Hpk1 kinase inhibitors

Abstract

The present application provides a compound having inhibitory activity on HPK1 kinase activity with the structure of formula (I) or formula (II) and a pharmaceutical composition comprising the compound. The present application also provides the use of the compound in preventing and / or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.

Description

TECHNICAL FIELD

[0001] The present application relates to a heterocyclic compound, in particular to a highly active HPK1 kinase inhibitor and uses thereof. BACKGROUND

[0002] HPK1 is one of the members of MAP4K family, mainly expressed in hematopoietic system cells, and acts as an intracellular negative regulator of T cell proliferation and signaling. After antigen stimulation of T cells, the linker protein SLP-76 in the cytoplasm is recruited to the lipid membrane TCR complex, providing a binding site for signal transduction related kinases to achieve TCR-mediated signal transmission to induce T cell activation. In this process, HPK1 is activated by tyrosine kinases Lck and Zap70, and is involved in the regulation of T cell receptor protein interaction. HPK1 phosphorylates the Ser376 site of the linker protein SLP-76, which binds to the scaffold protein 14-3-3 epsilon and is degraded by the proteasome, and this effect reduces the binding of SLP-76 to signal transduction related kinases and blocks TCR signal transduction, thereby inhibiting T cell activation and proliferation. On the other hand, HPK1 is also involved in the regulation of the maturation and activation of dendritic cells (DCs), especially the inhibition of the expression of proteins related to T cell activation in DC cells, such as CD80, CD86 and MHC complex, thereby affecting the role of DC in regulating T cell activation; the presentation of tumor antigens by activated DCs and the cooperation between DCs and T cells are one of the most important links in the anti-tumor immune system. In addition, there are a large number of immunosuppressive molecules in the tumor microenvironment, such as PGE2 and TGF-β, and the immunosuppressive effect mediated by these factors is also closely related to HPK1. In general, specific small molecule compounds that target and inhibit HPK1 can improve T cell function, enhance DC cell function, and at the same time reverse the tumor immunosuppressive microenvironment, thereby enhancing anti-tumor immune effects through multiple pathways, and thus playing a role in inhibiting tumor growth. However, there is currently a lack of effective HPK1 kinase activity inhibitors.

[0003] Therefore, there is still an urgent need in the prior art for effective HPK1 kinase activity inhibitors in order to provide more effective options for anti-tumor. SUMMARY

[0004] The present application unexpectedly discovers a compound having HPK1 kinase activity or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof, the compound of the present application has the following formula I or formula II structure:

[0005]

[0006] wherein,

[0007] R1represents hydrogen, (C1-C6)alkyl, halogen, (C1-C6)alkoxy, OR a , NR a R b , cyano or (C3-C6)cycloalkyl;

[0008] R2represents hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -O-(C1-C6)alkyl, -S-(C1-C6)alkyl, -S(O)-(C1-C6)alkyl, -S(O)2-(C1-C6)alkyl, -NR a R b , cyano, -COOR a , -CONR a R b , -OCONR a R b , -NR a COR b , -P(O)R a R b , -S(O)2NR a R b or -NR a S(O)2R b ;

[0009] R3represents hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, -(C0-C6alkylene)(C3-C8)cycloalkyl, -(C0-C6alkylene)(4-10 membered)heterocycloalkyl, -(C0-C6alkylene)(C6-C 10 )aryl or -(C0-C6alkylene)(5-10 membered)heteroaryl;

[0010] R4and R4' each independently represent hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, halogen; or R4and R4'together with the carbon atom to which they are attached form a 3-6 membered ring which can optionally contain 0, 1 or 2 heteroatoms selected from N, O, S;

[0011] R5represents hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl or (4-8 membered)heterocycloalkyl;

[0012] R6and R6' each independently represent hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl or halogen; or R6and R6'together with the carbon atom to which they are attached form a 3-6 membered ring which can optionally contain 0, 1 or 2 heteroatoms selected from N, O, S;

[0013] R7and R7independently of one another represent hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl or halogen; or R7together with R7form a 3- to 6-membered ring with the carbon atom to which they are attached, which ring can optionally further contain 0, 1 or 2 heteroatoms selected from N, O, S;

[0014] W1represents CR W1 or N;

[0015] W2represents CR W2 or N;

[0016] wherein R W1 and R W2 independently of one another represent hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -OR a , -NR a R b , cyano, -COOR a , -CONR a R b , -OCONR a R b , -NR a COR b , -P(O)R a R b , -S(O)2NR a R b , -NR a S(O)2R b , -SR a , -S(O)R a or -S(O)2R a ;

[0017] For the above-defined alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, these can optionally be substituted by 0, 1, 2 or 3 substituents selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, -(C1-C6alkylene)-O-(C1-C6)alkyl, (C3-C8)cycloalkyl, halo(C3-C8)cycloalkyl, halogen, -CN, oxo, -NR a R b , -OR a , -SR a , -(C1-C6alkylene)hydroxy, -C(O)R a , -N(R a )C(O)R a , -NR a C(O)OR a , -NR a SO2Ra -C(O)OR a -C(O)N R a R b -S(O)2N R a R b -S(O)R a -S(O)2R a -P(O)R a R b ;

[0018] wherein, R a , R b each independently represents hydrogen, (C1-C6)alkyl or halo(C1-C6)alkyl; or R a , R b together with the atoms to which they are attached form a 3-8 membered ring which optionally further contains 0, 1 or 2 heteroatoms selected from N, O, S;

[0019] m, n, o, r each independently represents 0, 1, 2, 3.

[0020] In a preferred embodiment of the present application, R1represents hydrogen, (C1-C6)alkyl, halogen or halo(C1-C6)alkyl.

[0021] In a preferred embodiment of the present application, R2represents hydrogen, halogen, (C1-C6)alkyl, -(C1-C6alkylene)hydroxy, (C2-C6)alkenyl, (C2-C6)alkynyl, -OR a , -NR a R b , cyano, -COOR a , -CONR a R b , -OCONR a R b , -NR a COR b , -P(O)R a R b , -S(O)2NR a R b , -NR a S(O)2R b , -SR a , -S(O)R a or -S(O)2R a ; wherein, R a , R b each independently represents hydrogen, (C1-C6)alkyl or halo(C1-C6)alkyl; or R a , R bTogether with adjacent atoms, they form a 3-8 membered ring, which may also contain 0, 1 or 2 heteroatoms selected from N, O or S.

[0022] In a preferred embodiment of the present invention, R3 represents hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6 alkylene)hydroxyl, -(C0-C6 alkylene)(C3-C8)cycloalkyl, -(C0-C6 alkylene)(4-10-membered)heterocyclic alkyl, -(C0-C6 alkylene)(C6-C 10 aryl, -(C0-C6 alkylene) (5-10 aryl), -(C0-C6 alkylene)COOR a -(C0-C6 alkylene)CONR a R b -(C0-C6 alkylene)P(O)R a R b -(C0-C6 alkylene)S(O)2NR a R b -(C0-C6 alkylene)SR a -(C0-C6 alkylene)S(O)R a or -(C0-C6 alkylene)S(O)2R a .

[0023] In a preferred embodiment of the present invention, R4 and R4' each independently represent hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, halogen, halo(C1-C6)alkyl, or hydroxy(C1-C6)alkyl; or R4 and R4' together form a 3-6 membered ring with the carbon atom attached thereto, wherein the ring may also contain 0, 1, or 2 heteroatoms selected from N, O, and S.

[0024] In a preferred embodiment of the present invention, R5 represents hydrogen, (C1-C6)alkyl, -(C1-C6 alkylene)hydroxyl, halogenated (C1-C6)alkyl, (C3-C8)cycloalkyl or (4-8) heterocyclic alkyl.

[0025] In a preferred embodiment of the present invention, R6 and R6' each independently represent hydrogen, (C1-C6)alkyl, -(C1-C6 alkylene)hydroxyl, halo(C1-C6)alkyl, (C2-C6)alkenyl or halogen; or R6 and R6' together form a 3-6 membered ring with the carbon atom attached thereto, which may also contain 0, 1 or 2 heteroatoms selected from N, O, and S.

[0026] In a preferred embodiment of the application, wherein R7and R7' each independently represent hydrogen, (Ci-C6)alkyl, -(Ci-C6alkylene)hydroxy, halo(Ci-C6)alkyl, (C2-C6)alkenyl or halogen; or R7and R7'together with the carbon atom to which they are attached form a 3-6 membered ring which can optionally contain 0, 1 or 2 heteroatoms selected from N, O, S.

[0027] Preferably, the compounds of the application have the following structure:

[0028]

[0029]

[0030]

[0031]

[0032] It is specifically noted that herein, when referring to a "compound" having a particular structural formula, stereoisomers, diastereomers, enantiomers, racemic mixtures and isotopic derivatives thereof are generally encompassed.

[0033] It is well known to those skilled in the art that a salt, solvate, hydrate of a compound is an alternative form of the compound, which can be converted to the compound under certain conditions, and therefore, it is specifically noted that herein, when referring to a compound, pharmaceutically acceptable salts thereof are generally encompassed, and further solvates and hydrates thereof are generally encompassed.

[0034] Similarly, when referring to a compound herein, prodrugs, metabolites and nitroso derivatives thereof are generally encompassed.

[0035] The pharmaceutically acceptable salts of the present application can be formed using, for example, inorganic or organic acids, as follows: "Pharmaceutically acceptable salt" refers to salts of a compound of the present application which are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. The salts can be prepared in situ during the final isolation and purification of the compounds of the application, 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 the appropriate acid. Also, where the compound of the present application carries an acidic moiety, suitable pharmaceutically acceptable salts thereof 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, nontoxic acid addition salts are salts of an amino group with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acid, or with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acid, or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts, and the like. Other pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0036] The pharmaceutically acceptable salts of the present application can be prepared by conventional methods, e.g., by dissolving the compound of the present application in an organic solvent which is miscible with water, such as acetone, methanol, ethanol, and acetonitrile, adding thereto an excess of aqueous solution of an organic or inorganic acid, so that the salt precipitates from the resulting mixture, removing the solvent and the remaining free acid, and isolating the precipitated salt.

[0037] The precursors or metabolites described herein can be precursors or metabolites known in the art, so long as the precursor or metabolite is convertible to the subject compound by in vivo metabolic processes. For example, "prodrugs" are those compounds that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use. The term "prodrug" refers to compounds that are rapidly converted, e.g., by hydrolysis in vivo, to the parent compound of the above formula, or N-demethylation of a compound of the present application.

[0038] The term "solvate" as used herein means a physical association between one or more solvent molecules (non-limiting examples of which are water, ethanol, and isopropanol) and one or more of the compounds of the present application. This physical association can, for example, be between a compound of the present application and a single solvent molecule or between a compound of the present application and a combination of solvent molecules. The physical association can be due to, for example, hydrogen bonding, to ionic interactions, to simple, non- polar physical mixing, or to a combination of these. Solvates are typically formed by the dissolution of the relevant compound in, or the combination of the relevant compound with, one or more solvent molecules. Solvates can be isolated from solution, or they can be prepared by recrystallization from a solvent. Solvates can contain stoichiometric or non-stoichiometric amounts of the solvent molecule. The term "solvate" encompasses both solution-phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods for preparing solvates are known in the art.

[0039] The term "stereoisomers" as used herein describes compounds which have the same molecular formula but differ in the arrangement of atoms in space. Such isomers are known as geometric isomers or cis-trans isomers. Geometric isomers are stable and can be separated by crystallization or chromatography. The term "stereoisomers" also describes compounds which are mirror images of one another and are, therefore, non-superimposable, mirror images called enantiomers. When the compound has more than one chiral center, it can be a "diastereomer" which is a mixture of enantiomers or it can be a "pure diastereomer" which is a single enantiomer. The term "stereoisomers" also describes compounds which differ in the configuration of a stereocenter, but are not mirror images of one another. Such compounds are called "racemates" when they are mixtures of enantiomers and are called "resolved stereoisomers" when they are pure diastereomers. The term "stereoisomers" also describes compounds which have the same molecular formula and atomic constitution, but differ in the arrangement of their atoms in space. It is intended that all of the isomeric forms of the compounds of the present application are embraced within the scope of this application. Diastereomers can be prepared by resolution of racemic mixtures by standard techniques, such as reverse phase HPLC. Enantiomers can be prepared by chiral chromatography of racemic mixtures or by reaction of appropriate chiral starting materials under kinetic control.

[0040] An "isotopically-labeled" compound of the application is a molecule of the application in which one or more atoms are replaced by an isotope of the atom. Typically, isotopes of hydrogen, carbon, nitrogen, oxygen and sulfur are preferred isotopes for inclusion in the compounds of the application. Isotopically-labeled compounds of this application can generally be prepared by carrying out the procedures disclosed in the schemes and examples below, by either: 2 H and 3 H; isotopes of carbon: 11 C, 13 C and 14 C; isotopes of chlorine: 35 Cl and 37 Cl; isotopes of fluorine: 18 F; isotopes of iodine: 123 I and 125 I; isotopes of nitrogen: 13 N and 15 N; isotopes of oxygen: 15 O, 17 O and 18 O and isotopes of sulfur 35 S. These isotopically-labeled compounds are useful in metabolic studies regulating gene expression, receptor binding studies, and determining specificity of interaction. Isotopically-labeled compounds of this application can generally be prepared by carrying out the procedures disclosed in the schemes and examples below, by either: 3 H and carbon 13 C, because of ease of preparation and detection. Certain heavier isotopes, such as deuterium ( 2 H), can increase metabolic stability or enhance the therapeutic advantages of a compound. Isotopically-labeled compounds of this application can generally be prepared by carrying out the procedures disclosed in the schemes and examples below, by either:

[0041] The present application also provides the use of a compound of the present application for the manufacture of a medicament for the prevention and / or treatment of cancer, a tumor, an inflammatory disease, an autoimmune disease, or an immune-mediated disease.

[0042] In addition, the present application provides a pharmaceutical composition for the prevention and / or treatment of cancer, a tumor, an inflammatory disease, an autoimmune disease, a neurodegenerative disease, an attention-related disease, or an immune-mediated disease, which comprises a compound of the present application as an active ingredient.

[0043] In addition, the present application provides a method for the prevention and / or treatment of cancer, a tumor, an inflammatory disease, an autoimmune disease, a neurodegenerative disease, an attention-related disease, or an immune-mediated disease, which comprises administering a compound of the present application to a mammal in need thereof.

[0044] Representative examples of inflammatory diseases, autoimmune diseases, and immune-mediated diseases can include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritides, gouty arthritis, osteoarthritis, juvenile arthritis, other arthritic conditions, lupus, systemic lupus erythematosus (SLE), skin-related diseases, psoriasis, eczema, dermatitis, allergic dermatitis, pain, lung diseases, lung inflammation, adult respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic lung inflammatory disease, chronic obstructive pulmonary disease (COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjogren's syndrome, autoimmune thyroid disease, urticaria (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 rhinosinusitis, leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), hairy cell leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), diffuse large B-cell lymphoma, and follicular lymphoma.

[0045] Representative examples of cancers or tumors can include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis cancer, hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, larynx cancer, hypopharynx cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine body cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urological cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumor, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), acute myelogenous leukemia (AML), chronic myelogenous 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, teratocarcinoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, or plasmacytoma.

[0046] When the compound of the present application or a pharmaceutically acceptable salt thereof is administered in combination with another anticancer agent or immune checkpoint inhibitor for the treatment of cancer or tumor, the compound of the present application or a pharmaceutically acceptable salt thereof can provide an enhanced anticancer effect.

[0047] Representative examples of the anticancer agent for the treatment of cancer or tumor can 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, daunorubicin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifen, flutamide, goserelin analogs, megestrol, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alpha, leucovorin, sirolimus, sirolimus lipidate, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crotetuzumab, dabrafenib, dacotuzumab, 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, seribantumab, sorafenib, sunitinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, velpatasarin, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, brentuximab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab ozogamicin, 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.

[0048] When the compound of the present application or a pharmaceutically acceptable salt thereof is administered in combination with another therapeutic agent for the treatment of inflammatory diseases, autoimmune diseases and immune-mediated diseases, the compound of the present application or a pharmaceutically acceptable salt thereof can provide an enhanced therapeutic effect.

[0049] Representative examples of therapeutic agents for the treatment of inflammatory diseases, autoimmune diseases and immune-mediated diseases can include, but are not limited to, steroidal drugs (e.g., prednisone, prednisolone, methylprednisolone, cortisone, hydrocortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNFa 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 from among them can be included in the pharmaceutical composition of the present application.

[0050] The compound of the present application or a pharmaceutically acceptable salt thereof can be orally or parenterally administered as an active ingredient in an effective amount ranging 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 a mammal including a human (body weight about 70 kg), and administered in a single or 4 divided doses per day, or in compliance with / incompliance with a predetermined time. The dose of the active ingredient can be adjusted according to various 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 physician's opinion). In some cases, an amount less than the above dose can be appropriate. An amount greater than the above dose can be used if it does not cause harmful side effects and the amount can be administered in divided doses per day.

[0051] In addition, the present application provides a method for preventing and / or treating a tumor, cancer, viral infection, organ transplant rejection, neurodegenerative disease, attention-related disease, or autoimmune disease, which comprises administering to a mammal in need thereof a compound of the present application or a pharmaceutical composition of the present application.

[0052] The pharmaceutical composition of the present application 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, for example, tablets, granules, powders, capsules, syrups, emulsions, microemulsions, solutions, or suspensions.

[0053] The pharmaceutical compositions of the present application for oral administration can be prepared by mixing the active ingredient with a carrier, for example, a cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, a surface active agent, a suspending agent, an emulsifying agent, and a diluent. Examples of the carriers employed in the injection compositions of the present application are water, a salt solution, a glucose solution, a glucose-like solution, an alcohol, a glycol, an ether (e.g., polyethylene glycol 400), an oil, a fatty acid, a fatty acid ester, a glyceride, a surface active agent, a suspending agent, and an emulsifying agent.

[0054] Other features of the application will become apparent in the course of the detailed description which follows, given for purposes of illustration and not intended to be limiting of the application, the following examples use the methods disclosed herein to prepare, isolate and characterize.

[0055] The compounds of the present application can be prepared in a number of ways known to one skilled in the art of organic synthesis, either by using the methods described below, or by using synthetic methods known in the art of synthetic organic chemistry, or by using modifications of these methods as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in solvents appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be compatible with the reagents and conditions proposed. This sometimes requires a judgment to modify the order of the synthetic steps or to select a different route to the final compound. DETAILED DESCRIPTION

[0056] Definitions

[0057] The terms, if not otherwise specified, used in the present application, including the specification and claims, are defined as follows. It must be noted that, as used in the specification and the appended claims, the singular form "a" includes plural referents unless the context clearly dictates otherwise. The conventional methods of mass spectrometry, nuclear magnetic, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are used, if not otherwise specified. In the present application, "or" or "and" means "and / or" if not otherwise specified.

[0058] In the specification and claims, given chemical formulae or names shall encompass all stereoisomers and racemates where the above-mentioned isomers are present. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the application. Many geometric isomers of C=C double bonds, C=N double bonds, ring systems, and the like can also be present in the described compounds, and all such isomers are encompassed within the scope of the present application. The present application describes the cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present application and they can be isolated in, or converted into, mixtures or separate isomers. The compounds of the present application can be isolated in optically active or racemic forms. All processes used to prepare compounds of the present application and intermediates used therein are considered to be part of the present application. When preparing enantiomeric or diastereomeric products, they can be separated by conventional methods, e.g., by chromatography or fractional crystallization. The end products of the present application are obtained as either the free (neutral) compounds or salts, depending upon the conditions used in the last step of the preparation. Both the free form and the salts of these end products are within the scope of the application. If desired, one form of a compound can be converted into another form. A free base or acid can be converted into a salt; a salt can be converted into the free compound or another salt; a mixture of isomeric compounds of the present application can be separated into the individual isomers. The compounds of the present application, free forms and salts, can exist in a variety of tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecule and the chemical bonds between the atoms of the molecule are rearranged accordingly. It is to be understood that all tautomeric forms, which can exist, are included within the present application.

[0059] Unless otherwise defined, the definition of substituents of the present application are independent of each other and not interdependent, e.g., for R a (or R a ) in different definitions of substituents are independent of each other. In particular, when a definition for R a (or R a ) is selected in one substituent, it does not mean that the same definition for R a (or R a ) is necessarily selected in other substituents. More particularly, for example (by no means an exhaustive list) for NR a R a , when the definition of R a (or R a ) is selected from hydrogen, it does not mean that R a (or R a ) is necessarily hydrogen in -C(O)-NR a R a .

[0060] Unless otherwise defined, when a substituent group is designated as "optionally substituted" the substituent group is selected from, for example, alkyl, cycloalkyl, aryl, heterocyclyl, halo, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine groups wherein the 2 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, sulfonamido such as -SO2NH2, substituted sulfonamido, nitro, cyano, carboxy, carbamoyl such as -CONH2, substituted carbamoyl such as -CONHalkyl, -CONHaryl, -CONHarylalkyl or where the nitrogen has two substituents selected from alkyl, aryl or arylalkyl, alkoxycarbonyl, aryl, substituted aryl, guanidino, heterocyclyl such as indolyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl and substituted heterocyclyl.

[0061] The term "alkyl" or "alkylene" as used herein is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "Ci-C6alkyl" denotes alkyl groups with one to six carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl).

[0062] The term "alkenyl" denotes straight or branched-chain hydrocarbon groups with one or more double bonds and typically having a length of from 2 to 20 carbon atoms. For example, "C2-C6alkenyl" contains two to six carbon atoms. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.

[0063] The term "alkynyl" denotes straight or branched-chain hydrocarbon groups with one or more triple bonds and typically having a length of from 2 to 20 carbon atoms. For example, "C2-C6alkynyl" contains two to six carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, and the like.

[0064] The term "alkoxy" or "alkyloxy" refers to -O-alkyl. "C1-C6alkoxy" (or alkyloxy) is intended to include C1, C2, C3, C4, C5, C6alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propyloxy (e.g., n- propyloxy and isopropyloxy), and t-butyloxy. Similarly, "alkylthio" or "thioalkoxy" denotes an alkyl group as defined above attached through a sulfur bridge; for example, methyl-S- and ethyl-S-.

[0065] The term "carbonyl" refers to the organic functional group (C=0) connected by a double bond between a carbon and an oxygen atom.

[0066] The term "aryl", by itself or as part of another substituent such as "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to a monocyclic, bicyclic or tricyclic ring system having from 5 to 12 ring members, wherein at least one ring is aromatic and wherein each ring in the system contains from 3 to 7 ring members. In certain embodiments of the application, "aryl" refers to aromatic ring systems including, but not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthyl. The term "aralkyl" or "arylalkyl" refers to an alkyl radical attached to an aryl ring. Non-limiting examples include benzyl, phenethyl, and the like. A fused aryl group can be attached to another group at a suitable position on either the cycloalkyl ring or the aromatic ring. Dashed lines drawn from the ring system indicate that the bond can be attached to any suitable ring atom.

[0067] The term "cycloalkyl" refers to a monocyclic or bicyclic ring system of cyclic alkyl groups, preferably having from 3 to 8 ring members. Monocyclic ring systems of cycloalkyl groups refer to C3-C8cycloalkyl groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". Bicyclic ring systems of cycloalkyl groups include bridged, spiro, or fused ring cycloalkyl groups.

[0068] The term "cycloalkenyl" refers to a monocyclic or bicyclic ring system of cyclic alkenyl groups, preferably having from 3 to 8 ring members. Monocyclic ring systems of cycloalkenyl groups refer to C3-C8cycloalkenyl groups, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and norbornenyl. Branched cycloalkenyl groups such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl". Bicyclic ring systems of cycloalkenyl groups include bridged, spiro, or fused ring cycloalkenyl groups.

[0069] "Halo" or "halogen" includes fluoro, chloro, bromo, and iodo. "Haloalkyl" is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (preferably 1 to 6 carbon atoms) and substituted with one or more halogens (preferably 1, 2, or 3 halogens). Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptafluoropropyl. Examples of haloalkyl also include "fluoroalkyl" which is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and substituted with one or more fluorine atoms.

[0070] "Haloalkoxy" or "haloalkyloxy" denotes an oxygen-bridged haloalkyl group as defined above having the specified number of carbon atoms (preferably 1 to 6 carbon atoms). For example, "halo C1-C6alkoxy" is intended to include C1, C2, C3, C4, C5, C6haloalkoxy groups. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" denotes a sulfur-bridged haloalkyl group as defined above having the specified number of carbon atoms (preferably 1 to 6 carbon atoms); for example, trifluoromethyl-S- and pentafluoroethyl-S-.

[0071] In the present disclosure, when referring to some substituent groups, 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.

[0072] In the present disclosure, when referring to cyclic groups (e.g., 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, which can have from 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms; 3-6 membered ring means that the cyclic group can be a 3-, 4-, 5-, or 6-membered ring, which can have from 3, 4, 5, or 6 ring atoms; 3-8 membered ring means that the cyclic group can be a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, which can have from 3, 4, 5, 6, 7, or 8 ring atoms; 3-9 membered ring means that the cyclic group can be a 3-, 4-, 5-, 6-, 7-, 8-, or 9-membered ring, which can have from 3, 4, 5, 6, 7, 8, or 9 ring atoms; 4-7 membered ring means that the cyclic group can be a 4-, 5-, 6-, or 7-membered ring, which can have from 4, 5, 6, or 7 ring atoms; 5-8 membered ring means that the cyclic group can be a 5-, 6-, 7-, or 8-membered ring, which can have from 5, 6, 7, or 8 ring atoms; 5-12 membered ring means that the cyclic group can be a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, which can have from 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms; 6-12 membered ring means that the cyclic group can be a 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, which can have from 6, 7, 8, 9, 10, 11, or 12 ring atoms. The ring atoms can be carbon atoms or heteroatoms, e.g., 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, e.g., heteroatoms selected from N, O, and S.

[0073] In the present disclosure, one or more halogens can each be independently selected from fluorine, chlorine, bromine, and iodine.

[0074] 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 polyaromatic heterocyclic ring which is fully unsaturated, partially unsaturated, and which contains carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; and includes any of the following polycyclic groups wherein any of the heterocyclic rings defined above are fused to a benzene ring. The nitrogen and sulfur heteroatoms can 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 heterocyclic rings can be attached to their side groups at any heteroatom or carbon atom that results in a stable structure. The heterocyclyl groups described herein can be substituted on a carbon or a nitrogen atom if the resulting compound is stable. The nitrogens in the heterocyclic ring can optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocyclic ring exceeds one, then these heteroatoms are not adjacent to one another. Preferably, the total number of S and O atoms in the heterocyclic ring is not more than one. When the term "heterocycle" is used, it is intended to include heteroaryl.Examples of heteroaryl groups include, but are not limited to, acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridinyl, indoleninyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isochromanyl, isochromenyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthizidinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinyl, perimidinyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienopyridinyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, 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, indolinyl, 1H-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro- quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl.The term "heteroaryl" can also include biaryl structures formed from the above defined "aryl" groups with monocyclic "heteroaryl" groups, such as, but not limited to, "-phenylbipyridyl-", "-phenylbipyrimidyl-", "-pyridylbiphenyl-", "-pyridylbipyrimidyl-", "-pyrimidylbiphenyl-"; wherein the present application also includes fused ring and spiro compounds containing, for example, the above heterocycles.

[0075] The term "heterocycloalkyl" as used herein refers to a monocyclic heterocycloalkyl ring system, or to a bicyclic heterocycloalkyl ring system, and also includes spiro or bridged heterocycloalkyl groups. Monocyclic heterocycloalkyl refers to a 3-8 membered, saturated or unsaturated, but not aromatic, ring system containing at least one ring member selected from O, N, S, P. Bicyclic heterocycloalkyl ring systems refer to a heterocycloalkyl ring fused to a phenyl, or a cycloalkyl, or a cycloalkenyl, or a heterocycloalkyl, or a heteroaryl.

[0076] The term "bridged cycloalkyl" as used herein refers to polycyclic compounds sharing two or more carbon atoms. It can be divided into bicyclic bridged cycloalkanes and polycyclic bridged cycloalkanes. The former consists of two alicyclic rings sharing two or more carbon atoms; the latter is a bridged cycloalkane consisting of three or more rings.

[0077] The term "spirocycloalkyl" as used herein refers to polycyclic hydrocarbons sharing one carbon atom (called spiro atom) between single rings.

[0078] The term "bridged heterocyclyl" as used herein refers to polycyclic compounds sharing two or more carbon atoms, at least one of which is selected from O, N, S. It can be divided into bicyclic bridged heterocycles and polycyclic bridged heterocycles.

[0079] The term "spiroheterocyclyl" as used herein refers to polycyclic hydrocarbons sharing one carbon atom (called spiro atom) between single rings, at least one of which is selected from O, N, S.

[0080] The term "substituted" as used herein means that at least one hydrogen atom has been replaced with a non-hydrogen group, provided that a stable compound results. A ring double bond as used herein is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0081] In cases wherein there are nitrogen atoms (e.g., amines) on the compounds of the present application, these nitrogen atoms can be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxides) to afford additional compounds of the present application. Thus, shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxide to afford derivatives of the present application.

[0082] When any variable occurs more than one time in any constituent or formula, its definition in each occurrence is independent of its definition in every other case. Thus, for example, if a group is shown to be substituted with 0 to 3 R groups, said group can optionally be substituted with up to three R groups, and at each occurrence R is independently selected from the definition of R. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0083] The term "patient" as used herein refers to an organism to be treated by the methods of the present application. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians / monkeys, equines, bovines, porcines, canines, felines, etc.) and most preferably refers to humans.

[0084] The term "effective amount" as used herein means that amount of a drug or pharmaceutical agent (i.e., a compound of the present application), which will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means an amount of a compound effective to improve the treatment, cure, prevent, or reduce the symptoms of a disease, condition, or disorder, or to reduce the speed of progression of a disease or condition, as compared to an untreated subject. An effective amount can be given 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 amounts effective to enhance normal physiological function.

[0085] The term "treatment" as used herein includes any effect that relieves, reduces, modulates, ameliorates, or eliminates a condition, disease, disorder, etc., or its symptoms.

[0086] The term "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, and / or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0087] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium stearate, calcium stearate or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion 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. Some examples of materials which have been used to form pharmaceutical compositions include lactose, calcium phosphate, corn starch, potato starch, cellulose acetate phthalate, sodium carboxymethylcellulose, talc, magnesium stearate, and gum arabic.

[0088] The term "pharmaceutical composition" means a composition comprising a compound of the present application in combination with at least one other pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" means a medium generally accepted in the art for the delivery of a biologically active agent to an animal, particularly a mammal, and includes, i.e., an adjuvant, excipient, or vehicle such as diluent, preservative, filler, flow regulator, disintegrating agent, wetting agent, emulsifying agent, suspending agent, sweetening agent, flavoring agent, perfuming agent, antibacterial agent, antifungal agent, lubricating agent, and dispersing agent, depending on the nature of the mode of administration and dosage form.

[0089] Specific Pharmaceutical and Medical Terms

[0090] The term "acceptable", as used herein, means no undue harmful effect on the general health of the subject of treatment of the active ingredients of the prescription.

[0091] The term "cancer", as used herein, means an uncontrolled abnormal growth of cells and, under certain conditions, the ability to metastasize (spread). This type of cancer includes, but is not limited to, solid tumors (e.g., bladder, bowel, brain, breast, uterine, cardiac, kidney, lung, lymphatic tissue (lymphoma), ovarian, pancreatic or other endocrine organ (e.g., thyroid), prostate, skin (melanoma), or blood tumors (e.g., non-leukemic leukemia).

[0092] The term "co-administration" or its grammatical equivalents, as used herein, means the administration of two or more selected therapeutic agents to a single patient in close enough time proximity as to provide a desired therapeutic effect.

[0093] The term "enhance" or "enhancing", as used herein, means an intended result that can be an increase or prolongation in potency or duration. Thus, in the context of enhancing the therapeutic effect of a drug, the term "enhancing" means the ability of a drug to increase or prolong the potency or duration of action in a system. "Enhancing value", as used herein, means the ability to maximize the enhancement of another therapeutic agent in a desired system.

[0094] The term "immune disease" means a disease or condition resulting from an adverse or deleterious reaction to an endogenous or exogenous antigen. The result is usually a dysfunction of cells, or destruction and dysfunction as a result, or destruction of organs or tissues that can produce the immune condition.

[0095] The terms "kit" and "product package" are synonymous.

[0096] The term "subject" or "patient" includes mammals and non-mammals. Mammals include, but are not limited to, mammals: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and house cats; laboratory animals such as rats, mice, and guinea pigs; and the like. Non-mammalian animals include, but are not limited to, birds, fish, and the like. In a preferred embodiment, the mammal is a human.

[0097] The terms "treatment," "treatment regime," or "therapy," as used herein, include alleviating, inhibiting or ameliorating a disease symptom or condition; inhibiting the onset of a complication; ameliorating or preventing an underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the progression of a disease or condition; abating a disease or symptom; causing regression of a disease or symptom; relieving a complication caused by a disease or symptom, or preventing and / or treating an indication caused by a disease or symptom.

[0098] As used herein, an improvement in a disease, symptom, or condition, with respect to a compound or pharmaceutical composition, means, inter alia, that the severity of the disease, symptom, or condition is improved, the onset of the disease, symptom, or condition is delayed, the progression of the disease, symptom, or condition is slowed, or the duration of the disease, symptom, or condition is lessened. The improvement can be attributed to or associated with the administration, whether fixed or contingent, whether continuous or intermittent.

[0099] Routes of administration

[0100] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, aural, nasal, and topical. In addition, parenteral administration includes, by way of illustration, intramuscular, subcutaneous, intravenous, intramedullary, intraventricular, intraperitoneal, intralymphatic, and intranasal.

[0101] In one aspect, the compounds described herein are administered in a manner that is local rather than systemic. In a particular embodiment, the long-acting formulation is administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. In addition, in another embodiment, the drug is administered by a targeted drug delivery system. For example, a liposome encapsulated with an organ-specific antibody. In this embodiment, the liposome is selectively directed to a particular organ and is taken up.

[0102] Pharmaceutical compositions and dosages

[0103] The present application also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of the present application formulated together with one or more pharmaceutically acceptable carriers (additives) and / or diluents and, optionally, one or more other therapeutic agents as described above. The compounds of the present application can be administered by any suitable means, for any of the above-mentioned uses, e.g., orally, such as tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nano-, micro-, spray-dried dispersions), syrups, and emulsions; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or nonaqueous solutions or suspensions); nasally, including to the nasal membranes, such as by inhalable sprays; topically, such as in creams or ointments; or rectally, such as in suppositories; or intratumorally. They can be administered alone, but generally are administered in admixture with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

[0104] Pharmaceutically acceptable carriers are formulated in accordance with a number of factors well within the purview of those skilled in the art. These factors include, but are not limited to: the type and nature of the active agent being formulated; the subject to which the composition containing the active agent is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include aqueous and nonaqueous liquid media and various solid and semi-solid dosage forms.

[0105] The above carriers can include a wide variety of different ingredients and additives in addition to the active agent, which are included in the formulation for a variety of reasons known to those skilled in the art, e.g., to stabilize the active agent, binders, etc. Descriptions of suitable pharmaceutically acceptable carriers and factors involved in selection of carriers can be found in a number of readily available sources, e.g., Allen L.V. Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012), Pharmaceutical Press.

[0106] The dosage regimen for compounds of the present application will, of course, depend on known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment(s) and the frequency and route of administration, the renal and hepatic function of the patient, and the dosage should the desired effect be unsatisfactory. Under normal conditions, oral daily dosage levels of each active ingredient for the desired effects will be from about 0.001 mg / day to about 10-5000 mg / day, preferably from about 0.01 mg / day to about 1000 mg / day, and most preferably from about 0.1 mg / day to about 250 mg / day, when used for the indicated effects. Intravenous dosage levels during constant rate infusion will most preferably be from about 0.01 mg / kg / min to about 10 mg / kg / min. Compounds of the present application can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times daily.

[0107] The compounds are generally administered in the form of a pharmaceutical composition in admixture with a suitable pharmaceutical diluent, excipient, or carrier (collectively referred to as a pharmaceutical carrier) selected with regard to the intended form of administration (e.g., oral tablets, capsules, elixirs, and syrups) and consistent with conventional pharmaceutical practice.

[0108] Dosage forms (pharmaceutical compositions) suitable for administration include about 1 milligram to about 2000 milligrams of active ingredient per dosage unit.

[0109] A typical capsule for oral administration contains at least one compound of the present application (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule.

[0110] A typical injectable formulation can be prepared by aseptically placing at least one compound of the present application (250 mg) into a bottle, freeze-drying and sealing. For use, the contents of the bottle are mixed with 2 mL of normal saline to create an injectable formulation.

[0111] The scope of the present application includes pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of the present application as an active ingredient, alone or in combination with a pharmaceutical carrier. Optionally, the compounds of the present application can be used in combination with other compounds of the present application or in combination with one or more other therapeutic agents (e.g., anti-cancer agents or other pharmaceutically active substances).

[0112] Regardless of the route of administration selected, the compounds of the present application, which can be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present application, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.

[0113] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present application can be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0114] The selected dosage level will depend on a variety of factors including the activity of the particular compound of the present application employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and pre-existing medical conditions of the patient being treated, and like factors well known in the medical arts.

[0115] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the application employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In general, a suitable daily dose of a compound of the application will be in the range from about 0.01 to about 50 mg / kg body weight per day. Generally, oral, intravenous, intracerebroventricular, and subcutaneous doses of the compounds of the application for patients will range from about 0.01 to about 50 mg / kg body weight per day. If desired, the effective daily dose can be divided into two, three, four, five, six, or more sub-doses that are administered separately at appropriate intervals during the day, optionally, in unit dosage forms. In certain aspects of the application, dosing is once daily.

[0116] While it is possible for a compound of the present application to be administered alone, it is preferable to present the compound as a pharmaceutical formulation (composition).

[0117] Kits / Products Packets

[0118] Kits / Products Packets are also described herein for use in the treatment of the indications described above. These kits can consist of a carrier, a packet, or a container box, which can be divided into compartments, for containing one or more containers, such as vials, test tubes, and the like, each containing one of the ingredients in the method. Suitable containers include bottles, vials, syringes, and test tubes. The containers are made of a material that is acceptable to the intended recipient of the pharmaceutical composition. For example, the containers can be formed from plastic, glass, or other material.

[0119] For example, a container can contain one or more of the compounds described herein, which can be present as a pharmaceutical composition, in combination with one or more of the other ingredients described herein. The container can have a sterile access port (for example the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits can further include one or more compounds, and instructions, a label, or packaging insert describing the use of the compounds in the methods described herein.

[0120] A typical kit can include one or more containers into which one or more of the materials described herein can be placed, and which can be packaged into a single kit for commercial sale and use. These kits can include, for example, a container that contains one or more of the compounds described herein, and which can be present as a pharmaceutical composition, in combination with one or more of the other ingredients described herein. The container can have a sterile access port (for example the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits can further include one or more compounds, and instructions, a label, or packaging insert describing the use of the compounds in the methods described herein.

[0121] Labels suitable for use in conjunction with the containers of the application include mathematically or machine-readable labels that are printed, embossed, or otherwise attached to the containers. Such labels include, for example, those that are hand-written, typed, or printed via a computer. The labels can be affixed to the containers using any suitable technique, including, for example, adhesive, heat, or pressure. The labels can be affixed to the containers prior to or after the containers are filled with the compounds described herein. The labels can be affixed to the containers in a manner that allows the labels to be removed from the containers, or the labels can be affixed to the containers in a manner that does not allow the labels to be removed from the containers.

[0122] All features described in the specification (including any accompanying claims, abstract, and drawings), and / or all elements of any method or process described, can be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, the features described herein are intended to be broadly applicable to any analogous or equivalent element.

[0123] The features described herein, or in any of the examples, can be combined in any combination. All features disclosed in the specification, including any described with respect to the examples, can be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, the features disclosed herein are not to be taken as exhaustive but rather are merely representative of the many alternatives with which the application can be practiced. The application is therefore to be understood as not limited by the features described or by any substituting means except as set forth in the claims and their equivalents.

[0124] The application will be further described with respect to the following examples. It should be understood that these examples are for illustrative purposes only and are not meant to limit the scope of the application. The following examples were prepared according to the procedures described unless otherwise indicated. All percentages, ratios, proportions, or parts, are by weight unless otherwise indicated.

[0125] The units in the weight / volume percentages in the present application are well known to those skilled in the art, for example, refer to the weight of solute in 100 ml of solution. Unless otherwise defined, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the application belongs. In addition, all methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application. The preferred methods and materials described herein are illustrative only and not intended to be limiting.

[0126] Examples

[0127] General procedures

[0128] When not included in the preparation route, the starting materials and reagents used in the present application are known products, which can be synthesized according to the methods known in the art, or can be obtained by purchasing commercially available products. The commercially available reagents used do not need further purification.

[0129] Room temperature refers to 20-30°C.

[0130] Unless otherwise specified, the reactions in the reaction examples are carried out under a nitrogen atmosphere. The nitrogen atmosphere refers to that the reaction bottle is connected to a nitrogen balloon of about 1 L.

[0131] The hydrogenation reaction is usually vacuumed and filled with hydrogen, and the operation is repeated 3 times. The hydrogen atmosphere refers to that the reaction bottle is connected to a hydrogen balloon of about 1 L.

[0132] Microwave reaction uses Initiator + microwave reactor.

[0133] The structure of the compounds of the present application 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 is measured by a (Bruker Ascend TM 500 type) nuclear magnetic instrument, and the measuring solvent is 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, br s = broad singlet, d = doublet, t = triplet, m = multiplet. The coupling constant is listed as J value, measured in Hz.

[0134] The measurement of LC-MS uses Thermo liquid chromatograph-mass spectrometer (UltiMate 3000+MSQ PLUS). The measurement of HPLC uses Thermo high pressure liquid chromatograph (UltiMate 3000). The reverse phase preparative chromatography uses Thermo (UltiMate 3000) reverse phase preparative chromatograph. The flash column chromatography uses Ajinomoto (FS-9200T) automatic column machine, and the silica gel pre-packed column uses San Tai (S-1000) silica gel pre-packed column. Pre-packed column. TLC silica gel plate is Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate, and the specification of TLC separation and purification product is 0.4mm-0.5mm.

[0135] The synthesis method of some intermediates in the application is as follows:

[0136]

[0137] The intermediate 1 is prepared by the following steps:

[0138]

[0139] First step: 1-methyl-3,5-dinitropyridin-2-one Int-1a (1.0g, 5.02mmol) is dissolved in methanol (50mL), and then ammonium methanol solution (7mol / L, 8.61mL, 60.27mmol) and 1-methylpiperidin-4-one Int-1b (625mg, 5.52mmol) are added in sequence. The reaction mixture is heated to 50℃ and stirred for 5 hours. After cooling to room temperature, it is left to stand for 48 hours, the reaction solution is concentrated under reduced pressure, and the residue is added into ethyl acetate (50mL) and filtered. The filtrate is concentrated under reduced pressure to obtain red solid Int-1c (1.0g), which is directly used in the next step reaction. ESI-MS (m / z): 194.4 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ 9.14 (d, J=2.5Hz, 1H), 8.36 (d, J=2.5Hz, 1H), 3.64 (s, 2H), 3.02 (t, J=6.0Hz, 2H), 2.74 (t, J=6.0Hz, 2H), 2.39 (s, 3H).

[0140] Second step: the compound Int-1c (1.0g) obtained in the above step is dissolved in methanol (30mL), and 10% Pd-C (400mg) is added, and the reaction is carried out under hydrogen atmosphere at room temperature for 6 hours. The palladium carbon is removed by filtration, and the filtrate is concentrated to obtain yellow solid Int-1d (800mg, yield 94%). ESI-MS (m / z): 164.2 [M+H] + .

[0141] Step 3: Compound Int-1d (100 mg, 0.61 mmol) was dissolved in acetic acid (3 mL), N-bromosuccinimide (109 mg, 0.61 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous sodium bicarbonate until no gas bubbles were generated, and the aqueous phase was extracted with methanol / dichloromethane (1 / 20, 50 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound Int-1e (38 mg, yield 25%). ESI-MS (m / z): 242.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ

[0142] 6.77 (s, 1H), 5.25 (s, 2H), 3.37 (s, 2H), 2.69 (t, J = 6.0 Hz, 2H), 2.60 (t, J = 6.0 Hz, 2H), 2.32 (s, 3H).

[0143] Step 4: Compound Int-1e (37 mg, 0.15 mmol) was dissolved in methanol (1 mL), and cuprous iodide (3 mg, 0.015 mmol), 1,10-phenanthroline (3 mg, 0.03 mmol), and cesium carbonate (99 mg, 0.30 mmol) were added. The reaction mixture was stirred at 100 °C for 2 hours after being purged with nitrogen and heated with a microwave. The reaction was cooled to room temperature, the reaction was concentrated, and the residue was purified by preparative thin layer chromatography (methanol / dichloromethane / triethylamine = 1 / 10 / 0.1) to give Int-1 as a yellow solid (20 mg, yield 67%). ESI-MS (m / z): 194.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 6.54 (s, 1H), 4.68 (s, 2H), 3.80 (s, 3H), 3.30 (s, 2H), 2.64 (t, J = 5.6 Hz, 2H), 2.59 (t, J = 5.7 Hz, 2H), 2.31 (s, 3H).

[0144]

[0145] Intermediate 2 was prepared from the following steps:

[0146]

[0147] First Step: Compound Int-le (230 mg, 0.94 mmol) was dissolved in ethanol (2 mL), and cuprous iodide (18 mg, 0.095 mmol), 1,10-phenanthroline (34 mg, 0.18 mmol) and cesium carbonate (619 mg, 1.90 mmol) were added. The reaction mixture was purged with nitrogen and heated to 100 °C in a microwave for 5 h. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (methanol / dichloromethane / triethylamine = 1 / 50 / 0.1) to give Int-2 (113 mg, 57% yield) as a yellow solid. ESI-MS (m / z): 208.5 [M+H] + .

[0148]

[0149] Intermediate 3 was prepared by the following steps:

[0150]

[0151] First Step: N-tert-butoxycarbonyl-4-piperidinone Int-3a (4.4 g, 22.1 mmol) and 1-methyl-3,5-dinitro-2-pyridinone Int-la (4.0 g, 20.1 mmol) were dissolved in methanol (150 mL), and ammonium hydroxide solution (7 N, 34.4 mL, 240.8 mmol) was added. The reaction was stirred at 60 °C for 6 h under nitrogen. The reaction was cooled to room temperature and stirred for another 2 days. The reaction was monitored by LCMS and was complete. The reaction was concentrated, ethyl acetate (150 mL) was added, and the mixture was stirred for half an hour and filtered. The filtrate was concentrated to give Int-3b (5.1 g, 91% yield) as a yellow solid. ESI-MS (m / z): 280.1 [M+H] + .

[0152] Second Step: Compound Int-3b (5.0 g, 17.9 mmol) was dissolved in methanol (50 mL), and 10% palladium on carbon (500 mg) was added. The mixture was stirred at room temperature under hydrogen atmosphere (hydrogen balloon) for 16 h. The reaction was complete, and the reaction was filtered. The filtrate was concentrated to give Int-3c (3.7 g, 84% yield) as a light yellow solid. ESI-MS (m / z): 250.2 [M+H] + .

[0153] Step 3: Compound Int-3c (3.7 g, 14.8 mmol) was dissolved in DMF (20 mL), N- bromosuccinimide (2.78 g, 15.6 mmol) and acetic acid (370 mg) were added. The reaction mixture was stirred at room temperature for 2 hours, the reaction was monitored by LCMS. Water (100 mL) was added, the aqueous phase was extracted with ethyl acetate (150 mL*3), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, the residue was separated by silica gel column chromatography to give yellow solid Int-3d (3.6 g, yield 74%). ESI-MS (m / z): 328.2 [M+H] + Step 4: Compound Int-3d (500 mg, 1.53 mmol) was dissolved in methanol (5 mL), sodium methoxide methanol solution (5 N, 0.33 mL, 1.65 mmol) was added. The reaction mixture was heated to 100 °C with microwave for 3 hours. The reaction was cooled to room temperature, the reaction was concentrated, the residue was separated by silica gel column chromatography to give yellow solid Int-3 (330 mg, yield 77%). ESI-MS (m / z): 280.2 [M+H] + .

[0154]

[0155] Intermediate 4 was prepared by the following steps:

[0156]

[0157] Step 1: Compound Int-4a (5 g, 25.09 mmol) and tetrahydro pyrrole (2.68 g, 37.64 mmol, 3.13 mL) were dissolved in toluene (50 mL), heated to reflux with a water separator for 18 hours. The reaction was concentrated, the residue was dissolved in 1,4-dioxane (50 mL), diethyl ethoxymethylidene malonate (5.97 g, 27.60 mmol, 5.53 mL) was added, the reaction mixture was heated to reflux and stirred for 6 hours. When the reaction was cooled to room temperature, ammonium acetate (3.29 g, 42.66 mmol) was added, then heated to reflux for 1 hour. The reaction was concentrated, the residue was purified by silica gel column chromatography (100% ethyl acetate) to give yellow solid compound Int-4b (2.3 g, yield 28%). ESI-MS (m / z): 323.4 [M+H] + ; 1HNMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 7.90 (s, 1H), 4.25 (s, 2H), 4.19 (q, J = 7.1 Hz, 2H), 3.54 (t, J = 5.8 Hz, 2H), 2.60 (t, J = 5.9 Hz, 2H), 1.42 (s, 9H), 1.25 (t, J = 7.1 Hz, 3H).

[0158] Second Step: Compound Int-4b (1.1 g, 3.41 mmol) was dissolved in DMF (20 mL), and cesium carbonate (1.67 g, 5.12 mmol) and iodomethane (484 mg, 3.41 mmol) were added successively at 0 °C. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with water, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound Int-4c (1.1 g, yield 95%) as a yellow oily liquid. ESI-MS (m / z): 337.3 [M+H] + ; 1 HNMR (500 MHz, DMSO-d6) δ 7.84 (s, 1H), 4.28 (s, 2H), 4.19 (q, J = 7.1 Hz, 2H), 3.57 (t, J = 5.9 Hz, 2H), 3.40 (s, 3H), 2.80 (t, J = 5.9 Hz, 2H), 1.41 (s, 9H), 1.24 (t, J = 7.1 Hz, 3H).

[0159] Third Step: Compound Int-4c (1.1 g, 3.27 mmol) was dissolved in ethanol (10 mL), and 1 N aqueous sodium hydroxide solution (9.8 mL) was added, and the mixture was stirred at room temperature for 2 hours. The pH was adjusted to 6 with 6 N aqueous hydrochloric acid solution, and then diluted with water (100 mL). The precipitate was filtered, and the filter cake was washed with water and dried to give compound Int-4d (830 mg, yield 82%) as a yellow solid. ESI-MS (m / z): 309.3 [M+H] + .

[0160] Fourth Step: Compound Int-4d (830 mg, 2.69 mmol) was dissolved in toluene (10 mL), and diphenyl phosphorazide (2.22 g, 8.08 mmol), benzyl alcohol (873 mg, 8.08 mmol), and N,N-diisopropylethylamine (1.39 mg, 10.77 mmol) were added, and the reaction mixture was heated to 120 °C and stirred for 16 hours. The reaction liquid was concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound Int-4e (930 mg, yield 83%) as a yellow solid. ESI-MS (m / z): 414.3 [M+H]+ ; 1 H NMR (500 MHz, methanol-d4) δ 7.84 (s, 1H), 7.48-7.31 (m, 6H), 5.21 (s, 2H), 4.36 (s, 2H), 3.71 (t, J = 6.3 Hz, 2H), 3.56 (s, 3H), 2.80-2.77 (m, 2H), 1.50 (s, 9H).

[0161] Step 5: Compound Int-4e (930 mg, 2.25 mmol) was dissolved in dichloromethane (10 mL), hydrochloric acid / dioxane solution (4 N, 2.25 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction was concentrated, and the residue was dissolved in methanol (10 mL), formaldehyde aqueous solution (1.09 g, 11.25 mmol, 35% content) and sodium triacetoxyborohydride (1.43 g, 6.75 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. The pH value was adjusted to 8 with saturated sodium bicarbonate aqueous solution, diluted with water (50 mL), and the aqueous phase was extracted with a mixed solvent of dichloromethane and methanol (v / v = 10 / 1). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain yellow solid compound Int-4f (700 mg, yield 95%). ESI-MS (m / z): 328.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.58 (s, 1H), 7.44-7.31 (m, 5H), 5.15 (s, 2H), 3.45 (s, 3H), 3.26-3.22 (m, 2H), 2.73 (t, J = 5.7 Hz, 2H), 2.60 (t, J = 5.8 Hz, 2H), 2.31 (s, 3H).

[0162] Step 6: Compound Int-4f (700 mg, 2.14 mmol) was dissolved in methanol (10 mL), 10% palladium-carbon (70 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The palladium-carbon was filtered off with diatomite, the filter cake was washed with methanol, and the filtrate was concentrated to obtain yellow solid compound Int-4 (380 mg, yield 92%). ESI-MS (m / z): 194.4 [M+H] + .

[0163] Intermediate 5

[0164] Intermediate 5 was prepared by the following steps:

[0165]

[0166] First Step: Compound Int-4b (520 mg, 1.61 mmol) was dissolved in DMF (5 mL), and lithium bis(trimethylsilyl)amide (1 N in tetrahydrofuran, 1.77 mL) was added dropwise at 0 °C in an ice bath. The mixture was stirred at 0 °C for 30 min. Then bromomethylcyclopropane (240 mg, 1.77 mmol) was added, and the reaction mixture was stirred at room temperature for another 2 h. After the reaction was completed, the reaction was quenched with water, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 1) to give compound Int-5a (410 mg, 67% yield) as a yellow oily liquid. ESI-MS (m / z): 377.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 7.84 (s, 1H), 4.30 (s, 2H), 4.20 (q, J = 7.1 Hz, 2H), 3.93 (d, J = 6.9 Hz, 2H), 3.59 (t, J = 5.8 Hz, 2H), 2.90 (t, J = 5.5 Hz, 2H), 1.43 (s, 9H), 1.26 (t, J = 7.1 Hz, 3H), 1.18-1.13 (m, 1H), 0.47-0.43 (m, 2H), 0.41-0.37 (m, 2H).

[0167] Second Step: Compound Int-5a (410 mg, 1.09 mmol) was dissolved in ethanol (2 mL), and 1 N aqueous sodium hydroxide solution (2.18 mL) was added. The reaction mixture was stirred at room temperature for 2 h. The pH value was adjusted to 6 with 6 N aqueous hydrochloric acid solution, and the reaction mixture was diluted with water (30 mL). The precipitate was filtered, and the filter cake was washed with water and dried to give compound Int-5b (240 mg, 63% yield) as a yellow solid. ESI-MS (m / z): 349.5 [M+H] + .

[0168] Third Step: Compound Int-5b (240 mg, 0.69 mmol) was dissolved in toluene (3 mL), and diphenyl phosphorazide (0.57 g, 2.07 mmol), benzyl alcohol (222 mg, 2.07 mmol), and N,N-diisopropylethylamine (445 mg, 3.45 mmol) were added. The reaction mixture was heated to 120 °C and stirred for 16 h. The reaction mixture was concentrated, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 1) to give compound Int-5c (100 mg, 32% yield) as a yellow solid. ESI-MS (m / z): 454.3 [M+H] + .

[0169] Fourth Step: Compound Int-5c (100 mg, 0.22 mmol) was dissolved in dichloromethane (2 mL), hydrochloric acid / dioxane solution (4 mol / L, 0.28 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, the residue was dissolved in methanol (2 mL), and aqueous formaldehyde solution (94 mg, 1.10 mmol, 35% content) and sodium triacetoxyborohydride (233 mg, 1.10 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The pH value was adjusted to 8 with saturated aqueous sodium bicarbonate solution, diluted with water (30 mL), and the aqueous phase was extracted with a mixed solvent of dichloromethane and methanol (v / v = 10 / 1). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain yellow solid compound Int-5d (80 mg, yield 98%). ESI-MS (m / z): 368.3 [M+H] + .

[0170] Fifth Step: Compound Int-5d (80 mg, 0.22 mmol) was dissolved in methanol (5 mL), and 10% palladium-carbon (8 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The palladium-carbon was filtered off with diatomite, the filter cake was washed with methanol, and the filtrate was concentrated to obtain yellow solid compound Int-5 (50 mg, yield 98%). ESI-MS (m / z): 234.4 [M+H] + .

[0171]

[0172] Intermediate 6 was prepared by the following steps:

[0173]

[0174] First Step: Compound Int-4b (1.28 g, 3.97 mmol) was dissolved in DMF (15 mL), and lithium bis(trimethylsilyl)amide (1 mol / L in THF, 4.76 mL) was added dropwise at 0°C in an ice bath. The mixture was stirred at 0°C for 30 min. Then 1-iodo-2-methoxyethane (739 mg, 3.97 mmol) was added, and the stirring was continued at 50°C for 16 hours. After the reaction was completed, the reaction was quenched with water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (PE / EA = 1 / 2) to obtain compound Int-6a (600 mg, 1.58 mmol) as a light yellow solid. ESI-MS (m / z): 381.6 [M+H] + .

[0175] Second Step: Compound Int-6a (850 mg, 2.23 mmol) was dissolved in ethanol (10 mL), 1 N sodium hydroxide aqueous solution (6.7 mL) was added, and the mixture was stirred at room temperature for 2 hours. The pH value was adjusted to 6 with 6 N hydrochloric acid aqueous solution, and then diluted with water (60 mL). The precipitate was filtered, the filter cake was washed with water, and dried to obtain compound Int-6b (700 mg, 1.99 mmol) in the form of a yellow solid in a yield of 88.9%. ESI-MS (m / z): 353.3 [M+H] + Third Step: Compound Int-6b (700 mg, 1.99 mmol) was dissolved in toluene (10 mL), diphenyl phosphorazide (1.64 g, 5.96 mmol), benzyl alcohol (644 mg, 5.96 mmol), and N,N-diisopropyl ethylamine (1.03 g, 7.95 mmol) were added, and the mixture was heated to 120°C and stirred for 16 hours. The reaction solution was concentrated, and the residue was separated by column chromatography (PE / EA = 2 / 3) to obtain compound Int-6c (650 mg, 1.42 mmol) in the form of a yellow solid in a yield of 71.5%. ESI-MS (m / z): 458.4 [M+H] + .

[0176] Fourth Step: Compound Int-6c (650 mg, 1.42 mmol) was dissolved in dichloromethane (5 mL), hydrochloric acid / dioxane solution (4 mol / L, 1.42 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was dissolved in methanol (5 mL), formaldehyde aqueous solution (415 mg, 4.26 mmol, 35% purity) and sodium triacetoxyborohydride (903 mg, 4.26 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The pH value was adjusted to 8 with saturated sodium bicarbonate aqueous solution, diluted with water (30 mL), and the aqueous phase was extracted with a mixed solvent of dichloromethane and methanol (v / v = 10 / 1). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound Int-6d (500 mg, 1.35 mmol) in the form of a yellow solid in a yield of 94.7%. ESI-MS (m / z): 372.4 [M+H] + .

[0177] Fifth Step: Compound Int-6d (500 mg, 1.09 mmol) was dissolved in methanol (10 mL), 10% palladium-carbon (50 mg, 10% wt) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The palladium-carbon was filtered off with diatomite, the filter cake was washed with methanol, and the filtrate was concentrated to obtain compound Int-6 (250 mg, 1.05 mmol) in the form of a yellow solid in a yield of 96.4%. ESI-MS (m / z): 238.6 [M+H] +.

[0178] Example 1

[0179] 3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-6- methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-2(lH)-one

[0180]

[0181] Compound 1 was prepared from the following steps:

[0182]

[0183] First Step: 2,5-dichloro-N-[2-(isopropylsulfonyl)phenyl]pyrimidin-4-amine la (70 mg, 0.20 mmol) and Int-1 (36 mg, 0.18 mmol) were dissolved in 1,4-dioxane (5 mL), BrettPhos Pd G3 (16 mg, 18 umol), BrettPhos (20 mg, 37 umol) and cesium carbonate (121 mg, 0.37 mmol) were added. The reaction system was replaced by nitrogen and heated to 100 °C with stirring for 18 hours. After the reaction solution was cooled to room temperature, the reaction solution was filtered with diatomite, and the filtrate was concentrated. The residue was purified by reverse phase preparative HPLC to obtain white solid lb (19 mg, yield 20%). ESI-MS (m / z): 503.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.41 (br s, 2H), 8.26 (s, 1H), 7.84 (dd, J = 7.9, 1.6 Hz, 1H), 7.69 (s, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.43 - 7.34 (m, 1H), 3.83 (s, 3H), 3.47 - 3.40 (m, 1H), 3.29 (s, 2H), 2.77 (t, J = 5.9 Hz, 2H), 2.65 (t, J = 5.9 Hz, 2H), 2.35 (s, 3H), 1.15 (d, J = 6.8 Hz, 6H).

[0184] Second step: Compound 1b (160 mg, 0.31 mmol) was dissolved in isopropanol (2 mL), concentrated hydrochloric acid (0.2 mL) was added, and the reaction mixture was heated to 85 °C and stirred for 18 hours. LCMS was used to monitor the formation of the product, and the reaction solution was concentrated, and the pH value was adjusted to about 8 with saturated aqueous sodium bicarbonate solution, and diluted with water (50 mL). The mixture was extracted with ethyl acetate / methanol (20 / 1, 50 mL*2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase preparative HPLC to obtain white solid 1 (120 mg, yield 77%). ESI-MS (m / z): 489.0 [M+H] + ; 1 H NMR (500 MHz, Chloroform-d) δ 10.97 (br s, 1H), 9.50 (s, 1H), 8.49 (d, J = 8.3 Hz, 1H), 8.20 (s, 1H), 8.14-8.01 (m, 2H), 7.94 (d, J = 7.9 Hz, 1H), 7.69 (t, J = 7.9 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 3.28 (br s, 2H), 3.26-3.17 (m, 1H), 2.75 (br s, 4H), 2.49 (s, 3H), 1.31 (d, J = 6.8 Hz, 6H).

[0185] Example 2

[0186] 3-((5-chloro-4-((2-(methylsulfmyl< sulfinyl>)phenyl)amino)pyrimidin-2-yl)amino)-6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one

[0187]

[0188] Example 3

[0189] 3-((5-chloro-4-((2-(methylsulfmyl< sulfinyl>)phenyl)amino)pyrimidin-2-yl)amino)-6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one

[0190]

[0191] Compounds 2 and 3 were prepared from the following steps:

[0192]

[0193] Step 1 : Compound 2a (1.0 g, 7.18 mmol) and 2,4,5-trichloropyrimidine 2b (1.45 g, 7.90 mmol) were dissolved in isopropanol (10 mL), N,N-diisopropylethylamine (1.21 g, 9.34 mmol, 0.90 mL) was added, and the reaction was heated to 85 °C and stirred for 40 h. After the reaction was cooled to room temperature, it was diluted with isopropanol (50 mL), and the reaction mixture was filtered, and the filter cake was washed with isopropanol (10 mL) and dried under reduced pressure to give compound 2c (1.72 g, 83% yield) as a white solid. ESI-MS (m / z): 286.1 [M+H] + Step 2: Compound 2c (300 mg, 1.05 mmol) was dissolved in dichloromethane (5 mL), and m-chloroperoxybenzoic acid (223 mg, 85% content, 1.10 mmol) was added under ice bath, and the reaction was stirred at 0 °C for 1 h. The reaction was diluted with water (10 mL) and ethyl acetate (10 mL), and the resulting suspension was filtered, and the filter cake was dried under reduced pressure to give compound 2d (217 mg, 68% yield) as a white solid. ESI-MS (m / z): 302.1 [M+H] + .

[0194] Step 3: Compound 2d (51 mg, 0.17 mmol) and Int-1 (30 mg, 0.15 mmol) were dissolved in 1,4-dioxane (5 mL), and BrettPhos Pd G3 (14 mg, 15 umol), BrettPhos (16 mg, 31 umol), and cesium carbonate (101 mg, 0.31 mmol) were added. After the reaction system was replaced with nitrogen, it was heated to 100 °C and stirred for 18 h. After the reaction was cooled to room temperature, it was filtered with celite, and the filtrate was concentrated. The residue was purified by reverse phase preparative HPLC to give compound 2e (27 mg, 37% yield) as a white solid. ESI-MS (m / z): 459.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) d 9.53 (s, 1H), 8.17 (s, 1H), 7.87-7.78 (m, 2H), 7.67 (d, J = 7.9 Hz, 1H), 7.63-7.58 (m, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.51 (s, 1H), 3.83 (s, 3H), 3.08-2.99 (m, 2H), 2.77-2.65 (m, 5H), 2.62-2.55 (m, 2H), 2.35 (s, 3H).

[0195] Step 4: Compound 2e (52 mg, 0.11 mmol) was dissolved in isopropanol (5 mL), concentrated hydrochloric acid (0.2 mL) was added, and the reaction mixture was heated to 85 °C with stirring for 18 h. The reaction was concentrated, and the residue was slurried with ethyl acetate to give a gray solid, which was further purified by reverse-phase preparative HPLC to give compound 2 (10 mg, 22% yield) and compound 3 (4 mg, 8% yield).

[0196] Compound 2: ESI-MS (m / z): 429.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) d 11.70 (s, 1H), 8.92 (s, 1H), 8.13 (s, 1H), 7.75 (s, 1H), 7.44 (dd, J = 8.0, 1.5 Hz, 1H), 7.40-7.36 (m, 2H), 7.32-7.27 (m, 2H), 2.79 (br s, 2H), 2.49-2.45 (m, 4H), 2.38 (s, 3H), 2.32 (s, 3H).

[0197] Compound 3: ESI-MS (m / z): 445.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) d 11.75 (s, 1H), 9.43 (s, 1H), 8.20 (s, 1H), 7.90 (dd, J = 7.5, 2.0 Hz, 1H), 7.83 (s, 1H), 7.70-7.65 (m, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.22 (br s, 1H), 2.84-2.71 (m, 2H), 2.68 (s, 3H), 2.48-2.45 (m, 4H), 2.32 (s, 3H).

[0198] Example 4

[0199] 3-((5-Chloro-4-((2-(methylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-6- methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-2(lH)-one

[0200]

[0201] Compound 4 was prepared in the following steps:

[0202]

[0203] First step: Dissolve compound 2c (182 mg, 0.63 mmol) in a mixture of acetic acid (1.19 g, 1.13 mL) and water (0.1 mL), add sodium tungstate dihydrate (10 mg, 0.031 mmol), stir the reaction mixture at room temperature for 30 minutes, then add hydrogen peroxide (1.44 g, 30% content, 12.73 mmol, 1.31 mL). Stir the reaction mixture at room temperature overnight. Dilute the reaction mixture with water (30 mL), filter the resulting suspension, and dry the filter cake under reduced pressure to obtain a mixture of compounds 4a and 2d (200 mg, ratio 8 / 2), which is used directly in the next step.

[0204] Second step: Dissolve the mixture of 4a and 2d (39 mg) obtained in the previous step and Int-1 (20 mg, 0.10 mmol) in 1,4-dioxane (3 mL), add BrettPhos Pd G3 (9 mg, 10 umol), BrettPhos (11 mg, 20 umol) and cesium carbonate (67 mg, 0.20 mmol). Replace the reaction system with nitrogen, then heat to 100°C and stir for 18 hours. Cool the reaction mixture to room temperature, filter the reaction mixture with celite, and concentrate the filtrate. Purify the residue by reverse phase preparative HPLC to obtain 4b as a white solid (10 mg). ESI-MS (m / z): 475.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.39-8.28 (m, 2H), 8.25 (s, 1H), 7.92 (dd, J = 8.0, 1.5 Hz, 1H), 7.71-7.62 (m, 2H), 7.40 (t, J = 7.6 Hz, 1H), 3.84 (s, 3H), 3.28 (s, 2H), 3.25 (s, 3H), 2.76 (t, J = 6.0 Hz, 2H), 2.65 (t, J = 5.9 Hz, 2H), 2.35 (s, 3H).

[0205] Third step: Dissolve compound 4b (35 mg, 0.073 mmol) in 1,4-dioxane (5 mL), add concentrated hydrochloric acid (0.2 mL), and heat the reaction mixture to 85°C and stir overnight. Concentrate the reaction mixture, slurry the residue with ethyl acetate to obtain a gray solid, and further purify the solid by reverse phase preparative HPLC to obtain 4 as a white solid (15 mg, yield 45%). ESI-MS (m / z): 445.2 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.81 (s, 1H), 9.28 (s, 1H), 8.30 (s, 1H), 8.28-8.18 (s, 1H), 8.02-7.96 (m, 2H), 7.83 (t, J = 8.5 Hz, 1H), 7.62 (s, 1H), 7.53-7.45 (m, 1H), 3.26 (s, 3H), 3.00 (s, 2H), 2.54-2.52 (m, 4H), 2.32 (s, 3H).

[0206] Example 5

[0207] 3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-6- methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-2(lH)-one

[0208]

[0209] Compound 5 was prepared in the following steps:

[0210]

[0211] First Step: (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethyl phosphine oxide 5a (50 mg, 0.15 mmol) and Int-1 (33 mg, 0.17 mmol) were dissolved in 1,4-dioxane (3 mL), BrettPhos Pd G3 (14 mg, 15 umol), BrettPhos (8 mg, 15 umol) and cesium carbonate (103 mg, 0.31 mmol) were added. The reaction system was replaced by nitrogen and heated to 100 °C and stirred overnight. After the reaction solution was cooled to room temperature, the reaction solution was filtered with diatomite, and the filtrate was concentrated to obtain the crude product of compound 5b (74 mg), which was directly used in the next step reaction. ESI-MS (m / z): 473.0 [M+H] + .

[0212] Second Step: The crude product of compound 5b (50 mg) obtained in the previous step was dissolved in hydrochloric acid dioxane solution (1 N, 5 mL), and the reaction solution was heated to 100 °C and stirred for 3 hours. The reaction solution was concentrated, and the residue was purified by reverse phase preparative HPLC to obtain compound 5 (12 mg). ESI-MS (m / z): 459.1 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.83 (s, 1H), 11.01 (s, 1H), 8.33 (s, 1H), 8.25 (s, 1H), 7.97 (s, 1H), 7.80 (s, 1H), 7.68-7.64 (m, 1H), 7.63-7.59 (m, 1H), 7.25 (t, J = 7.1 Hz, 1H), 3.09 (s, 2H), 2.54 (dd, J = 6.0, 3.2 Hz, 4H), 2.32 (s, 3H), 1.78 (s, 3H), 1.76 (s, 3H).

[0213] Example 6

[0214] 6-methyl-3-((4-((2-(methylthio)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)- 5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one

[0215]

[0216] Compound 6 was prepared in the following steps:

[0217]

[0218] First Step: 2-(methylthio)aniline 2a (100 mg, 0.71 mmol) and 2,4-dichloro-5- (trifluoromethyl)pyrimidine 6a (155 mg, 0.71 mmol) were dissolved in isopropanol (5 mL), N,N-diisopropylethylamine (120 mg, 0.93 mmol, 0.16 mL) was added, the reaction was heated to 85 °C and stirred for 3 hours. The reaction was concentrated, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 6b (125 mg, yield 54%) as a yellow solid. ESI-MS (m / z): 320.6 [M+H] + .

[0219] Second Step: Compound 6b (50 mg, 0.15 mmol) and Int-1 (33 mg, 0.17 mmol) were dissolved in 1,4-dioxane (5 mL), BrettPhos Pd G3 (14 mg, 15 umol), BrettPhos (8 mg, 15 umol) and cesium carbonate (101 mg, 0.31 mmol) were added. The reaction system was replaced with nitrogen and heated to 100 °C and stirred overnight. After the reaction was cooled to room temperature, the reaction was filtered with diatomite, the filtrate was concentrated, the residue was purified by preparative thin layer chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the crude compound 6c (74 mg), which was directly used in the next step. ESI-MS (m / z): 477.0 [M+H] +.

[0220] Step 3: The crude compound 6c (50 mg) from previous step was dissolved in hydrochloric acid in dioxane (1 N, 5 mL), and the reaction was heated to 100 °C with stirring for 3 h. The reaction was concentrated, and the residue was purified by reverse phase preparative HPLC to give compound 6 (2 mg, 2% yield over two steps). ESI-MS (m / z): 463.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.34 (s, 2H), 7.40 (d, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 7.25 (t, J = 7.4 Hz, 1H), 3.34 (s, 2H), 2.80 (s, 2H), 2.38 (s, 3H), 2.32 (s, 3H).

[0221] Example 7

[0222] 3-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6- methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-2(lH)-one

[0223]

[0224] Compound 7 was prepared by replacing 2-(methylthio)aniline with 2- (dimethylphosphoryl)aniline in the first step of Example 6, using similar methods and reaction procedures. ESI-MS (m / z): 493.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.93 - 7.78 (m, 3H), 7.73 (t, J = 7.2 Hz, 1H), 7.54 - 7.50 (m, 1H), 2.98 (br s, 2H), 2.70 - 2.64 (m, 4H), 2.45 (s, 3H), 1.79 (s, 3H), 1.77 (s, 3H).

[0225] Example 8

[0226] 3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-l,6- dimethyl-5,6,7,8-tetrahydro-l,6-naphthyridin-2(lH)-one

[0227]

[0228] Compound 8 was prepared in the following steps:

[0229]

[0230] First Step: Compound 5a (52 mg, 0.16 mmol) and Int-4 (32 mg, 0.16 mmol) were dissolved in 1,4-dioxane (5 mL), and BrettPhos G3 Pd (15 mg, 0.016 mmol), BrettPhos (17 mg, 0.033 mmol) and cesium carbonate (107 mg, 0.33 mmol) were added successively. After the reaction mixture was replaced with nitrogen, it was stirred at 100 °C overnight. LCMS detected that the reaction of compound 5a was complete. The reaction was cooled to room temperature, filtered over celite, and the filtrate was concentrated. The residue was purified by reverse phase preparative HPLC to give compound 8 (30 mg, 38% yield). ESI-MS (m / z): 473.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ

[0231] 11.00 (s, 1H), 8.30 (br s, 1H), 8.25 (s, 1H), 8.25 (s, 1H), 8.06 (s, 1H), 7.81 (s, 1H), 7.69-7.59 (m, 2H), 7.26 (t, J = 7.4 Hz, 1H), 3.48 (s, 3H), 3.12 (s, 2H), 2.72 (t, J = 5.8 Hz, 2H), 2.60 (t, J = 5.8 Hz, 2H), 2.32 (s, 3H), 1.78 (s, 3H), 1.75 (s, 3H).

[0232] Example 9

[0233] 2-((5-Chloro-2-((6-methyl-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridin-3- yl)amino)pyrimidin-4-yl)amino)benzoic acid

[0234]

[0235] Compound 9 was prepared in the following steps:

[0236]

[0237] First Step: Compound 9a (328 mg, 2.00 mmol) and compound 2b (403 mg, 2.20 mmol) were dissolved in isopropanol (5 mL), N, N-diisopropylethylamine (335 mg, 2.60 mmol, 0.45 mL) was added, and the reaction was heated to 85 °C and stirred for 18 hours. LCMS detection showed that the reaction of compound 9a was complete. After the reaction was cooled to room temperature, isopropanol (10 mL) was added for dilution, and filtration was performed. The filter cake was washed with isopropanol (10 mL), and dried under reduced pressure to obtain white solid compound 9b (485 mg, yield 78%). ESI-MS (m / z): 311.2 [M+H] + .

[0238] Second Step: Compound 9b (50 mg, 0.16 mmol) and Int-1 (34 mg, 0.17 mmol) were dissolved in 1,4-dioxane (5 mL), and BrettPhos G3 Pd (14 mg, 0.016 mmol), BrettPhos (8 mg, 0.016 mmol), and cesium carbonate (104 mg, 0.32 mmol) were added in sequence. After the reaction mixture was replaced with nitrogen, it was stirred at 100 °C overnight. LCMS detection showed that the reaction of compound 9b was complete. After the reaction was cooled to room temperature, celite filtration was performed, and the filtrate was concentrated. The residue was purified by preparative thin layer chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain crude compound 9c (75 mg), which was directly used in the next step reaction. ESI-MS (m / z): 468.8 [M+H] + .

[0239] Third Step: The crude compound 9c (75 mg) obtained in the previous step was dissolved in hydrochloric acid dioxane solution (4N, 5 mL), and the reaction was heated to 100 °C and stirred for 3 hours. The reaction was concentrated, and the residue was purified by preparative HPLC to obtain compound 9 (two-step reaction yield 5%). ESI-MS (m / z): 427.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 13.03 (br s, 1H), 11.90 (s, 1H), 8.61 (d, J = 8.4 Hz, 1H), 8.22 (s, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.97 (s, 1H), 7.95 (s, 1H), 7.50 (t, J = 7.2 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 3.41 (s, 3H), 2.80 (br s, 2H), 2.62 (t, J = 5.9 Hz, 2H), 2.47 (s, 3H).

[0240] Example 10

[0241] 3-((4-((2-(isopropylsulfonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one

[0242]

[0243] Compound 10 was prepared by the following steps:

[0244]

[0245] Step 1: Compound 10a (100 mg, 0.59 mmol) and compound 6a (129 mg, 0.59 mmol) were dissolved in isopropanol (5 mL), N, N-diisopropylethylamine (100 mg, 0.77 mmol) was added, the reaction was heated to 85 °C and stirred for 3 hours. LCMS showed that the reaction of compound 10a was completed. After the reaction was cooled to room temperature, the reaction was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1) to obtain white solid 10b (90 mg, yield 43%). ESI-MS (m / z): 348.2 [M+H] + .

[0246] Step 2: Compound 10b (70 mg, 0.20 mmol) was dissolved in dichloromethane (5 mL), m-chloroperoxybenzoic acid (69 mg, 0.40 mmol, content 80%) was added under ice bath, and the reaction was stirred at 0 °C for 1 hour. LCMS showed that the reaction of compound 10b was completed. The reaction was diluted with dichloromethane (10 mL), washed with saturated aqueous sodium bicarbonate solution (10 mL), and the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 10c (60 mg, yield 78%). ESI-MS (m / z): 380.4 [M+H] + .

[0247] Step 3: Compound 10c (60 mg, 0.15 mmol) and Int-1 (33 mg, 0.17 mmol) were dissolved in 1,4-dioxane (5 mL), and BrettPhos G3 Pd (14 mg, 0.015 mmol), BrettPhos (8 mg, 0.015 mmol) and cesium carbonate (102 mg 0.31 mmol) were added successively. After the reaction mixture was replaced with nitrogen, it was stirred at 100 °C overnight. LCMS showed that the reaction of compound 10c was complete. The reaction was cooled to room temperature, filtered over celite, and the filtrate was concentrated. The residue was purified by preparative thin layer chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 10d (84 mg, crude), which was used directly in the next step. ESI-MS (m / z): 537.1 [M+H] + .

[0248] Step 4: The crude compound 10d (84 mg) obtained in the previous step was dissolved in hydrochloric acid in dioxane (4 N, 5 mL), and the reaction was heated to 100 °C and stirred for 3 hours. The reaction was concentrated, and the residue was purified by reverse phase preparative HPLC to give compound 10 (6 mg, 7% yield over two steps). ESI-MS (m / z): 523.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) d 12.07 (s, 1H), 9.46 (s, 1H), 8.48 (s, 1H), 8.46 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.82 - 7.75 (m, 2H), 7.48 (t, J = 7.3 Hz, 1H), 3.45 (q, J = 6.8 Hz, 1H), 2.95 (br s, 2H), 2.55 (br s, 4H), 2.33 (s, 3H), 1.14 (s, 3H), 1.13 (s, 3H).

[0249] Example 11

[0250] 3-((5-Chloro-4-((2-(isopropylthio)phenyl)amino)pyrimidin-2-yl)amino)-6- methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-2(lH)-one

[0251]

[0252] Compound 11 was prepared in the following steps:

[0253]

[0254] Step 1 : Compound 10a (100 mg, 0.59 mmol) and compound la (109 mg, 0.59 mmol) were dissolved in isopropanol (5 mL), N, N-diisopropylpropylamine (100 mg, 0.77 mmol) was added, and the reaction was heated to 85 °C and stirred for 12 h. LCMS showed compound 10a was consumed completely. The reaction was cooled to room temperature, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1) to give white solid 11a (139 mg, yield 73%). ESI-MS (m / z): 314.3 [M+H] + .

[0255] Step 2: Compound 11a (129 mg, 0.41 mmol) was dissolved in dichloromethane (3 mL), m-chloroperoxybenzoic acid (70 mg, 85% content, 0.41 mmol) was added, and the reaction was stirred at 0 °C for 1 h. LCMS showed compound 11a was consumed completely. The reaction was diluted with dichloromethane (10 mL) and washed with saturated aqueous sodium bicarbonate solution (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give white solid 11b (120 mg, yield 88%). ESI-MS (m / z): 330.1 [M+H] + .

[0256] Step 3: Compound 11b (120 mg, 0.36 mmol) and intermediate Int-2 (75 mg, 0.36 mmol) were dissolved in dioxane (6 mL), BrettPhos G3 Pd (32 mg, 0.036 mmol), BrettPhos (19 mg, 0.036 mmol) and cesium carbonate (236 mg, 0.72 mmol) were added successively. The reaction mixture was stirred at 100 °C overnight after being replaced with nitrogen. LCMS showed compound 11b was consumed completely. The reaction was cooled to room temperature, filtered over celite, and the filtrate was concentrated, and the residue was purified by preparative thin layer chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the crude compound 11c. Part of the crude compound 11c was purified by reverse phase preparative HPLC to give compound 11c (8 mg). ESI-MS (m / z): 500.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6)

[0257] 9.70 (s, 1H), 8.18 (s, 1H), 7.81 (s, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.60-7.54 (m, 2H), 7.48 (t, J = 7.6 Hz, 1H), 4.28 (q, J = 7.0 Hz, 2H), 3.11-2.98 (m, 3H), 2.68 (t, J = 5.2 Hz, 2H), 2.63-2.58 (m, 2H), 2.35 (s, 3H), 1.28 (t, J = 7.0 Hz, 3H), 1.10 (d, J = 7.0 Hz, 3H), 0.98 (d, J = 6.7 Hz, 3H).

[0258] Fourth Step: The crude compound 11c (60 mg) from the previous step was dissolved in hydrochloric acid in dioxane (4 N, 5 mL) and the reaction was heated to 100 °C for 6 hours. The reaction was concentrated and the residue was purified by reverse phase preparative HPLC to give compound 11 (7 mg). ESI-MS (m / z): 457.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.75 (s, 1H), 8.93 (s, 1H), 8.19 (s, 1H), 7.86 (s, 1H), 7.77 (br s, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.48 (br s, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.29 (t, J = 7.4 Hz, 1H), 3.40-3.34 (m, 1H), 2.90 (s, 2H), 2.32 (s, 3H), 1.18 (s, 3H), 1.16 (s, 3H).

[0259] Example 12

[0260] 3-((5-Chloro-4-((2-(ethylthio)phenyl)amino)pyrimidin-2-yl)amino)-6-methyl-5,6,7,8- tetrahydro-l,6-naphthyridin-2(lH)-one

[0261]

[0262] Compound 12 was prepared in the following steps:

[0263]

[0264] First Step: Compound 12a (593 mg, 3.23 mmol) and compound la (495 mg, 3.23 mmol) were dissolved in isopropanol (25 mL), N, N-diisopropylethylamine (543 mg, 4.20 mmol) was added, heated to 90 °C and stirred for 24 hours. LCMS showed compound 12a was completely consumed. The reaction was cooled to room temperature, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give white solid 12b (571 mg, yield 58%). ESI-MS (m / z): 300.3 [M+H] + .

[0265] Second Step: Compound 12b (561 mg, 1.87 mmol) was dissolved in dichloromethane (7 mL), m-chloroperoxybenzoic acid (483 mg, 85% content, 2.80 mmol) in dichloromethane (7 mL) was added dropwise under ice bath, the reaction was stirred at 0 °C for 1 hour. LCMS showed compound 12b was completely consumed. The reaction was diluted with dichloromethane (10 mL) and washed with saturated aqueous sodium bicarbonate solution (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give white solid 12c (267 mg, yield 45%) and white solid 12d (312 mg, yield 50%).

[0266] Compound 12c: ESI-MS (m / z): 318.1 [M+H] + .

[0267] Compound 12d: ESI-MS (m / z): 334.0 [M+H] + .

[0268] Third Step: Compound 12c (100 mg, 0.31 mmol) and intermediate Int-2 (65 mg, 0.31 mmol) were dissolved in 1,4-dioxane (5 mL), BrettPhos G3 Pd (28 mg, 0.031 mmol), BrettPhos (16 mg, 0.031 mmol) and cesium carbonate (206 mg, 0.63 mmol) were added successively. The reaction mixture was stirred at 100 °C overnight after being replaced with nitrogen. LCMS showed compound 12c was completely consumed. The reaction was cooled to room temperature, filtered over celite and the filtrate was concentrated. The residue was purified by preparative thin layer chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the crude compound 12e. Part of the crude compound 12e was further purified by reverse phase preparative HPLC to give compound 12e (11 mg). ESI-MS (m / z): 487.1 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.17 (s, 1H), 7.76-7.72 (m, 2H), 7.68 (d, J = 7.6 Hz, 1H), 7.62-7.59 (m, 1H), 7.55-7.48 (m, 2H), 4.28 (q, J = 7.0 Hz, 2H), 3.10-2.94 (m, 3H), 2.78-2.73 (m, 1H), 2.67 (t, J = 5.2 Hz, 2H), 2.60-2.55 (m, 2H), 2.34 (s, 3H), 1.29 (t, J = 7.0 Hz, 3H), 0.98 (t, J = 7.3 Hz, 3H).

[0269] Fourth Step: The crude compound 12e (50 mg) from the previous step was dissolved in hydrochloric acid in dioxane (2 N, 5 mL) and the reaction was heated to 100 °C for 6 hours. The reaction was concentrated and the residue was purified by reverse phase preparative HPLC to give compound 12 (4 mg). ESI-MS (m / z): 443.1 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.72 (s, 1H), 8.93 (s, 1H), 8.15 (s, 1H), 7.78 (s, 1H), 7.58-7.49 (m, 2H), 7.42-7.29 (m, 3H), 2.89 (q, J = 7.3 Hz, 2H), 2.83 (br s, 2H), 2.50-2.45 (m, 2H), 2.32 (s, 3H), 1.14 (t, J = 7.3 Hz, 3H).

[0270] Example 13

[0271] 3-((5-Chloro-4-((2-(ethylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-6-methyl-5,6,7,8- tetrahydro-l,6-naphthyridin-2(lH)-one

[0272]

[0273] Compound 13 was prepared in the following steps:

[0274]

[0275] First Step: Compound 12d (50 mg, 0.15 mmol) and Intermediate Int-2 (31 mg, 0.15 mmol) were dissolved in 1,4-dioxane (5 mL), followed by the addition of BrettPhos G3 Pd (13 mg, 0.015 mmol), BrettPhos (8 mg, 0.015 mmol) and cesium carbonate (98 mg, 0.030 mmol). The reaction mixture was stirred at 100 °C overnight after being purged with nitrogen. LCMS showed the reaction of compound 12d was completed. The reaction mixture was cooled to room temperature, filtered over celite and the filtrate was concentrated. The residue was purified by preparative thin layer chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the crude compound 13a (75 mg), which was used directly in the next step.

[0276] Second Step: The crude compound 13a (75 mg) from the previous step was dissolved in hydrochloric acid in dioxane (2 N, 5 mL) and the reaction mixture was stirred at 100 °C for 6 h. The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC to give compound 13 (4 mg, 5% over two steps). ESI-MS (m / z): 475.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) d 11.82 (s, 1H), 9.29 (s, 1H), 8.31 (s, 1H), 8.27 (br s, 1H), 8.02 (s, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.85 (t, J = 7.9 Hz, 1H), 7.62 (br s, 1H), 7.49 (t, J = 7.8 Hz, 1H), 3.34 (d, J = 7.3 Hz, 2H), 2.99 (s, 2H), 2.55-2.50 (m, 4H), 2.32 (s, 3H), 1.06 (t, J = 7.3 Hz, 3H).

[0277] Example 14

[0278] 3-((5-Chloro-4-((2-(hydroxymethyl)phenyl)amino)pyrimidin-2-yl)amino)-6- methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-2(lH)-one

[0279]

[0280] Compound 14 was obtained using o-aminobenzyl alcohol instead of o-amino-N,N-dimethylbenzamide in the first step of Example 9, using similar methods and reaction procedures. ESI-MS (m / z): 413.3 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.74 (br s, 1H), 9.08 (br s, 1H), 8.17 (s, 1H), 7.82 (s, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.53 - 7.46 (m, 2H), 7.37 (td, J = 7.5, 1.5 Hz, 1H), 7.29 - 7.24 (m, 1H), 4.52 (s, 2H), 2.90 (s, 2H), 2.53 - 2.51 (m, 4H), 2.31 (s, 3H).

[0281] Example 15

[0282] 3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-1- (cyclopropylmethyl)-6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one

[0283]

[0284] Compound 15 was obtained by using Int-5 instead of Int-4 in the first step of Example 8, in a similar manner and procedure. ESI-MS (m / z): 513.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.32 (br s, 1H), 8.26 (s, 1H), 8.07 (s, 1H), 7.81 (s, 1H), 7.70 - 7.59 (m, 2H), 7.26 (t, J = 7.5 Hz, 1H), 3.96 (d, J = 6.9 Hz, 2H), 3.14 (s, 2H), 2.81 (t, J = 5.8 Hz, 2H), 2.61 (t, J = 5.7 Hz, 2H), 2.33 (s, 3H), 1.78 (s, 3H), 1.75 (s, 3H), 1.20 - 1.11 (m, 1H), 0.47 - 0.38 (m, 4H).

[0285] Example 16

[0286] 3-((5-chloro-4-((2-(methylsulfinyl< sulfinato>)phenyl)amino)pyrimidin-2-yl)amino)-1,6- dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one

[0287]

[0288] Compound 16 can be obtained by replacing 5a in the first step of Example 8 with 2d, using similar methods and reaction procedures. ESI-MS (m / z): 459.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 9.44 (s, 1H), 8.19 (s, 1H), 7.93 (s, 1H), 7.91 (dd, J = 7.6, 1.7 Hz, 1H), 7.70-7.62 (m, 2H), 7.57 (d, J = 7.8 Hz, 1H), 7.22 (br s, 1H), 3.42 (s, 3H), 2.85-2.72 (m, 2H), 2.68 (s, 3H), 2.67-2.63 (m, 2H), 2.55-2.53 (m, 2H), 2.33 (s, 3H).

[0289] Example 17

[0290] 3-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-1,6- dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one

[0291]

[0292] Compound 17 can be obtained by replacing 5a in the first step of Example 8 with 2c, using similar methods and reaction procedures. ESI-MS (m / z): 443.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.13 (s, 1H), 7.86 (s, 1H), 7.45 (dd, J = 7.9, 1.4 Hz, 1H), 7.41-7.36 (m, 2H), 7.35-7.26 (m, 2H), 3.42 (s, 3H), 2.81 (br s, 2H), 2.66 (t, J = 5.7 Hz, 2H), 2.55-2.54 (m, 2H), 2.38 (s, 3H), 2.33 (s, 3H).

[0293] Example 18

[0294] 3-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-1,6- dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one

[0295]

[0296] Example 19

[0297] 3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-1,6- dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one

[0298]

[0299] Compounds 18 and 19 were prepared in the following steps:

[0300]

[0301] Step 1: Compound Int-4 (20 mg, 0.10 mmol) and compound la (35 mg, 0.10 mmol) were dissolved in 1,4-dioxane (5 mL), cesium carbonate (67 mg, 0.20 mmol), BrettPhos (11 mg, 0.020 mmol) and BrettPhos Pd G3 (9 mg, 0.010 mmol) were added. The reaction mixture was heated to 100 °C with stirring for 18 h after purging with nitrogen. The reaction was cooled to room temperature, filtered with celite and the filtrate was concentrated. The residue was purified by preparative thin layer chromatography (dichloromethane / methanol = 10 / 1) to give the crude product, which was further separated by reverse phase preparative HPLC to give compound 18 (5 mg, 11% yield) and compound 19 (12 mg, 23% yield). Compound 18: ESI-MS (m / z): 468.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.12 (d, J = 5.7 Hz, 1H), 7.95-7.90 (m, 2H), 7.89-7.79 (m, 2H), 7.62 (br s, 1H), 7.51 (t, J = 7.7 Hz, 1H), 6.47 (d, J = 5.8 Hz, 1H), 3.45 (s, 3H), 3.35-3.33 (m, 1H), 2.89 (br s, 2H), 2.68 (t, J = 6.9 Hz, 2H), 2.58-2.54 (m, 2H), 2.31 (s, 3H), 1.09 (d, J = 6.9 Hz, 6H).

[0302] Compound 19: ESI-MS (m / z): 503.0 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.33 (s, 1H), 8.30 (br s, 1H), 8.13 (s, 1H), 7.91 (dd, J = 8.0, 1.6 Hz, 1H), 7.88 - 7.82 (m, 1H), 7.68 (br s, 1H), 7.49 (t, J = 7.7 Hz, 1H), 3.47 (s, 3H), 3.46 - 3.40 (m, 1H), 3.04 (br s, 2H), 2.71 (t, J = 6.1 Hz, 2H), 2.59 (t, J = 5.8 Hz, 2H), 2.33 (s, 3H), 1.14 (d, J = 6.8 Hz, 6H).

[0303] Example 20

[0304] 3-((4-((2-(Ethylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-1,6-dimethyl-5,6,7,8- tetrahydro-1,6-naphthyridin-2(1 H)-one

[0305]

[0306] Example 21

[0307] 3-((5-Chloro-4-((2-(ethylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-1,6-dimethyl- 5,6,7,8-tetrahydro-1,6-naphthyridin-2(1 H)-one

[0308]

[0309] Using 11c instead of 1a in the first step of example 18 / 19, compounds 20 and 21 can be obtained in a similar manner and reaction sequence.

[0310] Compound 20: ESI-MS (m / z): 455.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.11 (d, J = 5.7 Hz, 1H), 7.96 (dd, J = 7.8, 1.2 Hz, 1H), 7.89 (s, 1H), 7.88 - 7.79 (m, 2H), 7.60 (br s, 1H), 7.55 - 7.48 (m, 1H), 6.44 (d, J = 5.8 Hz, 1H), 3.45 (s, 3H), 3.21 (q, J = 7.3 Hz, 2H), 2.90 (br s, 2H), 2.68 (t, J = 5.9 Hz, 2H), 2.56 (t, J = 5.8 Hz, 2H), 2.31 (s, 3H), 0.98 (t, J = 7.4 Hz, 3H).

[0311] Compound 21: ESI-MS (m / z): 489.1 [M+H] + .

[0312] Example 22

[0313] 1,6-Dimethyl-3-((4-((2-(methylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)- 5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one

[0314]

[0315] Example 23

[0316] 3-((5-Chloro-4-((2-(methylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-1,6- dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one

[0317]

[0318] Using 4b instead of 1a in the first step of Example 18 / 19, compounds 22 and 23 can be obtained in a similar manner and reaction procedure.

[0319] Compound 22: ESI-MS (m / z): 441.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) d 9.04 (s, 1H), 8.12 (d, J = 5.7 Hz, 1H), 7.99 (dd, J = 7.9, 1.4 Hz, 1H), 7.88 (s, 1H), 7.86 - 7.77 (m, 2H), 7.66 (br s, 1H), 7.51 (t, J = 7.6 Hz, 1H), 6.42 (d, J = 5.7 Hz, 1H), 3.45 (s, 3H), 3.16 (s, 3H), 2.97 (br s, 2H), 2.69 (t, J = 5.8 Hz, 2H), 2.57 (t, J = 5.8 Hz, 2H), 2.32 (s, 3H).

[0320] Compound 23: ESI-MS (m / z): 475.0 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.30 (s, 1H), 8.21 (br s, 1H), 8.08 (s, 1H), 7.99 (dd, J = 8.0, 1.5 Hz, 1H), 7.83 (t, J = 8.0 Hz, 1H), 7.61 (br s, 1H), 7.50 (t, J = 7.6 Hz, 1H), 3.46 (s, 3H), 3.25 (s, 3H), 3.01 (br s, 2H), 2.71 (t, J = 6.0 Hz, 2H), 2.58 (t, J = 5.8 Hz, 2H), 2.33 (s, 3H).

[0321] Example 24

[0322] 3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-1- (cyclopropylmethyl)-6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one

[0323]

[0324] Using Int-5 instead of Int-4 in the first step of Example 18 / 19, compound 24 can be obtained in a similar manner and procedure. ESI-MS (m / z): 543.0 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.34 (s, 1H), 8.31 (br s, 1H), 8.14 (s, 1H), 7.91 (dd, J = 7.9, 1.6 Hz, 1H), 7.88-7.83 (m, 1H), 7.69 (s, 1H), 7.50-7.46 (m, 1H), 3.95 (d, J = 6.8 Hz, 2H), 3.47-3.41 (m, 1H), 3.05 (br s, 2H), 2.80 (t, J = 5.8 Hz, 2H), 2.60 (t, J = 5.7 Hz, 2H), 2.32 (s, 3H), 1.17-1.13 (m, 7H), 0.48-0.37 (m, 4H).

[0325] Example 25

[0326] 3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-1- (cyclopropylmethyl)-6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one

[0327]

[0328] Compound 25 was obtained by using 2-(difluoromethoxy)aniline instead of o-amino-N,N-dimethylbenzamide 9a in the first step of Example 9, in a similar manner and procedure. ESI-MS (m / z): 448.9 [M+H] + ; 1 HNMR (500 MHz, DMSO-d6) δ 11.74 (s, 5H), 8.81 (s, 5H), 8.17 (s, 5H), 7.81 (s, 5H), 7.59 (d, J = 7.6 Hz, 5H), 7.44 - 7.31 (m, 4H), 7.07 (t, J = 73.1 Hz, 1H), 3.36 - 3.33 (m, 2H), 3.31 - 3.27 (m, 2H), 2.83 (br s, 2H), 2.31 (s, 3H).

[0329] Example 26

[0330] 3-((5-Chloro-4-((2-ethoxyphenyl)amino)pyrimidin-2-yl)amino)-6-methyl-5,6,7,8- tetrahydro-l,6-naphthyridin-2(lH)-one

[0331]

[0332] Compound 26 was obtained by using 2-ethoxyaniline instead of o-amino-N,N- dimethylbenzamide 9a in the first step of Example 9, in a similar manner and procedure. ESI-MS (m / z): 427.2 [M+H] + ; 1 HNMR (500 MHz, DMSO-d6) δ 11.76 (s, 1H), 8.45 (s, 1H), 8.16 (s, 1H), 7.85 (s, 1H), 7.71 (br s, 1H), 7.55 (br s, 1H), 7.22 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 7.2 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 4.05 (q, J = 6.9 Hz, 2H), 2.94 (br s, 2H), 2.55 - 2.45 (m, 4H), 2.31 (s, 3H), 1.23 (t, J = 6.9 Hz, 4H).

[0333] Example 27

[0334] 3-((5-Chloro-4-((2-ethoxyphenyl)amino)pyrimidin-2-yl)amino)-6-methyl-5,6,7,8- tetrahydro-l,6-naphthyridin-2(lH)-one

[0335]

[0336] Compound 27 was obtained by using 2-ethylaniline (R)-a-methylbenzylamine instead of o-amino-N,N-dimethylbenzamide 9a in the first step of Example 9, in a similar manner and by using similar reaction procedures. ESI-MS (m / z): 411.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.94 (s, 1H), 8.10 (s, 1H), 7.72 (s, 1H), 7.40 (d, J = 7.0 Hz, 1H), 7.35-7.31 (m, 2H), 7.24 (d, J = 7.1 Hz, 1H), 7.19 (br s, 1H), 2.72 (br s, 2H), 2.56-2.52 (m, 2H), 2.46-2.42 (m, 4H), 2.31 (s, 3H), 1.08 (t, J = 7.6 Hz, 3H).

[0337] Example 28

[0338] 3-((5-chloro-4-((2-(cyclopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-6- methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-2(lH)-one

[0339]

[0340] Compound 28 was prepared by the following steps:

[0341]

[0342] First Step: Compound 28a (200 mg, 1.27 mmol) and sodium cyclopropylsulfinate (162 mg, 1.27 mmol) were dissolved in N-methylpyrrolidine (5 mL), and cuprous chloride (12 mg, 0.12 mmol) and quinoline (16 mg, 0.12 mmol) were added successively. The reaction was heated to 140 °C by microwave and stirred for 20 minutes. LCMS detected that the reaction of compound 28a was completed. The reaction was cooled to room temperature, filtered by diatomite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 28b (265 mg, yield 91%). ESI-MS (m / z): 228.3 [M+H] + .

[0343] Second Step: Compound 28b (245 mg, 1.08 mmol) was dissolved in a mixture of methanol (5 mL) and ammonia water (0.5 mL), and 10% palladium-carbon (65 mg) was added. The reaction was stirred at room temperature under hydrogen atmosphere for 4 hours. LCMS detection showed that the reaction of compound 28b was complete. The reaction was filtered through diatomite, and the filtrate was concentrated to obtain compound 28c (210 mg, yield 98%). ESI-MS (m / z): 198.5 [M+H] + .

[0344] Third Step: Compound 28c (200 mg, 1.01 mmol) was dissolved in DMF (10 mL), and sodium hydride (30 mg, 60% content, 0.75 mmol) was added. The reaction was stirred at 0°C for 30 minutes. Compound 2b (185 mg, 1.01 mmol) was dissolved in DMF (5 mL), and the solution was added dropwise to the reaction. The reaction was stirred at 0°C for 2 hours. LCMS detection showed that the reaction of compound 28c was complete. Saturated sodium bicarbonate aqueous solution (10 mL) was added to the reaction mixture, and the aqueous phase was extracted with dichloromethane (10 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 3) to obtain white solid 28d (75 mg, yield 21%). ESI-MS (m / z): 343.9 [M+H] + .

[0345] Fourth Step: Compound 28d (37 mg, 0.10 mmol) and intermediate Int-1 (20 mg, 0.10 mmol) were dissolved in 1,4-dioxane (5 mL), and BrettPhos G3 Pd (9 mg, 0.010 mmol), BrettPhos (5 mg, 0.010 mmol), and cesium carbonate (70 mg, 0.21 mmol) were added in sequence. The reaction mixture was replaced with nitrogen and then heated to 100°C and stirred overnight. LCMS detection showed that the reaction of compound 28d was complete. The reaction was cooled to room temperature, filtered through diatomite, and the filtrate was concentrated. The residue was purified by preparative thin layer chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain crude compound 28e (25 mg), which was directly used in the next reaction. ESI-MS (m / z): 501.2 [M+H] + .

[0346] Fifth Step: The crude compound 28e (25 mg) obtained in the previous step was dissolved in a hydrochloric acid dioxane solution (4N, 3 mL), and the reaction was heated to 100°C and stirred for 30 minutes. The reaction was concentrated, and the residue was purified by reverse phase preparative HPLC to obtain compound 28 (4 mg, yield 7% for two steps). ESI-MS (m / z): 487.2 [M+H] +; 1 H NMR (500 MHz, CDC13) δ 11.20 (br s, 1H), 9.35 (s, 1H), 8.46 (d, J = 7.4 Hz, 1H), 8.20 (s, 1H), 8.10-8.07 (m, 2H), 7.93 (d, J = 7.9 Hz, 1H), 7.67 (t, J = 7.9 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 3.27 (br s, 2H), 2.76-2.70 (m, 4H), 2.57-2.53 (m, 1H), 2.46 (s, 3H), 1.37-1.33 (m, 2H), 1.03-0.99 (m, 2H).

[0347] Example 29

[0348] 3-((5-chloro-4-((2-(ethylsulfinyl< sulfinyl>)phenyl)amino)pyrimidin-2-yl)amino)-1,6-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one

[0349]

[0350] Compound 29 can be obtained by replacing 5a with 28d in the first step of Example 8, using similar methods and reaction procedures. ESI-MS (m / z): 501.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.50-8.38 (m, 1H), 8.24 (s, 1H), 8.19 (s, 1H), 7.95-7.87 (m, 2H), 7.75 (t, J = 8.0 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H), 3.55 (s, 3H), 3.25-3.18 (m, 2H), 2.83-2.71 (m, 5H), 2.45 (s, 3H), 1.26-1.20 (m, 2H), 1.10-0.97 (m, 2H).

[0351] Example 30

[0352] 3-((5-chloro-4-((2-(ethylsulfinyl< sulfinyl>)phenyl)amino)pyrimidin-2-yl)amino)-1,6-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one

[0353]

[0354] Compound 30 was obtained by using 11b instead of 5a in the first step of Example 8, using similar methods and reaction procedures. ESI-MS (m / z): 473.1 [M+H] + ; 1 H NMR (500 MHz, CDC13) δ 9.45 (s, 1H), 8.19 (s, 1H), 7.95 (s, 1H), 7.84-7.76 (m, 1H), 7.72-7.65 (m, 1H), 7.65-7.54 (m, 2H), 7.24 (br s, 1H), 3.42 (s, 3H), 3.02-2.93 (m, 1H), 2.86-2.79 (m, 1H), 2.74-2.63 (m, 4H), 2.57-2.51 (m, 2H), 2.32 (s, 3H), 0.96 (t, J = 7.5 Hz, 3H).

[0355] Compounds 31-60 were obtained according to the synthetic routes and methods of synthesis of intermediates described above in the Examples. Analytical data for Examples 31-42 are shown in the table below.

[0356]

[0357]

[0358]

[0359]

[0360] Control Example 1 and Control Example 2

[0361] Control Example 1

[0362]

[0363] and Control Example 2

[0364]

[0365] Compounds I-5 and I-2 in WO2018102366 were obtained according to the methods and intermediates described in Method A in this patent, as Control Example 1 and Control Example 2, respectively.

[0366] Biological screening of HPK1 inhibitors and results

[0367] Test Example 1: Detection of the ability of compounds to inhibit HPK1 kinase activity (Method 1)

[0368] The reagents used are as follows

[0369]

[0370]

[0371] Experimental procedure

[0372] The specific operation is as follows: the enzyme reaction system buffer (10 mM MOPS, pH 7.2, 5 mM β-glycerol-phosphate, 10 mM MgCl2, 0.8 mM EDTA, 2 mM EGTA, 0.1 mM DTT) is configured; the tested compound (1 mM compound stock solution prepared in DMSO) is diluted with the buffer to a maximum concentration of 60 uM (containing 6% DMSO), and the compound is diluted 5 times with the buffer containing 6% DMSO to prepare a gradient concentration of 8 points; then the HPK1 kinase is diluted to 30 nM using the buffer. 2 μl of the HPK1 kinase diluent is added to each well of a Greiner 384-well microplate (item number: 784075), and 2 μl of the buffer is supplemented to the control well; after brief centrifugation, 1 μl of the diluted compound is added to the reaction well, and 1 μl of the buffer containing 6% DMSO is added to the control well; after brief centrifugation, it is incubated in a 25°C constant temperature incubator (Shanghai Yiheng Scientific Instrument Co., Ltd., item number: LRH-150) for 20 min. 3 μl of the reaction substrate (10 μM MBP and 20 μM ATP dissolved in distilled water) is added to each well, and after brief centrifugation, it is incubated in a 25°C constant temperature incubator for 60 min. The ADP-Glo Kinase Assay Kit is used to detect the enzyme activity, and the ADP-Glo Kinase Assay Kit detection is performed according to the operating instructions of the kit. The data is the half-inhibitory concentration IC 50 Description.

[0373]

[0374]

[0375] From the above table of HPK1 kinase inhibition data, the compounds of the present application have a kinase inhibition ability comparable to or better than that of the control compound, and have a unique structure-activity relationship characteristic.

[0376] Test Example 2: Detection of the agonistic ability of the compound on the secretion of the cytokine interleukin-2 (IL-2) of Jurkat cells and the effect of the compound on the activity of Jurkat cells (Method 2)

[0377] The required reagents and cells are as follows

[0378] Experimental reagents:

[0379]

[0380] Experimental cells:

[0381] Cells Cell type Brand Jurkat E6-1 Human T lymphocytic leukemia cells Institute of Cell Biology, Chinese Academy of Sciences

[0382] Experimental procedure

[0383] The specific operation is as follows: compound powder is dissolved in DMSO to 10 mM, 2 μl of compound is added to 998 μl of RPMI 1640 medium (10% FBS is contained in this test), and after vortex mixing, it is the highest concentration point. Compound solution is gradually diluted with 0.2% DMSO medium 3 times, a total of 8 concentration points. The solution treated with RPMI 1640 medium containing 0.1% DMSO is used as a control. 1x105 Jurkat E6-1 cells are added to each well of a Corning 96-well cell culture plate (item number: 3599), and then an equal volume of compound diluent is added, and the control group is added with 0.2% DMSO in RPMI 1640 medium, and placed in a 37°C cell incubator (Thermo Fisher Scientific, model: 3111) for 1 h. Then add Anti-human CD3 Antibody and Anti-human CD28 Antibody with a final concentration of 1 μg / ml, and incubate in a 37°C cell incubator for 24 h. Collect the culture supernatant, and use Human IL-2 DuoSet ELISA KIT to detect the IL-2 content in the cell supernatant. The Human IL-2 DuoSet ELISA detection is carried out according to the operating instructions of the kit. The IL-2 secretion data is described by the highest multiple ratio of the stimulation signal of the compound to the signal of 0.1% DMSO; collect the cells, and use Luminescent Cell Viability Assay kit to detect cell viability, and the cell viability data is described by the half-inhibitory concentration IC 50 Description.

[0384]

[0385]

[0386] From the above table of Jurkat cell stimulation and IL2 release experiment, it can be seen that the compound of the present application has lower inhibition degree on Jurkat cell activity compared with the control example.

[0387] Test example 3: detection of the agonistic ability of the compound to the cytokine interleukin-2 (IL-2) secreted by human PBMC cells

[0388] The reagents required for use are as follows

[0389]

[0390] Experimental cell source information:

[0391]

[0392]

[0393] Experimental procedure

[0394] The specific operation is as follows: After the human PBMC is taken out from the liquid nitrogen according to the standard operation, it is placed in a 37°C water bath pot for thawing and recovery, the cells are resuspended with RPMI 1640 culture medium (containing 10% FBS in this test), and washed twice by centrifugation; then the human PBMC cells are resuspended in RPMI 1640 culture medium for standby. Compound powder is dissolved in DMSO to 10mM, 2μl of compound is added to 998μl of RPMI 1640 culture medium, and vortexed to mix to the highest concentration point. Compound solution is gradually diluted with 0.2% DMSO culture medium by 3 times, a total of 8 concentration points. The RPMI 1640 culture medium solution containing 0.1% DMSO is treated as a control. Add 1×105 human PBMC cells to each well of a Corning 96-well cell culture plate (item number: 3599), then add an equal volume of compound diluent, and the control group is added with 0.2% DMSO in RPMI 1640 culture medium, and placed in a 37°C cell incubator (Thermo Fisher Scientific, model: 3111) for incubation for 1h. Then add Anti-human CD3 Antibody and Anti-human CD28 Antibody with a final concentration of 0.01μg / ml and 1μg / ml, and incubate in a 37°C cell incubator for 24h. Human IL-2 DuoSet ELISA KIT is used to detect the IL-2 content in the cell supernatant, and the Human IL-2 DuoSet ELISA detection is carried out according to the operation instruction of the kit. The data is described by the highest multiple ratio of the stimulation signal of the compound to the signal of 0.1% DMSO. The cells are collected and used Luminescent Cell Viability Assay kit is used to detect cell viability, and the cell viability data is described by the half inhibitory concentration IC50 of the compound.

[0395]

[0396]

[0397] From the above table Human PBMC cell stimulation release IL2 experiment, it can be seen that the compound of the present application has lower degree of inhibition on the activity of PBMC cells than the control.

Claims

1. Compounds having the structure of Formula I or Formula II, or pharmaceutically acceptable salts thereof: in, R1 indicates a halogen or a haloalkyl (C1-C6); R2 represents hydrogen, halogen, (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6 alkylene)-OR a -O-(C1-C6)alkyl, -S-(C1-C6)alkyl, -S(O)-(C1-C6)alkyl, -S(O)2-(C1-C6)alkyl, -S(O)2-(C3-C8)cycloalkyl, -S-(C1-C6)alkylene-COOR a -S(O)-(C1-C6)alkylene-COOR a -S(O)2-(C1-C6)alkylene-COOR a -S-(C1-C6)alkylene-C(O)NR a R b -NR a R b -COOR a -CONR a R b -OCONR a R b -NR a COR b -P(O)R a R b -S(O)2NR a R b or -NR a S(O)2R b ; R3 represents hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6 alkylene)hydroxyl, -(C0-C6 alkylene)OR a -(C0-C6 alkylene)(C3-C8) cycloalkyl; R4 and R4' each independently represent hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, or halogen; R5 represents hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C8)cycloalkyl, or (4-8) heterocyclic alkyl; R6 and R6' each independently represent hydrogen, (C1-C6)alkyl, -(C1-C6 alkylene)hydroxyl, or halogen; R7 and R7' each independently represent hydrogen, (C1-C6) alkyl, or halogen; W1 indicates CR W1 ; W2 indicates CR W2 ; Among them, R W1 and R W2 Each can be independently represented as hydrogen, halogen, (C1-C6) alkyl, or -OR. a - NR a R b , cyano, -COOR a -CONR a R b -OCONR a R b -NR a COR b -P(O)R a R b -S(O)2NR a R b -NR a S(O)2R b -SR a -S(O)R a -S(O)2R a ; For the alkyl, cycloalkyl, and heterocycloalkyl groups defined above, they may be substituted by any of 0, 1, 2, or 3 substituents selected from the following: (C1-C6)alkyl, (C2-C6)alkenyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, -(C1-C6 alkylene)-O-(C1-C6)alkyl, (C3-C8)cycloalkyl, halo(C3-C8)cycloalkyl, halogen, -CN, oxo, -NR a R b -OR a -SR a -(C1-C6 alkylene)hydroxyl, -C(O)R a -N(R) a )C(O)R a -NR a C(O)OR a -NR a SO2R a -C(O)OR a -C(O)NR a R b -S(O)2NR a R b -S(O)R a -S(O)2R a -P(O)R a R b ; Among them, R a R b Each can independently represent hydrogen, (C1-C6)alkyl, or halo(C1-C6)alkyl; m, n, o, and r each independently represent 0, 1, 2, or 3.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, R2 represents hydrogen, halogen, (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6 alkylene)-OR a -O-(C1-C6)alkyl, -S-(C1-C6)alkyl, -S(O)-(C1-C6)alkyl, -S(O)2-(C1-C6)alkyl, -S(O)2-(C3-C8)cycloalkyl, -S-(C1-C6)alkylene-COOR a -S(O)-(C1-C6)alkylene-COOR a -S(O)2-(C1-C6)alkylene-COOR a -S-(C1-C6)alkylene-C(O)NR a R b -CONR a R b -P(O)R a R b or- S(O)2NR a R b Among them, R a R b Each can be independently represented as hydrogen, (C1-C6)alkyl, or halo(C1-C6)alkyl.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R4 and R4' each independently represent hydrogen.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R5 represents hydrogen, (C1-C6)alkyl, or halo(C1-C6)alkyl.

5. The compound according to claim 1 or 2, wherein, R6 and R6' each independently represent hydrogen, (C1-C6) alkyl, or halogen.

6. The compound according to claim 1 or 2, wherein, R7 and R7' each independently represent hydrogen.

7. The compound according to claim 1 or 2, wherein, R W1 and R W2 Each can be used independently to represent hydrogen, halogen, or (C1-C6) alkyl.

8. A compound having the following structure:

9. A pharmaceutical composition comprising the compound of any one of claims 1-8 and a pharmaceutically usable carrier.

10. Use of the compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 9, in the preparation of a medicament for the prevention and / or treatment of cancer, tumors, inflammatory diseases, autoimmune diseases, or immune-mediated diseases.

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