H), 6.48 (d, J = 3.7 Hz, 1H), 5.05 (q, J = 9.2 Hz, 2H), 4.33 (d, J = 6.1 Hz, 2H), 3.73 - 3.62 (m, 2H), 3.18 (s, 3H), 3.16 - 3.08 (m, 2H).

[0217] Example 11

[0218] (S)-4,5-Dimethyl-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0219]

[0220] Compound 11 was prepared by the following steps:

[0221]

[0222] Step 1: Dissolve 6-(trifluoromethyl)pyridin-3-ol 11a (1.0 g, 6.13 mmol) in dimethyl sulfoxide (10 mL), add cesium carbonate (2.0 g, 6.13 mmol), stir at room temperature for 30 minutes, then add 2-fluoropyridine-5-carbaldehyde 11b (1.53 g, 12.26 mmol). After the reaction mixture is stirred for another 2 hours, the reaction is terminated. The reaction solution is diluted with ethyl acetate, washed successively with water and saturated brine, the organic phase is dried over anhydrous sodium sulfate, filtered and concentrated, and the residue is purified by silica gel column chromatography to obtain the product 11c (1.5 g, yield 91%). 1 HNMR (500 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.79 - 8.70 (m, 2H), 8.37 (dd, J = 8.6, 2.3 Hz, 1H), 8.05 (d, J = 1.0 Hz, 2H), 7.42 (d, J = 8.6 Hz, 1H).

[0223] Step 2: Dissolve compound 11c (1.53 g, 5.70 mmol) in ethanol (5 mL), add hydroxylamine hydrochloride (792 mg, 11.41 mmol), and stir at room temperature overnight. The reaction solution is concentrated to obtain the crude oxime, which is redissolved in acetic acid (5 mL), zinc powder (1.94 g, 29.66 mmol) is added, and the mixture is stirred at room temperature for 2 hours. LCMS is used to detect the completion of the reaction. The reaction mixture is filtered, the filtrate is concentrated to remove most of the acetic acid, diluted with ethyl acetate, and then basified to pH = 11 with NaOH solution (2N). The mixture is filtered, and the filtrate is concentrated to obtain compound 11d (1.3 g), which is directly used for the next step. ESI-MS (m / z): 270.5 [M + H] + 。

[0224] Step 2: Disperse compound 11d (383 mg), compound 1i (300 mg, 1.19 mmol), Pd2(dba)3 (217 mg, 0.23 mmol), t-BuONa (342 mg, 3.56 mmol) and X-Phos (113 mg, 0.23 mmol) in toluene (10 mL). After the system is purged with nitrogen, it is heated to 100 °C and reacted for 16 hours. LCMS is used to monitor the end of the reaction. The reaction solution is concentrated, and the residue is purified by silica gel column chromatography, and the crude product is further purified by preparative HPLC to obtain compound 11 (20 mg, yield 3%). ESI-MS (m / z): 486.4 [M + H] + ; 1HNMR(500MHz, DMSO-d6) δ 8.64 (d, J = 2.6 Hz, 1H), 8.17 (s, 1H), 8.14 (d, J = 2.2 Hz, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.92 - 7.86 (m, 2H), 7.18 (d, J = 8.4 Hz, 1H), 7.06 (br s, 1H), 4.40 - 4.30 (m, 2H), 4.12 (q, J = 6.8 Hz, 1H), 4.05 - 3.99 (m, 1H), 3.26 (d, J = 3.2 Hz, 1H), 2.94 (s, 3H), 1.96 - 1.88 (m, 1H), 1.85 - 1.76 (m, 1H), 1.24 (d, J = 6.8 Hz, 3H).

[0225] Example 12

[0226] (S)-2-(((6-(3,3-Difluorocyclobutoxy)pyridin-3-yl)methyl)amino)-4,5-dimethyl-4,5,9,10-tetrahydro

[0227] -6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0228]

[0229] Compound 12 was prepared by the following steps:

[0230]

[0231] First step: Dissolve 3,3-difluorocyclobutanol 12a (572 mg, 5.30 mmol) in N,N-dimethylformamide (20 mL), add cesium carbonate (3.98 g, 12.23 mmol) and 2-fluoropyridine-5-carbaldehyde 11b (0.51 g, 4.08 mmol), stir for 3 hours and then end the reaction. Dilute the reaction solution with ethyl acetate, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter and concentrate. The residue was purified by silica gel column chromatography to obtain compound 12b (0.55 g, yield 63%).

[0232] Step 2: Dissolve compound 12b (0.55 g, 2.58 mmol) in ethanol (20 mL), add hydroxylamine hydrochloride (358 mg, 5.16 mmol), and stir at room temperature overnight. Concentrate the reaction solution to obtain the crude oxime, redissolve it in acetic acid (10 mL), add zinc powder (997 mg, 15.25 mmol), and stir at 60 °C for 3 hours. Monitor the reaction by LCMS until completion. Filter the reaction mixture, concentrate the filtrate to remove most of the acetic acid, dilute with ethyl acetate, and basify to pH = 11 with NaOH solution (2N) under ice bath. Filter the mixture, concentrate the filtrate to obtain compound 12c (0.3 g), which is directly used in the next step of the reaction.

[0233] Step 3: Disperse compound 12c (135 mg), compound 1i (80 mg, 0.31 mmol), Pd2(dba)3 (57 mg, 0.063 mmol), t-BuONa (91 mg, 0.94 mmol), and X-Phos (30 mg, 0.063 mmol) in toluene (10 mL). After replacing the reaction system with nitrogen, heat to 100 °C and react for 5 hours. Monitor the reaction by LCMS until completion. Concentrate the reaction solution, purify the residue by preparative thin-layer chromatography, and then purify the crude product by preparative HPLC to obtain compound 12 (8 mg, yield 5%). ESI-MS (m / z): 431.2 [M+H] + ; 1 1H NMR (500 MHz, DMSO-d6) δ 8.23 (br s, 1H), 8.10 (s, 1H), 7.70 (dd, J = 8.4, 2.0 Hz, 1H), 7.00 (br s, 1H), 6.80 (d, J = 8.4 Hz, 1H), 5.12 - 5.03 (m, 1H), 4.40 - 4.25 (m, 2H), 4.15 - 4.10 (m, 1H), 4.05 - 4.00 (m, 1H), 3.31 - 3.25 (m, 1H), 3.20 - 3.07 (m, 2H), 2.94 (s, 3H), 2.70 - 2.60 (m, 2H), 1.97 - 1.88 (m, 1H), 1.84 - 1.76 (m, 1H), 1.23 (d, J = 6.7 Hz, 3H).

[0234] Example 13

[0235] (S)-4,5-Dimethyl-2-(((1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0236]

[0237] Compound 13 was prepared by the following steps:

[0238]

[0239] The first step: Dissolve 4-(Boc-aminomethyl)pyrazole 13b (0.3 g, 1.52 mmol) in N,N-dimethylformamide (10 mL), add 3-(trifluoromethyl)benzyl chloride 13a (443 mg, 2.28 mmol) and cesium carbonate (1.49 g, 4.56 mmol), and terminate the reaction after stirring at room temperature for 4 hours. Dilute the reaction solution with ethyl acetate, wash it with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter and concentrate to obtain compound 13c (0.51 g, yield 94%). ESI-MS (m / z): 356.5 [M+H] + 。

[0240] The second step: Dissolve compound 13c (0.51 g, 1.44 mmol) in dioxane (5 mL), add 4N hydrochloric acid in dioxane solution (1 mL), stir the reaction solution at room temperature overnight, and detect the completion of the reaction by LCMS. Concentrate the reaction solution to obtain compound 13d (0.36 g).

[0241] The third step: Disperse compound 13d (393 mg), compound 1i (300 mg, 1.19 mmol), Pd2(dba)3 (217 mg, 0.23 mmol), t-BuONa (342 mg, 3.56 mmol) and S-Phos (97 mg, 0.23 mmol) in toluene (20 mL), replace the nitrogen in the reaction system and heat to 100 °C for reaction for 16 hours. Monitor the end of the reaction by LCMS, concentrate the reaction solution, purify the residue by preparative thin-layer chromatography, and then purify the crude product by preparative HPLC to obtain compound 13 (200 mg, yield 35%). ESI-MS (m / z): 472.5 [M+H] + ; 1 1H NMR (500 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.73 (s, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.61 - 7.55 (m, 2H), 7.50 (d, J = 7.7 Hz, 1H), 7.42 (s, 1H), 6.69 (br s, 1H), 5.38 (s, 2H), 4.30 - 4.18 (m, 2H), 4.12 (q, J = 6.7 Hz, 1H), 4.07 - 4.00 (m, 1H), 3.31 - 3.24 (m, 1H), 2.95 (s, 3H), 2.57 - 2.52 (m, 2H), 1.97 - 1.89 (m, 1H), 1.86 - 1.75 (m, 1H), 1.23 (d, J = 6.7 Hz, 3H).

[0242] Example 14

[0243] (S)-2-(((1-(4-Fluorophenethyl)-1H-pyrazol-4-yl)methyl)amino)-4,5-dimethyl-4,5,9,10-tetrahydro

[0244] -6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0245]

[0246] Replace 3-trifluoromethylbenzyl chloride 13a in the first step of Example 13 with 4-fluorophenethyl bromide, and compound 14 can be obtained by a similar method and reaction steps. ESI-MS (m / z): 436.5 [M+H] + ; 1 HNMR (500 MHz, DMSO-d6) δ8.13 (s, 1H), 7.43 (s, 1H), 7.33 (s, 1H), 7.14 - 7.09 (m, 2H), 7.04 - 6.98 (m, 2H), 6.59 (br s, 1H), 4.22 (t, J = 7.2 Hz, 2H), 4.17 (dd, J = 11.7, 6.1 Hz, 2H), 4.14 - 4.08 (m, 1H), 4.03 - 3.98 (m, 1H), 3.29 - 3.22 (m, 1H), 3.01 (t, J = 7.2 Hz, 2H), 2.92 (s, 3H), 2.55–2.50 (m, 2H), 1.95 - 1.87 (m, 1H), 1.83 - 1.74 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H).

[0247] Example 15

[0248] (S)-2-(((1-(4-Fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-4,5-dimethyl-4,5,9,10-tetrahydro-6H,8H-

[0249] pyrido[3,2,1-de]pteridin-6-one

[0250]

[0251] Replace 3-trifluoromethylbenzyl chloride 13a in the first step of Example 13 with 4-fluorobenzyl chloride, and compound 15 can be obtained by a similar method and reaction steps. ESI-MS (m / z): 422.5 [M+H] + ; 1HNMR (500 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.63 (s, 1H), 7.36 (s, 1H), 7.27 - 7.22 (m, 2H), 7.15 - 7.10 (m, 2H), 6.66 (br s, 1H), 5.22 (s, 2H), 4.25 - 4.16 (m, 2H), 4.10 (q, J = 6.7 Hz, 1H), 4.03 - 3.97 (m, 1H), 3.29 - 3.22 (m, 1H), 2.93 (s, 3H), 2.53 - 2.49 (m, 2H), 1.95 - 1.86 (m, 1H), 1.83 - 1.72 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H).

[0252] Example 16

[0253] (S)-4,5-Dimethyl-2-(((6-((4-(trifluoromethyl)benzyl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0254]

[0255] Compound 16 was prepared by the following steps:

[0256]

[0257] First step: Dissolve 2-hydroxy-5-pyridinecarboxaldehyde 16a (0.5 g, 4.06 mmol) in N,N-dimethylformamide (30 mL), add cesium carbonate (3.97 g, 12.18 mmol) and 4-(trifluoromethyl)benzyl chloride 16b (1.03 g, 5.28 mmol), and stir the reaction mixture at room temperature overnight. Dilute the reaction mixture with ethyl acetate, wash with saturated brine, dry the organic phase over anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography to obtain compound 16c (0.91 g, yield 79%). ESI-MS (m / z): 282.3 [M + H] + ; 1 HNMR (500 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.80 (d, J = 2.4 Hz, 1H), 7.83 (dd, J = 9.5, 2.4 Hz, 1H), 7.74 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 6.56 (d, J = 9.5 Hz, 1H), 5.30 (s, 2H).

[0258] Step 2: Dissolve compound 16c (0.91 g, 3.24 mmol) in ethanol (20 mL), add hydroxylamine hydrochloride (449 mg, 6.47 mmol), and stir at room temperature overnight. Then continue to add zinc powder (993 mg, 15.19 mmol) and concentrated hydrochloric acid (0.5 mL) to the reaction mixture, and terminate the reaction after reacting at room temperature for 0.5 h. Alkalize the reaction solution with ammonia water to pH = 11, dilute with ethyl acetate, and wash with saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter and concentrate to obtain compound 16d (0.72 g), which is directly used for the next reaction. ESI-MS (m / z): 282.3 [M+H] + 。

[0259] Step 3: Disperse compound 16d (290 mg), compound 1i (200 mg, 0.79 mmol), Pd2(dba)3 (144 mg, 0.15 mmol), t-BuONa (228 mg, 2.37 mmol) and S-Phos (64 mg, 0.15 mmol) in toluene (20 mL). After replacing the reaction system with nitrogen, heat it to 100 °C and react for 16 h. Monitor the reaction by LCMS until it is completed, concentrate the reaction solution, purify the residue by preparative thin-layer chromatography, and then purify the crude product by preparative HPLC to obtain compound 16 (175 mg, yield 44%). ESI-MS (m / z): 499.5 [M+H] + ; 1 1H NMR (500 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.82 (d, J = 1.8 Hz, 1H), 7.75 - 7.71 (m, 2H), 7.66 - 7.62 (t, 2H), 7.57 (dd, J = 9.3, 2.3 Hz, 1H), 7.02 (br s, 1H), 6.51 (d, J = 9.3 Hz, 1H), 5.26 (s, 2H), 4.26 - 4.15 (m, 3H), 4.13 - 4.07 (m, 1H), 3.37 - 3.30 (m, 1H), 2.97 (s, 3H), 2.57 - 2.50 (m, 2H), 2.02 - 1.94 (m, 1H), 1.90 - 1.81 (m, 1H), 1.29 (d, J = 6.8 Hz, 3H).

[0260] Example 17

[0261] (S)-4,5-Dimethyl-2-(((6-((3-(trifluoromethyl)benzyl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0262]

[0263] Replace 4-(trifluoromethyl)benzyl chloride 16b in the first step of Example 16 with 3-(trifluoromethyl)benzyl chloride 13a, and compound 17 can be obtained by a similar method and reaction steps. ESI-MS (m / z): 499.5 [M+H] + ; 1 HNMR (500 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.82 (d, J = 1.8 Hz, 1H), 7.75 - 7.71 (m, 2H), 7.66 - 7.62 (m, 2H), 7.57 (dd, J = 9.3, 2.3 Hz, 1H), 7.02 (br s, 1H), 6.51 (d, J = 9.3 Hz, 1H), 5.26 (s, 2H), 4.26 - 4.15 (m, 3H), 4.13 - 4.07 (m, 1H), 3.37 - 3.30 (m, 1H), 2.97 (s, 3H), 2.57 - 2.50 (m, 2H), 2.02 - 1.94 (m, 1H), 1.90 - 1.81 (m, 1H), 1.29 (d, J = 6.8 Hz, 3H).

[0264] Example 18

[0265] (S)-2-(((2-(Cyclopropylmethyl)pyrimidin-5-yl)methyl)amino)-4,5-dimethyl-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0266]

[0267] Compound 18 was prepared by the following steps:

[0268]

[0269] First step: Disperse compound 18a (65 mg, 0.40 mmol), compound 1i (100 mg, 0.40 mmol), Pd2(dba)3 (36 mg, 0.04 mmol), t-BuONa (114 mg, 1.19 mmol) and S-Phos (32 mg, 0.079 mmol) in toluene (10 mL). After replacing the reaction system with nitrogen, heat it to 100 °C and react for 16 hours. Monitor the reaction by LCMS. After the reaction solution is concentrated, the residue is purified by preparative thin-layer chromatography, and the crude product is further prepared by Prep-HPLC to obtain a white solid 18 (52 mg, yield 34%). ESI-MS (m / z): 380.5 [M+H] + ; 1HNMR (500 MHz, DMSO-d6) δ 8.66 (s, 2H), 8.14 (s, 1H), 7.09 (br s, 1H), 4.42 - 4.29 (m, 2H), 4.12 (q, J = 6.7 Hz, 1H), 4.05 - 3.96 (m, 1H), 3.31 - 3.23 (m, 1H), 2.93 (s, 3H), 2.71 (d, J = 7.0 Hz, 2H), 2.55 - 2.51 (m, 2H), 1.96 - 1.88 (m, 1H), 1.84 - 1.74 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H), 1.19 - 1.09 (m, 1H), 0.47 - 0.38 (m, 2H), 0.24 - 0.14 (m, 2H).

[0270] Example 19

[0271] (S)-4,6-Dimethyl-N-((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)-5,6-dihydro-4H-pyrrolo[3,2,1-de]pteridin-2-amine

[0272]

[0273] Compound 19 was prepared by the following steps:

[0274]

[0275] The first step: Dissolve compound 19a (200 mg, 1.06 mmol) and 19b (808 mg, 3.19 mmol) in N,N-dimethylformamide (5 mL), add Cs2CO3 (1.39 g, 4.26 mmol), heat the reaction mixture to 100 °C and react for 2 hours. Monitor the reaction by LCMS until completion. Dilute the reaction mixture with water and extract with ethyl acetate. Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography to obtain white solid 19c (200 mg, yield 60%). ESI-MS (m / z): 253.5 [M - 55] + .

[0276] The second step: Dissolve compound 19c (200 mg, 0.64 mmol) in dioxane (5 mL), add concentrated hydrochloric acid (118 mg, 0.098 mL), stir the reaction mixture at room temperature for 1 hour. Monitor the reaction by LCMS until completion. Concentrate the reaction mixture under reduced pressure to obtain compound 19d (135 mg, yield 99%). ESI-MS (m / z): 209.7 [M + 1] +Step 3: Dissolve compound 19d (135 mg, 0.64 mmol) in THF (3 mL). Add NaH (77 mg, 1.92 mmol) under ice bath. After stirring for 5 minutes, add methyl iodide (137 mg, 0.97 mmol). Continue stirring for half an hour and monitor the reaction by LCMS until completion. Dilute the reaction solution with water and extract with ethyl acetate. Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography to obtain compound 19e (60 mg, yield 41%). ESI-MS (m / z): 223.6 [M+H] + 。

[0277] Step 4: Dissolve compound 19e (60 mg, 0.26 mmol) and 1e (103 mg, 0.40 mmol) in n-butanol (5 mL). Add trifluoroacetic acid (153 mg, 1.35 mmol). Heat the reaction solution to 150 °C by microwave for 4 hours and monitor the reaction by LCMS until completion. Concentrate the reaction solution and purify the residue by preparative HPLC to obtain compound 19 (20 mg, yield 16%). ESI-MS (m / z): 443.6 [M+H] + ; 1 1H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.18 (s, 1H), 7.92 - 7.81 (m, 3H), 7.49 (s, 1H), 7.28 (s, 1H), 6.09 (s, 1H), 5.47 (s, 2H), 4.36 (d, J = 5.4 Hz, 2H), 4.18 (dd, J = 12.3, 3.9 Hz, 1H), 4.07 (dd, J = 12.4, 2.9 Hz, 1H), 3.99 (s, 1H), 3.11 (s, 3H), 1.24 (d, J = 6.5 Hz, 3H).

[0278] Example 20

[0279] (S)-4,6-Dimethyl-N-((6-(3,3,3-trifluoropropyl)pyridin-3-yl)methyl)-5,6-dihydro-4H-pyrrolo

[0280] [3,2,1-de]pteridin-2-amine

[0281]

[0282] Compound 20 was prepared by the following steps:

[0283]

[0284] Step 1: Dissolve compound 19e (81 mg, 0.36 mmol) and 20a (112 mg, 0.55 mmol) in n-butanol (3 mL), add trifluoroacetic acid (41 mg, 0.36 mmol), heat the reaction mixture to 150 °C by microwave for 3 hours, and monitor the completion of the reaction by LCMS. Concentrate the reaction mixture, and purify the residue by preparative HPLC to obtain compound 20 (101 mg, yield 70%). ESI-MS (m / z): 391.4 [M+H] + ; 1 1H NMR (500 MHz, DMSO-d6) δ 8.54 (d, J = 1.8 Hz, 1H), 8.21 (s, 1H), 7.73 (dd, J = 8.0, 2.2 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.18 (d, J = 2.7 Hz, 1H), 4.57 (d, J = 5.8 Hz, 2H), 4.43 - 4.35 (m, 1H), 3.81 (dd, J = 12.9, 4.1 Hz, 1H), 3.50 (dd, J = 12.9, 8.6 Hz, 1H), 3.17 (s, 3H), 2.95 (dd, J = 9.2, 6.7 Hz, 2H), 2.75 - 2.63 (m, 2H), 1.45 (d, J = 6.4 Hz, 3H).

[0285] Example 21

[0286] (S)-8-(Difluoromethyl)-4,6-dimethyl-N-((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)-5,6-dihydro-4H-pyrrolo[3,2,1-de]pteridin-2-amine

[0287]

[0288] Compound 21 was prepared by the following steps:

[0289]

[0290] Step 1: Under nitrogen protection, dissolve compound 19e (0.6 g, 2.69 mmol) in anhydrous THF (10 mL), cool to -70 °C, add n-butyllithium (6.7 mL, 1.6 M, 10.78 mmol) dropwise, continue stirring for 15 minutes, and then add N,N-dimethylformamide (787 mg, 10.78 mmol). After reacting the reaction mixture at -70 °C for 2 hours, add saturated ammonium chloride aqueous solution (2 mL) to terminate the reaction. Dilute the reaction mixture with ethyl acetate and wash with saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography to obtain compound 21a (0.3 g, yield 44%). ESI-MS (m / z): 251.5 [M+H] + 。

[0291] Step 2: Dissolve compound 21a (0.45 g, 1.80 mmol) in dichloromethane (10 mL), add diethylaminosulfur trifluoride DAST (1.2 mL) dropwise under an ice bath, and then raise the temperature to room temperature and stir for 3 hours. Quench the reaction solution with saturated sodium bicarbonate aqueous solution (2 mL), dilute with dichloromethane, and wash with saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography to obtain compound 21b (0.25 g, yield 51%). ESI-MS (m / z): 273.4 [M+H] + 。

[0292] Step 3: Disperse compound 21b (100 mg, 0.36 mmol), compound 1e (122 mg, 0.47 mmol), Pd2(dba)3 (67 mg, 0.073 mmol), t-BuONa (105 mg, 1.10 mmol) and X-Phos (34 mg, 0.073 mmol) in toluene (3 mL). After replacing the nitrogen in the reaction system, heat to 100 °C and react for 16 hours. Monitor the reaction by LCMS until it is completed. Concentrate the reaction solution, and first purify the residue by silica gel column chromatography, and then purify the crude product by Prep-HPLC to obtain compound 21 (55 mg, yield 30%). ESI-MS (m / z): 493.3 [M+H] + ; 1HNMR(500MHz, DMSO-d6) δ 8.64 (s, 1H), 8.21 (s, 1H), 7.87 - 7.83 (m, 2H), 7.80 (s, 1H), 7.47 (s, 1H), 7.26 (t, J = 53.7 Hz, 1H), 6.39 (s, 1H), 5.45 (s, 2H), 4.74 - 4.68 (m, 1H), 4.31 (d, J = 5.8 Hz, 2H), 3.76 (dd, J = 12.6, 3.7 Hz, 1H), 3.46 (dd, J = 12.6, 2.2 Hz, 1H), 3.09 (s, 3H), 1.29 (d, J = 6.5 Hz, 3H).

[0293] Example 22

[0294] (S)-8-(Difluoromethyl)-4,5-dimethyl-N-((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)-5,6-dihydro-4H-pyrrolo[3,2,1-de]pteridin-2-amine

[0295]

[0296] Compound 22 was prepared by the following steps:

[0297]

[0298] First step: Dissolve compound 19a (5.0 g, 26.59 mmol), 22a (7.57 g, 31.91 mmol) and 18-crown-6 (2.11 g, 7.98 mmol) in dioxane (50 mL), add potassium carbonate (11.03 g, 79.78 mmol), heat the reaction system to 50 °C and react for 16 hours. Monitor the reaction by LCMS until completion. Dilute the reaction solution with ethyl acetate, wash it with water and saturated brine respectively, dry the organic phase with anhydrous sodium sulfate, filter and concentrate. The residue was triturated with ethyl acetate / petroleum ether (1 / 1) to obtain gray solid 22b (8 g, crude product), which was directly used for the next step of the reaction. ESI-MS (m / z): 345.4 [M + H] + .

[0299] Second step: Dissolve compound 22b (5.0 g, crude product) in dichloromethane (30 mL), add hydrochloric acid dioxane solution (4N, 18.1 mL), stir the reaction solution at room temperature for 16 hours, and monitor the reaction by LCMS until complete. Filter the reaction solution, collect the filter cake, and dry it under reduced pressure to obtain the hydrochloride salt of compound 22c (4.0 g, crude product), which was directly used for the next step of the reaction. ESI-MS (m / z): 245.6 [M + H] + .

[0300] Step 3: Dissolve the hydrochloride salt of compound 22c (4.0 g, crude product) in a mixture of dioxane (50 mL) and N,N-dimethylformamide (5 mL), add N,N-diisopropylethylamine (1.84 g, 14.21 mmol), heat the reaction solution to 100 °C and react for 16 hours. Monitor the reaction completion by LCMS. Concentrate the reaction solution, dilute the residue with ethyl acetate, and wash it successively with saturated ammonium chloride solution and saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography to obtain yellow solid 22d (1.6 g). ESI-MS (m / z): 209.6 [M+H] + 。

[0301] Step 4: Dissolve compound 22d (2.1 g, 10.06 mmol) in anhydrous N,N-dimethylformamide (15 mL), add NaH (401 mg, 60% content, 10.06 mmol) portionwise under ice bath. After stirring the reaction mixture for 30 minutes, add methyl iodide (1.43 g, 10.06 mmol, 0.93 mL). Raise the reaction solution to room temperature and stir for 16 hours. Monitor the reaction completion by LCMS. Dilute the reaction solution with ethyl acetate, wash it successively with water and saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter and concentrate to obtain yellow solid 22e (2.0 g, yield 89%). ESI-MS (m / z): 223.5 [M+H] + 。

[0302] Step 5: Under nitrogen protection, dissolve compound 22e (200 mg, 0.89 mmol) in anhydrous tetrahydrofuran (8 mL), cool the reaction solution to -70 °C, dropwise add n-butyllithium solution (2.5 M, 1.8 mL), stir for 30 minutes and then add N,N-dimethylformamide (262 mg, 3.59 mmol). Continue to stir the reaction mixture at -70 °C for 3 hours and then slowly raise it to room temperature. Quench the reaction solution with dilute hydrochloric acid (1 N), add ethyl acetate to dilute, and wash it successively with water and saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography to obtain compound 22f (150 mg, yield 66%). ESI-MS (m / z): 251.5 [M+H] + 。

[0303] Step 6: Dissolve compound 22f (150 mg, 0.59 mmol) in dichloromethane (5 mL). Dropwise add diethylaminosulfur trifluoride DAST (192 mg, 1.20 mmol, 0.16 mL) under ice bath, and then raise the temperature to room temperature and stir for 5 h. Quench the reaction mixture by adding saturated aqueous sodium bicarbonate solution (2 mL), dilute with dichloromethane, and wash with saturated brine. Dry the organic phase over anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography to obtain white solid 22g (150 mg, yield 73%). ESI-MS (m / z): 273.4 [M+H] + .

[0304] Step 7: Disperse compound 22g (110 mg, 0.40 mmol), compound 1e (134 mg, 0.52 mmol), Pd2(dba)3 (73 mg, 0.08 mmol), t-BuONa (116 mg, 1.21 mmol) and X-Phos (38 mg, 0.08 mmol) in toluene (4 mL). After replacing the reaction system with nitrogen, heat to 100 °C and react for 16 h. Monitor the reaction by LCMS until completion, concentrate the reaction mixture, and purify the residue by Prep-HPLC to obtain compound 22 (35 mg, yield 17%). ESI-MS (m / z): 493.2 [M+H] + ; 1 1H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 7.91 - 7.82 (m, 2H), 7.79 (s, 1H), 7.46 (s, 1H), 7.22 (t, J = 53.5 Hz, 1H), 6.45 - 6.29 (m, 2H), 5.45 (s, 2H), 4.30 (d, J = 6.0 Hz, 2H), 4.20 (dd, J = 12.5, 3.5 Hz, 1H), 4.09 (dd, J = 12.5, 3.5 Hz, 1H), 3.99 - 3.88 (m, 1H), 3.05 (s, 3H), 1.23 (d, J = 6.5 Hz, 3H).

[0305] Example 23

[0306] (S)-4-Isopropyl-6-methyl-N-((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)-5,6-dihydro-4H-pyrrolo[3,2,1-de]pteridin-2-amine

[0307]

[0308] Compound 23 was prepared by the following steps:

[0309]

[0310] Step 1: Dissolve compound 19e (0.2 g, 0.95 mmol) in anhydrous N,N-dimethylformamide (5 mL). Add NaH (115 mg, 60% content, 2.87 mmol) portionwise under an ice bath. After stirring the reaction mixture for 5 minutes, add isopropyl iodide (211 mg, 1.25 mmol, 0.12 mL). The reaction solution is warmed to room temperature and stirred for 3 hours. The reaction is monitored by LCMS until completion. The reaction solution is diluted with ethyl acetate, washed with saturated brine, and the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by silica gel column chromatography to obtain compound 23a (185 mg, yield 76%). ESI-MS (m / z): 251.5 [M+H] + 。

[0311] Step 2: Disperse compound 23a (100 mg, 0.39 mmol), compound 1e (132 mg, 0.51 mmol), Pd2(dba)3 (73 mg, 0.08 mmol), t-BuONa (115 mg, 1.20 mmol), and X-Phos (38 mg, 0.08 mmol) in toluene (5 mL). After purging the reaction system with nitrogen, heat it to 100 °C and react for 16 hours. The reaction is monitored by LCMS until completion. The reaction solution is concentrated, and the residue is purified by Prep-HPLC to obtain compound 23 (31 mg, yield 16%). ESI-MS (m / z): 471.2 [M+H] + ; 1 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.26 (s, 1H), 7.88 - 7.80 (m, 2H), 7.77 (s, 1H), 7.45 (s, 1H), 7.29 (d, J = 2.7 Hz, 1H), 6.51 (br s, 1H), 6.03 (d, J = 2.7 Hz, 1H), 5.44 (s, 2H), 4.85 - 4.79 (m, 1H), 4.29 (d, J = 5.8 Hz, 2H), 4.25 - 4.20 (m, 1H), 3.66 (dd, J = 12.6, 3.5 Hz, 11H), 3.25 - 3.20 (m, 1H), 1.41 (d, J = 6.4 Hz, 3H), 1.19 - 1.14 (m, 6H).

[0312] Example 24

[0313] (R)-5-(Methoxymethyl)-4-methyl-N-((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)

[0314] methyl)-5,6-dihydro-4H-pyrrolo[3,2,1-de]pteridine-6,6-d2-2-amine

[0315]

[0316] Compound 24 was prepared by the following steps:

[0317]

[0318] First step: Under nitrogen protection, SOCl2 (1.72 g, 14.47 mmol, 1.05 mL) was dissolved in anhydrous dichloromethane (100 mL). After the reaction solution was cooled to -70 °C, an anhydrous dichloromethane solution (10 mL) of imidazole (2.63 g, 38.60 mmol) and triethylamine (2.93 g, 28.95 mmol, 4.01 mL) was added dropwise. The reaction exothermed strongly, and the internal temperature of the reaction solution was controlled below -40 °C. After the addition was completed, the reaction solution was cooled to -70 °C again and stirred for 10 minutes, and then an anhydrous dichloromethane solution (10 mL) of compound 24a (2.0 g, 9.65 mmol) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction solution was diluted with dichloromethane, and 0.5 M aqueous citric acid solution was added, and the organic phase was separated. The obtained organic phase was washed successively with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 24b (2.43 g, crude product), which was directly used in the next step of the reaction.

[0319] Second step: The compound 24b (2.43 g) obtained in the previous step was dissolved in a mixed solution of acetonitrile (55 mL) and water (25 mL). Under ice bath, ruthenium trichloride (99 mg, 0.47 mmol) and sodium periodate (4.10 g, 19.19 mmol) were added successively. The reaction mixture was stirred at room temperature for 3 hours and then the reaction was terminated. The reaction solution was diluted with ethyl acetate, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 24c (2.2 g, crude product), which was directly used in the next step of the reaction.

[0320] Third step: Compound 19a (1.3 g, 6.91 mmol), 22a (2.23 g) and 18-crown-6 (91 mg, 0.34 mmol) were dissolved in dioxane (20 mL), potassium carbonate (2.87 g, 20.74 mmol) was added, and the reaction system was heated to 60 °C and reacted for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 24d (2.6 g, crude product), which was directly used in the next step of the reaction. ESI-MS (m / z): 377.5 [M+H] + 。

[0321] Step 4: Dissolve compound 24d (1.65 g, crude product) in dioxane (10 mL), add concentrated hydrochloric acid (1.33 mL), stir the reaction mixture at room temperature for 3 hours, and monitor the completion of the reaction by LCMS. Concentrate the reaction mixture to obtain the hydrochloride salt of compound 24e (1.2 g, crude product), which is directly used in the next step. ESI-MS (m / z): 277.4 [M+H] + 。

[0322] Step 5: Dissolve the hydrochloride salt of compound 24e (1.3 g, crude product) in a mixture of dioxane (20 mL) and N,N-dimethylformamide (2 mL), add N,N-diisopropylethylamine (2.68 g, 20.73 mmol, 3.43 mL), heat the reaction mixture to 100 °C and react for 16 hours, and monitor the completion of the reaction by LCMS. Concentrate the reaction mixture, dilute the residue with ethyl acetate, and wash it successively with saturated ammonium chloride solution and saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography to obtain compound 24f (0.56 g). ESI-MS (m / z): 241.5 [M+H] + 。

[0323] Step 6: Dissolve compound 24f (0.1 g, 0.41 mmol) in anhydrous N,N-dimethylformamide (5 mL), add NaH (49 mg, 60% content, 1.22 mmol) under ice bath, stir the reaction mixture for 5 minutes, and then add methyl iodide (70 mg, 0.49 mmol). Raise the reaction mixture to room temperature, stir for 3 hours, and monitor the completion of the reaction by LCMS. Dilute the reaction mixture with ethyl acetate, wash it with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography to obtain compound 24g (50 mg, yield 47%). ESI-MS (m / z): 255.5 [M+H] + 。

[0324] Step 7: Dissolve compound 24g (100 mg, 0.39 mmol) and 1e (100 mg, 0.39 mmol) in n-butanol (3 mL), add trifluoroacetic acid (134 mg, 1.18 mmol), heat the reaction mixture to 150 °C by microwave irradiation and react for 3 hours, and monitor the completion of the reaction by LCMS. Concentrate the reaction mixture, and purify the residue by preparative HPLC to obtain compound 24 (43 mg, yield 23%). ESI-MS (m / z): 475.4 [M+H] + ; 11H NMR (500 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.23 (s, 1H), 7.90 - 7.84 (m, 3H), 7.52 (s, 1H), 7.37 (s, 1H), 6.14 (s, 1H), 5.48 (s, 2H), 4.47 - 4.36 (m, 2H), 4.17 - 4.14 (m, 1H), 3.57 (dd, J = 10.0, 5.6 Hz, 1H), 3.46 (dd, J = 9.8, 7.3 Hz, 1H), 3.30 - 3.26 (m, 6H).

[0325] Example 25

[0326] (R)-6-(Methoxymethyl)-4,8-dimethyl-N-((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)-5,6-dihydro-4H-pyrrolo[3,2,1-de]pteridin-2-amine

[0327]

[0328] Compound 25 was prepared by the following steps:

[0329]

[0330] First step: Under nitrogen protection, SOCl2 (2.26 g, 19.00 mmol, 1.38 mL) was dissolved in anhydrous dichloromethane (50 mL). After the reaction solution was cooled to -70 °C, a solution of imidazole (3.98 g, 58.47 mmol) and triethylamine (2.96 g, 29.23 mmol, 4.05 mL) in anhydrous dichloromethane (10 mL) was added dropwise. The reaction exothermed violently, and the internal temperature of the reaction solution was controlled below -40 °C. After the addition was completed, the reaction solution was cooled back to -70 °C and stirred for 10 minutes, and then a solution of compound 25a (3.0 g, 14.62 mmol) in anhydrous dichloromethane (10 mL) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction solution was diluted with dichloromethane, and 0.5 M aqueous citric acid solution was added, and the organic phase was separated. The obtained organic phase was washed successively with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 25b (3.6 g), which was directly used in the next step. Second step: The compound 25b (3.6 g) obtained in the previous step was dissolved in acetonitrile (50 mL), ruthenium(III) chloride (99 mg, 0.47 mmol) was added, and then an aqueous solution of sodium periodate (4.10 g, 19.19 mmol, dissolved in 50 mL of water) was added dropwise under ice bath. After the addition was completed, the reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 25c (3.5 g, the yield of the two-step reaction was 46%).1 HNMR (500 MHz, DMSO-d6) δ 5.14 - 5.06 (m, 1H), 4.13 - 4.06 (m, 1H), 3.85 - 3.78 (m, 1H), 3.73 - 3.65 (m, 2H), 3.31 (s, 3H), 1.47 (s, 9H). Step 3: Dissolve compound 19a (2.0 g, 10.64 mmol), 25c (3.70 g, 13.83 mmol) and 18-crown-6 (281 mg, 1.06 mmol) in dioxane (50 mL), add potassium carbonate (4.41 g, 31.91 mmol), heat the reaction system to 80 °C and react for 16 hours, monitor the reaction by LCMS until completion. Dilute the reaction solution with ethyl acetate, wash it with water and saturated brine respectively, dry the organic phase with anhydrous sodium sulfate, filter and concentrate to obtain compound 25d (3.8 g, crude product), which is directly used for the next step of reaction. ESI-MS (m / z): 375.4 [M+H] + . Step 4: Dissolve the compound 25d (3.8 g) obtained in the previous step in dichloromethane (40 mL), add hydrochloric acid dioxane solution (4N, 12.66 mL), stir the reaction solution at room temperature for 16 hours, monitor the reaction by LCMS until complete. Concentrate the reaction solution to obtain the hydrochloride of compound 25e (3.0 g, crude product), which is directly used for the next step of reaction. ESI-MS (m / z): 275.5 [M+H] + .

[0331] Step 5: Dissolve the hydrochloride of compound 25e (3.6 g, crude product) in a mixture of dioxane (50 mL) and N,N-dimethylformamide (5 mL), add N,N-diisopropylethylamine (7.47 g, 57.77 mmol, 9.57 mL), heat the reaction solution to 90 °C and react for 16 hours, monitor the reaction by LCMS until complete. Concentrate the reaction solution, dilute the residue with ethyl acetate, wash it successively with saturated ammonium chloride solution and saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography to obtain compound 25f (0.84 g). ESI-MS (m / z): 239.6 [M+H] + .

[0332] Step 6: Dissolve compound 25f (150 mg, 0.62 mmol) in anhydrous N,N-dimethylformamide (2 mL). Add NaH (75 mg, 60% content, 1.89 mmol) under ice bath. After stirring the reaction mixture for 30 minutes, add methyl iodide (133 mg, 0.94 mmol). Let the reaction solution warm to room temperature and stir for 3 hours. Monitor the reaction by LCMS until completion. Dilute the reaction solution with ethyl acetate, wash it with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography to obtain compound 25g (130 mg, yield 81%). ESI-MS (m / z): 253.5 [M+H] + 。

[0333] Step 7: Under nitrogen protection, dissolve compound 25g (130 mg, 0.51 mmol) in anhydrous tetrahydrofuran (3 mL). Cool the reaction solution to -70 °C, add n-butyllithium solution (2.5 M, 0.82 mL) dropwise, stir for 30 minutes, and then add methyl iodide (292 mg, 2.06 mmol). Continue to stir the reaction mixture at -70 °C for 1 hour and then slowly warm it to room temperature. Quench the reaction solution with saturated ammonium chloride aqueous solution, dilute it with ethyl acetate, and wash it successively with water and saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter and concentrate to obtain compound 25h (100 mg, crude product). ESI-MS (m / z): 267.4 [M+H] + 。

[0334] Step 8: Disperse compound 25h (100 mg, crude product), compound 1e (124 mg, 0.48 mmol), Pd2(dba)3 (68 mg, 0.074 mmol), t-BuONa (108 mg, 1.12 mmol) and X-Phos (35 mg, 0.074 mmol) in toluene (5 mL). After purging the reaction system with nitrogen, heat it to 100 °C and react for 16 hours. Monitor the reaction by LCMS until completion. Concentrate the reaction solution, purify the residue by silica gel column chromatography to obtain a crude product, and then purify it by Prep-HPLC to obtain compound 25 (13 mg). ESI-MS (m / z): 487.4 [M+H] + ; 1HNMR(500MHz, DMSO-d6) δ 8.65 (s, 1H), 8.29 (br s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.45 (s, 1H), 6.33 (br s, 1H), 5.80 (s, 1H), 5.45 (s, 2H), 4.63 (s, 1H), 4.29 (d, J = 6.0 Hz, 2H), 3.57 (s, 2H), 3.43 (dd, J = 9.5, 7.0 Hz, 1H), 3.34 - 3.30 (m, 1H), 3.24 (s, 3H), 3.01 (s, 3H), 2.33 (s, 3H).

[0335] Example 26

[0336] 8,8 - Difluoro - 6 - methyl - N - ((1 - ((6 - (trifluoromethyl)pyridin - 3 - yl)methyl)-1H - pyrazol - 4 - yl)methyl)-6,7,8,9 - tetrahydro - 3,5,6,9a - tetraazabenzo[cd]azulene - 4 - amine

[0337]

[0338] Compound 26 was prepared by the following steps:

[0339]

[0340] First step: At room temperature, compound 19a (400 mg, 2.13 mmol) and triphenylphosphine (1.67 g, 6.38 mmol) were dissolved in anhydrous tetrahydrofuran (15 mL). Under nitrogen protection, N,N - diisopropylethylamine (1.37 g, 10.64 mmol) and diisopropyl azodicarboxylate (1.29 g, 6.38 mmol, 1.25 mL) were added successively. After stirring for 30 minutes, a solution of compound 26a (898 mg, 4.26 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise. After the reaction mixture was heated to 70 °C and reacted for 16 hours, the reaction was terminated. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography to obtain compound 26b (500 mg, yield 61%). ESI - MS (m / z): 325.4 [M - 55] + .

[0341] Second step: Compound 26b (500 mg, 1.31 mmol) was dissolved in dichloromethane (5 mL), and hydrochloric acid dioxane solution (4N, 1.64 mL) was added. The reaction solution was stirred at room temperature for 16 hours, and the reaction was monitored by LCMS until completion. The reaction solution was filtered, the filter cake was collected, and dried under reduced pressure to obtain the hydrochloride of compound 26c (360 mg, yield 86%).

[0342] Step 3: Dissolve the hydrochloride salt of compound 26c (360 mg, 1.13 mmol) in a mixture of dioxane (5 mL) and N,N-dimethylformamide (1 mL), add N,N-diisopropylethylamine (732 mg, 5.67 mmol), heat the reaction solution to 100 °C and react for 4 hours. Monitor the reaction completion by LCMS. Concentrate the reaction solution, dilute the residue with ethyl acetate, and wash it successively with saturated ammonium chloride solution and saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography to obtain white solid 26d (250 mg, yield 90%). ESI-MS (m / z): 245.5 [M+H] + 。

[0343] Step 4: Dissolve compound 26d (300 mg, 1.23 mmol) in anhydrous N,N-dimethylformamide (5 mL), add NaH (122 mg, 60% content, 3.07 mmol) portionwise under ice bath. After stirring the reaction mixture for 15 minutes, add methyl iodide (261 mg, 1.84 mmol, 0.17 mL). Raise the reaction solution to room temperature, stir for 4 hours and monitor the reaction completion by LCMS. Dilute the reaction solution with ethyl acetate, wash it with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter and concentrate to obtain compound 26e (290 mg, yield 91%). ESI-MS (m / z): 259.5 [M+H] + 。

[0344] Step 5: Dissolve compound 26e (100 mg, 0.38 mmol) and 1e (148 mg, 0.57 mmol) in n-butanol (4 mL), add trifluoroacetic acid (44 mg, 0.38 mmol), heat the reaction solution to 150 °C by microwave and react for 6 hours. Monitor the reaction completion by LCMS. Concentrate the reaction solution, purify the residue by preparative HPLC to obtain compound 26 (17 mg, yield 9%). ESI-MS (m / z): 479.5 [M+H] + ; 1 1H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 7.90 - 7.80 (m, 3H), 7.52 - 7.40 (m, 2H), 6.26 (d, J = 2.5 Hz, 1H), 5.46 (s, 2H), 4.73 (t, J = 12.0 Hz, 2H), 4.37 (d, J = 6.0 Hz, 2H), 4.17 (t, J = 12.0 Hz, 2H), 3.26 (s, 3H).

[0345] Example 27

[0346] (R)-4,6-Dimethyl-N-((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)-5,6-dihydro-4H-pyrrolo[3,2,1-de]pteridin-2-amine

[0347]

[0348] Replace (R)-1-(BOC-amino)-2-propanol methanesulfonate 19b in the first step of Example 19 with (S)-1-(BOC-amino)-2-propanol methanesulfonate. Using a similar method and reaction steps, compound 27 can be obtained. ESI-MS (m / z): 443.6 [M+H] + ; 1 HNMR (500 MHz, DMSO-d6) δ 12.19 (br s, 1H), 8.64 (s, 1H), 8.34 (br s, 1H), 7.92 - 7.83 (m, 3H), 7.53 (s, 1H), 7.44 (d, J = 2.5 Hz, 1H), 6.20 (s, 1H), 5.49 (s, 2H), 4.44 (s, 2H), 4.29 - 4.06 (m, 3H), 3.22 (s, 3H), 1.29 (d, J = 6.5 Hz, 3H).

[0349] Example 28

[0350] (R)-N-((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)-7a,8,10,11-tetrahydro

[0351] -7H-[1,4]oxazino[3,4-h]pyrrolo[3,2,1-de]pteridin-2-amine

[0352]

[0353] Compound 28 was prepared by the following steps:

[0354]

[0355] Step 1: At room temperature, dissolve compound 19a (300 mg, 1.60 mmol) and triphenylphosphine (1.26 g, 4.79 mmol) in anhydrous tetrahydrofuran (10 mL). Under nitrogen protection, successively add N,N-diisopropylethylamine (1.03 g, 7.98 mmol) and diisopropyl azodicarboxylate (967 mg, 4.79 mmol, 0.94 mL). After stirring for 30 minutes, continue to dropwise add an anhydrous tetrahydrofuran solution (5 mL) of compound 28a (866 mg, 3.99 mmol). After the reaction mixture is heated to 70 °C and reacted for 16 hours, the reaction is terminated. The reaction solution is concentrated, and the residue is purified by silica gel column chromatography to obtain compound 28b (200 mg, yield 32%). ESI-MS (m / z): 331.4 [M - 55] + 。

[0356] Step 2: Dissolve compound 28b (200 mg, 0.51 mmol) in dichloromethane (2 mL), add hydrochloric acid dioxane solution (4 N, 1.29 mL), and stir the reaction solution at room temperature for 16 hours. Monitor the reaction by LCMS until it is complete. The reaction solution is concentrated to obtain compound 28c (100 mg, crude product), which is directly used in the next step. ESI-MS (m / z): 251.5 [M + H] + 。

[0357] Step 3: Dissolve compound 28c (100 mg) and 1e (122 mg, 0.47 mmol) in n-butanol (4 mL), add trifluoroacetic acid (45 mg, 0.39 mmol), and heat the reaction solution to 150 °C by microwave for 5 hours. Monitor the reaction by LCMS until it is complete. The reaction solution is concentrated, and the residue is purified by preparative HPLC to obtain compound 28 (13 mg). ESI-MS (m / z): 471.5 [M + H] + ; 1 1H NMR (500 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.63 (s, 1H), 8.36 (br s, 1H), 8.01 - 7.79 (m, 3H), 7.65 - 7.44 (m, 2H), 6.23 (s, 1H), 5.48 (s, 2H), 4.56 - 4.40 (m, 3H), 4.29 - 4.25 (m, 1H), 4.13 - 4.02 (m, 3H), 3.93 - 3.82 (m, 1H), 3.62 - 3.52 (m, 2H), 3.24 - 3.17 (m, 1H).

[0358] Example 59 (W284)

[0359] (S)-4,5-dimethyl-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-3-yl)methyl)amino

[0360] (base)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0361]

[0362] Compound 59 was prepared by the following steps:

[0363]

[0364] First step: Dissolve compound 59a (2 g, 12.69 mmol) and N-methyl-N-methoxyamine hydrochloride (1.86 g, 19.04 mmol) in dichloromethane (20 mL), add EDCI (3.65 g, 19.04 mmol), HOBt (2.57 g, 19.04 mmol) and N,N-diisopropylpropylamine (4.92 g, 38.08 mmol). The reaction was stirred at room temperature for 12 hours. The reaction was monitored by LCMS until completion. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain a colorless oily liquid 59b (2.2 g, yield 86%). ESI-MS (m / z): 201.4 [M+H] + 。

[0365] Second step: Dissolve compound 59c (371 mg, 1.64 mmol) in dry tetrahydrofuran (10 mL). After replacing the reaction system with nitrogen, stir at -78 °C for 5 minutes. Dropwise add n-butyllithium (0.72 mL, 2.5 M, 1.79 mmol) into the reaction solution, and stir the reaction solution at -78 °C for 30 minutes. Subsequently, add compound 59b (300 mg, 1.50 mmol, dissolved in 1 mL of dry tetrahydrofuran) into the reaction solution. Stir the reaction solution at -78 °C for 2 hours. After the reaction system was restored to room temperature, the reaction solution was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain a white solid compound 59d (80 mg, yield 19%). ESI-MS (m / z): 287.2 [M+H] + ; 1 1H NMR (500 MHz, CDCl3) δ 9.43 (s, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.61 (d, J = 6.7 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.94 (dd, J = 8.4, 2.2 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H).

[0366] Step 3: Dissolve compound 59d (200 mg, 0.70 mmol) in methanol (8 mL), slowly add sodium borohydride (40 mg, 1.05 mmol) at 0 °C, and continue to stir the reaction solution at 0 °C for 4 hours. Monitor the end of the reaction by LCMS. Quench the reaction with saturated aqueous ammonium chloride solution, and then extract with ethyl acetate. Wash the organic phase with saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 59e (201 mg, yield 99%). ESI-MS (m / z): 289.2 [M+H] + 。

[0367] Step 4: Dissolve compound 59e (100 mg, 0.35 mmol) in dry tetrahydrofuran (5 mL), then add sodium hydride (24 mg, 60% content, 0.6 mmol) at 0 °C, and stir the reaction solution at 0 °C for half an hour. Then successively add carbon disulfide (80 mg, 1.05 mmol) and iodomethane (148 mg, 1.05 mmol), and continue to stir the reaction at 0 °C for 2 hours. Monitor the end of the reaction by LCMS. Quench the reaction solution with saturated aqueous ammonium chloride solution at 0 °C, and extract with ethyl acetate. Wash the organic phase with saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 59f (98 mg, yield 75%). ESI-MS (m / z): 379.1 [M+H] + 。

[0368] Step 5: Dissolve compound 59f (98 mg, 0.26 mmol) and tributyltin hydride (150 mg, 0.52 mmol) in toluene (5 mL), and add azobisisobutyronitrile (5 mg, 0.03 mmol). After replacing the nitrogen in the reaction system, stir at 80 °C for 12 hours. Monitor the end of the reaction by LCMS. Drop the reaction solution into ice water to quench it, and extract with ethyl acetate. Wash the organic phase with saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 59g (40 mg, yield 57%). ESI-MS (m / z): 273.2 [M+H] + 。

[0369] Step 6: Dissolve 59g (40 mg, 0.15 mmol) of the compound in N-methylpyrrolidone (3 mL), add zinc cyanide (35 mg, 0.30 mmol), Pd2(dba)3 (27 mg, 0.03 mmol) and S-Phos (12 mg, 0.03 mmol). After replacing the reaction system with nitrogen, stir at 150 °C for 2 hours under microwave conditions. Monitor the reaction by LCMS until completion. Filter the reaction solution through diatomaceous earth and concentrate the filtrate. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain white solid 59h (21 mg, yield 55%). ESI-MS (m / z): 264.4 [M+H] + .

[0370] Step 7: Dissolve 59h (21 mg, 0.08 mmol) of the compound in methanol (5 mL) and ammonia water (1 mL), add Raney Nickel (0.5 mL, aqueous suspension). After replacing the reaction system with hydrogen, stir at room temperature for 12 hours. Monitor the reaction by LCMS until completion. Filter the reaction solution through diatomaceous earth and concentrate the filtrate. Purify the residue by silica gel column chromatography (dichloromethane / methanol = 5 / 1) to obtain compound 59i (20 mg, yield 94%). ESI-MS (m / z): 268.3 [M+H] + .

[0371] Step 8: Dissolve 59i (20 mg, 0.08 mmol) and compound 1i (13 mg, 0.05 mmol) in n-butanol (3 mL), add p-toluenesulfonic acid monohydrate (9 mg, 0.05 mmol). Stir the reaction solution at 160 °C for 3 hours under microwave conditions. After the reaction solution is cooled to room temperature, concentrate it under reduced pressure. Purify the residue by preparative HPLC to obtain white solid compound 59 (9 mg, yield 25%). ESI-MS (m / z): 484.3 [M+H] + ; 1 1H NMR (500 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.44 (s, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.82 (s, 1H), 7.67 (dd, J = 7.9, 1.6 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.02 (br s, 1H), 4.43 - 4.30 (m, 2H), 4.19 (s, 2H), 4.10 (q, J = 6.7 Hz, 1H), 4.02 - 3.97 (m, 1H), 3.31 - 3.22 (m, 3H), 2.90 (s, 3H), 1.93 - 1.87 (m, 1H), 1.83 - 1.74 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H).

[0372] According to the synthetic routes and synthetic methods of intermediates described in the above embodiments, the compounds of the following embodiments were obtained.

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380] Example 91 (W221)

[0381] (S)-4,5-Dimethyl-2-(((6-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0382]

[0383] Compound 91 was prepared by the following steps:

[0384]

[0385] First step: Dissolve 2-(trifluoromethyl)pyrimidin-5-ol 91a (1.0 g, 6.09 mmol), 6-fluoro-nicotinonitrile 91b (1.01 g, 7.31 mmol) and cesium carbonate (3.97 g, 12.19 mmol) in DMF (10 mL), and stir overnight at 80 °C. Monitor the reaction by LCMS until it is completed. Dilute the reaction solution with ethyl acetate, wash it successively with water and saturated brine, dry the organic phase over anhydrous sodium sulfate, concentrate it, and purify it by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain a yellow oil 91c (1.3 g, yield 80%).

[0386] Step 2: Dissolve and disperse compound 91c (1.3 g, 4.88 mmol) and Raney Nickel (0.5 mL, aqueous suspension) in methanol (2 mL) and ammonia water (0.2 mL), purge and replace with a hydrogen balloon, and stir overnight at room temperature. Monitor the reaction by LCMS. After the reaction is completed, dilute the reaction solution with methanol, filter it through a diatomaceous earth filter layer by suction, concentrate the organic phase to obtain yellow oil 91d (700 mg, yield 53%). ESI-MS (m / z): 271.3 [M+H] + 。

[0387] Step 3: Dissolve compound 1i (150 mg, 593 μmol), compound 91d (192 mg, 712 μmol) and p-toluenesulfonic acid monohydrate (11 mg, 59 μmol) in n-butanol (2 mL), and react at 160 °C under microwave for 2 hours. Monitor the reaction by LCMS. Purify the reaction solution by reverse-phase preparative HPLC to obtain white solid 91 (68 mg, yield 23%). ESI-MS (m / z): 487.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 9.03 (s, 2H), 8.12 (d, J = 2.3 Hz, 1H), 7.92 (dd, J = 8.4, 2.4 Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H), 7.05 (br s, 1H), 4.45 - 4.32 (m, 2H), 4.11 (q, J = 6.8 Hz, 1H), 4.03 - 3.97 (m, 1H), 3.35 - 3.22 (m, 2H), 2.92 (s, 3H), 2.52 - 2.48 (m, 2H), 1.95 - 1.88 (m, 1H), 1.84 - 1.75 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H).

[0388] Example 92 (W232)

[0389] (S)-4,5-Dimethyl-2-(((6-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0390]

[0391] Compound 92 was prepared by the following steps:

[0392]

[0393] Step 1: Dissolve 3-(trifluoromethyl)pyrazole 92a (89 mg, 0.66 mmol) and 3-cyano-6-chloromethylpyridine 92b (100 mg, 0.66 mmol) in N,N-dimethylformamide (5 mL), add potassium carbonate (181 mg, 1.31 mmol), and react the reaction mixture at room temperature for 6 hours. Monitor the end of the reaction by LCMS. Dilute the reaction mixture with saturated aqueous sodium chloride solution and extract with ethyl acetate. Wash the organic phase with saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 3) to obtain the brown liquid compound 92c (142 mg, yield 86%). ESI-MS (m / z): 253.2 [M+H] + 。

[0394] Step 2: Dissolve compound 92c (142 mg, 0.56 mmol) in methanol (9 mL) and ammonia water (1 mL), add Raney Nickel (0.5 mL, aqueous suspension), replace the hydrogen in the reaction system, and stir at room temperature for 12 hours. Filter the reaction mixture through diatomaceous earth, and concentrate the filtrate. Purify the residue by silica gel column chromatography (dichloromethane / methanol = 5 / 1) to obtain the colorless oily liquid 92d (79 mg, yield 55%). ESI-MS (m / z): 257.3 [M+H] + 。

[0395] Step 3: Dissolve compound 92d (80 mg, 0.31 mmol) and compound 1i (53 mg, 0.21 mmol) in n-butanol (3 mL), add p-toluenesulfonic acid monohydrate (40 mg, 0.21 mmol), and stir the reaction mixture at 160 °C for 3 hours under microwave conditions. After the reaction mixture is cooled to room temperature, concentrate it under reduced pressure, and purify the residue by preparative reverse-phase HPLC to obtain the white solid compound 92 (19 mg, yield 13%). ESI-MS (m / z): 473.3 [M+H] + ; 11H NMR (500 MHz, DMSO-d6) δ 8.49 (d, J = 1.7 Hz, 1H), 8.07 (d, J = 1.2 Hz, 1H), 7.72 (dd, J = 8.0, 2.1 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.04 (t, J = 5.7 Hz, 1H), 6.74 (d, J = 2.2 Hz, 1H), 5.48 (s, 2H), 4.46 - 4.32 (m, 2H), 4.10 (q, J = 6.8 Hz, 1H), 4.04 - 3.96 (m, 1H), 3.40 - 3.23 (m, 3H), 2.90 (s, 3H), 1.96 - 1.87 (m, 1H), 1.85 - 1.74 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H).

[0396] Example 93 (W223)

[0397] (S)-4,5-Dimethyl-2-(((1-(4,4,4-trifluorobutyl)-1H-pyrazol-4-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0398]

[0399] Compound 93 was prepared by the following steps:

[0400]

[0401] First step: 1,1,1-Trifluoro-4-iodobutane 93a (289 mg, 1.22 mmol), 4-(BOC-aminomethyl)pyrazole 13b (200 mg, 1.01 mmol), and cesium carbonate (660 mg, 2.03 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the white solid target compound 93b (230 mg, yield 73%). ESI-MS (m / z): 308.4 [M+H] + .

[0402] Second step: Compound 93b (200 mg, 650 μmol) was dissolved in dichloromethane (10 mL), and hydrochloric acid-dioxane solution (1 M, 3.25 mL) was added to the above reaction solution. The reaction mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was concentrated to obtain the white solid target product 93c (134 mg), which was directly used in the next step. ESI-MS (m / z): 208.3 [M+H] +。

[0403] Step 3: Dissolve compound 93c (103 mg, obtained from Step 2), 1i (126 mg, 0.5 mmol), and p-toluenesulfonic acid monohydrate (9 mg, 50 μmol) in n-butanol (4 mL). The reaction mixture was reacted at 160 °C under microwave for 2 hours. After the reaction was completed, the reaction mixture was purified by reverse-phase preparative HPLC to obtain the white solid target compound 93 (25 mg, 9% yield in two steps). ESI-MS (m / z): 424.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 7.58 (s, 1H), 7.37 (s, 1H), 6.60 (t, J = 6.0 Hz, 1H), 4.26 - 4.17 (m, 2H), 4.10 (t, J = 6.9 Hz, 3H), 4.04 - 3.99 (m, 1H), 3.30 - 3.23 (m, 2H), 2.95 (s, 3H), 2.54 - 2.49 (m, 2H), 2.23 - 2.12 (m, 2H), 1.95 - 1.91 (m, 2H), 1.82 - 1.78 (m, 1H), 1.22 (d, J = 6.7 Hz, 3H).

[0404] Example 94 (W252)

[0405] (S)-4,5-Dimethyl-2-(((6-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0406]

[0407] Compound 94 was prepared by the following steps:

[0408]

[0409] Step 1: Dissolve compound 94a (52 mg, 0.23 mmol) and 94b (25 mg, 0.21 mmol) in dimethyl sulfoxide (2 mL), add copper(I) iodide (4 mg, 0.021 mol), anhydrous potassium phosphate (88 mg, 0.42 mol) and 2,2,6,6-tetramethyl-3,5-heptanedione (8 mg, 0.042 mol). After replacing the reaction system with nitrogen, heat it to 100 °C and stir for 2 hours. After the reaction is complete, quench the reaction with water, and extract the aqueous phase with ethyl acetate. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate. The residue is separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain white solid 94c (50 mg, yield 90%). ESI-MS (m / z): 266.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.79 (d, J = 2.5 Hz, 1H), 8.77 - 8.73 (m, 1H), 8.49 - 8.44 (m, 1H), 8.41 - 8.38 (m, 1H), 7.50 (t, J = 8.5 Hz, 2H).

[0410] Step 2: Dissolve compound 94c (50 mg, 0.19 mmol) in a mixed solution of methanol (10 mL) and ammonia water (1 mL), add Raney nickel (0.1 mL, aqueous suspension), and stir the mixture at room temperature under a hydrogen atmosphere for 16 hours. After the reaction is complete, filter through diatomaceous earth, wash the filter cake with methanol, and concentrate the filtrate to obtain white solid 94d (45 mg, yield 88%). ESI-MS (m / z): 270.3 [M+H] + 。

[0411] Step 3: Dissolve compound 94d (45 mg, 0.17 mmol) and 1i (36 mg, 0.14 mmol) in 1,4-dioxane (5 mL), add Pd2(dba)3 (15 mg, 0.017 mol), Sphos (14 mg, 0.034 mol) and cesium carbonate (109 mg, 0.34 mol). After replacing the reaction system with nitrogen, heat it to 100 °C and stir for 16 hours. After the reaction solution is cooled to room temperature, filter the reaction solution through diatomaceous earth and concentrate the filtrate. The residue is purified by reverse-phase preparative HPLC to obtain white solid 94 (6 mg, yield 7%). ESI-MS (m / z): 486.3 [M+H] + ; 11H NMR (500 MHz, DMSO-d6) δ 8.61 - 8.59 (m, 1H), 8.29 - 8.23 (m, 2H), 7.92 - 7.86 (m, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 8.5 Hz, 1H), 7.13 - 7.05 (m, 1H), 4.49 - 4.35 (m, 2H), 4.17 - 4.08 (m, 1H), 4.05 - 3.98 (m, 1H), 3.29 - 3.24 (m, 1H), 2.94 (s, 3H), 2.55 - 2.50 (m, 2H), 1.97 - 1.88 (m, 1H), 1.85 - 1.73 (m, 1H), 1.23 (d, J = 7.0 Hz, 3H).

[0412] Example 95 (W253)

[0413] (S)-2-(((6-(Difluoro(6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-3-yl)methyl)amino)-4,5-dimethyl-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0414]

[0415] Compound 95 was prepared by the following steps:

[0416]

[0417] First step: Dissolve compound 59d (80 mg, 0.28 mmol) in dichloromethane (2 mL). Slowly add diethylaminosulfur trifluoride (2.44 g, 15.14 mmol) dropwise to the reaction system at 0 °C. Stir the reaction solution at 0 °C for 4 hours. Monitor the end of the reaction by LCMS. Drop the reaction solution into saturated sodium bicarbonate aqueous solution, and extract with ethyl acetate. Wash the organic phase with saturated sodium chloride aqueous solution, dry over anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain white solid 95a (83 mg, yield 96%). ESI-MS (m / z): 309.0 [M+H] + .

[0418] Step 2: Dissolve compound 95a (83 mg, 0.27 mmol) in N-methylpyrrolidone (3 mL), add zinc cyanide (63 mg, 0.54 mmol), Pd2(dba)3 (50 mg, 0.05 mmol) and S-Phos (22 mg, 0.05 mmol). After replacing the reaction system with nitrogen, stir at 150 °C for 2 hours under microwave conditions. After the reaction solution is cooled to room temperature, filter it through diatomaceous earth, and concentrate the filtrate. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain white solid 95b (66 mg, yield 82%). ESI-MS (m / z): 300.1 [M+H] + .

[0419] Step 3: Dissolve compound 95b (66 mg, 0.22 mmol) in methanol (5 mL) and ammonia water (1 mL), add Raney Nickel (0.5 mL, aqueous suspension). After replacing the reaction system with hydrogen, stir at room temperature for 12 hours. Filter the reaction solution through diatomaceous earth, and concentrate the filtrate. Purify the residue by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain colorless oily liquid 95c (66 mg, yield 99%). ESI-MS (m / z): 304.2 [M+H] + .

[0420] Step 4: Dissolve compound 95c (66 mg, 0.22 mmol) and compound 1i (37 mg, 0.15 mmol) in n-butanol (3 mL), add p-toluenesulfonic acid monohydrate (25 mg, 0.15 mmol). Stir the reaction solution at 160 °C for 3 hours under microwave conditions. After the reaction solution is cooled to room temperature, concentrate it under reduced pressure, and purify the residue by preparative reverse-phase HPLC to obtain white solid compound 95 (8 mg, yield 9%). ESI-MS (m / z): 520.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.59 (s, 1H), 8.31 (d, J = 7.7 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.97 (d, J = 9.4 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.13 (t, J = 5.8 Hz, 1H), 4.52 - 4.38 (m, 2H), 4.11 (q, J = 6.7 Hz, 1H), 4.04 - 3.96 (m, 1H), 3.31 - 3.24 (m, 1H), 2.89 (s, 3H), 2.52 - 2.47 (m, 2H), 1.95 - 1.86 (m, 1H), 1.83 - 1.73 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H).

[0421] Example 96 (W256)

[0422] (S)-2-(((6-(4-Fluorobenzyl)pyridin-3-yl)methyl)amino)-4,5-dimethyl-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0423]

[0424] Compound 96 was prepared by the following steps:

[0425]

[0426] First step: Dissolve compound 96a (1.0 g, 7.0 mmol), Boc2O (2.29 g, 10.52 mmol) and N,N-diisopropylethylamine (1.81 g, 14.03 mmol, 2.44 mL) in dichloromethane (10 mL), and stir overnight at room temperature. Monitor the reaction by LCMS until it is completed. Dilute the reaction solution with dichloromethane, wash it successively with water, saturated ammonium chloride solution, and saturated sodium bicarbonate aqueous solution. Dry the organic phase over anhydrous sodium sulfate, filter and concentrate to obtain a colorless oil 96b (1.6 g, yield 94%). ESI-MS (m / z): 243.3 [M+H] + .

[0427] Second step: Disperse compound 96b (200 mg, 824 μmol), 4-fluorobenzylboronic acid pinacol ester 96c (194 mg, 824 μmol), Pd(t-Bu3P)2 (42 mg, 82 μmol) and potassium carbonate (227 mg, 1.65 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL). After replacing the reaction system with nitrogen, heat it to 100 °C and stir overnight. Monitor the reaction by LCMS until it is completed. Dilute the reaction solution with ethyl acetate, wash it successively with water and saturated brine. Dry the organic phase over anhydrous sodium sulfate, filter and concentrate, and then purify it by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain a yellow oil 96d (180 mg, yield 69%). ESI-MS (m / z): 317.5 [M+H] + .

[0428] Third step: Dissolve compound 96d (180 mg, 568 μmol) and 1,4-dioxane hydrochloride solution (4 M, 0.5 mL) in dichloromethane (2 mL), and stir overnight at room temperature. Monitor the reaction by LCMS until it is completed. Concentrate the reaction solution to obtain a yellow solid 96e (140 mg, yield 97%). ESI-MS (m / z): 217.5 [M+H] + .

[0429] Step 4: Dissolve compound 1i (50 mg, 197 μmol), compound 96e (64 mg, 296 μmol) and p-toluenesulfonic acid monohydrate (4 mg, 19 μmol) in n-butanol (2 mL), and react at 160 °C under microwave for 2 hours. Monitor the end of the reaction by LCMS. Purify the reaction solution by reverse-phase preparative HPLC to obtain white solid 95 (28 mg, yield 33%). ESI-MS (m / z): 433.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.44 (d, J = 2.2 Hz, 1H), 7.64 (dd, J = 8.0, 2.2 Hz, 1H), 7.28 (dd, J = 8.3, 5.6 Hz, 2H), 7.20 (d, J = 7.9 Hz, 1H), 7.09 (t, J = 8.8 Hz, 2H), 7.02 (s, 1H), 4.42 - 4.31 (m, 2H), 4.11 (q, J = 6.8 Hz, 1H), 4.03 - 3.97 (m, 3H), 3.28 - 3.24 (m, 1H), 2.92 (s, 3H), 2.55 - 2.48 (m, 2H), 1.94 - 1.87 (m, 1H), 1.83 - 1.76 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H).

[0430] Example 97 (W312)

[0431] (S)-2-(((6-((2-Cyclopropylpyrimidin-5-yl)oxy)pyridin-3-yl)methyl)amino)-4,5-dimethyl-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0432]

[0433] Compound 97 was prepared by the following steps:

[0434]

[0435] Step 1: Dissolve compound 97a (800 mg, 6.13 mmol), compound 97b (748 mg, 6.13 mmol) and cesium carbonate (2.40 g, 7.35 mmol) in N,N-dimethylformamide (15 mL), and stir the reaction solution at room temperature for 12 hours. After the reaction is completed, filter the reaction solution, concentrate the filtrate to obtain a crude product. Purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the target compound 97c (950 mg, yield 66%). ESI-MS (m / z): 233.2 [M+H] + .

[0436] Step 2: Dissolve intermediate 97c (500 mg, 2.15 mmol), cyclopropylboronic acid (923 mg, 10.75 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (314 mg, 429 μmol) and potassium carbonate (549 mg, 4.30 mmol) in a mixed solution of 1,4-dioxane (10 mL) and water (2 mL). After replacing the nitrogen in the reaction system, heat the reaction mixture to 100 °C and react for 4 hours. After the reaction is completed, filter the reaction solution through diatomaceous earth, and concentrate the filtrate to obtain the crude product. The crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the target compound 97d (290 mg, yield 56%). ESI-MS (m / z): 239.4 [M+H] + 。

[0437] Step 3: Dissolve intermediate 97d (100 mg, 419 μmol) and Raney Nickel (0.1 mL, aqueous suspension) in a mixed solution of methanol (10 mL) and ammonia water (1 mL). Stir the reaction solution at room temperature for 12 hours under a hydrogen atmosphere. After the reaction is completed, filter the reaction solution, and concentrate the filtrate to obtain the crude product 97e (101 mg), which is directly used in the next step. ESI-MS (m / z): 243.5 [M+H] + 。

[0438] Step 4: Dissolve intermediate 97e (101 mg, obtained from the third step), intermediate 1i (106 mg, 419 μmol) and p-toluenesulfonic acid monohydrate (8 mg, 42 μmol) in n-butanol (4 mL). React the reaction solution under microwave conditions at 160 °C for 2 hours. After the reaction is completed, purify the reaction solution by reverse-phase preparative HPLC to obtain the target product 97 (34 mg, two-step reaction yield 17%). ESI-MS (m / z): 459.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.55 (s, 2H), 8.06 (d, J = 2.5 Hz, 1H), 7.85 (dd, J = 8.0, 2.5 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 7.01 (br s, 1H), 4.40 - 4.30 (m, 2H), 4.11 (q, J = 7.0 Hz, 1H), 4.03 - 3.98 (m, 1H), 3.30 - 3.25 (m, 2H), 2.93 (s, 3H), 2.53 - 2.48 (m, 2H), 2.26 - 2.21 (m, 1H), 1.93 - 1.78 (m, 2H), 1.23 (d, J = 7.0 Hz, 3H), 1.07 - 0.96 (m, 4H).

[0439] Example 98 (W188)

[0440] (S)-2-(((6-((4,4-difluorocyclohexyl)oxy)pyridin-3-yl)methyl)amino)-4,5-dimethyl-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0441]

[0442] Replace 3,3-difluorocyclobutan-1-ol 12a in the first step of Example 12 with 4,4-difluorocyclohexan-1-ol. Using a similar method and reaction steps, compound 98 can be obtained. ESI-MS (m / z): 459.2 [M+H] + ; 1 HNMR (500 MHz, DMSO-d6) δ 8.09 (d, J = 2.3 Hz, 1H), 7.66 (dd, J = 8.6, 2.4 Hz, 1H), 6.98 (br s, 1H), 6.74 (d, J = 8.4 Hz, 1H), 5.15 (br s, 1H), 4.40 - 4.24 (m, 2H), 4.11 (q, J = 6.7 Hz, 1H), 4.06 - 3.98 (m, 1H), 3.32 - 3.24 (m, 1H), 2.94 (s, 3H), 2.55 - 2.48 (m, 2H), 2.10 - 1.72 (m, 10H), 1.22 (d, J = 6.7 Hz, 3H).

[0443] Example 99 (W193)

[0444] (S)-4,5-dimethyl-2-(((6-((5-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0445]

[0446] Compound 99 is prepared by the following steps:

[0447]

[0448] Step 1: Dissolve 5-(trifluoromethyl)pyridin-3-ol 99a (500 mg, 3.07 mmol) and 6-chloro-3-cyanopyridine 99b (509 mg, 3.68 mmol) in N,N-dimethylformamide (10 mL), add cesium carbonate (2.0 g, 6.14 mmol), and stir overnight at 80 °C. Monitor the reaction by LCMS until completion. Dilute the reaction mixture with ethyl acetate, wash successively with water and saturated brine, dry the organic phase over anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain a colorless oil 99c (600 mg, yield 73%). ESI-MS (m / z): 266.0 [M+H] + 。

[0449] Step 2: Dissolve intermediate 99c (550 mg, 2.07 mmol) in methanol (2 mL), add Raney nickel (0.5 mL, aqueous suspension) and ammonia (0.2 mL) successively. Evacuate and refill the system with hydrogen gas through a hydrogen balloon, and stir overnight under the hydrogen balloon. Monitor the reaction by LCMS until completion. Dilute the reaction mixture with methanol, filter by suction, concentrate the filtrate and purify by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain a white solid 99d (400 mg, yield 71%). ESI-MS (m / z): 270.3 [M+H] + 。

[0450] Step 3: Dissolve compound 1i (50 mg, 197 μmol), compound 99d (79 mg, 296 μmol) and p-toluenesulfonic acid monohydrate (4 mg, 19 μmol) in n-butanol (2 mL), and react at 160 °C under microwave irradiation for 2 h. Monitor the reaction by LCMS until completion. Purify the reaction mixture by reverse-phase preparative HPLC to obtain a white solid 99 (19 mg, yield 20%). ESI-MS (m / z): 486.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.83 (d, J = 1.8 Hz, 1H), 8.76 (d, J = 2.6 Hz, 1H), 8.15 - 8.08 (m, 2H), 7.88 (dd, J = 8.4, 2.4 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.04 (br s, 1H), 4.46 - 4.32 (m, 2H), 4.11 (q, J = 6.7 Hz, 1H), 4.07 - 3.99 (m, 1H), 3.31 - 3.24 (m, 1H), 2.93 (s, 3H), 2.55 - 2.51 (m, 2H), 1.96 - 1.88 (m, 1H), 1.87 - 1.73 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H).

[0451] Example 100 (W239)

[0452] (S)-4,5-Dimethyl-2-(((6-((2-(trifluoromethyl)pyridin-4-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0453]

[0454] Replace 5-(trifluoromethyl)pyridin-3-ol 99a in the first step of Example 99 with 2-(trifluoromethyl)pyridin-4-ol, and compound 100 can be obtained by a similar method and reaction steps. ESI-MS (m / z): 486.3 [M+H] + ; 1 HNMR (500 MHz, DMSO-d6) δ 8.71 (d, J = 5.6 Hz, 1H), 8.24 (d, J = 2.4 Hz, 1H), 7.93 (dd, J = 8.4, 2.4 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.42 (dd, J = 5.6, 2.3 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 7.07 (t, J = 6.2 Hz, 1H), 4.47 - 4.36 (m, 2H), 4.12 (q, J = 6.8 Hz, 1H), 4.05 - 3.98 (m, 1H), 3.29 - 3.24 (m, 1H), 2.93 (s, 3H), 2.55 - 2.49 (m, 2H), 1.96 - 1.88 (m, 1H), 1.85 - 1.77 (m, 1H), 1.23 (d, J = 6.7 Hz, 3H).

[0455] Example 101 (W213)

[0456] (S)-4,5-Dimethyl-2-((4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)amino)-4,5,9,10-tetrahydro

[0457] -6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0458]

[0459] Replace 5-(trifluoromethyl)pyridin-3-ol 99a and 6-chloro-3-cyanopyridine 99b in the first step of Example 99 with 4-hydroxybenzonitrile and 5-fluoro-2-(trifluoromethyl)pyridine, and compound 101 can be obtained by a similar method and reaction steps. ESI-MS (m / z): 485.3 [M+H] + ;1 1H NMR (500 MHz, DMSO-d6) δ 8.52 (d, J = 2.8 Hz, 1H), 7.90 - 7.85 (m, 1H), 7.50 - 7.45 (m, 1H), 7.44 - 7.39 (m, 2H), 7.18 - 7.11 (m, 2H), 7.10 - 7.01 (m, 1H), 4.50 - 4.35 (m, 2H), 4.15 - 4.10 (m, 1H), 4.06 - 3.97 (m, 1H), 3.31 - 3.23 (m, 1H), 2.93 (s, 3H), 2.55 - 2.49 (m, 2H), 1.98 - 1.87 (m, 1H), 1.86 - 1.74 (m, 1H), 1.23 (d, J = 6.4 Hz, 3H).

[0460] Example 102 (W214)

[0461] (S)-4,5-Dimethyl-2-(((6-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0462]

[0463] Compound 102 was prepared by the following steps:

[0464]

[0465] First step: Dissolve compound 102a (500 mg, 2.48 mmol) in N,N-dimethylformamide (8 mL), add sodium hydride (105 mg, 60% content, 2.62 mmol) at 0 °C, and stir the reaction mixture for half an hour. Add compound 99b (344 mg, 2.48 mmol) to the reaction mixture, and continue to stir the reaction mixture at 0 °C for 2 hours. Monitor the end of the reaction by LCMS. Quench the reaction mixture with saturated aqueous ammonium chloride solution, and extract with ethyl acetate. Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain white solid 102b (606 mg, yield 81%). ESI-MS (m / z): 304.3 [M+H] + .

[0466] Second step: Dissolve compound 102b (606 mg, 2.0 mmol) in hydrochloric acid dioxane (4 M, 5 mL), and stir the reaction mixture at room temperature for 1 hour. Monitor the end of the reaction by LCMS. Concentrate the reaction mixture to obtain the crude product of compound 102c, which is directly used in the next step. ESI-MS (m / z): 204.5 [M+H]+ .

[0467] Step 3: Dissolve the crude product of compound 102c obtained in the previous step in N,N-dimethylformamide (5 mL), add potassium carbonate (502 mg, 3.63 mmol) and trifluoroethyl trifluoromethanesulfonate (280 mg, 1.21 mmol), and stir the reaction mixture at room temperature for 12 hours. Monitor the reaction by LCMS until completion. Dilute the reaction mixture with saturated brine and extract with ethyl acetate. Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to obtain the crude product of compound 102d, which is directly used in the next step. ESI-MS (m / z): 286.4 [M+H] + .

[0468] Step 4: Dissolve the crude product of 102d obtained in the previous step in methanol (9 mL) and ammonia water (1 mL), add Raney Nickel (0.5 mL, aqueous suspension), replace the hydrogen in the reaction system and stir at room temperature for 12 hours. Monitor the reaction by LCMS until completion. Filter the reaction mixture through diatomaceous earth and concentrate the filtrate. Purify the residue by silica gel column chromatography (dichloromethane / methanol = 5 / 1) to obtain a yellow oily liquid 102e (171 mg, yield 29% over three steps). ESI-MS (m / z): 290.4 [M+H] + .

[0469] Step 5: Dissolve compound 102e (160 mg, 0.55 mmol) and compound 1i (94 mg, 0.37 mmol) in n-butanol (4 mL), add p-toluenesulfonic acid monohydrate (71 mg, 0.37 mmol), and stir the reaction mixture at 160 °C for 3 hours under microwave conditions. After the reaction mixture is cooled to room temperature, concentrate it under reduced pressure, and purify the residue by reverse-phase preparative HPLC to obtain a white solid compound 102 (20 mg, yield 7%). ESI-MS (m / z): 506.3 [M+H] + ; 11H NMR (400 MHz, DMSO) δ 8.11 - 8.06 (m, 1H), 7.68 - 7.62 (m, 1H), 6.99 (br s, 1H), 6.75 - 6.68 (m, 1H), 5.21 - 4.92 (m, 1H), 4.75 - 4.65 (m, 1.5H), 4.38 - 4.22 (m, 2H), 4.11 (q, J = 6.8 Hz, 1H), 4.06 - 3.97 (m, 1H), 3.76 - 3.66 (m, 1.5H), 3.32 - 3.22 (m, 2H), 3.21 - 3.13 (m, 1H), 2.93 (s, 3H), 2.88 - 2.79 (m, 1H), 2.60 - 2.50 (m, 2H), 2.00 - 1.88 (m, 3H), 1.84 - 1.73 (m, 1H), 1.70 - 1.50 (m, 2H), 1.22 (d, J = 6.8 Hz, 3H).

[0470] Example 103 (W195)

[0471] (S)-4,5-Dimethyl-2-(((5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0472]

[0473] Replace 5-(trifluoromethyl)pyridin-3-ol 99a and 6-chloro-3-cyanopyridine 99b in the first step of Example 99 with 6-(trifluoromethyl)pyridin-3-ol and 6-chloro-5-methyl-3-cyanopyridine, and using a similar method and reaction steps, compound 103 can be obtained. ESI-MS (m / z): 500.2 [M + H] + ; 1 1H NMR (500 MHz, DMSO-d6) δ 8.61 (d, J = 2.5 Hz, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.92 (d, J = 1.5 Hz, 1H), 7.83 (dd, J = 8.6, 2.5 Hz, 1H), 7.75 (d, J = 1.5 Hz, 1H), 7.02 (t, J = 5.6 Hz, 1H), 4.40 - 4.29 (m, 2H), 4.11 (q, J = 6.7 Hz, 1H), 4.04 - 3.98 (m, 1H), 3.29 - 3.22 (m, 1H), 2.93 (s, 3H), 2.55 - 2.49 (m, 2H), 2.30 (s, 3H), 1.93 - 1.86 (m, 1H), 1.82 - 1.77 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H).

[0474] Example 104 (W198)

[0475] 4-Methyl-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro

[0476] -6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0477]

[0478] Compound 104 was prepared by the following steps:

[0479]

[0480] First step: 2,4-Dichloropyrido[3,2-d]pyrimidine 1f (0.70 g, 3.50 mmol) and glycine methyl ester hydrochloride 104a (0.66 g, 5.25 mmol) were dissolved in tetrahydrofuran (10 mL), N,N-diisopropylethylamine (1.36 g, 10.50 mmol, 1.83 mL) was added, and the mixture was stirred overnight at room temperature. The reaction was monitored by LCMS until completion, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain a yellow oil 104b (0.70 g, yield 79%). ESI-MS (m / z): 275.3 [M+Na] + .

[0481] Second step: Compound 104b (0.70 g, 2.77 mmol) was dissolved in tetrahydrofuran (30 mL), aqueous hydrochloric acid solution (6 M, 0.46 mL) and platinum dioxide (62 mg, 0.28 mmol) were added, the reaction system was purged with hydrogen using a hydrogen balloon, and the mixture was stirred for 48 hours under the pressure of a hydrogen balloon at room temperature. The reaction was monitored by LCMS until completion. The reaction solution was diluted with methanol, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain a gray solid 104c (0.35 g, yield 56%). ESI-MS (m / z): 225.5 [M+H] + .

[0482] Step 3: Dissolve compound 104c (100 mg, 0.45 mmol) and methyl iodide (94 mg, 0.67 mmol) in acetonitrile (2 mL), add cesium carbonate (290 mg, 0.89 mmol), and react at 50 °C for 2 h. Monitor the reaction by LCMS until completion. Dilute the reaction solution with dichloromethane, filter, concentrate the filtrate, and purify it by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain yellow solid 104d (80 mg, yield 75%). ESI-MS (m / z): 239.5 [M+H] + 。

[0483] Step 4: Dissolve compound 104d (50 mg, 209 μmol), compound 11d (67 mg, 251 μmol), and p-toluenesulfonic acid monohydrate (4 mg, 21 μmol) in n-butanol (2 mL), and react at 160 °C under microwave irradiation for 2 h. Monitor the reaction by LCMS until completion. Purify the reaction solution by reverse-phase preparative HPLC to obtain white solid 104 (40 mg, yield 40%). ESI-MS (m / z): 472.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J = 2.7 Hz, 1H), 8.12 (d, J = 2.5 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.89 (dd, J = 8.5, 2.6 Hz, 1H), 7.85 (dd, J = 8.5, 2.6 Hz, 1H), 7.17 (dd, J = 8.4, 0.7 Hz, 1H), 7.03 (br s, 1H), 4.37 (d, J = 6.4 Hz, 2H), 4.00 (s, 2H), 3.73 - 3.62 (m, 2H), 2.91 (s, 3H), 2.53 - 2.47 (m, 2H), 1.89 - 1.78 (m, 2H).

[0484] Example 105 (W199)

[0485] (S)-5-Methyl-4-(methyl-d3)-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0486]

[0487] Compound 105 was prepared by the following steps:

[0488]

[0489] Step 1: Dissolve 2,4-dichloropyrido[3,2-d]pyrimidine 1f (2.0 g, 3.5 mmol) and L-alanine methyl ester hydrochloride 105a (1.81 g, 13.0 mmol) in tetrahydrofuran (20 mL), add N,N-diisopropylethylamine (3.88 g, 30.0 mmol, 5.22 mL), and stir overnight at room temperature. Monitor the reaction by LCMS until completion, concentrate the reaction solution, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain a yellow oil 105b (2.5 g, yield 93%). ESI-MS (m / z): 267.3 [M+H] + 。

[0490] Step 2: Dissolve compound 105b (2.5 g, 9.37 mmol) in tetrahydrofuran (30 mL), add aqueous hydrochloric acid solution (6 M, 1.56 mL) and platinum dioxide (212 mg, 0.94 mmol), replace the hydrogen in the reaction system with a hydrogen balloon, and stir for 48 hours under the pressure of the hydrogen balloon at room temperature. Monitor the reaction by LCMS until completion. Dilute the reaction solution with methanol, filter, concentrate the filtrate, and purify it by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain a gray solid 105c (0.8 g, yield 35%). ESI-MS (m / z): 239.5 [M+H] + 。

[0491] Step 3: Dissolve compound 105c (100 mg, 0.42 mmol) and iodomethane-d3 (121 mg, 0.84 mmol) in acetonitrile (10 mL), add cesium carbonate (273 mg, 0.84 mmol), and react at 50 °C for 2 hours. Monitor the reaction by LCMS until completion. Dilute the reaction solution with dichloromethane, filter, concentrate the filtrate, and purify it by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain a white solid 105d (80 mg, yield 74%). ESI-MS (m / z): 256.3 [M+H] + 。

[0492] Step 4: Dissolve compound 105d (50 mg, 195 μmol), compound 11d (63 mg, 234 μmol) and p-toluenesulfonic acid monohydrate (4 mg, 19 μmol) in n-butanol (2 mL), and react at 160 °C under microwave for 2 hours. Monitor the reaction by LCMS until completion. Purify the reaction solution by reverse-phase preparative HPLC to obtain a white solid 105 (33 mg, yield 34%). MS (ESI): m / z 489.2 [M+H] + ; 11H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J = 2.6 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.89 (dd, J = 8.5, 2.6 Hz, 1H), 7.85 (dd, J = 8.5, 2.6 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.06 (br s, 1H), 4.45 - 4.31 (m, 2H), 4.11 (q, J = 6.8 Hz, 1H), 4.04 - 3.96 (m, 1H), 3.30 - 3.22 (m, 1H), 2.62 - 2.50 (m, 2H), 1.96 - 1.87 (m, 1H), 1.84 - 1.73 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H).

[0493] Example 106 (W190)

[0494] (S)-5-(Methoxymethyl)-4-methyl-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0495]

[0496] Compound 106 was prepared by the following steps:

[0497]

[0498] First step: Dissolve 2,4-dichloropyrido[3,2-d]pyrimidine 1f (2 g, 10.00 mmol) and O-methyl-L-serine methyl ester hydrochloride 106a (2.45 g, 15.00 mmol) in tetrahydrofuran (20 mL), add N,N-diisopropylethylamine (3.88 g, 30.00 mmol, 5.22 mL), and stir overnight at room temperature. Monitor the reaction by LCMS until it is completed, concentrate the reaction solution, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain a yellow oil 106b (2.5 g, yield 84%). ESI-MS (m / z): 297.2 [M+H] + 。

[0499] Step 2: Dissolve compound 106b (2.5 g, 8.43 mmol) in tetrahydrofuran (30 mL), add aqueous hydrochloric acid solution (6 N, 1.40 mL) and platinum dioxide (191 mg, 0.84 mmol). Replace the hydrogen in the reaction system with a hydrogen balloon and stir at room temperature under the pressure of the hydrogen balloon for 48 hours. Monitor the end of the reaction by LCMS. Dilute the reaction solution with methanol, filter through diatomaceous earth, concentrate the filtrate and purify it by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain a gray solid 106c (2.0 g, yield 88%). ESI-MS (m / z): 269.3 [M+H] + 。

[0500] Step 3: Dissolve compound 106c (500 mg, 1.86 mmol) and methyl iodide (343 mg, 2.42 mmol) in acetonitrile (10 mL), add cesium carbonate (1.21 g, 372 mmol), and react at 50 °C for 2 hours. Monitor the end of the reaction by LCMS. Dilute the reaction solution with dichloromethane, filter, concentrate the filtrate and purify it by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain a white solid 106d (350 mg, yield 66%). ESI-MS (m / z): 283.3 [M+H] + 。

[0501] Step 4: Dissolve compound 106d (50 mg, 176 μmol), compound 11d (71 mg, 265 μmol) and p-toluenesulfonic acid monohydrate (3 mg, 17 μmol) in n-butanol (2 mL), and react at 160 °C under microwave for 2 hours. Monitor the end of the reaction by LCMS. Purify the reaction solution by reverse-phase preparative HPLC to obtain a white solid 106 (6 mg, yield 7%). ESI-MS (m / z): 516.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J = 2.7 Hz, 1H), 8.13 (d, J = 2.4 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.89 (dd, J = 8.5, 2.6 Hz, 2H), 7.85 (dd, J = 8.5, 2.6 Hz, 2H), 7.17 (d, J = 8.4 Hz, 1H), 6.99 (br s, 1H), 4.45 - 4.32 (m, 2H), 4.22 (t, J = 2.8 Hz, 1H), 4.02 - 3.95 (m, 1H), 3.71 - 3.60 (m, 2H), 3.40 - 3.30 (m, 1H), 3.15 (s, 3H), 2.96 (s, 3H), 2.55 - 2.47 (m, 2H), 1.88 (d, J = 7.6 Hz, 1H), 1.74 (s, 1H).

[0502] Example 107 (W192)

[0503] (S)-5-(Hydroxymethyl)-4-methyl-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0504]

[0505] Compound 107 was prepared by the following steps:

[0506]

[0507] First step: Dissolve 106d (250 mg, 0.88 mmol) in dichloromethane (2 mL), and then add boron tribromide (2.21 g, 8.84 mmol, 0.85 mL) dropwise at 0 °C. After the addition is complete, react at 0 °C for two hours. Monitor the end of the reaction by LCMS. Carefully quench the reaction solution with sodium bicarbonate solution, extract with dichloromethane, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. The residue is purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain white solid 107a (100 mg, yield 42%). ESI-MS (m / z): 269.3 [M+H] + 。

[0508] Second step: Dissolve compound 107a (30 mg, 111 μmol), compound 11d (45 mg, 167 μmol) and p-toluenesulfonic acid monohydrate (2 mg, 11 μmol) in n-butanol (2 mL), and react at 160 °C under microwave for 2 hours. Monitor the end of the reaction by LCMS. Purify the reaction solution by reverse-phase preparative HPLC to obtain white solid 107 (9 mg, yield 17%). ESI-MS (m / z): 501.6 [M+H] + ; 11H NMR (500 MHz, DMSO-d6) δ 8.64 (d, J = 2.6 Hz, 1H), 8.27 (s, 1H), 8.13 (d, J = 2.5 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.89 (dd, J = 8.6, 2.5 Hz, 2H), 7.86 (dd, J = 8.6, 2.5 Hz, 2H), 7.17 (d, J = 8.4 Hz, 1H), 6.95 (br s, 1H), 4.44 - 4.30 (m, 2H), 4.08 - 3.97 (m, 2H), 3.76 - 3.65 (m, 2H), 3.40 - 3.30 (m, 1H), 2.96 (s, 3H), 2.52 - 2.47 (m, 2H), 1.92 - 1.86 (m, 1H), 1.83 - 1.72 (s, 1H).

[0509] Example 108 (W207)

[0510] (S)-5-(Hydroxymethyl)-4-(methyl-d3)-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0511]

[0512] Compound 108 was prepared by the following steps:

[0513]

[0514] First step: Dissolve compound 106c (200 mg, 0.74 mmol) and deuterated iodomethane (215 mg, 1.49 mmol) in acetonitrile (5 mL), add cesium carbonate (485 mg, 1.49 mmol), and react at 50 °C for 2 hours. Monitor the reaction by LCMS until completion. Dilute the reaction solution with dichloromethane, filter, concentrate the filtrate, and purify it by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain yellow solid 108a (200 mg, yield 94%). ESI-MS (m / z): 286.3 [M+H] + .

[0515] Step 2: Dissolve 108a (200 mg, 0.87 mmol) in dichloromethane (2 mL). Add boron tribromide (2.19 g, 8.75 mmol, 0.84 mL) dropwise at 0 °C. After the addition, react for two hours at 0 °C. Monitor the reaction completion by LCMS. Quench the reaction mixture carefully with sodium bicarbonate solution, extract with dichloromethane, dry the combined organic phases over anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain white solid 108b (150 mg, yield 75%). ESI-MS (m / z): 272.3 [M+H] + 。

[0516] Step 3: Dissolve compound 108b (50 mg, 184 μmol), compound 11d (59 mg, 220 μmol) and p-toluenesulfonic acid monohydrate (3.5 mg, 18 μmol) in n-butanol (2 mL). React under microwave conditions at 160 °C for 2 hours. Monitor the reaction completion by LCMS. Purify the reaction mixture by reverse-phase preparative HPLC to obtain white solid 108 (41 mg, yield 44%). ESI-MS (m / z): 505.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.64 (d, J = 2.7 Hz, 1H), 8.15 (d, J = 2.4 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.92 (dd, J = 8.4, 2.5 Hz, 1H), 7.87 (dd, J = 8.5, 2.7 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 5.07 (br s, 1H), 4.52 - 4.37 (m, 2H), 4.14 (s, 1H), 4.07 - 4.00 (m, 1H), 3.80 - 3.68 (m, 2H), 3.35 - 3.29 (m, 1H), 2.56 - 2.50 (m, 2H), 1.97 - 1.88 (m, 1H), 1.82 - 1.71 (m, 1H).

[0517] Example 109 (W220)

[0518] (S)-5-((R)-1-Hydroxyethyl)-4-methyl-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0519]

[0520] Compound 109 was prepared by the following steps:

[0521]

[0522] Step 1: Dissolve 2,4-dichloropyrido[3,2-d]pyrimidine 1f (1.0 g, 5.0 mmol) and L-threonine methyl ester hydrochloride 109a (1.10 g, 6.5 mmol) in tetrahydrofuran (10 mL), add N,N-diisopropylethylamine (1.94 g, 15.0 mmol, 2.61 mL), and stir overnight at room temperature. Monitor the reaction by LCMS. After the reaction is completed, concentrate the reaction solution, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain a yellow oil 109b (1.3 g, yield 87%). ESI-MS (m / z): 297.3 [M+H] + 。

[0523] Step 2: Dissolve compound 109b (1.3 g, 4.38 mmol) in tetrahydrofuran (20 mL), add aqueous hydrochloric acid solution (6 M, 0.73 mL) and platinum dioxide (99 mg, 0.44 mmol). Replace the hydrogen in the reaction system with a hydrogen balloon, and stir for 48 hours under the pressure of the hydrogen balloon at room temperature. Monitor the reaction by LCMS. Dilute the reaction solution with methanol, filter through diatomaceous earth, concentrate the filtrate, and purify it by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain a gray solid 109c (0.4 g, yield 33%). ESI-MS (m / z): 269.3 [M+H] + 。

[0524] Step 3: Dissolve compound 109c (150 mg, 0.56 mmol) and methyl iodide (118 mg, 0.84 mmol) in acetonitrile (3 mL), add cesium carbonate (363 mg, 1.12 mmol), and react at 50 °C for 2 hours. Monitor the reaction by LCMS. Dilute the reaction solution with dichloromethane, filter, concentrate the filtrate, and purify it by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain a white solid 109d (100 mg, yield 63%). ESI-MS (m / z): 283.4 [M+H] + 。

[0525] Step 4: Dissolve compound 109d (50 mg, 176 μmol), compound 11d (57 mg, 212 μmol) and p-toluenesulfonic acid monohydrate (3.3 mg, 17 μmol) in n-butanol (2 mL), and react under microwave at 160 °C for 2 hours. Monitor the reaction by LCMS. Purify the reaction solution by reverse-phase preparative HPLC to obtain a white solid 109 (40 mg, yield 44%). ESI-MS (m / z): 516.3 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J = 2.6 Hz, 1H), 8.19 (s, 1H), 8.13 (d, J = 2.4 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.89 (dd, J = 8.5, 2.5 Hz, 1H), 7.86 (dd, J = 8.5, 2.5 Hz, 2H), 7.17 (d, J = 8.4 Hz, 1H), 7.02 (t, J = 6.4 Hz, 1H), 4.93 (br s, 1H), 4.47 - 4.27 (m, 2H), 4.17 - 4.06 (m, 1H), 3.93 - 3.83 (m, 2H), 3.17 - 3.10 (m, 1H), 3.07 (s, 3H), 2.52 - 2.47 (m, 2H), 1.98 - 1.88 (m, 1H), 1.82 - 1.68 (m, 1H), 1.09 (d, J = 6.2 Hz, 3H).

[0526] Example 110 (W231)

[0527] (S)-5-((S)-1-Hydroxyethyl)-4-methyl-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0528]

[0529] Compound 110 was prepared by the following steps:

[0530]

[0531] First step: Dissolve 2,4-dichloropyrido[3,2-d]pyrimidine 1f (3.0 g, 15.0 mmol) and L-allothreonine methyl ester hydrochloride 110a (3.31 g, 19.5 mmol) in dichloromethane (30 mL), add N,N-diisopropylethylamine (5.82 g, 45.0 mmol, 7.84 mL), and stir overnight at room temperature. Monitor the reaction by LCMS until it is completed, concentrate the reaction solution, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain a yellow oil 110b (3.8 g, yield 85%). ESI-MS (m / z): 297.3 [M+H] +Step 2: Dissolve compound 110b (1.5 g, 5.06 mmol) in tetrahydrofuran (20 mL), add aqueous hydrochloric acid solution (6 N, 0.84 mL) and platinum dioxide (114.80 mg, 0.51 mmol). Replace the hydrogen in the reaction system with a hydrogen balloon and stir for 48 hours under the pressure of the hydrogen balloon at room temperature. Monitor the reaction by LCMS until it is completed. Dilute the reaction solution with methanol, filter, concentrate the filtrate, and purify it by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain gray solid 110c (0.5 g, yield 36%). ESI-MS (m / z): 269.5 [M+H] + 。

[0532] Step 3: Dissolve compound 110c (100 mg, 0.37 mmol) and methyl iodide (79 mg, 0.56 mmol) in acetonitrile (3 mL), add cesium carbonate (242 mg, 0.74 mmol), and react at 50 °C for 2 hours. Monitor the reaction by LCMS until it is completed. Dilute the reaction solution with dichloromethane, filter, concentrate the filtrate, and purify it by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain white solid 110d (80 mg, yield 76%). ESI-MS (m / z): 283.3 [M+H] + 。

[0533] Step 4: Dissolve compound 110d (50 mg, 176 μmol), compound 11d (57 mg, 212 μmol) and p-toluenesulfonic acid monohydrate (3.3 mg, 17 μmol) in n-butanol (2 mL), and react at 160 °C under microwave for 2 hours. Monitor the reaction by LCMS until it is completed. Purify the reaction solution by reverse-phase preparative HPLC to obtain white solid 110 (44 mg, yield 48%). ESI-MS (m / z): 516.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.65 (d, J = 2.7 Hz, 1H), 8.17 - 8.13 (m, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.92 (dd, J = 8.4, 2.5 Hz, 1H), 7.87 (dd, J = 8.6, 2.7 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 7.10 - 6.90 (m, 1H), 5.05 (d, J = 4.8 Hz, 1H), 4.52 - 4.34 (m, 2H), 4.16 - 4.02 (m, 3H), 3.25 - 3.17 (m, 1H), 3.05 (s, 3H), 2.55 - 2.47 (m, 2H), 1.99 - 1.90 (m, 1H), 1.80 - 1.70 (m, 1H), 1.04 (d, J = 6.4 Hz, 3H).

[0534] Example 111 (W241)

[0535] (S)-2-(((6-((6-(Trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-5,6,8a,9,10,11-hexahydro-4H,8H-pyrido[3,2,1-de]pyrrolo[2,1-h]pteridin-8-one

[0536]

[0537] Compound 111 was prepared by the following steps:

[0538]

[0539] First step: Dissolve 2,4-dichloropyrido[3,2-d]pyrimidine 1f (1.00 g, 5.00 mmol) and L-proline methyl ester hydrochloride 111a (1.08 g, 6.50 mmol) in tetrahydrofuran (10 mL), add N,N-diisopropylethylamine (1.94 g, 15.00 mmol, 2.61 mL), and stir overnight at room temperature. Monitor the end of the reaction by LCMS, concentrate the reaction solution, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain a yellow solid 111b (1.20 g, yield 82%). ESI-MS (m / z): 293.2 [M+H] + .

[0540] Second step: Dissolve compound 111b (1.20 g, 4.10 mmol) in tetrahydrofuran (20 mL), add aqueous hydrochloric acid solution (6N, 0.70 mL) and platinum dioxide (94 mg, 0.41 mmol), replace the hydrogen in the reaction system with a hydrogen balloon, and stir for 48 hours under the pressure of the hydrogen balloon at room temperature. Monitor the end of the reaction by LCMS. Dilute the reaction solution with methanol, filter, concentrate the filtrate, and purify it by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain a yellow solid 111c (0.60 g, yield 55%). ESI-MS (m / z): 265.3 [M+H] + .

[0541] Third step: Dissolve compound 111c (50 mg, 188 μmol), compound 11d (67 mg, 251 μmol) and p-toluenesulfonic acid monohydrate (3.6 mg, 18 μmol) in n-butanol (2 mL), and react at 160 °C under microwave for 2 hours. Monitor the end of the reaction by LCMS. Purify the reaction solution by reverse-phase preparative HPLC to obtain a white solid 111 (15 mg, yield 16%). ESI-MS (m / z): 498.3 [M+H] + ; 11H NMR (500 MHz, DMSO-d6) δ 8.64 (d, J = 2.6 Hz, 1H), 8.13 (d, J = 2.3 Hz, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.90 (dd, J = 8.5, 2.6 Hz, 1H), 7.86 (dd, J = 8.5, 2.6 Hz, 2H), 7.17 (d, J = 8.4 Hz, 1H), 7.06 (t, J = 6.4 Hz, 1H), 4.44 - 4.32 (m, 2H), 4.14 - 4.04 (m, 2H), 3.62 - 3.54 (m, 1H), 3.49 - 3.40 (m, 1H), 3.25 - 3.16 (m, 1H), 2.52 - 2.47 (m, 2H), 2.26 - 2.20 (m, 1H), 2.00 - 1.75 (m, 5H).

[0542] Example 112 (W242)

[0543] (8aS,10S)-10-Hydroxy-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-5,6,8a,9,10,11-hexahydro-4H,8H-pyrido[3,2,1-de]pyrrolo[2,1-h]pteridin-8-one

[0544]

[0545] Compound 112 was prepared by the following steps:

[0546]

[0547] First step: Dissolve 2,4-dichloropyrido[3,2-d]pyrimidine 1f (1.0 g, 5.0 mmol) and cis-4-hydroxy-L-proline methyl ester hydrochloride 112a (943 mg, 6.50 mmol) in tetrahydrofuran (10 mL), add N,N-diisopropylethylamine (1.94 g, 15.0 mmol, 2.61 mL), and stir overnight at room temperature. Monitor the reaction by LCMS until completion, concentrate the reaction solution, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain yellow solid 112b (1.3 g, yield 84%). ESI-MS (m / z): 309.2 [M+H] + .

[0548] Step 2: Dissolve compound 112b (1.3 g, 4.21 mmol) in tetrahydrofuran (10 mL), add aqueous hydrochloric acid solution (6 N, 0.70 mL) and platinum dioxide (95 mg, 0.42 mmol). Replace the hydrogen in the reaction system with a hydrogen balloon and stir for 48 hours under the pressure of the hydrogen balloon at room temperature. Monitor the reaction by LCMS until it is completed. Dilute the reaction solution with methanol, filter it, concentrate the filtrate and purify it by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain white solid 112c (0.80 g, yield 67%). ESI-MS (m / z): 281.3 [M+H] + .

[0549] Step 3: Dissolve compound 112c (50 mg, 178 μmol), compound 11d (57 mg, 213 μmol) and p-toluenesulfonic acid monohydrate (3.4 mg, 17 μmol) in n-butanol (2 mL) and react under microwave conditions at 160 °C for 2 hours. Monitor the reaction by LCMS until it is completed. Purify the reaction solution by reverse-phase preparative HPLC to obtain white solid 112 (23 mg, yield 25%). ESI-MS (m / z): 514.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.64 (d, J = 2.6 Hz, 1H), 8.13 (d, J = 2.3 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.89 (dd, J = 8.5, 2.6 Hz, 1H), 7.86 (dd, J = 8.5, 2.6 Hz, 2H), 7.17 (d, J = 8.4 Hz, 1H), 7.06 (t, J = 4.3 Hz, 1H), 5.14 (br s, 1H), 4.45 - 4.29 (m, 4H), 4.15 - 4.08 (m, 1H), 3.80 - 3.70 (m, 1H), 3.54 - 3.40 (m, 2H), 3.25 - 3.17 (m, 1H), 2.50 - 2.39 (m, 1H), 2.15 - 2.09 (m, 1H), 2.04 - 1.89 (m, 2H), 1.86 - 1.77 (m, 1H).

[0550] Example 113 (W247)

[0551] (S)-5-((S)-1-Methoxyethyl)-4-methyl-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0552]

[0553] Compound 113 was prepared by the following steps:

[0554]

[0555] Step 1: Dissolve compound 110c (100 mg, 0.37 mmol) in tetrahydrofuran (2 mL), add silver carbonate (431 mg, 1.86 mmol), cesium carbonate (242 mg, 0.74 mmol) and methyl iodide (158 mg, 1.12 mmol, 69 μL), stir at 60 °C under nitrogen protection for 16 hours, and monitor the end of the reaction by LCMS. Dilute the reaction solution with methanol, filter, concentrate the filtrate and purify it by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain yellow oil 113a (60 mg, yield 54%). ESI-MS (m / z): 297.3 [M+H] + 。

[0556] Step 2: Dissolve compound 113a (60 mg, 202 μmol), compound 11d (65 mg, 242 μmol) and p-toluenesulfonic acid monohydrate (3.8 mg, 20 μmol) in n-butanol (2 mL), and react at 160 °C under microwave for 2 hours. Monitor the end of the reaction by LCMS. Purify the reaction solution by reverse-phase preparative HPLC to obtain white solid 113 (23 mg, yield 21%). ESI-MS (m / z): 530.3 [M+H] + ; 1 1H NMR (500 MHz, DMSO-d6) δ 8.64 (d, J = 2.7 Hz, 1H), 8.14 (d, J = 2.5 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.91 (dd, J = 8.4, 2.5 Hz, 1H), 7.86 (dd, J = 8.6, 2.7 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.01 (br s, 1H), 4.39 (d, J = 6.2 Hz, 2H), 4.31 (d, J = 1.9 Hz, 1H), 4.12 - 4.03 (m, 1H), 3.75 - 3.68 (m, 1H), 3.30 - 3.21 (m, 1H), 3.20 (s, 3H), 3.02 (s, 3H), 2.52 - 2.47 (m, 2H), 1.96 - 1.89 (m, 1H), 1.80 - 1.70 (m, 1H), 1.00 (d, J = 6.4 Hz, 3H).

[0557] Example 114 (W243)

[0558] (S)-5-((R)-1-Methoxyethyl)-4-methyl-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0559]

[0560] Replace 110c in the first step of Example 113 with intermediate 109c, and compound 114 can be obtained by a similar method and reaction steps. ESI-MS (m / z): 530.3 [M+H] + ; 1 HNMR (500 MHz, DMSO-d6) δ 8.64 (d, J = 2.6 Hz, 1H), 8.15 (d, J = 2.3 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.92 (dd, J = 8.4, 2.5 Hz, 1H), 7.87 (dd, J = 8.6, 2.7 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.06 (br s, 1H), 4.45 - 4.33 (m, 2H), 4.17 - 4.10 (m, 1H), 4.07 (d, J = 4.8 Hz, 1H), 3.60 - 3.51 (m, 1H), 3.20 - 3.11 (m, 4H), 3.07 (s, 3H), 2.55 - 2.49 (m, 2H), 2.02 - 1.93 (m, 1H), 1.81 - 1.69 (m, 1H), 1.08 (d, J = 6.4 Hz, 3H).

[0561] Example 115 (W244)

[0562] (S)-4-(2-Methoxyethyl)-5-methyl-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0563]

[0564] Compound 115 was prepared by the following steps:

[0565]

[0566] Step 1: Sodium hydride (84 mg, 60% content, 2.10 mmol) was dissolved in dry DMF (1 mL). Compound 105c (100 mg, 0.42 mmol, dissolved in 1 mL DMF) was added at 0 °C. Under nitrogen protection, the mixture was stirred at 0 °C for 1 hour. Then 1-bromoethyl methyl ether (117 mg, 0.84 mmol) was added, and the reaction mixture was stirred at 0 °C for 2 hours. The reaction was monitored by TLC. After quenching with water, the mixture was extracted with ethyl acetate (2×20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1 to 4 / 1) to obtain yellow solid 115a (95 mg, yield 76%). ESI-MS (m / z): 297.3 [M+H] + 。

[0567] Step 4: Compound 115a (90 mg, 0.30 mmol), compound 11d (81 mg, 0.30 mmol) and p-toluenesulfonic acid monohydrate (5.7 mg, 0.03 mmol) were dissolved in n-butanol (3 mL). The reaction was carried out at 160 °C under microwave irradiation for 3 hours. The reaction was monitored by LCMS. The reaction mixture was purified by reversed-phase preparative HPLC to obtain white solid 115 (23 mg, yield 15%). ESI-MS (m / z): 530.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J = 2.7 Hz, 1H), 8.11 (d, J = 2.5 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.90 - 7.83 (m, 2H), 7.18 (d, J = 8.4 Hz, 1H), 7.08 (br s, 1H), 4.48 - 4.28 (m, 2H), 4.16 (q, J = 6.7 Hz, 1H), 4.09 - 3.98 (m, 2H), 3.30 - 3.15 (m, 5H), 2.55 - 2.50 (m, 2H), 1.99 - 1.89 (m, 1H), 1.84 - 1.75 (m, 1H), 1.23 (d, J = 6.8 Hz, 3H).

[0568] Example 116 (W249)

[0569] (S)-4-Ethyl-5-methyl-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0570]

[0571] Replace deuterated iodomethane in the third step of Example 105 with iodoethane. Using a similar method and reaction steps, compound 116 can be obtained. ESI-MS (m / z): 499.9 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J = 2.6 Hz, 1H), 8.12 (d, J = 2.3 Hz, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.92 - 7.83 (m, 2H), 7.18 (d, J = 8.4 Hz, 1H), 7.06 (br s, 1H), 4.45 - 4.31 (m, 2H), 4.16 (q, J = 6.7 Hz, 1H), 4.06 - 3.99 (m, 1H), 3.89 - 3.77 (m, 1H), 3.32 - 3.25 (m, 2H), 3.15 - 3.07 (m, 1H), 2.00 - 1.90 (m, 1H), 1.86 - 1.74 (m, 1H), 1.25 (d, J = 6.7 Hz, 3H), 1.06 (t, J = 7.1 Hz, 3H).

[0572] Example 117 (W237)

[0573] (S)-5-Isopropyl-4-methyl-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0574]

[0575] Replace O-methyl-L-serine methyl ester hydrochloride 106a in the first step of Example 106 with L-valine methyl ester hydrochloride. Using a similar method and reaction steps, compound 117 can be obtained. ESI-MS (m / z): 514.5 [M+H] + ; 1HNMR(500MHz, DMSO-d6) δ 8.64 (d, J = 2.6 Hz, 1H), 8.14 (d, J = 2.4 Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.91 (dd, J = 8.5, 3.0 Hz, 1H), 7.86 (dd, J = 8.5, 3.0 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.02 (brs, 1H), 4.45 - 4.33 (m, 2H), 4.18 - 4.12 (m, 1H), 3.99 (d, J = 3.8 Hz, 1H), 3.22 - 3.15 (m, 1H), 3.01 (s, 3H), 2.55 - 2.49 (m, 2H), 2.18 - 2.13 (m, 1H), 2.01 - 1.93 (m, 1H), 1.80 - 1.69 (m, 1H), 0.94 (d, J = 7.0 Hz, 3H), 0.75 (d, J = 6.9 Hz, 3H).

[0576] Example 118 (W279)

[0577] (S)-4-Ethyl-5-isopropyl-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0578]

[0579] Replace O-methyl-L-serine methyl ester hydrochloride 106a in the first step of Example 106 with L-valine methyl ester hydrochloride, and then replace methyl iodide in the third step with iodoethane. Compound 118 can be obtained by a similar method and reaction steps. ESI-MS (m / z): 526.4 [M + H] + ; 11H NMR (500 MHz, DMSO-d6) δ 8.61 (d, J = 2.2 Hz, 1H), 8.11 (d, J = 1.6 Hz, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.88 (dd, J = 8.4, 2.0 Hz, 1H), 7.83 (dd, J = 8.6, 2.1 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.01 (br s, 1H), 4.47 - 4.31 (m, 2H), 4.17 - 4.11 (m, 1H), 4.06 - 3.95 (m, 2H), 3.35 - 3.26 (m, 2H), 3.21 - 3.15 (m, 1H), 3.10 - 3.00 (m, 1H), 2.09 - 2.01 (m, 1H), 1.99 - 1.93 (m, 1H), 1.76 - 1.67 (m, 1H), 1.02 (t, J = 6.7 Hz, 3H), 0.93 (d, J = 6.9 Hz, 3H), 0.74 (d, J = 6.8 Hz, 3H).

[0580] Example 119 (W255)

[0581] (S)-5-Ethyl-4-methyl-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0582]

[0583] Replace O-methyl-L-serine methyl ester hydrochloride 106a in the first step of Example 106 with L-2-aminobutyric acid methyl ester hydrochloride, and compound 119 can be obtained by a similar method and reaction steps. ESI-MS (m / z): 500.0 [M + H] + ; 1HNMR(500MHz, DMSO-d6) δ 8.62 (d, J = 2.6 Hz, 1H), 8.12 (d, J = 2.3 Hz, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.89 (dd, J = 8.5, 2.5 Hz, 2H), 7.85 (dd, J = 8.5, 2.5 Hz, 2H), 7.16 (d, J = 8.4 Hz, 1H), 7.00 (t, J = 6.3 Hz, 1H), 4.43 - 4.31 (m, 2H), 4.15 - 4.10 (m, 1H), 4.07 - 4.00 (m, 1H), 3.30 - 3.25 (m, 1H), 2.94 (s, 3H), 2.55 - 2.49 (m, 2H), 1.99 - 1.89 (m, 1H), 1.85 - 1.70 (m, 3H), 0.68 (t, J = 7.4 Hz, 3H).

[0584] Example 120 (W265)

[0585] (S)-5-Cyclopropyl-4-methyl-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0586]

[0587] Replace O-methyl-L-serine methyl ester hydrochloride 106a in the first step of Example 106 with L-cyclopropylglycine methyl ester hydrochloride, and compound 120 can be obtained by a similar method and reaction steps. ESI-MS (m / z): 512.4 [M + H] + ; 1 HNMR(500MHz, DMSO-d6) δ 8.62 (d, J = 2.5 Hz, 1H), 8.13 (d, J = 2.3 Hz, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.90 (dd, J = 8.5, 2.4 Hz, 1H), 7.85 (dd, J = 8.7, 2.6 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.07 (br s, 1H), 4.46 - 4.29 (m, 2H), 4.14 - 4.06 (m, 1H), 3.47 (d, J = 8.7 Hz, 1H), 3.20 - 3.12 (m, 1H), 3.01 (s, 3H), 2.54 - 2.49 (m, 2H), 2.00 - 1.90 (m, 1H), 1.84 - 1.72 (m, 1H), 0.93 - 0.83 (m, 1H), 0.56 - 0.47 (m, 2H), 0.45 - 0.31 (m, 2H).

[0588] Example 121 (W266)

[0589] (S)-4-Ethyl-5-((S)-1-hydroxyethyl)-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0590]

[0591] Compound 121 was prepared by the following steps:

[0592]

[0593] First step: Dissolve compound 110c (230 mg, 0.86 mmol) in acetonitrile (5 mL), add cesium carbonate (557 mg, 1.71 mmol) and iodoethane (200 mg, 1.28 mmol), and stir the reaction solution at 50 °C for 12 hours. Dilute the reaction solution with saturated brine and extract with ethyl acetate. Dry the organic phase with anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 121a (265 mg, yield 70%). ESI-MS (m / z): 297.2 [M+H] + 。

[0594] Second step: Dissolve compound 11d (65 mg, 0.24 mmol) and compound 121a (48 mg, 0.16 mmol) in n-butanol (5 mL), add p-toluenesulfonic acid monohydrate (28 mg, 0.16 mmol), and stir the reaction solution at 160 °C for 3 hours under microwave conditions. After the reaction solution is cooled to room temperature, concentrate it under reduced pressure, and purify the residue by reversed-phase preparative HPLC to obtain white solid compound 119 (8 mg, yield 6%). ESI-MS (m / z): 530.5 [M+H] + ; 11H NMR (500 MHz, DMSO-d6) δ 8.62 (d, J = 2.2 Hz, 1H), 8.12 (d, J = 1.6 Hz, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.89 (dd, J = 8.4, 2.0 Hz, 1H), 7.84 (dd, J = 8.6, 2.1 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.94 (br s, 1H), 5.01 (d, J = 4.8 Hz, 1H), 4.49 - 4.27 (m, 2H), 4.13 - 4.05 (m, 2H), 4.04 - 3.95 (m, 2H), 3.24 - 3.14 (m, 2H), 2.50 - 2.43 (m, 2H), 1.95 - 1.87 (m, 1H), 1.79 - 1.66 (m, 1H), 1.06 - 0.99 (m, 6H).

[0595] Example 122 (W272)

[0596] (S)-5-(2-Hydroxypropan-2-yl)-4-methyl-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0597]

[0598] Replace O-methyl-L-serine methyl ester hydrochloride 106a in the first step of Example 106 with (S)-methyl 2-amino-3-hydroxy-3-methylbutanoate hydrochloride, and compound 122 can be obtained by a similar method and reaction steps. ESI-MS (m / z): 530.3 [M+H] + ; 1 1H NMR (500 MHz, DMSO-d6) δ 8.60 (d, J = 3.0 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.96 - 7.92 (m, 1H), 7.91 - 7.87 (m, 1H), 7.85 - 7.80 (m, 1H), 7.16 - 7.12 (m, 1H), 7.01 - 6.94 (m, 1H), 4.68 (s, 1H), 4.46 - 4.30 (m, 2H), 4.17 - 4.11 (m, 1H), 3.86 (s, 1H), 3.09 (s, 3H), 3.08 - 3.03 (m, 1H), 2.58 - 2.52 (m, 2H), 2.00 - 1.89 (m, 1H), 1.77 - 1.66 (m, 1H), 1.15 (s, 3H), 0.91 (s, 3H).

[0599] Example 123 (W276)

[0600] (8aS,9S)-9-Hydroxy-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino

[0601] -5,6,8a,9,10,11-hexahydro-4H,8H-pyrido[3,2,1-de]pyrrolo[2,1-h]pteridin-8-one

[0602]

[0603] Replace cis-4-hydroxy-L-proline 112a in the first step of Example 112 with trans-3-hydroxy-L-proline methyl ester hydrochloride, and compound 123 can be obtained by a similar method and reaction steps. ESI-MS (m / z): 514.3 [M+H] + ; 1 HNMR (500 MHz, DMSO-d6) δ 8.62 (d, J = 2.5 Hz, 1H), 8.11 (d, J = 2.3 Hz, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.88 (dd, J = 8.5, 2.5 Hz, 2H), 7.85 (dd, J = 8.5, 2.5 Hz, 2H), 7.15 (d, J = 8.4 Hz, 1H), 7.05 (t, J = 6.3 Hz, 1H), 5.27 (d, J = 5.0 Hz, 1H), 4.43 - 4.32 (m, 3H), 4.15 - 4.06 (m, 1H), 3.74 (d, J = 6.4 Hz, 1H), 3.65 - 3.55 (m, 1H), 3.46 - 3.35 (m, 1H), 3.24 - 3.13 (m, 1H), 2.52 - 2.45 (m, 2H), 2.13 - 2.04 (m, 1H), 1.99 - 1.87 (m, 1H), 1.85 - 1.67 (m, 2H).

[0604] Example 124 (W278)

[0605] (S)-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-5,6,8a,9,11,12-hexahydro-4H,8H-[1,4]oxazino[3,4-h]pyrido[3,2,1-de]pteridin-8-one

[0606]

[0607] Replace L-proline methyl ester hydrochloride 111a in the first step of Example 111 with (S)-morpholine-3-carboxylic acid methyl ester hydrochloride, and compound 124 can be obtained by a similar method and reaction steps. ESI-MS (m / z): 514.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.62 (d, J = 2.5 Hz, 1H), 8.12 (d, J = 2.3 Hz, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.88 (dd, J = 8.4, 2.5 Hz, 2H), 7.85 (dd, J = 8.4, 2.5 Hz, 2H), 7.16 (d, J = 8.5 Hz, 1H), 7.13 (brs, 1H), 4.38 (d, J = 6.3 Hz, 2H), 4.24 - 4.19 (m, 1H), 4.13 - 4.09 (m, 2H), 3.90 - 3.85 (m, 2H), 3.48 - 3.37 (m, 3H), 2.86 - 2.76 (m, 1H), 2.55 - 2.48 (m, 2H), 1.93 - 1.75 (m, 2H).

[0608] Example 125 (W281)

[0609] (S)-4-Ethyl-5-((R)-1-hydroxyethyl)-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0610]

[0611] Replace 110c in the first step of Example 121 with intermediate 109c, and compound 125 can be obtained by a similar method and reaction steps. ESI-MS (m / z): 530.4 [M+H] + ; 11H NMR (500 MHz, DMSO-d6) δ 8.62 (d, J = 2.5 Hz, 1H), 8.12 (d, J = 2.5 Hz, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.89 (dd, J = 8.0, 2.0 Hz, 1H), 7.84 (dd, J = 9.0, 2.5 Hz, 1H), 7.17 (d, J = 8.5 Hz, 1H), 6.99 (br s, 1H), 4.87 (d, J = 5.5 Hz, 1H), 4.50 - 4.40 (m, 1H), 4.36 - 4.28 (m, 1H), 4.20 - 4.10 (m, 2H), 3.92 (d, J = 4.5 Hz, 1H), 3.86 - 3.77 (m, 1H), 3.18 - 3.05 (m, 2H), 2.55 - 2.43 (m, 2H), 2.00 - 1.90 (m, 1H), 1.80 - 1.70 (m, 1H), 1.05 (d, J = 6.5 Hz, 3H), 0.99 (t, J = 7.5 Hz, 1H).

[0612] Example 126 (W308)

[0613] (R)-5-((S)-1-Fluoroethyl)-4-methyl-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)

[0614] amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0615]

[0616] Compound 126 was prepared by the following steps:

[0617]

[0618] First step: Dissolve compound 109 (30 mg, 58 μmol) in dichloromethane (2 mL), add diethylaminosulfur trifluoride (19 mg, 116 μmol) under an ice bath at 0 °C, and stir the mixture at 0 °C for 2 hours. After the reaction is complete, quench the reaction with water, and extract the aqueous phase with ethyl acetate. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate. The residue was separated by reverse preparative HPLC to obtain white solid compound 126 (4.5 mg, yield 15%). ESI-MS (m / z): 518.3 [M + H] + ; 11H NMR (500 MHz, DMSO-d6) δ 8.62 (d, J = 2.6 Hz, 1H), 8.12 (d, J = 2.3 Hz, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.88 (dd, J = 8.5, 2.5 Hz, 1H), 7.85 (dd, J = 8.5, 2.5 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.08 (br s, 1H), 5.16 - 4.96 (m, 1H), 4.45 - 4.31 (m, 3H), 4.13 - 4.05 (m, 1H), 3.31 - 3.20 (m, 1H), 3.02 (s, 3H), 2.55 - 2.47 (m, 2H), 1.97 - 1.89 (m, 1H), 1.80 - 1.68 (m, 1H), 1.30 - 1.20 (m, 3H).

[0619] Example 127 (W280)

[0620] (S)-4-Methyl-5-phenyl-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino

[0621] -4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0622]

[0623] Replace O-methyl-L-serine methyl ester hydrochloride 106a in the first step of Example 106 with L-phenylglycine methyl ester hydrochloride, and compound 127 can be obtained by a similar method and reaction steps. ESI-MS (m / z): 548.3 [M + H] + ; 1 1H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J = 2.6 Hz, 1H), 8.14 (d, J = 2.3 Hz, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.91 (dd, J = 8.3, 2.4 Hz, 1H), 7.85 (dd, J = 8.6, 2.6 Hz, 1H), 7.40 - 7.29 (m, 3H), 7.25 - 7.15 (m, 3H), 7.12 (br s, 1H), 5.19 (s, 1H), 4.47 - 4.35 (m, 2H), 4.06 - 3.99 (m, 1H), 3.40 - 3.30 (m, 1H), 2.83 (s, 3H), 2.60 - 2.50 (m, 2H), 1.98 - 1.91 (m, 1H), 1.84 - 1.72 (m, 1H).

[0624] Example 128 (W263)

[0625] (S)-4,5-Dimethyl-2-(((6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxy)pyridin-3-yl)methyl)

[0626] amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0627]

[0628] Replace 5-(trifluoromethyl)pyridin-3-ol 99a in the first step of Example 99 with 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole, and by a similar method and reaction steps, compound 128 can be obtained. ESI-MS (m / z): 489.3 [M+H] + ; 1 HNMR (500 MHz, DMSO-d6) δ 8.15 (d, J = 2.3 Hz, 1H), 7.90 (dd, J = 8.4, 2.3 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.05 (t, J = 5.5 Hz, 1H), 6.53 (s, 1H), 4.47 - 4.31 (m, 2H), 4.10 (q, J = 6.8 Hz, 1H), 4.05 - 3.96 (m, 1H), 3.69 (s, 3H), 3.30 - 3.23 (m, 1H), 2.92 (s, 3H), 2.52 - 2.47 (m, 2H), 1.95 - 1.85 (m, 1H), 1.83 - 1.72 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H).

[0629] Example 129 (W369)

[0630] (S)-4,5-Dimethyl-2-(((6-((1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)pyridin-3-yl)methyl)

[0631] amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0632]

[0633] Replace 5-(trifluoromethyl)pyridin-3-ol 99a in the first step of Example 99 with 3-hydroxy-1-methyl-5-trifluoromethyl-1H-pyrazole, and by a similar method and reaction steps, compound 129 can be obtained. ESI-MS (m / z): 489.3 [M+H] + ; 1HNMR (500 MHz, DMSO-d6) δ 8.13 (d, J = 2.3 Hz, 1H), 7.84 (dd, J = 8.4, 2.4 Hz, 1H), 7.08 - 7.02 (m, 2H), 6.71 (s, 1H), 4.43 - 4.31 (m, 2H), 4.12 (q, J = 6.8 Hz, 1H), 4.05 - 3.99 (m, 1H), 3.89 (s, 3H), 3.33 - 3.23 (m, 2H), 2.94 (s, 3H), 2.01 - 1.90 (m, 1H), 1.86 - 1.73 (m, 1H), 1.24 (d, J = 6.7 Hz, 3H).

[0634] Example 130 (W354)

[0635] (S)-2-(((6-((1-Cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxy)pyridin-3-yl)methyl)amino)-4,5-

[0636] dimethyl-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0637]

[0638] Compound 130 was prepared by the following steps:

[0639]

[0640] First step: Ethyl trifluoroacetoacetate 130a (1.7 g, 9.21 mmol) and cyclopropylhydrazine hydrochloride 130b (1.0 g, 9.21 mmol) were dissolved in 20 mL of ethanol and reacted at 80 °C overnight. The reaction solution was concentrated, and the residue was triturated with petroleum ether and filtered to obtain brown solid compound 130c (800 mg, yield 45%). ESI-MS (m / z): 193.2 [M+H] + .

[0641] Second step: Compound 130c (300 mg, 1.56 mmol) and compound 97b (229 mg, 1.87 mmol) were dissolved in 10 mL of acetonitrile, cesium carbonate (763 mg, 2.34 mmol) was added, and the reaction was carried out at room temperature overnight. LCMS monitored that the raw materials reacted completely. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine respectively, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography to obtain colorless oily compound 130d (350 mg, yield 76%). ESI-MS (m / z): 295.3 [M+H] + .

[0642] Step 3: Dissolve compound 130d (350 mg, 1.19 mmol) in 30 mL of methanol, add Raney nickel (0.5 mL, aqueous suspension), 3 mL of ammonia water, and react overnight at room temperature under a hydrogen atmosphere. Monitor the reaction by LCMS until the raw materials are completely reacted. Filter the reaction solution through diatomaceous earth, wash the filter cake with methanol, and concentrate the filtrate to obtain light gray oily compound 130e (350 mg, yield 98%). ESI-MS (m / z): 299.1 [M+H] + 。

[0643] Step 4: Dissolve compound 1i (50 mg, 0.2 mmol) and compound 130e (77 mg, 0.25 mmol) in n-butanol (2 mL), add p-toluenesulfonic acid monohydrate (3.7 mg, 0.02 mmol), and react at 160 °C for 3 hours under microwave conditions. Monitor the reaction by LCMS until the raw materials are completely reacted. Purify the reaction solution directly by reverse preparative HPLC to obtain white solid compound 130 (45 mg, yield 44%). ESI-MS (m / z): 515.4 [M+H] + ; 1 1H NMR (500 MHz, DMSO-d6) δ 12.92 (br s, 1H), 8.23 (d, J = 2.3 Hz, 1H), 7.97 (dd, J = 8.4, 2.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 6.55 (s, 1H), 4.62 - 4.51 (m, 2H), 4.32 (q, J = 6.9 Hz, 1H), 4.04 - 3.94 (m, 1H), 3.48 (dt, J = 7.4, 3.8 Hz, 1H), 3.33 - 3.28 (m, 1H), 3.06 (s, 3H), 2.64 (t, J = 6.3 Hz, 2H), 2.03 - 1.94 (m, 1H), 1.90 - 1.78 (m, 1H), 1.37 (d, J = 6.9 Hz, 3H), 1.07 - 1.02 (m, 2H), 0.99 - 0.86 (m, 2H).

[0644] Example 131 (W366)

[0645] (S)-4,5-Dimethyl-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)thio)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0646]

[0647] Replace 5-(trifluoromethyl)pyridin-3-ol 99a in the first step of Example 99 with 6-trifluoromethyl-pyridine-3-thiol. Using a similar method and reaction steps, compound 131 can be obtained. ESI-MS (m / z): 501.7 [M+H] + ; 1 HNMR (500 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.41 (d, J = 2.2 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.72 (dd, J = 8.2, 2.2 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.05 (t, J = 6.4 Hz, 1H), 4.46 - 4.31 (m, 2H), 4.11 (q, J = 7.0 Hz, 2H), 4.04 - 3.98 (m, 1H), 3.32 - 3.23 (m, 2H), 2.91 (s, 3H), 2.56 - 2.47 (m, 2H), 1.97 - 1.89 (m, 1H), 1.86 - 1.74 (m, 1H), 1.23 (d, J = 6.7 Hz, 3H).

[0648] Example 132 (W383)

[0649] (S)-5-((methoxy-d3)methyl)-4-(methyl-d3)-2-(((6-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0650]

[0651] Compound 132 is prepared by the following steps:

[0652]

[0653] First step: Dissolve compound 106c (1.0 g, 3.72 mmol) and cesium carbonate (2.43 g, 7.44 mmol) in acetonitrile (10 mL), and add deuterated iodomethane (701 mg, 4.84 mmol). The reaction mixture is stirred at room temperature for 12 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow solid 132a (693 mg, yield 65%). ESI-MS (m / z): 286.3 [M+H] + .

[0654] Step 2: Dissolve compound 132a (200 mg, 0.7 mmol) in dichloromethane (10 mL), and slowly add boron tribromide (876 mg, 3.5 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for an additional 2 h. The reaction was quenched by slowly adding the reaction mixture to saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 132b (108 mg, yield 58%). ESI-MS (m / z): 272.4 [M+H] + 。

[0655] Step 3: Dissolve compound 132b (108 mg, 0.4 mmol) in acetonitrile (8 mL), and add silver oxide (461 mg, 1.99 mmol) and iodomethane-d3 (115 mg, 0.8 mmol). The reaction mixture was stirred at 50 °C for 12 h. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give a yellow liquid 132c (68 mg, yield 59%). ESI-MS (m / z): 289.4 [M+H] + 。

[0656] Step 4: Dissolve compound 91d (100 mg, 0.38 mmol) and compound 132c (68 mg, 0.24 mmol) in n-butanol (3 mL), add p-toluenesulfonic acid monohydrate (40 mg, 0.24 mmol), and stir the reaction mixture at 160 °C for 3 h under microwave irradiation. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative reverse-phase HPLC to give a white solid compound 140 (21 mg, yield 10%). ESI-MS (m / z): 523.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 9.04 (s, 2H), 8.14 (s, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 6.99 (s, 1H), 4.45 - 4.31 (m, 2H), 4.22 (s, 1H), 4.01 - 3.92 (m, 1H), 3.70 - 3.60 (m, 2H), 3.40 - 3.30 (m, 1H), 2.54 - 2.47 (m, 2H), 1.95 - 1.84 (m, 1H), 1.78 - 1.68 (m, 1H).

[0657] Example 133 (W377)

[0658] (S)-5-(Hydroxymethyl)-4,5-dimethyl-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0659]

[0660] Compound 133 was prepared by the following steps:

[0661]

[0662] First step: Dissolve 2,4-dichloropyrido[3,2-d]pyrimidine 1f (4.0 g, 20.0 mmol) and 2-methyl-L-serine methyl ester hydrochloride 133a (4.07 g, 24.0 mmol) in dichloromethane (30 mL), add N,N-diisopropylethylamine (7.75 g, 59.99 mmol, 10.45 mL), and stir overnight at room temperature. Monitor the reaction by LCMS until completion. Dilute the reaction solution with dichloromethane, wash it with water and saturated brine respectively, dry the organic phase with anhydrous sodium sulfate, filter and concentrate to obtain a white solid 133b (5.0 g, yield 84%). ESI-MS (m / z): 297.3 [M+H] + .

[0663] Second step: Dissolve compound 133b (5.0 g, 16.85 mmol) in tetrahydrofuran (50 mL), add aqueous hydrochloric acid solution (6 M, 5.62 mL) and platinum dioxide (382 mg, 1.69 mmol), replace the hydrogen in the reaction system with a hydrogen balloon, and stir for 48 hours under the pressure of the hydrogen balloon at room temperature. Monitor the reaction by LCMS until completion. Dilute the reaction solution with methanol, filter, and concentrate the filtrate to obtain a white solid 133c (4.0 g, yield 88%). ESI-MS (m / z): 269.3 [M+H] + .

[0664] Third step: Dissolve compound 133c (1.5 g, 5.58 mmol) and methyl iodide (1.58 g, 11.16 mmol) in acetonitrile (5 mL), add cesium carbonate (3.64 g, 11.16 mmol), and stir the reaction mixture at room temperature for 48 hours. Monitor the reaction by LCMS until completion. Dilute the reaction solution with ethyl acetate, filter, wash it with water and saturated brine respectively, dry the organic phase with anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain a yellow solid 133d (1.1 g, yield 69%). ESI-MS (m / z): 283.3 [M+H] + .

[0665] Step 4: Dissolve compound 133d (50 mg, 176 μmol), compound 11d (62 mg, 229 μmol) and p-toluenesulfonic acid monohydrate (3.3 mg, 17 μmol) in n-butanol (2 mL), and react at 160 °C under microwave for 3 hours. Monitor the reaction by LCMS until it is completed. Purify the reaction solution by reverse-phase preparative HPLC to obtain white solid 133 (38 mg, yield 41%). ESI-MS (m / z): 516.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.64 (d, J = 2.6 Hz, 1H), 8.14 (d, J = 2.3 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.91 (dd, J = 8.5, 2.5 Hz, 2H), 7.87 (dd, J = 8.5, 2.5 Hz, 2H), 7.18 (d, J = 8.4 Hz, 1H), 6.92 (t, J = 7.5 Hz, 1H), 5.06 (t, J = 5.5 Hz, 1H), 4.47 - 4.32 (m, 2H), 3.80 - 3.70 (m, 2H), 3.69 - 3.61 (m, 1H), 3.60 - 3.52 (m, 1H), 2.96 (s, 3H), 2.54 - 2.48 (m, 2H), 1.92 - 1.75 (m, 2H), 1.34 (s, 3H).

[0666] Example 134 (W380)

[0667] (S)-5-(Hydroxymethyl)-4,5-dimethyl-2-(((2-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0668]

[0669] Compound 134 was prepared by the following steps:

[0670]

[0671] Step 1: Dissolve 2-chloropyrimidine-5-carbaldehyde 134a (800 mg, 5.61 mmol) in tetrahydrofuran (20 mL). Sequentially add acetic acid (0.5 mL) and 2,4-dimethoxybenzylamine (985 mg, 5.89 mmol) to the reaction solution. After reacting for 4 hours until aldehyde 134a is completely converted to imine, add sodium cyanoborohydride (1.06 g, 16.84 mmol) and react overnight. After monitoring the reaction by LCMS and it is completed, add water to quench the reaction, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate the organic phase to obtain compound 134b. It is directly used for the next step of the reaction. ESI-MS (m / z): 294.3 [M+H] + .

[0672] Step 2: Dissolve the above product 134b in dichloromethane (15 mL). Add triethylamine (1.21 mL, 8.71 mmol) to the reaction solution, and add di-tert-butyl dicarbonate (800 mg, 5.61 mmol) at 0 °C. After reacting at room temperature for 30 minutes, monitor the reaction by LCMS until it is completed. Add water to quench the reaction, extract with dichloromethane, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain a yellow oily liquid 134c (720 mg, overall yield of two steps 32%). ESI-MS (m / z): 394.2 [M+H] + .

[0673] Step 3: Dissolve 5-hydroxy-2-(trifluoromethyl)pyridine 11a (328 mg, 2.01 mmol) and potassium tert-butoxide (308 mg, 2.74 mmol) in N-methylpyrrolidone (10 mL). After stirring the reaction solution at room temperature for one hour, add compound 134c (720 mg, 1.83 mmol) to it, and continue to react at 80 °C for 24 hours. After monitoring the reaction by LCMS and it is completed, add water to quench the reaction, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain a yellow oily liquid 134d (638 mg, yield 67%). ESI-MS (m / z): 521.4 [M+H] + .

[0674] Step 4: Dissolve 134d (638 mg, 1.23 mmol) in trifluoroacetic acid (5 mL), and stir the reaction solution at room temperature for 30 minutes. After monitoring the reaction by LCMS and completion of the reaction, trifluoroacetic acid was removed by distillation under reduced pressure. The pH was adjusted to 8 with 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain a yellow oily liquid 134e (145 mg, yield 43%). ESI-MS (m / z): 271.4 [M+H] + .

[0675] Step 5: Dissolve compound 133d (45 mg, 159.16 μmol), compound 134e (52 mg, 191 μmol) and p-toluenesulfonic acid monohydrate (3 mg, 16 μmol) in n-butanol (3 mL), and react at 160 °C under microwave for 3 hours. Monitor the reaction by LCMS until completion. The reaction solution was purified by reversed-phase preparative HPLC to obtain a white solid 134 (27 mg, yield 33%). ESI-MS (m / z): 517.5 [M+H] + ; 1 1H NMR (500 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.65 (s, 2H), 8.02 (s, 2H), 6.94 (t, J = 6.1 Hz, 1H), 5.06 (t, J = 5.5 Hz, 1H), 4.36 (d, J = 6.2 Hz, 2H), 3.77 - 3.71 (m, 1H), 3.69 (dd, J = 11.3, 5.7 Hz, 1H), 3.65 - 3.59 (m, 1H), 3.55 (dd, J = 11.4, 5.4 Hz, 1H), 2.96 (s, 3H), 2.49 - 2.44 (m, 2H), 1.89 - 1.77 (m, 2H), 1.34 (s, 3H).

[0676] Example 135 (W382)

[0677] (S)-5-(Hydroxymethyl)-2-(((6-(2-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethoxy)pyridin-3-yl)methyl)amino)-4,5-dimethyl-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0678]

[0679] Example 136 (W381)

[0680] (S)-5-(Hydroxymethyl)-2-(((6-(2-(5-methoxy-4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethoxy)pyridin-3-yl)methyl)amino)-4,5-dimethyl-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0681]

[0682] Compounds 135 and 136 were prepared by the following steps:

[0683]

[0684] First step: Ethyl trifluoroacetoacetate 130a (508 mg, 6.68 mmol) and 135a (1.23 g, 6.68 mmol) were dissolved in ethanol (15 mL), and the reaction solution was stirred at 80 °C for 16 h. After monitoring the reaction by LCMS and completion, ethanol was removed by distillation under reduced pressure, followed by extraction with water and ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain white solid 135b (778 mg, yield 59%). ESI-MS (m / z): 197.5 [M+H] + .

[0685] Second step: Compound 135b (678 mg, 3.46 mmol), 6-fluoro-nicotinonitrile 91b (422 mg, 3.46 mmol) and cesium carbonate (2.25 g, 6.91 mmol) were added to N,N-dimethylformamide (20 mL), and the reaction was carried out at 80 °C for 5 h. After monitoring the reaction by LCMS and completion, N,N-dimethylformamide was removed by distillation under reduced pressure, followed by extraction with water and ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain white solid 135c (443 mg, yield 43%). ESI-MS (m / z): 299.3 [M+H] + .

[0686] Step 3: Sodium hydride (59 mg, 1.48 mmol, 60% content) was added to a solution of compound 135c (221 mg, 0.74 mmol) in tetrahydrofuran (10 mL) at 0 °C under a nitrogen atmosphere. After the reaction mixture was stirred at room temperature for one hour, methyl iodide (210 mg, 1.48 mmol) was added thereto at 0 °C, and the mixture was continuously stirred at room temperature for 24 hours. After the reaction was monitored by LCMS to completion, the reaction was quenched by adding ice water, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a mixture of colorless oily liquids 135d and 135d' (100 mg, the ratio of 135d to 135d' was approximately 4:1). ESI-MS (m / z): 313.3&327.3 [M+H] + 。

[0687] Step 4: The mixture of compounds 135d and 135d' (100 mg) was dissolved in methanol (10 mL). Ammonia water (1 mL) and Raney nickel (0.1 mL, aqueous suspension) were successively added to the reaction system. The hydrogen was displaced by a hydrogen balloon, and the reaction was carried out at room temperature under a hydrogen atmosphere for 3 hours. The reaction was monitored by LCMS to completion. The reaction mixture was diluted with methanol, filtered by suction, and the filtrate was concentrated to obtain a mixture of brown oily liquids 135e and 135e' (81 mg, the ratio of 135e to 135e' was approximately 4:1). ESI-MS (m / z): 317.3&331.4 [M+H] + 。

[0688] Step 5: Compound 133d (50 mg, 177 μmol), the mixture of compounds 135e and 135e' (81 mg), and p-toluenesulfonic acid monohydrate (3.3 mg, 18 μmol) were dissolved in n-butanol (3 mL), and the reaction was carried out at 160 °C under microwave irradiation for 3 hours. The reaction was monitored by LCMS to completion. The reaction mixture was purified by reversed-phase preparative HPLC to obtain white solid 135 (27 mg, yield 23%) and by-product white solid 136.

[0689] Compound 135: ESI-MS (m / z): 563.3 [M+H] + ; 11H NMR (500 MHz, DMSO-d6) δ 8.08 (d, J = 2.3 Hz, 1H), 7.65 (dd, J = 8.4, 2.4 Hz, 1H), 6.86 - 6.78 (m, 1H), 6.68 (d, J = 8.5 Hz, 1H), 6.19 (s, 1H), 5.05 (t, J = 5.5 Hz, 1H), 4.53 (t, J = 5.4 Hz, 2H), 4.37 - 4.28 (m, 4H), 3.85 (s, 3H), 3.78 - 3.68 (m, 2H), 3.67 - 3.58 (m, 1H), 3.55 (dd, J = 11.2, 5.3 Hz, 1H), 2.96 (s, 3H), 2.50 - 2.44 (m, 2H), 1.89 - 1.78 (m, 2H), 1.33 (s, 3H).

[0690] Compound 136: ESI-MS (m / z): 577.4 [M + H] + ; 1 1H NMR (500 MHz, DMSO-d6) δ 8.09 (d, J = 2.3 Hz, 1H), 7.66 (dd, J = 8.5, 2.4 Hz, 1H), 6.82 (t, J = 5.7 Hz, 1H), 6.70 (d, J = 8.5 Hz, 1H), 5.05 (t, J = 5.5 Hz, 1H), 4.54 (t, J = 5.3 Hz, 2H), 4.38 - 4.29 (m, 4H), 3.90 (s, 3H), 3.76 - 3.67 (m, 2H), 3.65 - 3.59 (m, 1H), 3.55 (dd, J = 11.3, 5.4 Hz, 1H), 2.96 (s, 3H), 2.49 - 2.42 (m, 2H), 2.03 (s, 3H), 1.88 - 1.76 (m, 2H), 1.33 (s, 3H).

[0691] Example 137 (W335)

[0692] (S)-2-(((6-((6-Cyclopropylpyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,5-dimethyl-4,5,9,10-

[0693] tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0694]

[0695] Replacing 2-chloro-5-hydroxypyrimidine 97a in the first step of Example 97 with 6-bromopyridin-3-ol and using a similar method and reaction steps, Compound 137 can be obtained. ESI-MS (m / z): 458.5 [M + H] + ;1 1H NMR (500 MHz, DMSO-d6) δ 8.21 (d, J = 2.5 Hz, 1H), 8.05 (d, J = 2.5 Hz, 1H), 7.81 (dd, J = 8.5, 2.5 Hz, 1H), 7.43 (dd, J = 8.0, 2.5 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.05 - 6.98 (m, 2H), 4.39 - 4.29 (m, 2H), 4.11 (q, J = 6.8 Hz, 1H), 4.04 - 3.98 (m, 1H), 3.32 - 3.22 (m, 1H), 2.92 (s, 3H), 2.55 - 2.47 (m, 2H), 2.14 - 2.09 (m, 1H), 1.95 - 1.90 (m, 1H), 1.82 - 1.75 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H), 0.96 - 0.85 (m, 4H).

[0696] Example 138 (W271)

[0697] (S)-4,5-Dimethyl-2-(((6-(4-(trifluoromethyl)benzyl)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro

[0698] -6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0699]

[0700] Replace the 4-fluorobenzylboronic acid pinacol ester 96c in the second step of Example 96 with 4-(trifluoromethyl)benzylboronic acid pinacol ester, and compound 138 can be obtained by a similar method and reaction steps. ESI-MS (m / z): 483.5 [M + H] + ; 1 1H NMR (500 MHz, DMSO-d6) δ 8.43 (d, J = 2.2 Hz, 1H), 7.65 (d, J = 2,5 Hz, 1H), 7.62 (d, J = 7.9 Hz, 2H), 7.46 (d, J = 7.9 Hz, 2H), 7.24 (d, J = 8.0 Hz, 1H), 7.00 (br s, 1H), 4.40 - 4.32 (m, 2H), 4.13 (s, 2H), 4.09 (q, J = 6.7 Hz, 1H), 4.02 - 3.97 (m, 1H), 3.35 - 3.25 (m, 2H), 2.90 (s, 3H), 2.55 - 2.45 (m, 2H), 1.92 - 1.85 (m, 1H), 1.82–1.72 (m, 1H), 1.20 (d, J = 6.8 Hz, 3H).

[0701] Example 139 (W268)

[0702] (S)-5-(Hydroxymethyl)-4-methyl-2-(((6-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0703]

[0704] Replacing 11d in the second step of Example 107 with intermediate 91d gives compound 139. ESI-MS (m / z): 503.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 9.04 (s, 2H), 8.23 (s, 1H), 8.13 (d, J = 2.3 Hz, 1H), 7.93 (dd, J = 8.4, 2.4 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.94 (t, J = 6.4 Hz, 1H), 4.45 - 4.29 (m, 2H), 4.07 - 3.98 (m, 2H), 3.75 - 3.67 (m, 2H), 3.35 - 3.30 (m, 1H), 2.96 (s, 3H), 2.52 - 2.46 (m, 2H), 1.92 - 1.84 (m, 1H), 1.82 - 1.71 (m, 1H).

[0705] Example 140 (W376)

[0706] (S)-5-(Hydroxymethyl)-4,5-dimethyl-2-(((6-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyridin-3-yl)methyl)

[0707] amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0708]

[0709] Replacing 11d in the fourth step of Example 133 with intermediate 91d and using a similar method and reaction steps gives compound 140. ESI-MS (m / z): 517.3 [M+H] + ; 11H NMR (500 MHz, DMSO-d6) δ 9.06 (s, 2H), 8.19 (d, J = 2.3 Hz, 1H), 7.97 (dd, J = 8.5, 2.3 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 5.26 (br s, 1H), 4.50 (d, J = 5.9 Hz, 2H), 3.87 - 3.78 (m, 1H), 3.73 - 3.68 (m, 1H), 3.65 - 3.54 (m, 2H), 3.05 (s, 3H), 2.58 - 2.49 (m, 2H), 1.95 - 1.80 (m, 2H), 1.41 (s, 3H).

[0710] Example 141 (W261)

[0711] (S)-5-((S)-1-Hydroxyethyl)-4-(methyl-d3)-2-(((6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0712]

[0713] Starting from intermediate 110c, replacing methyl iodide in the fourth step of Example 110 with deuterated methyl iodide, compound 141 can be obtained. ESI-MS (m / z): 519.3 [M + H] + ; 1 1H NMR (500 MHz, DMSO-d6) δ 8.62 (d, J = 2.5 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H), 7.89 (dd, J = 8.5, 2.5 Hz, 1H), 7.85 (dd, J = 8.5, 2.5 Hz, 1H), 7.16 (d, J = 8.5 Hz, 1H), 6.93 (br s, H), 4.43 - 4.32 (m, 2H), 4.11 - 4.02 (m, 3H), 3.26 - 3.17 (m, 2H), 2.53 - 2.45 (m, 2H), 1.94 - 1.85 (m, 1H), 1.80 - 1.70 (m, 1H), 1.00 (d, J = 6.4 Hz, 3H).

[0714] Example 142 (W257)

[0715] (S)-5-((S)-1-Hydroxyethyl)-4-methyl-2-(((6-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyridin-3-yl)methyl)amino)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one

[0716]

[0717] Compound 142 can be obtained by replacing 11d in the fourth step of Example 110 with intermediate 91d. ESI-MS (m / z): 517.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 9.03 (s, 2H), 8.13 (d, J = 2.3 Hz, 1H), 7.93 (dd, J = 8.4, 2.4 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.95 (t, J = 6.1 Hz, 1H), 4.99 (d, J = 4.9 Hz, 1H), 4.44 - 4.32 (m, 2H), 4.12 - 4.01 (m, 3H), 3.25 - 3.15 (m, 1H), 3.02 (s, 3H), 2.52 - 2.46 (m, 2H), 1.95 - 1.86 (m, 1H), 1.80 - 1.67 (m, 1H), 1.00 (d, J = 6.4 Hz, 3H).

[0718] According to the synthetic routes and synthetic methods of intermediates described in the above examples, the compounds of the following examples were obtained.

[0719]

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726]

[0727]

[0728]

[0729]

[0730]

[0731]

[0732]

[0733]

[0734]

[0735]

[0736]

[0737]

[0738]

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748]

[0749] Biological screening and results of Wnt pathway inhibitors

[0750] Experimental Example 1: Construction of Colo205-LUC-TCF / LEF-M1 reporter cell line

[0751] 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, at the exponential growth phase of the cells, the luciferase reporter plasmid (Promega) driven by the TCF / LEF transcription factor was transfected by lipo3000 liposome. This plasmid carried a resistance gene and could be used for resistance screening. 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 the culture continued. Thereafter, the resistant medium was replaced every 2 days, and the suspended cells were discarded. The original medium was centrifuged to remove cells and debris and then retained as the adaptation medium. When the cells grew to confluence in the culture dish, the cells were digested, counted, and subcultured into a 96-well plate so that the average number of cells in each well was 1.5 cells / well. The adaptation medium was used during subculture. The remaining cells were cryopreserved. After subculture, the cells were cultured for 4 hours to allow them to adhere, and then the number of cells in each well was observed under a microscope. The wells with only 1 cell in each well were marked as monoclonal wells. Then, the cells were cultured normally, the medium was replaced every 2 days, and observations were made. For the wells where the early monoclonal cells continued to grow, a second marking was carried out, and the medium could be replaced with a normal medium with resistance. When a monoclonal well grew to confluence in the 96-well plate, it was digested and subcultured into a 24-well culture plate. After the 24-well plate grew to confluence, it was subcultured into 1 96-well plate and 1 6-well plate. At least 6 wells of cells in the 96-well plate, 3 of which were added with a known Wnt inhibitor and the other 3 were not treated. After 24 hours, a fluorescence detection reagent was added to the cells in the 96-well plate to detect the fluorescence intensity. The cell line in which fluorescence was expressed without treatment and the fluorescence decreased after inhibition was selected for further culture. The Colo205-LUC-TCF / LEF-M1 cell line was one of the cell lines screened above. Its growth curve, cell morphology, and cell growth status were similar to those of the original Colo205 cells, and the ratio of the fluorescence signals with and without inhibitor treatment was relatively large among all cell lines. The ratio could reach 4-5 times when inhibited at 4 hours, which was fully applicable to the subsequent screening of Wnt inhibitors.

[0752] Experimental Example 2: Detection of the inhibitory ability of a compound on the Colo205-LUC-TCF / LEF M1 reporter cell line. The Colo205-LUC-TCF / LEF M1 cell line was a reporter tool cell stably transfected with the pGL4.49-LUC2-TCF / LEF vector. Its β-catenin Wnt pathway was continuously activated. After adding an inhibitor, the Wnt pathway was inhibited, and the expression level of firefly luciferase regulated by the TCF / LEF cis-element on the vector decreased. Subsequently, after adding a detection substrate, the detected light signal decreased accordingly, thereby detecting the inhibitory effect of the compound.

[0753] Add 100 μL of the compound with a maximum concentration of 20 μM to each well of a 96-well cell culture plate, and perform a 3-fold serial dilution of the compound concentration. Then, inoculate 10,000 stably transfected colo205 cells expressing the reporter gene and 100 μL of culture medium into each well, and set up corresponding positive and negative control wells at the same time. Place the cells in a 5% CO2 cell culture incubator and culture them at 37 °C for 4 h. After 4 h, remove the culture medium, add 100 μL of the reagent (Promega) containing the corresponding firefly luciferase substrate to each well, and measure the activity of the luciferase reporter gene. Read the luminescence intensity using SpectraMax in the full wavelength mode. The light signal intensity of the cells treated only with DMSO serves as the positive control, and the light signal intensity of the cell-free well serves as the negative control. Calculate the IC50 concentration of each compound. The Colo 205 reporter gene assay data are summarized in Table 1.

[0754] Table 1

[0755]

[0756]

[0757]

[0758]

[0759] Test Example 3: Proliferation Inhibition Test of Compounds on Wnt Mutant Cell Lines (Colo205 and DU4475) and Non-Wnt Mutant Cell Lines (Hela and RKO)

[0760] The cell lines used in the test were the Colo205 and DU4475 cell lines in which the Wnt pathway was constitutively activated and their proliferation was Wnt pathway-dependent; while the HELA and RKO cell lines in which the Wnt pathway was not activated under normal conditions and their proliferation was not dependent on the Wnt pathway were used as control cell lines to determine that the inhibitory effect of the compounds of the present invention on Wnt-dependent proliferation was not caused by other non-specific toxicities.

[0761] The Colo205, Du4475, HELA, and RKO cell lines cultured in their respective media were treated during the logarithmic growth phase. After collecting the cells, a uniform cell suspension with a known concentration was prepared. Then, the cell suspension was added to a 96-well cell culture plate so that each well contained 1000 cells. It was placed in a 5% CO2 cell culture incubator and cultured at 37°C for 20 - 24 h. The next day, the completely dissolved compound diluted in a 3-fold gradient was added to each cell culture well, and the final highest concentration in the cell culture well was 20 μM. Culturing continued for 96 h. In this experiment, the cell viability detection assay of Promega was used for detection. The more the cells proliferated, the stronger the final signal intensity. The detection instrument was SpectraMax in the full wavelength mode. The well with only DMSO added was used as the positive control well, and the well without inoculated cells was the negative control well. Calculate the IC50 values of the proliferation inhibition of each compound on Wnt continuously activated or proliferation-dependent cells, as well as the IC50 values of the proliferation inhibition on Wnt-unactivated or proliferation-independent cells, and evaluate the inhibitory effect of the compound on the Wnt pathway and its toxic effect on normal cells (Table 2).

[0762] Table 2

[0763]

[0764]

[0765]

[0766]

[0767]

[0768]

[0769] Test Example 4: Proliferation Inhibition Test of Compounds on NCI-H929 and HepG2 Cell Lines. The cell lines used in the experiment were NCI-H929 and HepG2 cell lines with continuously activated Wnt pathways and Wnt pathway-dependent proliferation; to determine the inhibitory effect of the compounds of the present invention on Wnt-dependent proliferation.

[0770] The NCI-H929 and HepG2 cell lines cultured in their respective media were treated during the logarithmic growth phase. After collecting the cells, a uniform cell suspension with a known concentration was prepared. Then, the cell suspension was added to a 96-well cell culture plate so that each well contained 4000 cells. It was placed in a 5% CO2 cell culture incubator and cultured at 37°C for 20 - 24 h. The next day, the completely dissolved compound diluted in a 3-fold gradient was added to each cell culture well, with the final highest concentration in the cell culture well being 20 μM, and the culture continued for 96 h. In this experiment, the cell viability detection assay from Promega was used for detection. The more the cells proliferated, the stronger the final signal intensity. The detection instrument was SpectraMax, in the full wavelength mode. The wells with only DMSO added served as positive control wells, and the wells without inoculated cells were negative control wells. The IC50 values for the proliferation inhibition of each compound on Wnt continuously activated or proliferation-dependent cells, as well as the IC50 values for the proliferation inhibition of Wnt-unactivated or proliferation-independent cells, were calculated to evaluate the inhibitory effect of the compound on the Wnt pathway and the toxic effect on normal cells (Table 3).

[0771] Table 3

[0772]

[0773]

[0774]

[0775] Experimental Example 5: Tumor Growth Inhibition Test of Compound 11 on NCI-H929 Mouse Xenograft Model

[0776] In this study, the in vivo antitumor activity of Compound 11 was evaluated using a human myeloma cell NCI-H929 SCID xenograft model.

[0777] Female SCID mice were subcutaneously inoculated with human myeloma cells NCI-H929 to establish an NCI-H929 SCID xenograft model. After the tumors grew to an average tumor volume of about 80 mm 3 or so, the tumor-bearing mice were randomly divided into 2 groups according to the tumor volume: the solvent-treated control group and the 30 mg / kg Compound 11 group. Compound 11 was administered orally once a day for a dosing period of 21 days. The tumor volume was measured every other day, and the body weight and tumor volume were measured on Day 21 (Table 4 and Figure 1 ).

[0778] Table 4 Effect of Compound 11 on Tumor Size in NCI-H929 SCID Xenograft Model

[0779]

[0780] ***: P < 0.001 compared with the negative control group.

Claims

1. A compound for inhibiting the activity of the Wnt pathway, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, wherein the compound has the following structure:

2. A pharmaceutical composition comprising the compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof.

3. Use of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or the pharmaceutical composition according to claim 2 in the preparation of a medicament for preventing and / or treating cancer, an inflammatory disease or an autoimmune disease.

4. Use of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or the pharmaceutical composition according to claim 2 in the preparation of a medicament for preventing and / or treating a tumor or an immune-mediated disease.

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