A highly active hpk1 kinase inhibitor

Abstract

The present application provides a kind of compound with inhibiting HPK1 kinase activity of structure (I) and 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

[0001] This application claims priority to Chinese Patent Application No. 202110378424.1, filed on April 8, 2021, entitled “A highly active HPK1 kinase inhibitor”, the contents of which are incorporated herein by reference in its entirety. TECHNICAL FIELD

[0002] The present application relates to a heterocyclic compound, in particular to a highly active HPK1 kinase inhibitor and its use. BACKGROUND

[0003] HPK1 is one of the members of the 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 and induce T cell activation. In this process, HPK1 is activated by tyrosine kinases Lck and Zap70 phosphorylation, which participates 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 dendritic cell (DC) maturation and activation, especially inhibiting 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 DC and the cooperation between DC and T cells is 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 playing a role in inhibiting tumor growth through multiple pathways to enhance anti-tumor immune effects.

[0004] Therefore, there is still an urgent need in the art for effective HPK1 kinase activity inhibitors in order to provide more effective options for anti-tumor. SUMMARY

[0005] The present invention surprisingly found a compound of formula (I) and pharmaceutically acceptable salts or stereoisomers thereof having inhibitory activity on HPK1 kinase. Therefore, in a first aspect, the present invention provides a compound having the structure of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof:

[0006]

[0007] wherein

[0008] X represents N or CR 10 ;

[0009] R1 represents hydrogen, C1-C6 alkyl, haloC1-C6 alkyl, C3-C6 cycloalkyl, haloC3-C6 cycloalkyl, halogen, cyano or -C(O)NH2;

[0010] R2 represents hydrogen, halogen, hydroxyl, (C1-C6)alkyl, (C2-C6)alkenyl, -(C0-C6alkylene)(C3-C8)cycloalkyl, -(C0-C6alkylene)(4-8 membered)heterocycloalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl(C0-C6alkylene)oxy, (4-8 membered)heterocycloalkyl(C0-C6alkylene)oxy;

[0011] R3 represents hydrogen or C1-C6 alkyl, C3-C6 alkenyl, C3-C6 cycloalkyl, hydroxy(C1-C6 alkyl), haloC1-C6 alkyl, 4-8 membered heterocycloalkyl;

[0012] R4 represents hydrogen or C1-C6 alkyl; and the C1-C6 alkyl can be optionally substituted with a substituent selected from halogen, -OR a , -SR a , -P(O)R a R b , -S(O)2R a , -S(O)(NH)R a , -S(O)R a , -S(O)2NR a R b , -C(O)NR a R b , -C(O)OH, -OC(O)NR a R b , -NR a C(O)R b , -NR a S(O)2R b ;

[0013] R5 and R 5’each independently represents hydrogen, C1-C6alkyl, (C2-C6)alkenyl, halogen, halogenated C1-C6alkyl, or hydroxy(C1-C6alkyl);

[0014] or R5and R 5’ together with the carbon atom to which they are attached form a 3-6 membered ring, which ring can optionally further contain 0, 1 or 2 heteroatoms selected from N, O, S;

[0015] R6and R 6’ each independently represents hydrogen, C1-C6alkyl, (C2-C6)alkenyl, halogen, halogenated C1-C6alkyl, or hydroxy(C1-C6alkyl);

[0016] or R6and R 6’ together with the carbon atom to which they are attached form a 3-6 membered ring, which ring can optionally further contain 0, 1 or 2 heteroatoms selected from N, O, S;

[0017] p represents 1 or 2;

[0018] R7and R 7’ each independently represents hydrogen, C1-C6alkyl, (C2-C6)alkenyl, halogen, halogenated C1-C6alkyl, or hydroxy(C1-C6alkyl);

[0019] or R7and R 7’ together with the carbon atom to which they are attached form a 3-6 membered ring, which ring can optionally further contain 0, 1 or 2 heteroatoms selected from N, O, S;

[0020] W represents

[0021] wherein A represents

[0022] represents that the ring contains a single or double bond;

[0023] when the chemical bond between A and A' is a double bond, A' represents CR a or N, and B represents CR b ;

[0024] when the chemical bond between A and A' is a single bond, A' represents CHR a , and B represents CHR b or is absent;

[0025] R8and R9each independently represent hydrogen or C1-C6alkyl; or R8and R9together with W1and W2may form a 3-6 membered ring;

[0026] W1represents C, and W2represents CH or N;

[0027] R M and R N each independently represent hydrogen or C1-C6 alkyl;

[0028] R 10 represents hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, -(C0-C6alkylene)(C3-C8)cycloalkyl, -(C0-C6alkylene)4-10 membered heterocycloalkyl, -(C0-C6alkylene)(C6-C 10 )aryl, -(C0-C6alkylene)5-10 membered heteroaryl,

[0029] or, when X represents CR 10 , R 10 may form, together with the adjacent R2, a (5-10 membered)cycloalkyl or 5-10 membered heterocycloalkyl;

[0030] For the above defined cycloalkyl, heterocycloalkyl, aryl, heteroaryl, it can be optionally substituted by 0, 1, 2 or 3 substituents selected from (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)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)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 ;

[0031] R a , R b each independently represent hydrogen, C1-C6 alkyl, hydroxy(C1-C6 alkyl), halo C1-C6 alkyl;

[0032] m, n each independently represent 0, 1 or 2.

[0033] In one embodiment of the present application, W represents

[0034] wherein A represents

[0035] represents that the ring contains a single bond or a double bond;

[0036] o each independently represents 0 or 1;

[0037] R8represents hydrogen or C1-C6alkyl;

[0038] R9each independently represents hydrogen or C1-C6alkyl;

[0039] or R8and the adjacent R9together with the carbon atom to which they are attached form a 3-6 membered ring;

[0040] W2, R M , R N as described above.

[0041] In one embodiment of the present application, W represents or

[0042] represents that the ring contains a single bond or a double bond;

[0043] o each independently represents 0 or 1;

[0044] R8represents hydrogen or C1-C6alkyl;

[0045] R9each independently represents hydrogen or C1-C6alkyl;

[0046] or R8and the adjacent R9together with the carbon atom to which they are attached form a 3-6 membered ring;

[0047] W2, R M , R N as described in claim 1.

[0048] In one embodiment of the present application, W is an aromatic heterocycle, preferably an aromatic lactam.

[0049] In one embodiment of the present application, W is a saturated heterocycle, preferably a saturated lactam.

[0050] In one preferred embodiment of the present application, wherein ring W represents or

[0051] In a further preferred embodiment of the present application, ring W represents

[0052] In a further preferred embodiment of the present application, ring W represents W represents

[0053] In a preferred embodiment of the present application, wherein R1represents hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, cyano or -C(O)NH2; more preferably, R1represents hydrogen, halogen, C1-C6alkyl or C1-C6haloalkyl.

[0054] In a preferred embodiment of the present application, wherein R2represents hydroxy, (C1-C6)alkyl, -(C0-C6alkylene)(C3-C8)cycloalkyl, -(C0-C6alkylene)(4-8 membered)heterocycloalkyl, (C1-C6)alkoxy; more preferably, R2represents C1-C6alkyl, C1-C6alkoxy or C3-C6cycloalkyl.

[0055] In a preferred embodiment of the present application, wherein R3represents hydrogen or C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl; more preferably, R3represents hydrogen or C1-C6alkyl.

[0056] In a preferred embodiment of the present application, wherein R4represents hydrogen or C1-C6alkyl; and said C1-C6alkyl can optionally be substituted with a substituent selected from the group consisting of halogen, -OR a , -SR a , -P(O)R a R b , -S(O)2R a , -S(O)(NH)R a , -S(O)R a , -S(O)2NR a R b , -C(O)NR a R b , -C(O)OH; more preferably, R4represents hydrogen or C1-C6alkyl.

[0057] In a preferred embodiment of the present application, wherein R5, R 5’ each independently represents hydrogen, halogen, C1-C6alkyl or haloC1-C6alkyl.

[0058] In a preferred embodiment of the present application, wherein R6, R 6’ each independently represents hydrogen, halogen, C1-C6alkyl or haloC1-C6alkyl.

[0059] In a preferred embodiment of the present application, wherein R7, R 7’ each independently represents hydrogen, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl or hydroxy(C1-C6 alkyl).

[0060] In a preferred embodiment of the present application, wherein R8represents hydrogen or C1-C6 alkyl.

[0061] In a preferred embodiment of the present application, wherein R9represents hydrogen or C1-C6 alkyl.

[0062] In a preferred embodiment of the present application, wherein R 10 represents hydrogen, halogen, (C1-C6)alkyl, -(C0-C6alkylene)(C3-C8)cycloalkyl, -(C0-C6alkylene)4-10 membered heterocycloalkyl; more preferably, R 10 represents hydrogen, halogen or (C1-C6)alkyl.

[0063] In a preferred embodiment of the present application, wherein R M represents hydrogen or C1-C6 alkyl.

[0064] In a preferred embodiment of the present application, wherein R a , R b each independently represents hydrogen, C1-C6 alkyl or halogenated C1-C6 alkyl.

[0065] Preferably, the compound of the present application has the following structure:

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075] In addition, the present application also provides a pharmaceutical composition comprising the compound of the present application and a pharmaceutically acceptable carrier.

[0076] In addition, the present application also provides a use of a compound or a pharmaceutical composition of the present application in the preparation of a medicament for preventing and / or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.

[0077] In addition, the present application also provides a use of a compound of the present application for preventing and / or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.

[0078] It is particularly noted that, herein, when referring to a "compound" having a specific structural formula, it generally also encompasses its stereoisomers, diastereoisomers, enantiomers, racemic mixtures and isotopic derivatives.

[0079] It is well known to those skilled in the art that a salt, solvate, hydrate of a compound is an alternative existing form of the compound, which can be converted into the compound under certain conditions, therefore, it is particularly noted that herein when referring to a compound, it generally also includes its pharmaceutically acceptable salt, and further includes its solvate and hydrate.

[0080] Similarly, herein when referring to a compound, it generally also includes its prodrugs, metabolites and nitroxides.

[0081] 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 or salts of compounds 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 present 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 compounds of the present application carry 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.

[0082] 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.

[0083] The precursors or metabolites described in this invention can be precursors or metabolites known in the art, as long as they can be metabolized and transformed in vivo to form the target compound. For example, "prodrug" refers to those prodrugs of the compounds of this invention that, within a reasonable medical judgment, are suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, etc., and have a reasonable benefit / risk ratio and are effective for their intended use. The term "prodrug" refers to a compound that is rapidly transformed in vivo to produce the parent compound of the above formula, for example, through in vivo metabolism, or through N-demethylation of the compounds of this invention.

[0084] The term "solvate" as used in this invention refers to the physical association of the compound of this invention with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. The solvent molecules in the solvate may be present in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric solvent molecules. "Solvate" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0085] The "stereoisomerism" described in this invention is divided into conformational isomerism and configurational isomerism. Configurational isomerism can be further divided into cis-trans isomerism and optical isomerism. Conformational isomerism refers to the phenomenon where organic molecules with a certain configuration undergo different spatial arrangements of atoms or groups of atoms due to the rotation or twisting of carbon or carbon single bonds. Common examples include the structures of alkanes and cycloalkanes, such as the chair conformation and boat conformation in the cyclohexane structure. "Stereoisomers" refer to compounds of this invention containing one or more asymmetric centers, thus allowing them to exist as racemic mixtures and racemic mixtures, single enantiomers, diastereomer mixtures, and single diastereomers. The compounds of this invention have asymmetric centers, each of which produces two optical isomers. The scope of this invention includes all possible optical isomers and diastereomer mixtures, as well as pure or partially pure compounds. The compounds of this invention can exist as tautomers, which have different hydrogen bonding sites through one or more double bond shifts. For example, ketones and their enol forms are ketone-enol tautomers. All tautomers and mixtures thereof are included in the compounds of this invention. All enantiomers, diastereomers, racemates, mesomates, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof of all compounds of formula (I) are included within the scope of this invention.

[0086] 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. The inclusion of isotopic atoms in compounds of the application can afford insight into a compound's distribution, transport, and / or metabolism in a tissue of interest. In particular, deuterium 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, as diagnostic tools, as probes in biological assays, and the like. In particular, deuterium 3 H and carbon 13 C are useful because of their ease of incorporation, relative safety, and non- interfering mass. Certain heavier isotopes such as hydrogen 2 H), can increase metabolic stability (half-life) or decrease the number of active sites in a molecule. Isotopically-labeled compounds of this application can generally be prepared by carrying out the procedures disclosed in the schemes and examples below, by either (a) simply substituting an isotopically-labeled reagent for a non-labeled reagent in accordance with standard techniques or (b) carrying out the reactions described in the schemes and examples below where appropriate isotopically-labeled reagents are used.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] Representative examples of cancer 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.

[0092] Representative examples of therapeutic agents for treating 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.

[0093] 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 can be administered in divided doses per day.

[0094] In addition to the above, the present application also 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.

[0095] 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 the conventional methods, such as tablets, granules, powders, capsules, syrups, emulsions, microemulsions, solutions, or suspensions.

[0096] Other features of the present application will become apparent in the course of the detailed description of exemplary embodiments, which are given for the purpose of illustration and not intended to be limiting thereof, the following examples were prepared, isolated, and characterized using the methods disclosed herein.

[0097] The compounds of the application can be prepared in a number of ways known to one skilled in the art of organic synthesis, using the methods described below as well as synthetic methods known to those skilled in the art of organic synthesis or by modifications thereof, 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. Those skilled in the art will recognize which solvents are appropriate to use in the transformations of the present application. It will be understood by those skilled in the art of organic synthesis that the order of synthetic steps can be varied for the synthesis of the compounds of the present application. It will also be appreciated by one skilled in the art that protection and deprotection of various chemical groups can be affected by a wide variety of procedures as described in the literature for such manipulations. DETAILED DESCRIPTION

[0098] TERMINOLOGY

[0099] 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 forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Unless otherwise indicated, conventional methods of mass spectroscopy, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed. In the present application, "or" or "and" shall mean "and / or" unless stated otherwise.

[0100] In the specification and claims, a given chemical formula or name shall encompass all stereo and optical isomers and racemates thereof unless otherwise indicated. All chiral (enantiomeric and diastereomeric) and racemic forms of the compounds of the application are within the scope of the present application unless it is specifically indicated otherwise. Many geometric isomers of C=C double bonds, C=N double bonds, ring systems, etc. can also be present in the compounds, and all such isomers are encompassed by the present application. The present application describes the cis- and trans- (or E- and Z-) geometric isomers of the compounds of the application and they can be isolated in their mixtures or in their separate forms. The compounds of the application can be isolated in their optically active or racemic forms. All processes used to prepare the compounds of the 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, such as by chromatography or fractional crystallization. The end products of the application are obtained as either free (neutral) or salt forms. Both the free forms 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. Free bases can be converted to salts; salts can be converted into free compounds or another salt; mixtures of isomeric compounds of the present application can be separated into the individual isomers. The compounds of the application, their 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 will be understood that all tautomeric forms, which can exist, are included within the present application.

[0101] Unless otherwise defined, the substituents of the present invention are defined independently of each other rather than being interrelated. For example, for R in the substituents a (or R a ’), they are independent of each other in the definitions of different substituents. Specifically, for R a (or R a ’), when selecting a definition in one substituent, it does not mean that the R a (or R a ’) has the same definition in other substituents. More specifically, for example (only listing non-exhaustively), for NR a R a ’, when the definition of R a (or R a ’) is selected from hydrogen, it does not mean that in -C(O)-NR a R a ’, R a (or R a ’) must be hydrogen.

[0102] Unless otherwise defined, when a substituent is labeled as “optionally substituted”, the substituent is selected from, for example, the following substituents such as alkyl, cycloalkyl, aryl, heterocyclic group, halogen, hydroxyl, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine groups (where the two amino substituents are selected from alkyl, aryl or arylalkyl), alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkylthio, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfonamido such as -SO2NH2, substituted sulfonamido, nitro, cyano, carboxyl, carbamoyl such as -CONH2, substituted carbamoyl such as -CONHalkyl, -CONHaryl, -CONHarylalkyl or the case of having two substituents selected from alkyl, aryl or arylalkyl on nitrogen, alkoxycarbonyl, aryl, substituted aryl, guanidyl, heterocyclic group, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, etc. and substituted heterocyclic group.

[0103] The terms "alkyl" or "alkylene" as used herein are intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms. For example, "Ci-C6alkyl" denotes alkyl groups having from 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and i-propyl), butyl (e.g., n-butyl, i-butyl, t-butyl), and pentyl (e.g., n-pentyl, i-pentyl, neopentyl).

[0104] The term "alkenyl" denotes straight or branched-chain hydrocarbon groups containing one or more double bonds and typically having a length of from 2 to 20 carbon atoms. For example, "C2-C6alkenyl" contains from 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.

[0105] The term "alkynyl" denotes straight or branched-chain hydrocarbon groups containing one or more triple bonds and typically having a length of from 2 to 20 carbon atoms. For example, "C2-C6alkynyl" contains from two to six carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1 -propynyl, 1 -butynyl, and the like.

[0106] The term "alkoxy" or "alkyloxy" refers to -O-alkyl. "Ci-C6alkoxy" (or alkyloxy) is intended to include Ci, C2, C3, C4, C5, C6alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propyloxy (e.g., n-propyloxy and i-propyloxy), and t-butyloxy. Similarly, "alkylthio" or "thioalkoxy" denotes an alkyl group as defined above attached to the rest of the molecule by a sulfur bridge; for example, methyl-S- and ethyl-S-.

[0107] The term "carbonyl" refers to the organic functional group (C=0) connected by a double bond between a carbon and an oxygen atom.

[0108] The term "aryl", alone or in combination with other terms, means a monocyclic, bicyclic or tricyclic ring system having from 5 to 12 ring members in which 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" means an aromatic ring system which includes, but is not limited to, phenyl, biphenyl, indanyl, 1 -naphthyl, 2-naphthyl, and tetrahydronaphthyl. The term "aralkyl" or "arylalkyl" means an alkyl residue 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. The dashed line drawn through a ring in the ring system indicates that the bond can be attached to any suitable ring atom.

[0109] The term "cycloalkyl" refers to monocyclic or bicyclic cyclic alkyl groups, preferably having 3 to 8 ring members. Monocyclic cyclic alkyl groups refer to C3-C8 cyclic alkyl 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 cyclic alkyl groups include bridged, spirocyclic, or fused ring cyclic alkyl groups.

[0110] The term "cycloalkenyl" refers to monocyclic or bicyclic cyclic alkenyl groups, preferably having 3 to 8 ring members. Monocyclic cyclic alkenyl groups refer to C3-C8 cyclic alkenyl 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 cyclic alkenyl groups include bridged, spirocyclic, or fused ring cyclic alkenyl groups.

[0111] "Halo" or "halogen" includes fluorine, chlorine, bromine, and iodine. "Haloalkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms 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" intended to include 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 fluorine atoms.

[0112] "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, "haloCi-C6alkoxy" is intended to include Ci, C2, C3, C4, C5, C6 haloalkoxy 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-.

[0113] In the present disclosure, when referring to some substituent groups, C x1 -C x2The expression "C0-C8", for example, indicates that the group contains 0, 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. The expression "C1-C8", for example, indicates that the group contains 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. The expression "C2-C8", for example, indicates that the group contains 2, 3, 4, 5, 6, 7, or 8 carbon atoms. The expression "C3-C8", for example, indicates that the group contains 3, 4, 5, 6, 7, or 8 carbon atoms. The expression "C4-C8", for example, indicates that the group contains 4, 5, 6, 7, or 8 carbon atoms. The expression "C0-C6", for example, indicates that the group contains 0, 1, 2, 3, 4, 5, or 6 carbon atoms. The expression "C1-C6", for example, indicates that the group contains 1, 2, 3, 4, 5, or 6 carbon atoms. The expression "C2-C6", for example, indicates that the group contains 2, 3, 4, 5, or 6 carbon atoms. The expression "C3-C6", for example, indicates that the group contains 3, 4, 5, or 6 carbon atoms.

[0114] In the present disclosure, the expression "x1-x2-membered ring" when referring to a cyclic group (e.g., aryl, heteroaryl, cycloalkyl, and heterocycloalkyl) indicates that the number of ring atoms of the group can be x1 to x2. For example, a 3-12 membered cyclic group can be a 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 membered ring, which can have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms; a 3-6 membered ring indicates that the cyclic group can be a 3, 4, 5, or 6 membered ring, which can have 3, 4, 5, or 6 ring atoms; a 3-8 membered ring indicates that the cyclic group can be a 3, 4, 5, 6, 7, or 8 membered ring, which can have 3, 4, 5, 6, 7, or 8 ring atoms; a 3-9 membered ring indicates that the cyclic group can be a 3, 4, 5, 6, 7, 8, or 9 membered ring, which can have 3, 4, 5, 6, 7, 8, or 9 ring atoms; a 4-7 membered ring indicates that the cyclic group can be a 4, 5, 6, or 7 membered ring, which can have 4, 5, 6, or 7 ring atoms; a 5-8 membered ring indicates that the cyclic group can be a 5, 6, 7, or 8 membered ring, which can have 5, 6, 7, or 8 ring atoms; a 5-12 membered ring indicates that the cyclic group can be a 5, 6, 7, 8, 9, 10, 11, or 12 membered ring, which can have 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms; a 6-12 membered ring indicates that the cyclic group can be a 6, 7, 8, 9, 10, 11, or 12 membered ring, which can have 6, 7, 8, 9, 10, 11, or 12 ring atoms. The ring atoms can be carbon atoms or heteroatoms, for example, 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, for example, heteroatoms selected from N, O, and S.

[0115] In the present disclosure, one or more halogen can each independently be selected from fluorine, chlorine, bromine, and iodine.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] The term "spirocycloalkyl" as used herein refers to polycyclic hydrocarbons sharing one carbon atom (called spiro atom) between single rings.

[0120] 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.

[0121] 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.

[0122] 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 between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0123] 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 peroxide) 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.

[0124] 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.

[0125] 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.

[0126] 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 administration route. The term also includes within its scope amounts effective to enhance normal physiological function.

[0127] The term "treatment" as used herein includes any effect that relieves, reduces, modulates, ameliorates, or eliminates a condition, disease, disorder, etc., or its symptoms.

[0128] 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.

[0129] 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 carbonate, talc, stearic acid, magnesium stearate, sodium starch glycolate, magnesium aluminium silicate, corn starch, gelatin, talc, magnesium carbonate, sugars, sodium benzoate, sodium acetate, sodium chloride, and any combination thereof.

[0130] 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.

[0131] Specific Pharmaceutical and Medical Terms

[0132] 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.

[0133] 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).

[0134] 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.

[0135] 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.

[0136] 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.

[0137] The terms "kit" and "product package" are synonymous.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] Routes of administration

[0142] 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.

[0143] 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.

[0144] Pharmaceutical compositions and dosages

[0145] The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of the present invention formulated with one or more pharmaceutical carriers (additives) and / or diluents, and optionally one or more of the other therapeutic agents described above. The compounds of the present invention can be administered in any suitable manner for any of the above-described uses, such as orally, in tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually; sublingually; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., in the form of sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to a nasal membrane, such as by inhalation sprays; topically, such as in the form of creams or ointments; or rectally, such as in the form of suppositories; or intratumorally. They can be administered alone, but are typically administered using a pharmaceutical carrier chosen based on the selected route of administration and standard pharmaceutical practice.

[0146] Pharmaceutical carriers are formulated based on a number of factors known to those skilled in the art. These factors include, but are not limited to: the type and nature of the active agent being formulated; the subject to whom the composition containing the active agent is to be administered; the intended route of administration of the composition; and the targeted therapeutic indication. Pharmaceutical carriers include aqueous and non-aqueous liquid media as well as various solid and semi-solid dosage forms.

[0147] The aforementioned carriers may include a variety of different components and additives besides the active agent. These other components are included in the formulation for various reasons known to those skilled in the art, such as stabilizing agents, binders, etc. Descriptions of suitable pharmaceutical carriers and the factors involved in carrier selection can be found in several readily available sources, such as Allen LV Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012), Pharmaceutical Press.

[0148] 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 a constant rate infusion will 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.

[0149] 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.

[0150] Dosage forms (pharmaceutical compositions) suitable for administration include about 1 milligram to about 2000 milligrams of active ingredient per dosage unit.

[0151] 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.

[0152] 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.

[0153] 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).

[0154] 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.

[0155] 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.

[0156] 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.

[0157] 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 throughout the day, optionally, in unit dosage forms. In certain aspects of the application, dosing is once daily.

[0158] 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).

[0159] Kits / Products Packets

[0160] 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.

[0161] For example, a container can contain one or more of the compounds described herein, which can be present as a pharmaceutical composition, in admixture with 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 a compound, and instructions for use in the methods described herein, a label, or a package insert.

[0162] A typical kit can include one or more containers into which one or more of the materials described herein can be placed, for example, for commercial sale and use. Such kits can include, for example, a container and a compound, and instructions for use in the methods described herein, a label, or a package insert. The kits can further include other reagents useful for practicing the methods described herein, such as buffers and diluents, filters, needles, syringes, delivery devices, packages, containers, vials, and / or tubes, with or without enclosures containing instructions for use. All of the instructions can be included.

[0163] Labels suitable for use in conjunction with the containers include those made from stainless steel, aluminum, paper, plastic or other suitable materials. Labels can be printed, embossed or etched. Labels can be re-usable or disposable. Labels can be attached to containers by any suitable means, such as adhesives.

[0164] All of the features described in this specification (including any accompanying claims, abstract and / or drawings) and / or all of the steps of any method or process described in this specification can be combined in any combination, unless the context explicitly indicates otherwise.

[0165] The features of the application that are described above, or features of the embodiments described above, can be combined with each other in any combination. All of the features that are disclosed in this specification (including any accompanying claims, abstract and / or drawings) can be combined in any combination, except to the extent that the context explicitly indicates otherwise. Thus, for example, the features of any dependent claim can be combined with the features of the claims to which such dependent claims refer. All of the features described in this specification that are antecedents of the claims to which the application is directed, can not only be at the particular point of their disclosure in the specification, but can also carry the implicit promise that the feature in question can be claimed in any manner permitted by claimant.

[0166] The application is further defined by reference to the following examples. It should be understood that these examples are only by way of illustration and are not intended as an imposition of limitations on the scope of the application. The methods of the following examples were carried out unless otherwise specified, in accordance with conventional procedures or as suggested by the manufacturer of the reagent. Unless otherwise indicated, all percentages, ratios, proportions, or parts are by weight.

[0167] 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.

[0168] Examples

[0169] General procedures

[0170] 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 are not required to be further purified.

[0171] Room temperature refers to 20-30 °C.

[0172] Unless otherwise specified in the reaction examples, the reactions are carried out under a nitrogen atmosphere. The nitrogen atmosphere refers to the reaction flask being connected to a nitrogen balloon of about 1 L.

[0173] The hydrogenation reaction is usually vacuumed and filled with hydrogen, and the operation is repeated 3 times. The hydrogen atmosphere refers to the reaction flask being connected to a hydrogen balloon of about 1 L.

[0174] Microwave reaction uses Initiator + microwave reactor.

[0175] 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.

[0176] The measurement of LC-MS uses a Thermo liquid chromatograph-mass spectrometer (UltiMate 3000+MSQ PLUS). The measurement of HPLC uses a Thermo high-pressure liquid chromatograph (UltiMate 3000). The reverse-phase preparative chromatography uses a Thermo (UltiMate 3000) reverse-phase preparative chromatograph. The flash column chromatography uses an Ajinomoto (FS-9200T) automatic column machine, and the silica gel pre-packed column uses a San Tay (S-1000) silica gel pre-packed column. Pre-packed column. Thin layer chromatography silica gel plate with Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate, the specification used for thin layer chromatography separation and purification of the product is 0.4mm-0.5mm.

[0177] The synthesis method of some intermediates in the application is as follows:

[0178] Intermediate 1

[0179]

[0180] Intermediate 1 is prepared by the following steps:

[0181]

[0182] First step: 1-methyl-3,5-dinitropyridin-2-one Int-1a (1.0 g, 5.02 mmol) was dissolved in methanol (50 mL), and then ammonium methanol solution (7 mol / L, 8.61 mL, 60.27 mmol) and 1-methylpiperidin-4-one Int-1b (625 mg, 5.52 mmol) were added in sequence. The reaction mixture was heated to 50°C and stirred for 5 hours. After cooling to room temperature, it was left to stand for 48 hours, and the reaction solution was concentrated under reduced pressure. The residue was added with ethyl acetate (50 mL) and then filtered. The filtrate was concentrated under reduced pressure to obtain red solid Int-1c (1.0 g), which was directly used in the next step reaction. ESI-MS (m / z): 194.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 9.14 (d, J = 2.5 Hz, 1H), 8.36 (d, J = 2.5 Hz, 1H), 3.64 (s, 2H), 3.02 (t, J = 6.0 Hz, 2H), 2.74 (t, J = 6.0 Hz, 2H), 2.39 (s, 3H).

[0183] Second step: The compound Int-1c (1.0 g) obtained in the previous step was dissolved in methanol (30 mL), and 10% Pd-C (400 mg) was added. The reaction was carried out under hydrogen atmosphere at room temperature for 6 hours. The palladium carbon was removed by filtration, and the filtrate was concentrated to obtain yellow solid Int-1d (800 mg, yield 94.70%). ESI-MS (m / z): 164.2 [M+H] + .

[0184] 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 solution 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

[0185] 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).

[0186] 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. The reaction was cooled to room temperature, and the reaction was concentrated, and the residue was purified by preparative thin layer chromatography (methanol / dichloromethane / triethylamine = 1 / 10 / 0.1) to give yellow solid Int-1 (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).

[0187] Intermediate 2

[0188]

[0189] Intermediate 2 was prepared from the following steps:

[0190]

[0191] Step 1: Compound Int-1e (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 then microwaved to 100 °C with stirring for 5 hours. The reaction mixture was cooled to room temperature, filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (methanol / dichloromethane / triethylamine = 1 / 50 / 0.1) to give a yellow solid Int-2 (113 mg, yield 57%). ESI-MS (m / z): 208.5 [M+H] + .

[0192] Intermediate 3

[0193]

[0194] Intermediate 3 is prepared by the following steps:

[0195]

[0196] Step 1: Compound Int-1e (100 mg, 0.41 mmol) and trimethylcycloborane (148 mg, 1.19 mmol) were dissolved in dioxane (1.5 mL) and water (0.15 mL). Potassium carbonate (171 mg, 1.24 mmol) and Pd(dppf)Cl2 (30 mg, 0.041 mmol) were added. After purging the reaction system with nitrogen, it was microwaved to 140 °C and stirred for 1 hour. The reaction was cooled to room temperature, and the reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 20) to give a yellow solid Int-3 (50 mg, yield 68%). ESI-MS (m / z): 178.6 [M+H] + .

[0197] Intermediate 4

[0198]

[0199] Intermediate 4 is prepared by the following steps:

[0200]

[0201] First Step: Compound Int-1e (350 mg, 1.45 mmol) and vinylpotassium trifluoroborate (387 mg, 2.89 mmol) were dissolved in 1,4-dioxane (1.5 mL) and water (0.15 mL), potassium carbonate (399 mg, 2.89 mmol) and Pd(dppf)Cl2(105 mg, 0.14 mmol) were added. The reaction was heated to 120 °C in a microwave reactor for 1 hour with stirring under nitrogen. After the reaction was cooled to room temperature, it was filtered with celite, the filtrate was concentrated, and the residue was separated by column chromatography (methanol / dichloromethane = 1 / 20) to give Int-4a (136 mg, yield 49%) as a yellow solid. ESI-MS (m / z): 190.7 [M+H] + ; 1 H NMR (500 MHz, CDC13) δ 6.85 (dd, J = 17.2, 11.0 Hz, 1H), 6.66 (s, 1H), 6.16 (dd, J = 17.3, 1.9 Hz, 1H), 5.49 (dd, J = 11.0, 1.9 Hz, 1H), 3.67-3.63 (m, 2H), 3.55 (s, 2H), 3.00 (t, J = 6.1 Hz, 2H), 2.80 (t, J = 6.1 Hz, 2H), 2.49 (s, 3H).

[0202] Second Step: Compound Int-4a (60 mg, 0.31 mmol) was dissolved in methanol (5 mL), 10% palladium on carbon (20 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction was filtered with celite, and the filtrate was concentrated to give intermediate 4 (37 mg, yield 61%). ESI-MS (m / z): 192.7 [M+H] + .

[0203] Intermediate 5

[0204]

[0205] Intermediate 5 was prepared by the following steps:

[0206]

[0207] First Step: Dissolve compound Int-1e (100 mg, 0.41 mmol) in a mixture solvent of toluene (3 mL) and water (0.3 mL), add cyclopropylboronic acid (42 mg, 0.49 mmol), potassium phosphate (306 mg, 1.45 mmol), tricyclohexylphosphine (23 mg, 0.082 mmol) and palladium acetate (9 mg, 0.041 mmol). Replace the reaction system with nitrogen and heat to 100 °C for 18 hours with stirring. After the reaction is cooled to room temperature, filter the reaction solution with diatomite, concentrate the filtrate, and separate the residue by column chromatography (methanol / dichloromethane = 1 / 20) to obtain yellow solid Int-5 (61 mg, yield 72%). ESI-MS (m / z): 204.2 [M+H] + .

[0208] Intermediate 6

[0209]

[0210] Intermediate 6 is prepared by the following steps:

[0211]

[0212] First Step: Dissolve N-tert-butoxycarbonyl-4-piperidinone Int-6a (4.4 g, 22.1 mmol) and 1-methyl-3,5-dinitro-2-pyridinone Int-1a (4.0 g, 20.1 mmol) in methanol (150 mL), and add an ammonia methanol solution (7 N, 34.4 mL, 240.8 mmol). Stir at 60 °C for 6 hours under nitrogen protection. After the reaction solution is cooled to room temperature, continue stirring for 2 days. Monitor the reaction by LCMS until it is completed. Concentrate the reaction solution, add ethyl acetate (150 mL), stir for half an hour, filter, and concentrate the filtrate to obtain yellow solid Int-6b (5.1 g, yield 91%). ESI-MS (m / z): 280.1 [M+H] + .

[0213] Second Step: Dissolve compound Int-6b (5.0 g, 17.9 mmol) in methanol (50 mL), and add 10% palladium on carbon (500 mg). Stir the mixture at room temperature for 16 hours under a hydrogen atmosphere (hydrogen balloon). After the reaction is completed, filter the reaction solution, and concentrate the filtrate to obtain light yellow solid Int-6c (3.7 g, yield 84%). ESI-MS (m / z): 250.2 [M+H] + .

[0214] Step 3: Compound Int-6c (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-6d (3.6 g, yield 74%). ESI-MS (m / z): 328.2 [M+H] + Step 4: Compound Int-6d (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-6 (330 mg, yield 77%). ESI-MS (m / z): 280.2 [M+H] + .

[0215] Example 1

[0216] 3-(((5-chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-3-yl)amino)pyrimidin-4-yl)amino)methyl)-l-methylpyridin-2(lH)-one

[0217]

[0218] Compound 1 was prepared from the following steps:

[0219]

[0220] Step 1: 2,4,5-trichloropyrimidine la (57 mg, 0.31 mmol) and 3-(aminomethyl)-l-methyl- 1,2-dihydropyridin-2-one hydrochloride lb (50 mg, 0.28 mmol) were dissolved in isopropanol (2 mL), N,N-diisopropylethylamine (85 mg, 0.65 mmol, 0.11 mL) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction was filtered, the solid was washed with isopropanol and dried to give white solid lc (62 mg, yield 75%). ESI-MS (m / z): 285.2 [M+H] + .

[0221] Step 2: Compound lc (62 mg, 0.21 mmol) and Int-1 (42 mg, 0.21 mmol) were dissolved in 1,4-dioxane (5 mL), BrettPhos Pd G3 (19 mg, 0.021 mmol), BrettPhos (23 mg, 0.043 mmol) and cesium carbonate (141 mg, 0.43 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 silica gel column chromatography (methanol / dichloromethane = 1 / 30) to obtain the crude product, which was separated by reverse phase preparative HPLC to obtain white solid 1 (25 mg, yield 26%). ESI-MS (m / z): 442.3 [M+H] + ; 1 HNMR (500 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.86 (s, 1H), 7.69-7.61 (m, 2H), 7.56 (s, 1H), 7.08 (d, J = 6.8 Hz, 1H), 6.19 (t, J = 6.8 Hz, 1H), 4.37 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 3.50 (s, 3H), 3.12 (s, 2H), 2.70 (t, J = 6.0 Hz, 2H), 2.60 (t, J = 5.9 Hz, 2H), 2.33 (s, 3H).

[0222] Example 2

[0223] 3-(((5-chloro-2-((2-ethoxy-6-methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-3-yl)amino)pyrimidin-4-yl)amino)methyl)-l-methylpyridin-2(lH)-one

[0224]

[0225] Compound 2 can be obtained by replacing Int-1 with Int-2 in the second step of Example 1, using similar methods and reaction procedures. ESI-MS (m / z): 456.1 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.87 (s, 1H), 7.69 (t, J = 5.9 Hz, 1H), 7.64 (dd, J = 6.7, 2.0 Hz, 1H), 7.48 (s, 1H), 7.12 - 7.06 (m, 1H), 6.18 (t, J = 6.8 Hz, 1H), 4.38 (d, J = 5.9 Hz, 2H), 4.30 (q, J = 7.0 Hz, 2H), 3.50 (s, 3H), 3.09 (s, 2H), 2.67 (d, J = 5.9 Hz, 2H), 2.59 (d, J = 5.7 Hz, 2H), 2.32 (s, 3H), 1.32 (t, J = 7.0 Hz, 3H).

[0226] Example 3

[0227] 3-(((2-((2-ethoxy-6-methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)amino)methyl)-l-methylpyridin-2(lH)-one

[0228] -4-yl)amino)methyl)-l-methylpyridin-2(lH)-one

[0229]

[0230] Using 2,4-dichloro-5-trifluoromethylpyrimidine to replace 2,4,5-trichloropyrimidine la in the first step of Example 1, then using Int-2 to replace Int-1 in the second step of Example 1, Compound 3 can be obtained in a similar manner and by using similar reaction procedures. ESI-MS (m / z): 490.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.87 (s, 1H), 7.69 (t, J = 5.9 Hz, 1H), 7.64 (dd, J = 6.7, 2.0 Hz, 1H), 7.48 (s, 1H), 7.12 - 7.06 (m, 1H), 6.18 (t, J = 6.8 Hz, 1H), 4.38 (d, J = 5.9 Hz, 2H), 4.30 (q, J = 7.0 Hz, 2H), 3.50 (s, 3H), 3.09 (s, 2H), 2.67 (d, J = 5.9 Hz, 2H), 2.59 (d, J = 5.7 Hz, 2H), 2.32 (s, 3H), 1.32 (t, J = 7.0 Hz, 3H).

[0231] Example 4

[0232] 5-(((5-chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-3- yl)amino)pyrimidin-4-yl)amino)methyl)pyridin-2(lH)-one

[0233]

[0234] Using 5-(aminomethyl)-l,2-dihydropyridin-2-one instead of 3-(aminomethyl)-l- methyl-l,2-dihydropyridin-2-one hydrochloride lb in the first step of Example 1, compound 4 can be obtained in a similar manner and reaction sequence. ESI-MS (m / z): 428.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.96 (s, 1H), 7.74 (s, 1H), 7.68 (t, J = 5.9 Hz, 1H), 7.40 (dd, J = 9.4, 2.6 Hz, 1H), 7.20 (br s, 1H), 6.27 (d, J = 9.4 Hz, 1H), 4.29 (d, J = 5.6 Hz, 2H), 3.88 (s, 3H), 3.34 - 3.30 (m, 2H), 2.74 (t, J = 5.8 Hz, 2H), 2.63 (t, J = 5.9 Hz, 2H), 2.33 (s, 3H).

[0235] Example 5

[0236] 3-(((5-chloro-2-((2,6-dimethyl-5,6,7,8-tetrahydro-l,6-naphthyridin-3- yl)amino)pyrimidin-4-yl)amino)methyl)-l-methylpyridin-2(lH)-one

[0237]

[0238] Using Int-3 instead of Int-l in the second step of Example 1, compound 5 can be obtained in a similar manner and reaction sequence. ESI-MS (m / z): 426.2 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.91 (s, 1H), 7.63 (dd, J = 6.8, 2.0 Hz, 1H), 7.50-7.40 (m, 2H), 7.08-6.96 (m, 1H), 6.18 (t, J = 6.8 Hz, 1H), 4.29 (d, J = 5.9 Hz, 2H), 3.47 (s, 3H), 3.19 (s, 2H), 2.76 (t, J = 6.0 Hz, 2H), 2.62 (t, J = 6.0 Hz, 2H), 2.31 (s, 3H), 2.30 (s, 3H).

[0239] Example 6

[0240] 3-(((5-chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-3- yl)amino)pyrimidin-4-yl)amino)methyl)-l,4,6-trimethylpyridin-2(lH)-one

[0241]

[0242] Compound 6 was prepared by the following steps:

[0243]

[0244] First step: To a suspension of sodium hydride (202 mg, 5.06 mmol, 60% content) in DMF (5 mL) was added a solution of compound 6a (500 mg, 3.37 mmol) in DMF (5 mL) at 0 °C under nitrogen atmosphere. After stirring for 30 min, iodomethane (718 mg, 5.06 mmol, 0.31 mL) was added and the mixture was stirred at room temperature for 16 h. The reaction was diluted with ethyl acetate and washed with water and saturated brine successively. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 6b (230 mg, yield 42%) as a yellow solid. ESI-MS (m / z): 163.1 [M+H] + .

[0245] Second step: Compound 6b (230 mg, 1.42 mmol) was dissolved in methanol (5 mL), and Raney Ni (0.5 mL, suspension in water) and ammonia (0.5 mL) were added. The mixture was stirred at room temperature for 16 h under hydrogen atmosphere (hydrogen balloon). The reaction was filtered through celite, and the filter cake was washed with methanol. The filtrate was concentrated to give compound 6c (200 mg), which was used directly in the next step. ESI-MS (m / z): 167.1 [M+H] + .

[0246] Step 3: Compound 6c (135 mg) was dissolved in isopropanol (2 mL), N, N- diisopropylethylamine (159 mg, 1.23 mmol, 0.21 mL) and 2,4,5-trichloropyrimidine 1a (150 mg, 0.81 mmol) were added, the mixture was stirred at room temperature for 16 hours. The reaction was concentrated, the residue was separated by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain white solid 6d (130 mg). ESI-MS (m / z): 313.2 [M+H] + Step 4: Compound 6d (71 mg, 0.22 mmol) and Int-1 (40 mg, 0.20 mmol) were dissolved in 1,4-dioxane (4 mL), cesium carbonate (202 mg, 0.62 mmol), BrettPhos (22 mg, 0.041 mmol) and BrettPhos Pd G3 (18 mg, 0.020 mmol) were added. The reaction system was replaced by nitrogen and heated to 100 °C and stirred for 16 hours. After the reaction solution was cooled to room temperature, the reaction solution was concentrated, the residue was purified by preparative thin layer chromatography (dichloromethane / methanol = 10 / 1) to obtain the crude product, which was further separated by reverse phase preparative HPLC to obtain compound 6 (10 mg, yield 10%). ESI-MS (m / z): 470.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) d 8.07 (s, 1H), 7.94 (s, 1H), 7.69 (s, 1H), 7.07 (br s, 1H), 6.05 (s, 1H), 4.44 (d, J = 5.5 Hz, 2H), 3.88 (s, 3H), 3.46 - 3.40 (m, 5H), 2.75 (br s, 2H), 2.65 (t, J = 5.5 Hz, 2H), 2.34 (s, 3H), 2.30 (s, 3H), 2.12 (s, 3H).

[0247] Example 7

[0248] 3-(((5-chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)amino)pyrimidin-4-yl)amino)methyl)-4,6-dimethylpyridin-2(1H)-one

[0249]

[0250] Using 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one instead of 3- (aminomethyl)-1-methyl-1,2-dihydropyridin-2-one hydrochloride 1b in the first step of Example 1, compound 7 can be obtained by similar methods and reaction procedures. ESI-MS (m / z): 456.0 [M+H]+ ; 1 HNMR (500 MHz, DMSO-d6) δ 11.59 (br s, 1H), 8.09 (s, 1H), 7.94 (s, 1H), 7.69 (s, 1H), 7.20 (br s, 1H), 5.89 (s, 1H), 4.42 (br s, 2H), 3.89 (s, 3H), 3.42 (s, 2H), 2.75 (br s, 2H), 2.65 (br s, 2H), 2.34 (s, 3H), 2.12 (s, 6H).

[0251] Example 8

[0252] 4-(((5-chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-3- yl)amino)pyrimidin-4-yl)amino)methyl)pyridin-2(lH)-one

[0253]

[0254] Compound 8 was obtained by replacing 3-(aminomethyl)-l-methyl-l,2- dihydropyridin-2-one hydrochloride lb in the first step of Example 1 with 4- (aminomethyl)-l,2-dihydropyridin-2-one in a similar manner and reaction procedure. ESI-MS (m / z): 428.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.90 (s, 1H), 7.83 (t, J = 6.1 Hz, 1H), 7.62 (s, 1H), 7.31 (d, J = 6.7 Hz, 1H), 6.11 (dd, J = 6.8, 1.7 Hz, 1H), 6.08 (s, 1H), 4.41 (d, J = 5.8 Hz, 2H), 3.86 (s, 3H), 3.22 (s, 2H), 2.71 (t, J = 5.9 Hz, 2H), 2.61 (t, J = 5.9 Hz, 2H), 2.33 (s, 3H).

[0255] Example 9

[0256] 3-(((5-chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-3- yl)amino)pyrimidin-4-yl)amino)methyl)-l-ethylpyridin-2(lH)-one

[0257]

[0258] Compound 9 was prepared by the following steps:

[0259]

[0260] First Step: Compound 9a (700 mg, 5.83 mmol) was dissolved in DMF (10 mL), cesium carbonate (2.28 g, 6.99 mmol) was added, then iodoe thane (1.36 g, 8.74 mmol, 0.70 mL) was added dropwise, the reaction mixture was stirred at room temperature overnight. The reaction solution was diluted with water, the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain white solid 9b (730 mg, yield 84%). ESI-MS (m / z): 149.4 [M+H] + ; 1 HNMR (500 MHz, Chloroform-d) δ 7.80 (dd, J = 7.0, 2.0 Hz, 1H), 7.57 (dd, J = 7.0, 2.0 Hz, 1H), 6.28 (t, J = 7.0 Hz, 1H), 4.05 (q, J = 7.0 Hz, 2H), 1.40 (t, J = 7.0 Hz, 3H).

[0261] Second Step: Compound 9b (100 mg, 0.67 mmol) was dissolved in methanol (5 mL), Raney Ni (0.3 mL, aqueous suspension) and ammonia water (1 mL) were added. The mixture was stirred at room temperature under hydrogen atmosphere (hydrogen balloon) overnight. The reaction solution was filtered with celite, the filter cake was washed with methanol, and the filtrate was concentrated to obtain compound 9c (100 mg), which was directly used in the next step reaction.

[0262] Third Step: Compound 9c (100 mg) was dissolved in isopropanol (5 mL), N, N- diisopropylethylamine (169 mg, 1.31 mmol, 0.23 mL) and 2, 4, 5-trichloropyrimidine 1a (180 mg, 0.98 mmol) were added, the reaction mixture was stirred at room temperature overnight. The reaction solution was filtered, the filter cake was washed with isopropanol, and dried to obtain white solid 9d (100 mg). ESI-MS (m / z): 299.2 [M+H] + .

[0263] Step 4: Compound 9d (50 mg, 0.16 mmol) and Int-1 (32 mg, 0.16 mmol) were dissolved in 1,4-dioxane (5 mL), cesium carbonate (108 mg, 0.33 mmol), BrettPhos (9 mg, 0.016 mmol) and BrettPhos PdG3 (15 mg, 0.016 mmol) were added. The reaction was heated to 100 °C overnight after purging with nitrogen. The reaction was cooled to room temperature, concentrated, and 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 9 (8 mg, 11% yield). ESI-MS (m / z): 456.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) d 8.00 (s, 1H), 7.91 (s, 1H), 7.66-7.62 (m, 2H), 7.56 (s, 1H), 7.08 (dd, J = 7.0, 2.0 Hz, 1H), 6.20 (t, J = 7.0 Hz, 1H), 4.39 (d, J = 6.0 Hz, 2H), 3.98 (q, J = 7.0 Hz, 2H), 3.85 (s, 3H), 3.18 (s, 2H), 2.70 (t, J = 6.0 Hz, 2H), 2.60 (t, J = 6.0 Hz, 2H), 2.32 (s, 3H), 1.25 (t, J = 7.0 Hz, 3H).

[0264] Example 10

[0265] 3-(((5-chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-3-yl)amino)pyrimidin-4-yl)amino)methyl)-l,5,6-trimethylpyridin-2(lH)-one

[0266]

[0267] Compound 10 can be obtained by replacing 3-cyano-2-hydroxy-4,6-dimethylpyridine with 2-hydroxy-3-cyano-5,6-dimethylpyridine in the first step of Example 9, using similar methods and reaction procedures. ESI-MS (m / z): 470.1 [M+H] + ; 1HNMR (500 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.93 (s, 1H), 7.58 (t, J = 6.0 Hz, 1H), 7.56 (s, 1H), 6.94 (s, 1H), 4.36 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 3.52 (s, 3H), 3.19 (s, 2H), 2.71 (t, J = 6.0 Hz, 2H), 2.60 (t, J = 6.0 Hz, 2H), 2.33 (s, 3H), 2.27 (s, 3H), 1.99 (s, 3H).

[0268] Example 11

[0269] 3-(((5-chloro-2-((2-cyclopropyl-6-methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-3- yl)amino)pyrimidin-4-yl)amino)methyl)-l-methylpyridin-2(lH)-one

[0270]

[0271] Using 3-(aminomethyl)pyridin-2(lH)-one instead of 3-(aminomethyl)-l-methyl- 1,2-dihydropyridin-2-one hydrochloride lb in the first step of Example 1, compound 11 can be obtained in a similar manner and reaction procedure. ESI-MS (m / z): 428.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.68 (br s, 1H), 8.00 (s, 1H), 7.90 (s, 1H), 7.65-7.62 (m, 1H), 7.56 (s, 1H), 7.33-7.28 (m, 1H), 7.13-7.09 (m, 1H), 6.15 (t, J = 6.6 Hz, 1H), 4.35 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 3.17 (s, 2H), 2.69 (d, J = 5.9 Hz, 2H), 2.60 (d, J = 5.7 Hz, 2H), 2.33 (s, 3H).

[0272] Example 12

[0273] 3-(((5-chloro-2-((2-cyclopropyl-6-methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-3- yl)amino)pyrimidin-4-yl)amino)methyl)-l-methylpyridin-2(lH)-one

[0274]

[0275] Compound 12 was obtained by using Int-5 instead of Int-1 in the second step of Example 1, with similar method and reaction procedure. ESI-MS (m / z): 452.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.90 (s, 1H), 7.62 (dd, J = 6.7, 2.0 Hz, 1H), 7.36 (t, J = 6.0 Hz, 1H), 7.34 (s, 1H), 6.97 (d, J = 6.9 Hz, 1H), 6.15 (t, J = 6.8 Hz, 1H), 4.29 (d, J = 6.0 Hz, 2H), 3.46 (s, 3H), 3.20 (s, 2H), 2.71 (t, J = 6.0 Hz, 2H), 2.61 (t, J = 6.0 Hz, 2H), 2.31 (s, 3H), 2.23 - 2.12 (m, 1H), 0.85 - 0.75 (m, 4H).

[0276] Example 13

[0277] 3-(((5-chloro-2-((2-ethyl-6-methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-3-yl)amino)pyrimidin-4-yl)amino)methyl)-l-methylpyridin-2(lH)-one

[0278]

[0279] Compound 13 was obtained by using Int-4 instead of Int-1 in the second step of Example 1, with similar method and reaction procedure. ESI-MS (m / z): 440.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.89 (s, 1H), 7.62 (dd, J = 6.8, 2.0 Hz, 1H), 7.37 (d, J = 6.0 Hz, 1H), 7.36 (s, 1H), 6.98 (d, J = 6.9 Hz, 1H), 6.16 (t, J = 6.8 Hz, 1H), 4.27 (d, J = 6.0 Hz, 2H), 3.46 (s, 3H), 3.22 (s, 2H), 2.78 (t, J = 6.0 Hz, 2H), 2.69 - 2.61 (m, 4H), 2.32 (s, 3H), 1.07 (t, J = 7.5 Hz, 3H).

[0280] Example 14

[0281] 3-(((5-chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-3- yl)amino)pyrimidin-4-yl)amino)methyl)-l-methylpyrrolidin-2-one

[0282]

[0283] Using 3-(aminomethyl)-l-methylpyrrolidin-2-one instead of 3-(aminomethyl)-l- methyl- 1,2-dihydropyridin-2-one hydrochloride lb in the first step of Example 1, compound 14 can be obtained in a similar manner and reaction procedure. ESI-MS (m / z): 432.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.96 (s, 1H), 7.61 (s, 1H), 7.38 - 7.33 (m, 1H), 3.88 (s, 3H), 3.65 - 3.58 (m, 1H), 3.50 - 3.40 (m, 3H), 3.27 - 3.24 (m, 2H), 2.79 - 2.73 (m, 6H), 2.66 - 2.62 (m, 2H), 2.34 (s, 3H), 2.08 - 2.02 (m, 1H), 1.78 - 1.72 (m, 1H).

[0284] Example 15

[0285] 5-(((5-chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-3- yl)amino)pyrimidin-4-yl)amino)methyl)pyrrolidin-2-one

[0286]

[0287] Using 5-aminomethyl-2-pyrrolidinone instead of 3-(aminomethyl)-l-methyl- 1,2- dihydropyridin-2-one hydrochloride lb in the first step of Example 1, compound 15 can be obtained in a similar manner and reaction procedure. ESI-MS (m / z): 418.4 [M+H] + ; 1HNMR (500 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.95 (s, 1H), 7.75 (br s, 1H), 7.67 (s, 1H), 7.27 (t, J = 5.9 Hz, 1H), 3.89 (s, 3H), 3.82-3.77 (m, 1H), 3.53-3.47 (m, 1H), 3.41 (s, 2H), 3.36-3.30 (m, 1H), 2.75 (t, J = 5.9 Hz, 2H), 2.64 (t, J = 6.3 Hz, 2H), 2.34 (s, 3H), 2.13-2.03 (m, 3H), 1.78-1.71 (m, 1H).

[0288] Example 16

[0289] 3-(((2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-3-yl)amino)-5- methylpyrimidin-4-yl)amino)methyl)-l-methylpyridin-2(lH)-one

[0290]

[0291] Compound 16 was obtained by using 2,4-dichloro-5-methylpyrimidine instead of 2,4,5-trichloropyrimidine la in the first step of Example 1, using similar methods and reaction procedures. ESI-MS (m / z): 422.3 [M+H] + ; 1 HNMR (500 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.95 (s, 1H), 7.75 (br s, 1H), 7.67 (s, 1H), 7.27 (t, J = 5.9 Hz, 1H), 3.89 (s, 3H), 3.82-3.77 (m, 1H), 3.53-3.47 (m, 1H), 3.41 (s, 2H), 3.36-3.30 (m, 1H), 2.75 (t, J = 5.9 Hz, 2H), 2.64 (t, J = 6.3 Hz, 2H), 2.34 (s, 3H), 2.13-2.03 (m, 3H), 1.78-1.71 (m, 1H).

[0292] Example 17

[0293] 3-(((5-fluoro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-3-yl)amino)pyrimidin-4-yl)amino)methyl)-l-methylpyridin-2(lH)-one

[0294]

[0295] Compound 17 was obtained by using 2,4-dichloro-5-fluoropyrimidine instead of 2,4,5-trichloropyrimidine la in the first step of Example 1, using similar methods and reaction procedures. ESI-MS (m / z): 426.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.03 (s, 1H), 8.00-7.91 (m, 2H), 7.64 (dd, J = 6.7, 2.0 Hz, 1H), 7.43 (s, 1H), 7.19 (dd, J = 7.0, 1.8 Hz, 1H), 6.19 (t, J = 6.8 Hz, 1H), 4.37 (d, J = 5.9 Hz, 2H), 3.87 (s, 3H), 3.50 (s, 3H), 3.47 (br s, 2H), 2.88 (br s, 2H), 2.79 (t, J = 5.8 Hz, 2H), 2.49 (s, 3H).

[0296] Example 18

[0297] 4-(((5-chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-3- yl)amino)pyrimidin-4-yl)amino)methyl)-l-methylpyridin-2(lH)-one

[0298]

[0299] Compound 33 was obtained by using 4-(aminomethyl)-l-methyl- 1,2-dihydropyridin-2-one instead of 3-(aminomethyl)-l-methyl-l,2-dihydropyridin-2-one hydrochloride lb in the first step of Example 1, using similar methods and reaction procedures. ESI-MS (m / z): 442.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.03 (s, 1H), 8.00-7.91 (m, 2H), 7.64 (dd, J = 6.7, 2.0 Hz, 1H), 7.43 (s, 1H), 7.19 (dd, J = 7.0, 1.8 Hz, 1H), 6.19 (t, J = 6.8 Hz, 1H), 4.37 (d, J = 5.9 Hz, 2H), 3.87 (s, 3H), 3.50 (s, 3H), 3.47 (br s, 2H), 2.88 (br s, 2H), 2.79 (t, J = 5.8 Hz, 2H), 2.49 (s, 3H).

[0300] Example 19

[0301] 3-(((5-chloro-2-((2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)amino)pyrimidin-4-yl)amino)methyl)-1-methylpyridin-2(1H)-one

[0302]

[0303] Compound 19 was prepared from the following steps:

[0304]

[0305] First Step: Compound 1b (244 mg, 0.85 mmol) and Int-7 (200 mg, 0.71 mmol) were dissolved in 1,4-dioxane (5 mL), cesium carbonate (700 mg, 2.15 mmol), BrettPhos (76 mg, 0.14 mmol) and BrettPhos PdG3 (64 mg, 0.071 mmol) were added. The reaction system was replaced with nitrogen and heated to 120 °C for 16 hours with stirring. After the reaction solution was cooled to room temperature, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 19a crude (300 mg), which was directly used in the next step reaction. ESI-MS (m / z): 528.1 [M+H] + .

[0306] Second Step: The 19a crude (300 mg) obtained in the previous step was dissolved in acetonitrile (5 mL), and p-toluenesulfonic acid monohydrate (323 mg, 1.70 mmol) was added. The reaction mixture was heated to 70 °C and stirred for 2 hours. The reaction solution was concentrated to obtain the crude product of compound 19 (240 mg), and 20 mg of which was purified by reverse phase preparative HPLC to obtain compound 19 (1 mg). ESI-MS (m / z): 428.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.84 (s, 1H), 7.69-7.60 (m, 2H), 7.53 (s, 1H), 7.09 (d, J = 6.9 Hz, 1H), 6.18 (t, J = 6.8 Hz, 1H), 4.37 (d, J = 5.9 Hz, 2H), 3.85 (s, 3H), 3.52 (s, 2H), 3.49 (s, 3H), 2.96 (t, J = 5.8 Hz, 2H), 2.59 (t, J = 5.8 Hz, 2H).

[0307] Example 20

[0308] 2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-3-yl)amino)-4-(((l- methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)amino)pyrimidine-5-carbonitrile

[0309]

[0310] Compound 20 was obtained by using 2,4-dichloro-5-cyanopyrimidine instead of 2,4,5-trichloropyrimidine la in the first step of Example 1, in a similar manner and procedure. ESI-MS (m / z): 433.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.24-8.19 (m, 1H), 8.16 (s, 1H), 7.71 (s, 1H), 7.63-7.60 (m, 1H), 6.98-6.94 (m, 1H), 6.15-6.12 (m, 1H), 4.16 (d, J = 6.1 Hz, 2H), 3.85 (s, 3H), 3.47 (s, 3H), 3.14 (br s, 2H), 2.73 (d, J = 6.1 Hz, 2H), 2.63-2.60 (m, 2H), 2.33 (s, 3H).

[0311] Example 21

[0312] 3-(((5-chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-3-yl)amino)pyrimidin-4- yl)amino)methyl)-l,5-dimethylpyridin-2(lH)-one

[0313]

[0314] Compound 21 was prepared by the following steps:

[0315] First Step: 3-bromo-2-hydroxy-5-methylpyridine 21a (200 mg, 1.06 mmol) was dissolved in tetrahydrofuran (5 mL), NaH (50 mg, 1.28 mmol, content 60%) was added at 0 °C, the reaction solution was stirred for 30 minutes. Iodomethane (227 mg, 1.60 mmol) was added dropwise to the reaction solution, the reaction solution was continued to stir at 0 °C for 2 hours. The reaction solution was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 3) to give compound 21b (200 mg, yield 93%). ESI-MS (m / z): 202.5 [M+H] +Step 2: Compound 21b (180 mg, 0.89 mmol) was dissolved in DMF (5 mL), Pd(PPh3)4(103 mg, 0.09 mmol) and Zn(CN)2(105 mg, 0.89 mmol) were added, and the reaction system was replaced with nitrogen and heated to 130 °C by microwave for 4 h. 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 silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 4) to obtain white solid 21c (122 mg, yield 92%). ESI-MS (m / z): 149.4 [M+H] + .

[0316] Step 3: Compound 21c (120 mg, 0.81 mmol) was dissolved in methanol (5 mL) and ammonia water (0.5 mL), Raney Nickel (0.3 mL, water suspension) and BOC anhydride (212 mg, 0.97 mmol) were added, and the mixture was stirred at room temperature under hydrogen atmosphere (hydrogen balloon) overnight. The reaction solution was filtered with diatomite, and the filtrate was concentrated. The residue was dissolved in 4N hydrochloric acid dioxane solution (5 mL), and the reaction solution was stirred at room temperature for 1 h. The reaction solution was concentrated to obtain the crude product of compound 21d, which was directly used in the next step. ESI-MS (m / z): 153.8 [M+H] + .

[0317] Step 4: The crude product of compound 21d obtained in the previous step and 2,4,5-trichloropyrimidine 1a (169 mg, 0.92 mmol) were dissolved in i-PrOH (5 mL), N,N-diisopropylethylamine (357 mg, 2.76 mmol) was added, and the reaction solution was stirred at 90 °C overnight. After the reaction solution was cooled to room temperature, the reaction solution was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 4) to obtain white solid 21e (98 mg, yield 36%). ESI-MS (m / z): 300.2 [M+H] + .

[0318] Step 5: Compound 21e (50 mg, 0.17 mmol) and Int-1 (36 mg, 0.18 mmol) were dissolved in 1,4-dioxane (5 mL), BrettPhos G3 Pd (15 mg, 17 umol), BrettPhos (9 mg, 17 umol) and cesium carbonate (109 mg, 0.34 mmol) were added. The reaction was heated to 100 °C with stirring overnight after purging with nitrogen. The reaction was cooled to room temperature, and the reaction was filtered with celite. The filtrate was concentrated. The residue was purified by preparative thin layer chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the crude product of compound 21. The crude product was purified by reverse phase preparative HPLC to give compound 21 (6 mg, yield 8%). ESI-MS (m / z): 456.2 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) d 7.99 (s, 1H), 7.89 (s, 1H), 7.62 (t, J = 6.0 Hz, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 6.97 (s, 1H), 4.37 (d, J = 5.8 Hz, 2H), 3.86 (s, 3H), 3.45 (s, 3H), 3.16 (s, 2H), 2.70 (t, J = 5.7 Hz, 2H), 2.60 (t, J = 5.9 Hz, 2H), 2.33 (s, 3H), 1.96 (s, 3H).

[0319] Example 22

[0320] 3-(((2-((2-Methoxy-6-methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-3-yl)amino)pyrimidin-4- yl)amino)methyl)-l-methylpyridin-2(lH)-one

[0321]

[0322] Compound 22 was obtained by using 2,4-dichloropyrimidine instead of 2,4,5- trichloropyrimidine la in the first step of Example 1, using similar methods and reaction procedures. ESI-MS (m / z): 408.3 [M+H] + ; 1HNMR (500 MHz, DMSO-d6) δ 8.08 (br s, 1H), 7.83 (d, J = 5.8 Hz, 1H), 7.68 (br s, 1H), 7.63 (dd, J = 6.7, 1.9 Hz, 1H), 7.28 (s, 1H), 7.19 (br s, 1H), 6.19 (t, J = 6.8 Hz, 1H), 6.10 (br s, 1H), 4.30 (br s, 2H), 3.88 (s, 3H), 3.49 (s, 3H), 3.19 (br s, 2H), 2.70 (t, J = 6.6 Hz, 2H), 2.62 (t, J = 5.7 Hz, 2H), 2.33 (s, 3H).

[0323] Example 23

[0324] 3-(((5-chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-3- yl)amino)pyrimidin-4-yl)amino)methyl)-l,4-dimethylpyridin-2(lH)-one

[0325]

[0326] Compound 23 was prepared from the following steps:

[0327]

[0328] First step: 3-bromo-2-hydroxy-4-methylpyridine 23a (200 mg, 1.06 mmol) was dissolved in tetrahydrofuran (5 mL), NaH (50 mg, 1.28 mmol, content 60%) was added at 0 °C, the reaction solution was stirred for 30 minutes. Iodomethane (227 mg, 1.60 mmol) was added dropwise to the reaction solution, the reaction solution was continued to stir at 0 °C for 2 hours. The reaction solution was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by filtration. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 3) to give yellow oil 23b (210 mg, yield 98%). ESI-MS (m / z): 202.5 [M+H] + .

[0329] Second step: Compound 23b (210 mg, 1.04 mmol) was dissolved in DMF (5 mL), Pd(PPh3)4(120 mg, 0.11 mmol) and Zn(CN)2(122 mg, 1.04 mmol) were added, the reaction system was replaced by nitrogen and heated to 130 °C by microwave for 4 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 silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 4) to obtain white solid 23c (143 mg, yield 92%). ESI-MS (m / z): 149.4 [M+H] + .

[0330] Third step: Compound 23c (143 mg, 0.97 mmol) was dissolved in methanol (5 mL) and ammonia water (0.5 mL), Raney Nickel (0.3 mL, water suspension) and BOC anhydride (253 mg, 1.16 mmol) were added, and the mixture was stirred at room temperature under hydrogen atmosphere (hydrogen balloon) overnight. The reaction solution was filtered with diatomite, and the filtrate was concentrated. The residue was dissolved in 4N hydrochloric acid dioxane solution (5 mL), and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain the crude product of compound 23d, which was directly used in the next step. ESI-MS (m / z): 153.5 [M+H] + .

[0331] Fourth step: The crude product of compound 23d obtained in the previous step and 2,4,5-trichloropyrimidine (176 mg, 0.96 mmol) were dissolved in i-PrOH (5 mL), DIEA (372 mg, 2.88 mmol) was added, and the reaction solution was stirred at 90 °C overnight. After the reaction solution was cooled to room temperature, the reaction solution was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 4) to obtain white solid 23e (161 mg, yield 56%). ESI-MS (m / z): 300.2 [M+H] + .

[0332] Step 5: Compound 23e (50 mg, 0.17 mmol) and Int-1 (32 mg, 0.17 mmol) were dissolved in 1,4-dioxane (5 mL), BrettPhos G3 Pd (15 mg, 17 umol), BrettPhos (9 mg, 17 umol) and cesium carbonate (109 mg, 0.34 mmol) were added. The reaction was heated to 100 °C with stirring overnight after purging with nitrogen. The reaction was cooled to room temperature, and the reaction was filtered with celite. The filtrate was concentrated. The residue was purified by preparative thin layer chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the crude compound 23, which was purified by reverse phase preparative HPLC to give compound 23 (7 mg, 9% yield). ESI-MS (m / z): 456.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) d 8.07 (s, 1H), 7.95 (s, 1H), 7.71 (s, 1H), 7.56 (d, J = 6.9 Hz, 1H), 7.14 (t, J = 5.4 Hz, 1H), 6.12 (d, J = 7.0 Hz, 1H), 4.47 (d, J = 5.4 Hz, 2H), 3.88 (s, 3H), 3.43 (s, 5H), 2.76 (t, J = 5.8 Hz, 2H), 2.65 (t, J = 5.9 Hz, 2H), 2.34 (s, 3H), 2.16 (s, 3H).

[0333] Example 24

[0334] 3-(((5-chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-3- yl)amino)pyrimidin-4-yl)amino)methyl)pyrrolidin-2-one

[0335]

[0336] Compound 24 was prepared from the following steps:

[0337]

[0338] First Step: Dissolve compound 3-(hydroxymethyl)pyrrolidin-2-one 24a (258 mg, 2.24 mmol), phthalimide (362 mg 2.4, 7 mmol) and triphenylphosphine (646 mg, 2.47 mmol) in THF (5 mL), slowly add diisopropyl azodicarboxylate (498 mg, 2.47 mmol, 0.48 mL) dropwise at 0 °C. The reaction mixture is warmed to room temperature and stirred for 18 hours. The reaction is complete by LCMS. The reaction is concentrated and the residue is purified by silica gel column chromatography to give white solid 24b (335 mg, yield 61%). ESI-MS (m / z): 245.5 [M+H] + .

[0339] Second Step: Dissolve compound 24b (335 mg, 1.37 mmol) in ethanol (5 mL), add hydrazine hydrate (171 mg, 2.74 mmol, 0.17 mL, 80% content). The reaction mixture is warmed to 85 °C and stirred for 2 hours, then cooled to room temperature. The reaction is filtered and the filtrate is concentrated to give compound 24c crude (156 mg), which is used directly in the next step.

[0340] Third Step: Dissolve compound 24c crude (156 mg) and 2,4,5-trichloropyrimidine 1a (501 mg, 2.73 mmol) in i-PrOH (5 mL), add DIPEA (529 mg, 4.10 mmol). The reaction mixture is stirred at room temperature for 18 hours. The reaction is concentrated. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give white solid 24d (300 mg, yield 84%). ESI-MS (m / z): 261.2 [M+H] + .

[0341] Fourth Step: Dissolve compound 24d (54 mg, 0.20 mmol) and Int-1 (40 mg, 0.20 mmol) in 1,4-dioxane (4 mL), add cesium carbonate (134 mg, 0.41 mmol), BrettPhos (22 mg, 0.041 mmol) and BrettPhos PdG3 (18 mg, 0.020 mmol). The reaction system is replaced with nitrogen and heated to 110 °C and stirred for 16 hours. The reaction is cooled to room temperature and concentrated. The residue is purified by preparative thin layer chromatography to give crude product, which is separated by reverse phase preparative HPLC to give compound 24 (17 mg, yield 20%). ESI-MS (m / z): 418.2 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.96 (s, 1H), 7.74 (br s, 1H), 7.61 (s, 1H), 7.35-7.31 (m, 1H), 3.88 (s, 3H), 3.65-3.59 (m, 1H), 3.48-3.37 (m, 3H), 3.21-3.11 (m, 2H), 2.74 (t, J = 5.9 Hz, 2H), 2.69-2.61 (m, 3H), 2.34 (s, 3H), 2.14-2.06 (m, 1H), 1.85-1.76 (m, 1H).

[0342] Example 25

[0343] 4-(((5-chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-3-yl)amino)pyrimidin-4-yl)amino)methyl)piperidin-2-one

[0344]

[0345] Using 4-(aminomethyl)piperidin-2-one instead of 3-(aminomethyl)-l-methyl-l,2- dihydropyridin-2-one hydrochloride lb in the first step of Example 1, compound 25 can be obtained in a similar manner and reaction procedure. ESI-MS (m / z): 432.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.94 (s, 1H), 7.64 (s, 1H), 7.43 (s, 1H), 7.39 (t, J = 5.9 Hz, 1H), 3.88 (s, 3H), 3.41 (s, 2H), 3.31-3.27 (m, 2H), 3.21-3.14 (m, 1H), 3.10-3.03 (m, 1H), 2.75 (t, J = 5.9 Hz, 2H), 2.64 (t, J = 5.9 Hz, 2H), 2.34 (s, 3H), 2.23-2.15 (m, 2H), 1.94-1.83 (m, 1H), 1.81-1.74 (m, 1H), 1.36-1.27 (m, 1H).

[0346] Example 26

[0347] 3-(((2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)amino)methyl)-l-methylpyridin-2(lH)-one

[0348] -4-yl)amino)methyl)-l-methylpyridin-2(lH)-one

[0349]

[0350] Compound 26 was obtained by using 2,4-dichloro-5-trifluoromethylpyrimidine instead of 2,4,5-trichloropyrimidine la in the first step of Example 1, using similar methods and reaction procedures. ESI-MS (m / z): 476.2 [M+H] + ; 1 HNMR (500 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.06 (s, 1H), 7.74 (s, 1H), 7.64 (d, J = 6.5 Hz, 1H), 7.57 (br s, 1H), 7.01 (d, J = 6.8 Hz, 1H), 6.19 (t, J = 6.8 Hz, 1H), 4.39 (d, J = 5.2 Hz, 2H), 3.84 (s, 3H), 3.50 (s, 3H), 3.12 (s, 2H), 2.71 (d, J = 6.9 Hz, 2H), 2.60 (t, J = 5.9 Hz, 2H), 2.33 (s, 3H).

[0351] Example 27

[0352] (R)-3-(1-((5-chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3- yl)amino)pyrimidin-4-yl)amino)ethyl)-1-methylpyridin-2(1H)-one

[0353]

[0354] Compound 27 was prepared by the following steps:

[0355]

[0356] First step: Compound 27a (500 mg, 4.06 mmol) was dissolved in DMF (5 mL), cesium carbonate (1.59 g, 4.87 mmol) and iodomethane (692 mg, 4.87 mmol) were added at 0 °C ice bath, the reaction was raised to room temperature and stirred for 16 hours. After the reaction was completed, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (40 mL*2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain white solid compound 27b (290 mg, yield 52%). 1H NMR (500 MHz, CDC13) δ 10.37 (s, 1H), 8.04 (dd, J = 7.0.4.5 Hz, 1H), 7.63 (dd, J = 6.5, 2, 0 Hz, 1H), 6.32 (t, J = 7.0 Hz, 1H), 3.64 (s, 3H). Second step: Compound 27b (200 mg, 1.46 mmol) was dissolved in DCE (5 mL), cesium carbonate (950 mg, 2.92 mmol) and S-tert-butylsulfmamide (212 mg, 1.75 mmol) were added, the mixture was stirred at 65 °C for 16 hours. After the reaction was completed, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL*2). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 27c (330 mg, yield 94%) as a light yellow oil. ESI-MS (m / z): 241.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.15 (dd, J = 6.0.2.0 Hz, 1H), 8.05 (dd, J = 6.5, 2, 5 Hz, 1H), 6.41 (t, J = 7.0 Hz, 1H), 3.52 (s, 3H), 1.15 (s, 9H).

[0357] Third step: Compound 27c (35 mg, 0.14 mmol) was dissolved in DCM (3 mL), methyl magnesium bromide (1 mol / L in THF, 0.29 mL) was added under nitrogen protection at -78 °C, the mixture was stirred at -78 °C for 2 hours. After the reaction was completed, the reaction was quenched by adding saturated ammonium chloride solution (20 mL), the mixture was extracted with ethyl acetate (20 mL*2). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 27d (30 mg, yield 80%) as a light yellow oil. ESI-MS (m / z): 257.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 7.61 (dd, J = 7.0.2.0 Hz, 1H), 7.46 (dd, J = 6.5, 2, 0 Hz, 1H), 6.25-6.20 (m, 1H), 5.68 (d, J = 10.5 Hz, 1H), 4.42-4.37 (m, 1H), 3.44 (s, 3H), 1.29 (d, J = 6.5 Hz, 3H), 1.10 (s, 9H). The stereochemical configuration of the newly generated chiral center of compound 27d was assumed to be R-type.

[0358] Fourth Step: Compound 27d (30 mg, 0.11 mmol) was dissolved in MeOH (2 mL), hydrochloric acid dioxane solution (4 mol / L, 0.12 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain white solid compound 27e (22 mg, yield 99%). ESI-MS (m / z): 153.1 [M+H] + .

[0359] Fifth Step: Compound 27e (22 mg, 0.11 mmol) was dissolved in isopropanol (2 mL), 2,4,5-trichloropyrimidine 1a (32 mg, 0.17 mmol) and N,N-diisopropylethylamine (30 mg, 0.23 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by preparative thin layer chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain white solid compound 27f (31 mg, yield 88%). ESI-MS (m / z): 299.1 [M+H] + .

[0360] Sixth Step: Compound Int-1 (20 mg, 0.10 mmol) and compound 27f (31 mg, 0.10 mmol) were dissolved in 1,4-dioxane (3 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. After the reaction mixture was replaced with nitrogen, it was heated to 100°C and stirred for 18 hours. The reaction solution was filtered with diatomite, the filtrate was concentrated, and the residue was purified by preparative thin layer chromatography (dichloromethane / methanol = 10 / 1) to obtain a crude product, which was separated by reverse phase preparative HPLC to obtain white solid compound 27 (3 mg, yield 6%). ESI-MS (m / z): 299.1 [M+H] + ; 1 HNMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.99 (s, 1H), 7.67-7.63 (m, 1H), 7.57 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.37-7.33 (m, 1H), 6.26-6.19 (m, 1H), 5.35-5.26 (m, 1H), 3.87 (s, 3H), 3.49 (s, 3H), 3.45-3.43 (m, 2H), 2.77-2.71 (m, 2H), 2.68-2.60 (m, 2H), 2.37 (s, 3H), 1.44 (d, J = 6.8 Hz, 3H).

[0361] Following the synthetic routes and methods of synthesis of intermediates described in the above examples, the following examples were prepared.

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369] Biological screening of HPK1 inhibitors and results

[0370] Test Example 1: Detection of the ability of compounds to inhibit HPK1 kinase activity (Method 1)

[0371] The reagents used are as follows

[0372]

[0373] Experimental procedure

[0374] 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 (compound stock solution of 1 mM 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 obtain 8 points of gradient concentrations; 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 added to the control well; after 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 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 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 operation instruction of the kit. The data is described by the half inhibitory concentration IC50 of the compound.

[0375] Compound No. IC50 (nM) Compound No. IC50 (nM) 1 <0.1 2 88 3 45.73 5 18.52 6 2.6 7 <0.1 8 5.43 9 16.12 10 98.54 11 4.98 13 82.59 14 18.99 16 34.42 17 82.82 19 8.52 21 94.75 23 0.16 24 0.71 25 33.99 26 1.35 27 1.92 28 18.35 29 19.43 30 29.78 31 11.80 32 0.85 33 13.56 34 43.51 35 42.28 36 3.44 37 8.03 38 12.82 39 19.01 40 2.06 42 81.06 43 4.26 44 0.48 45 29.40 46 44.97 47 20.97 48 17.94 49 5.78 50 9.67 51 14.61 52 9.00 53 2.69

[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 (Method 2)

[0377] The reagents and cells required for use are as follows

[0378] Experimental reagents:

[0379] Reagent Brand Cat No. Storage Condition RPMI1640 BI 01-100-1ACS 4℃ FBS BI 04-002-1A -80℃ BSA Amresco 0332-1KG 4℃ Phosphate Buffer Solution BI 02-024-1ACS 4℃ Tween-20 Solarbio T8220 RT Anti-human CD3 Antibody invitrogen 16-0037-85 4℃ Anti-human CD28Antibody invitrogen 16-0289-85 4℃ Human IL-2 DuoSet ELISA R&D DY202 4℃

[0380] Experimental cells:

[0381] Cell Cell Type Brand Jurkat E6-1 Human T Lymphocyte Leukemia Cells Institute of Cell Biology, Chinese Academy of Sciences

[0382] Experimental steps

[0383] The 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) to prepare the highest concentration point. The compound solution is gradually diluted with 0.2% DMSO medium by 3 times, and a total of 8 concentration points are prepared. The RPMI 1640 medium solution 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 then incubated in a 37°C cell incubator (Thermo Fisher Scientific, model number: 3111) for 1 h. Then 1 μg / ml Anti-human CD3 Antibody and 1 μg / ml Anti-human CD28 Antibody are added to a final concentration, and incubated in a 37°C cell incubator for 24 h. The IL-2 content in the cell supernatant is detected by Human IL-2 DuoSet ELISA KIT, and the Human IL-2 DuoSet ELISA detection is performed 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.

[0384]

[0385]

[0386]

[0387] Test Example 3: Detection of the agonistic ability of the compound on the secretion of cytokine interleukin-2 (IL-2) of human PBMC cells (Method 3)

[0388] The reagents required for use are as follows

[0389]

[0390]

[0391] Information on the source of experimental cells:

[0392]

[0393] Experimental steps

[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℃ water bath pot for thawing and recovery, the cells are resuspended with RPMI 1640 culture medium (containing 10% FBS in this test), and centrifuged and washed twice; then the human PBMC cells are resuspended in RPMI 1640 culture medium for standby. Compound powder is dissolved in DMSO to 10mM, 2ul of compound is added to 998ul of RPMI 1640 culture medium, and vortexed to mix to obtain the highest concentration point. The compound solution is gradually diluted with 0.2% DMSO culture medium for 3 times, and a total of 8 concentration points. The RPMI 1640 culture medium solution containing 0.1% DMSO is treated as a control. 1x105 human PBMC cells are added to each well of a corning 96-well cell culture plate (model number: 3599), then an equal volume of compound diluent is added, and the control group is added with 0.2% DMSO-containing RPMI 1640 culture medium, and placed in a 37℃ cell incubator (Thermo Fisher Scientific, model number: 3111) for incubation for 1h. Then 0.01ug / ml Anti-human CD3 Antibody and 1ug / ml Anti-human CD28 Antibody are added to a final concentration, and placed in a 37℃ cell incubator for incubation for 24h. The IL-2 content in the cell supernatant is detected by Human IL-2 DuoSet ELISA KIT, 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.

[0395]

[0396]

[0397]

[0398] The above results show that the compound of the present application can significantly increase IL-2.

Claims

1. A compound having the following structure:

2. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and Pharmaceutically usable carriers.

3. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 2 in the preparation of a medicament for the prevention and / or treatment of inflammatory diseases and autoimmune diseases by inhibiting HPK1 kinase.

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