WO2022214008A1

WO2022214008A1 - Highly active hpk1 kinase inhibitor

Info

Publication number: WO2022214008A1
Application number: PCT/CN2022/085445
Authority: WO
Inventors: 陈宇锋; 时永强; 吕萌; 杨寒; 温俏冬; 武朋; 刘灿丰; 陈凯旋; 王友平; 何南海
Original assignee: 杭州阿诺生物医药科技有限公司
Priority date: 2021-04-08
Filing date: 2022-04-07
Publication date: 2022-10-13
Also published as: CN116848103A; TW202304906A

Abstract

A compound having a structure of formula (I) or formula (II) and having the activity of inhibiting HPK1 kinase and a pharmaceutical composition comprising said compound and a use thereof in the prevention and/or treatment of cancer, tumors, inflammatory diseases, autoimmune diseases or immune mediated diseases.

Description

Highly active HPK1 kinase inhibitor

This application claims priority to Chinese Patent Application No. 202110377409.5 filed with the State Intellectual Property Office of China on April 8, 2021, entitled "Highly Active HPK1 Kinase Inhibitor", the content of which is incorporated herein by reference in its entirety.

technical field

The present invention relates to a heterocyclic compound, in particular to a highly active HPK1 kinase inhibitor and use thereof.

Background technique

HPK1, a member of the MAP4K family, is mainly expressed in cells of the hematopoietic system and acts as an intracellular negative regulator of T cell proliferation and signaling. After antigen stimulation of T cells, the adaptor protein SLP-76 in the cytoplasm is recruited to the lipid membrane TCR complex, providing binding sites for signal transduction-related kinases to achieve TCR-mediated signal transmission and induce T cell activation. In this process, HPK1 is activated by phosphorylation by the tyrosine kinases Lck and Zap70, and is involved in the regulation of T cell receptor protein interactions. HPK1 phosphorylates the Ser376 site of the adaptor protein SLP-76, so that SLP-76 binds to the scaffold protein 14-3-3ε and is degraded by the proteasome, and this effect reduces the binding of SLP-76 to signal transduction-related kinases It blocked TCR signal transduction, which in turn inhibited T cell activation and proliferation. On the other hand, HPK1 is also involved in regulating the maturation and activation of dendritic cells (DCs), especially inhibiting the expression of T-cell activation-related proteins such as CD80, CD86 and MHC complexes in DCs, thereby affecting DC regulation The role of T cell activation; the presentation of tumor antigens by activated DCs and the mutual cooperation between DCs 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 such as PGE2 and TGF-β in the tumor microenvironment, and the immunosuppressive effects mediated by these factors are also related to HPK1. Overall, small molecule compounds that specifically target and inhibit HPK1 can improve T cell function, enhance DC cell function and simultaneously reverse the tumor immunosuppressive microenvironment. effect. However, there is currently a lack of effective inhibitors of HPK1 kinase activity.

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

SUMMARY OF THE INVENTION

The present invention has unexpectedly found a compound having the activity of inhibiting HPK1 kinase or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof. The compound of the present invention has the following structure of formula I or formula II:

in,

R ₁ represents hydrogen, (C ₁ -C ₆ )alkyl, halogen, (C ₁ -C ₆ )alkoxy, OR ^a , NR ^a R ^b , cyano or (C ₃ -C ₆ )cycloalkyl;

R ₂ represents hydrogen, halogen, (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ )alkynyl, -O-(C ₁ -C ₆ )alkyl, -S-(C ₁ -C ₆ )alkyl, -S(O)-(C ₁ -C ₆ )alkyl, -S(O) ₂ -(C ₁ -C ₆ )alkyl, -NR ^a R ^b , cyano, -COOR ^a , -CONR ^a R ^b , -OCONR ^a R ^b , -NR ^a COR ^b , -P(O)R ^a R ^b , -S(O) ₂ NR ^a R ^b or -NR ^a S(O) ₂ R ^b ;

R ₃ represents hydrogen, (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, -(C ₀ -C ₆ alkylene)(C ₃ -C ₈ )cycloalkyl, -(C ₀ -C ₆ alkylene) (4-10 membered) heterocycloalkyl, -(C ₀ -C ₆ alkylene)(C ₆ -C ₁₀ ) aryl or -(C ₀ -C ₆ alkylene ) (5-10 yuan) heteroaryl;

R ₄ and R ₄ ′ each independently represent hydrogen, (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, halogen; or R ₄ and R _{4 ′} together form the carbon atom to which it is attached 3-6 membered ring, the ring can also optionally contain 0, 1 or 2 heteroatoms selected from N, O, S;

R ₅ represents hydrogen, (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, (C ₃ -C ₈ )cycloalkyl or (4-8 membered)heterocycloalkyl;

R ₆ and R _6' each independently represent hydrogen, (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl or halogen; or R ₆ and R _6' together form the carbon atom to which it is attached 3-6 membered ring, the ring can also optionally contain 0, 1 or 2 heteroatoms selected from N, O, S;

R ₇ and R _7' each independently represent hydrogen, (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl or halogen; or R ₇ and R _7' together form the carbon atom to which it is attached 3-6 membered ring, the ring can also optionally contain 0, 1 or 2 heteroatoms selected from N, O, S;

W ₁ means CR ^W1 or N;

W ₂ means CR ^W2 or N;

wherein, R ^W1 and R ^W2 each independently represent hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, -OR ^a , - NR ^a R ^b , cyano, -COOR ^a , -CONR ^a R ^b , -OCONR ^a R ^b , -NR ^a COR ^b , -P(O)R ^a R ^b , -S(O) ₂ NR ^a R ^b , -NR ^a S(O) ₂ R ^b , -SR ^a , -S(O) R ^a or -S(O) ₂ R ^a ;

For alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl as defined above, it may be optionally substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, halo(C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkoxy, -(C ₁ -C ₆ -idene Alkyl)-O-( _C1 - _C6 )alkyl, (C3 _- _C8 )cycloalkyl, halo(C3 _- _C8 )cycloalkyl, halogen, -CN, oxo, -NR ^a R ^b , -OR ^a , -SR ^a , -(C ₁ -C ₆ alkylene)hydroxyl, -C(O)R ^a , -N(R ^a )C(O)R ^a , -NR ^a C (O)OR ^a , -NR ^a SO ₂ R ^a , -C(O)OR ^a , -C(O)N R ^a R ^b , -S(O) ₂ N R ^a R ^b , -S(O)R ^a , -S(O) ₂ R ^a , -P(O)R ^a R ^b ;

Wherein, R ^a and R ^b each independently represent hydrogen, (C ₁ -C ₆ )alkyl or halogenated (C ₁ -C ₆ )alkyl; or R ^a and R ^b together with the adjacent atoms A 3-8 membered ring is formed, and the ring can optionally contain 0, 1 or 2 heteroatoms selected from N, O, and S;

m, n, o, and r each independently represent 0, 1, 2, and 3.

In a preferred technical solution of the present invention, wherein, R ₁ represents hydrogen, (C ₁ -C ₆ )alkyl, halogen or halogenated (C ₁ -C ₆ )alkyl.

In a preferred technical solution of the present invention, wherein, R ₂ represents hydrogen, halogen, (C ₁ -C ₆ ) alkyl, -(C ₁ -C ₆ alkylene) hydroxyl, (C ₂ -C ₆ ) alkenyl , (C ₂ -C ₆ )alkynyl, -OR ^a , -NR ^a R ^b , cyano, -COOR ^a , -CONR ^a R ^b , -OCONR ^a R ^b , -NR ^a COR ^b , -P(O ) R ^a R ^b , -S(O) ₂ NR ^a R ^b , -NR ^a S(O) ₂ R ^b , -SR ^a , -S(O) R ^a or -S(O) ₂ R ^a ; wherein , R ^a , R ^b each independently represent hydrogen, (C ₁ -C ₆ ) alkyl or halogenated (C ₁ -C ₆ ) alkyl; or R ^a , R ^b together with the adjacent atoms together form A 3-8 membered ring, the ring may optionally contain 0, 1 or 2 heteroatoms selected from N, O and S.

In the preferred technical solution of the present invention, wherein, R ₃ represents hydrogen, (C ₁ -C ₆ ) alkyl, halogenated (C ₁ -C ₆ ) alkyl, -(C ₁ -C ₆ alkylene) hydroxyl , -(C ₀ -C ₆ alkylene) (C ₃ -C ₈ ) cycloalkyl, -(C ₀ -C ₆ alkylene) (4-10 membered) heterocycloalkyl, -(C ₀ - C ₆ alkylene) (C ₆ -C ₁₀ ) aryl, -(C ₀ -C ₆ alkylene) (5-10 membered) heteroaryl, -(C ₀ -C ₆ alkylene) COOR ^a , -(C ₀ -C ₆ alkylene) CONR ^a R ^b , -(C ₀ -C ₆ alkylene) P(O)R ^a R ^b , -(C ₀ -C ₆ alkylene) S ( O) ₂ NR ^a R ^b , -(C ₀ -C ₆ alkylene)SR ^a , -(C ₀ -C ₆ alkylene)S(O)R ^a or -(C ₀ -C ₆ alkylene) )S(O) ₂ R ^a .

In a preferred technical solution of the present invention, wherein, R ₄ and R ₄ ' each independently represent hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, halogen, halogenated (C _{1 )} -C ₆ ) alkyl or hydroxy (C ₁ -C ₆ ) alkyl; or R ₄ and R _4' together with the carbon atom connected to it form a 3-6 membered ring, the ring may also optionally contain O, 1 or 2 heteroatoms selected from N, O, S.

In a preferred technical solution of the present invention, wherein, R ₅ represents hydrogen, (C ₁ -C ₆ ) alkyl, -(C ₁ -C ₆ alkylene) hydroxyl, halogenated (C ₁ -C ₆ ) alkyl , (C ₃ -C ₈ )cycloalkyl or (4-8 membered) heterocycloalkyl.

In the preferred technical solution of the present invention, wherein, R ₆ and R _6' each independently represent hydrogen, (C ₁ -C ₆ ) alkyl, -(C ₁ -C ₆ alkylene) hydroxyl, halogenated (C 6 ) ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl or halogen; or R ₆ and R _6' together with the carbon atom connected to it form a 3-6-membered ring, the ring may also optionally contain 0, 1 or 2 heteroatoms selected from N, O, S.

In the preferred technical solution of the present invention, wherein, R ₇ and R _7' each independently represent hydrogen, (C ₁ -C ₆ ) alkyl, -(C ₁ -C ₆ alkylene) hydroxyl, halogenated (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl or halogen; or R ₇ and R _7' together with the carbon atom connected to it form a 3-6-membered ring, the ring may also optionally contain 0, 1 or 2 heteroatoms selected from N, O, S.

Preferably, the compound of the present invention has the following structure:

It is particularly noted that in this text, when referring to a "compound" having a specific structural formula, its stereoisomers, diastereomers, enantiomers, racemic mixtures and isotopes are generally also encompassed derivative.

It is well known to those skilled in the art that salts, solvates and hydrates of a compound are alternative existing forms of the compound, and they can all be converted into the compound under certain conditions. When referring to a compound, it generally includes its pharmaceutically acceptable salts, and further includes its solvates and hydrates.

Similarly, when referring to a compound herein, prodrugs, metabolites and nitrogen oxides thereof are generally also included.

The pharmaceutically acceptable salts of the present invention can be formed using, for example, the following inorganic or organic acids: "Pharmaceutically acceptable salts" refers to salts that, within the scope of sound medical judgment, are suitable for use in contact with humans and lower levels of and other animal tissues, without undue toxicity, irritation, allergic reactions, etc., can be called a reasonable benefit/risk ratio. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base or free acid with a suitable reagent, as outlined below. For example, the free base functionality can be reacted with a suitable acid. In addition, when the compounds of the present invention bear an acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts, such as alkali metal salts (eg, sodium or potassium salts); and alkaline earth metal salts (eg, calcium or magnesium salts) . Examples of pharmaceutically acceptable non-toxic acid addition salts are amino groups with inorganic acids (eg, hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric) or organic acids (eg, acetic, oxalic, maleic, tartaric, citric acid, succinic acid or malonic acid), or by using other methods in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, sodium alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, Camphorsulfonate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerin Phosphate, gluconate, hernisulfate, heptanoate, caproate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malic acid salt, maleate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectic acid Salt, persulfate, 3-phenylpropionate, phosphate, bitter salt, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluene Sulfonate, undecanoate, valerate, etc. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, where appropriate, nontoxic ammonium salts, quaternary ammonium salts, and ammonium cations formed with counter ions, for example, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower Alkyl sulfonates and aryl sulfonates.

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

The precursors or metabolites described in the present invention may be those known in the art, as long as the precursors or metabolites can be metabolized in vivo to form the target compound. For example, "prodrugs" refer to those prodrugs of the compounds of the present invention which, within the scope of sound medical judgment, are suitable for use in contact with human and lower animal tissues without undue toxicity, irritation, allergic response, etc., Have a reasonable benefit/risk ratio and be valid for its intended use. The term "prodrug" refers to a compound that is rapidly transformed in vivo to yield the parent compound of the above formula, eg, by in vivo metabolism, or N-demethylation of a compound of the present invention.

"Solvate" as used herein means a physical association of a compound of the present invention with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. In certain instances, such as when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid, the solvate will be capable of isolation. Solvent molecules in a solvate may exist in regular and/or disordered arrangements. Solvates may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses both solution phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

The "stereoisomerism" mentioned in the present invention is divided into conformational isomerism and configurational isomerism. Configurational isomerism can also be divided into cis-trans isomerism and optical isomerism (ie optical isomerism). A certain configuration of organic molecules due to the rotation or distortion of carbon and carbon single bonds, a stereoisomerism phenomenon in which each atom or atomic group of the molecule has different arrangements in space. The common structures of alkane and cycloalkane compounds Such as the chair conformation and boat conformation appearing in the cyclohexane structure. "Stereoisomer" means when the compounds of the present invention contain one or more asymmetric centers and are thus available as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and single diastereomers. The compounds of the present invention have asymmetric centers, each of which produces two optical isomers, and the scope of the present invention includes all possible optical isomers and diastereoisomeric mixtures and pure or partially pure compounds . The compounds described herein may exist in tautomeric forms having different points of attachment of the hydrogen through displacement of one or more double bonds. For example, a ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included in the compounds of the present invention. Enantiomers, diastereomers, racemates, mesomers, cis-trans isomers, tautomers, geometric isomers of all compounds of formula (I) or formula (II) isomers, epimers and mixtures thereof, etc., are all included in the scope of the present invention.

"Isotopic derivatives" of the present invention refer to molecules in which compounds are isotopically labeled in this patent. Isotopes commonly used as isotopic labels are: hydrogen isotopes, ² H and ³ H; carbon isotopes: ¹¹ C, ¹³ C and ¹⁴ C; chlorine isotopes: ³⁵ Cl and ³⁷ Cl; fluorine isotopes: ¹⁸ F; iodine isotopes: ¹²³ I and ¹²⁵ I; nitrogen isotopes: ¹³ N and ¹⁵ N; oxygen isotopes: ¹⁵ O, ¹⁷ O and ¹⁸ O and sulfur isotopes ³⁵ S. These isotopically labeled compounds can be used to study the distribution of medicinal molecules in tissues. In particular, deuterium ³ H and carbon ¹³ C are more widely used because of their ease of labeling and detection. Substitution of certain heavy isotopes, such as deuterium ( ² H), can enhance metabolic stability, prolong half-life and thus provide therapeutic advantages for the purpose of reducing dosage. Isotopically-labeled compounds are generally synthesized from labeled starting materials, and their synthesis is accomplished using known synthetic techniques as for non-isotopically-labeled compounds.

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

Furthermore, the present invention provides a pharmaceutical composition for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease, comprising the present invention compound as active ingredient.

In addition, the present invention provides a method for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease, comprising: A mammal in need thereof is administered a compound of the present invention.

Representative examples of inflammatory, autoimmune, and immune-mediated diseases may include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis , other arthritic conditions, lupus, systemic lupus erythematosus (SLE), skin-related disorders, psoriasis, eczema, dermatitis, atopic dermatitis, pain, lung disease, lung inflammation, adult respiratory distress syndrome (ARDS) , pulmonary sarcoidosis, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease (COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia-reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjögren's syndrome, autoimmune thyroid disease, urticaria (rubella), multiple sclerosis, scleroderma, organ transplant rejection, xenotransplantation, idiopathic Thrombocytopenic purpura (ITP), Parkinson's disease, Alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, allergic sinusitis, leukemia, lymphoma, B cell lymphoma, T-cell lymphoma, myeloma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hairy cell leukemia, Ho Jie King's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), diffuse large B-cell lymphoma, and follicular lymphoma.

Representative examples of cancers or tumors may include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neurocytoma, rectal cancer , colon cancer, familial adenomatous polyposis cancer, hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, endometrial cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, brain tumors such as Glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphoblastic leukemia ( ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder carcinoma, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, Osteosarcoma, chondrosarcoma, sarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, or plasmacytoma.

A compound of the present invention or a pharmaceutically acceptable salt thereof may provide enhanced anticancer effects when administered in combination with another anticancer agent or immune checkpoint inhibitor for the treatment of cancer or tumors .

Representative examples of anticancer agents for treating cancer or tumors may include, but are not limited to, cell signal transduction inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carbamide mustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin , epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifen, flutamide, gonarelin analogues, mediclidinium Progesterone, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alfa, calcium folinate, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brinyb, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dabrafenib Cantinib, danucetib, dasatinib, multivitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lavatinib Patinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motisanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib , regorafenib, rigosertib, rucaparib, ruxolitinib, cicatinib, saridegib, sorafenib, sunitinib, tiratinib, tivantinib, tivozanib, tofacitinib, Trametinib, vandetanib, veliparib, vemurafenib, vemodagi, volasertib, alemtuzumab, bevacizumab, belemtuzumab vedotin, catuxetone Antibiotic, Cetuximab, Denosumab, Gemtuzumab, Ipilimumab, Nimotuzumab, Ofatumumab, Panitumumab, Rituximab, Tosimer Monoclonal antibody, trastuzumab, PI3K inhibitor, CSF1R inhibitor, A2A and/or A2B receptor antagonist, IDO inhibitor, anti-PD-1 antibody, anti-PD-L1 antibody, LAG3 antibody, TIM-3 antibody and anti-CTLA-4 antibodies or any combination thereof.

The compounds of the present invention, or pharmaceutically acceptable salts thereof, may provide enhancement when administered in combination with additional therapeutic agents useful in the treatment of inflammatory, autoimmune, and immune-mediated diseases therapeutic effect.

Representative examples of therapeutic agents for the treatment of inflammatory diseases, autoimmune diseases, and immune-mediated diseases may include, but are not limited to, steroidal drugs (eg, prednisone, prednisone, methylhydroponil) sone, cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNFα agents (eg, etanercept, infliximab, adalix monoclonal antibodies, etc.), calcineurin inhibitors (eg, tacrolimus, pimecrolimus, etc.), and antihistamines (eg, diphenhydramine, hydroxyzine, loratadine, ebaz) Cetirizine, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one therapeutic agent selected from them may be included in the pharmaceutical composition of the present invention.

The compound of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally as an active ingredient in an effective amount ranging from 0.1 to 2,000 mg/kg body weight/day, in mammals including humans (about 70 kg body weight), Preferably from 1 to 1,000 mg/kg body weight/day, and administered in single or 4 divided doses per day, or on/off schedule. The dosage of the active ingredient can be adjusted according to a number of relevant factors, such as the condition of the subject to be treated, the type and severity of the disease, the rate of administration, and the opinion of the physician. In some cases, amounts less than the above doses may be appropriate. An amount greater than the above dose may be used if it does not cause adverse side effects and the amount may be administered in divided doses per day.

In addition, the present invention also provides a method for preventing and/or treating tumors, cancer, viral infections, organ transplant rejection, neurodegenerative diseases, attention-related diseases or autoimmune diseases, comprising A compound of the present invention or a pharmaceutical composition of the present invention is administered to a mammal in need thereof.

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

Pharmaceutical compositions of the present invention for oral administration can be prepared by admixing the active ingredient with a carrier such as: cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, hard Magnesium fatty acid, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers and diluents. Examples of carriers employed in the injectable compositions of the present invention are water, saline solutions, glucose solutions, glucose-like solutions, alcohols, glycols, ethers (eg, polyethylene glycol 400), oils, Fatty acids, fatty acid esters, glycerides, surfactants, suspending and emulsifying agents.

Other features of this invention will become apparent in the course of describing exemplary embodiments of this invention, which are given to illustrate the invention and not to limit it, and the following examples were prepared using the methods disclosed in this invention. , isolation and characterization.

The compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis, using the methods described below as well as synthetic methods known in the art of synthetic organic chemistry or by variations thereof known to those skilled in the art. Compounds of the present invention were synthesized. Preferred methods include, but are not limited to, those described below. Reactions are carried out in a solvent or solvent mixture suitable for the kit materials used and for the transformation being effected. Those skilled in the art of organic synthesis will understand that the functionality present on the molecule is consistent with the proposed transformation. This sometimes requires the discretion to alter the order of synthetic steps or starting materials to obtain the desired compounds of the invention.

Detailed ways

the term

Unless otherwise stated, terms used in the present application, including the specification and claims, are defined as follows. It must be noted that, in the specification and the appended claims, the singular form "a" includes the plural unless the context clearly dictates otherwise. Conventional methods of mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology were used unless otherwise stated. In this application, the use of "or" or "and" means "and/or" unless stated otherwise.

In the specification and claims, a given chemical formula or name shall encompass all stereo and optical isomers and racemates in which such isomers exist. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the present invention. Numerous geometric isomers of C=C double bonds, C=N double bonds, ring systems, etc. may also exist in the compounds, and all such stable isomers are encompassed by the present invention. The present invention describes cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention, and which may be isolated as a mixture of isomers or as separate isomeric forms. The compounds of the present invention can be isolated in optically active or racemic forms. All methods used to prepare the compounds of the present invention and intermediates prepared therein are considered part of this invention. In the preparation of enantiomeric or diastereomeric products, they can be separated by conventional methods, eg by chromatography or fractional crystallization. Depending on the process conditions, the final product of the invention is obtained in free (neutral) or salt form. Both free forms and salts of these final products are within the scope of the present invention. If desired, one form of a compound can be converted into another. Free bases or acids can be converted into salts; salts can be converted into free compounds or another salt; mixtures of isomeric compounds of the present invention can be separated into individual isomers. The compounds of the present invention, their free forms and salts, may exist in various 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 thereby rearranged. It is to be understood that all tautomeric forms that may exist are encompassed by the present invention.

Unless otherwise defined, the definitions of the substituents of the present invention are each independent rather than interrelated, for example, for R ^a (or R ^a ') in a substituent, it is independent in the definitions of different substituents . Specifically, selecting a definition for ^Ra (or ^Ra ') in one substituent does not mean that ^Ra (or ^Ra ') has the same definition in other substituents. More specifically, for example (to list only non-exhaustive) for NR ^a R ^a ', when the definition of R ^a (or R ^a ') is selected from hydrogen, it does not mean that in -C(O)-NR In ^a R ^a ', R ^a (or R ^a ') must be hydrogen.

Unless otherwise defined, when a substituent is annotated as "optionally substituted", the substituent is selected from, for example, substituents such as alkyl, cycloalkyl, aryl, heterocyclyl, halo, hydroxy, alkane oxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine groups (wherein the 2 amino substituents are selected from alkyl, aryl or arylalkyl), alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkylthio group, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfonamido such as -SO ₂ _NH2 , substituted sulfonamido, nitro, cyano, carboxyl, carbamoyl such as _-CONH2 , substituted carbamoyl such as -CONH alkyl, -CONH aryl, -CONH arylalkyl or at nitrogen In the case of having two substituents selected from alkyl, aryl or arylalkyl, alkoxycarbonyl, aryl, substituted aryl, guanidino, heterocyclic groups such as indolyl, imidazolyl, Furyl, thienyl, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, etc. and substituted heterocyclyl.

The terms "alkyl" or "alkylene" as used herein are intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms. For example, " _C1 - _C6 alkyl" means an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (eg n-propyl and isopropyl), butyl (eg n-butyl, isobutyl, tert-butyl) and Pentyl (eg n-pentyl, isopentyl, neopentyl).

The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing one or more double bonds and usually 2 to 20 carbon atoms in length. For example, "C2-C6 alkenyl" contains two to six carbon atoms. Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.

The term "alkynyl" refers to a straight or branched chain hydrocarbon group containing one or more triple bonds and usually 2 to 20 carbon atoms in length. For example, "C2 _- _C6alkynyl " contains two to six carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, and the like.

The term "alkoxy" or "alkyloxy" refers to -O-alkyl. "C ₁ -C ₆ alkoxy" (or alkyloxy) is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ alkoxy. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy), and t-butoxy. Similarly, "alkylthio" or "thioalkoxy" represents an alkyl group, as defined above, having the indicated number of carbon atoms attached through a sulfur bridge; eg, methyl-S- and ethyl-S-.

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

The term "aryl", alone or as part of a larger moiety such as "aralkyl", "aralkoxy" or "aryloxyalkyl", refers to a single ring having a total of 5 to 12 ring members , bicyclic or tricyclic ring systems, wherein at least one ring in the system is aromatic and wherein each ring in the system contains from 3 to 7 ring members. In certain embodiments of the present invention, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthalene base. The term "aralkyl" or "arylalkyl" refers to 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 the cycloalkyl or aromatic ring. For example, dashed lines drawn from a ring system indicate that the bond may be attached to any suitable ring atom.

The term "cycloalkyl" refers to a monocyclic or bicyclic cyclic alkyl group, preferably having 3 to 8 ring members. A monocyclic cyclic alkyl group refers to a C3 _- _C8 cyclic alkyl group, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norbornyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". Bicyclic cyclic alkyl groups include bridged, spiro or fused ring cycloalkyl groups.

The term "cycloalkenyl" refers to a monocyclic or bicyclic cyclic alkenyl group, preferably having 3 to 8 ring members. _Monocyclic cyclic alkenyl refers to C3 _- C8 cyclic alkenyl, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and norbornyl. Branched cycloalkenyl groups such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl". Bicyclic cyclic alkenyl groups include bridged, spiro or fused ring cyclic alkenyl groups.

"Halo" or "halogen" includes fluorine, chlorine, bromine and iodine. "Haloalkyl" is intended to include branched and straight chain saturated aliphatic aliphatic groups having the indicated number of carbon atoms (preferably 1 to 6 carbon atoms) substituted with 1 or more halogens (preferably 1, 2 or 3 halogens) hydrocarbon group. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoroethyl propyl and heptachloropropyl. Examples of haloalkyl groups also include "fluoroalkyl groups" which are intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms and substituted with one or more fluorine atoms.

"Haloalkoxy" or "haloalkyloxy" means a haloalkyl group, as defined above, having the indicated number of carbon atoms (preferably 1 to 6 carbon atoms) attached through an oxygen bridge. For example, " _haloC1 - _C6alkoxy " is intended to include _C1 , _C2 , C3, _C4 , _C5 , _C6 _haloalkoxy . Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" represents a haloalkyl group as defined above having the indicated number of carbon atoms (preferably 1 to 6 carbon atoms) attached through a sulfur bridge; eg trifluoromethyl base-S- and pentafluoroethyl-S-.

In the present disclosure, the expression C _x1 -C _x2 is used when referring to some substituent groups, which means that the number of carbon atoms in the substituent groups may be x1 to x2. For example, C ₀ -C ₈ indicates that the group contains 0, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and C ₁ -C ₈ indicates that the group contains 1, 2, 3 , 4, 5, 6, 7 or 8 carbon atoms, C ₂ -C ₈ means the group contains 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C ₃ -C ₈ means the group The group contains 3, 4, 5, 6, 7 or 8 carbon atoms, C ₄ -C ₈ means the group contains 4, 5, 6, 7 or 8 carbon atoms, and C ₀ -C ₆ means the A group contains 0, 1, 2, 3, 4, 5 or 6 carbon atoms, C ₁ -C ₆ means the group contains 1, 2, 3, 4, 5 or 6 carbon atoms, C ₂ -C ₆ indicates that the group contains 2, 3, 4, 5 or 6 carbon atoms and C3 _- _C6 indicates that the group contains 3, 4, 5 or 6 carbon atoms.

In this disclosure, the expression "x1-x2 membered ring" is used when referring to cyclic groups (eg, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl), which refers to the ring atoms of the group The number may be x1 to x2. For example, the 3-12 membered cyclic group can be a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; 3-6 membered ring means that the cyclic group can be a 3, 4, 5 or 6 membered ring, and the number of ring atoms can be 3, 4, 5 or 6 ; 3-8 membered ring means that the cyclic group can be a 3, 4, 5, 6, 7 or 8 membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7 or 8; 3-9 Ring member means that the cyclic group can be a 3, 4, 5, 6, 7, 8 or 9 membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7, 8 or 9; 4-7 Ring member means that the cyclic group can be 4, 5, 6 or 7 membered ring, and the number of ring atoms can be 4, 5, 6 or 7; 5-8 membered ring means that the cyclic group can be 5, 6, 7 or 8 membered ring, the number of ring atoms can be 5, 6, 7 or 8; 5-12 membered ring means that the cyclic group can be 5, 6, 7, 8, 9, 10, 11 or 12-membered ring, the number of ring atoms can be 5, 6, 7, 8, 9, 10, 11 or 12; 6-12-membered ring means that the cyclic group can be 6, 7, 8, 9, 10, 11- or 12-membered ring, the number of ring atoms may be 6, 7, 8, 9, 10, 11 or 12. The ring atoms may be carbon atoms or heteroatoms, eg heteroatoms selected from N, O and S. When the ring is a heterocycle, the heterocycle may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more ring heteroatoms, eg selected from N, O and S of heteroatoms.

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

The term "heteroaryl" means a stable 3-, 4-, 5-, 6-, or 7-membered aromatic monocyclic or aromatic bicyclic or 7-, 8-, 9-, 10-, 11-, 12-membered Aromatic polycyclic heterocycles, which are fully unsaturated, partially unsaturated, and which contain carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; and include Any of the following polycyclic groups wherein any heterocycle as defined above is fused to a benzene ring. Nitrogen and sulfur heteroatoms can optionally be oxidized. Nitrogen atoms are substituted or unsubstituted (ie, N or NR, where R is H or, if defined, another substituent). Heterocycles can be attached to their pendant groups at any heteroatom or carbon atom that results in a stable structure. The heterocyclyl groups described herein may be substituted on a carbon or nitrogen atom if the resulting compound is stable. The nitrogens in the heterocycle may be optionally quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not greater than one. When the term "heterocycle" is used, it is intended to include heteroaryl groups. Examples of heteroaryl groups include, but are not limited to, acridinyl, azetidinyl, acridine, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothienyl, benzoxanyl azolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carboline, chromanyl, chromenyl, cinnoline, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2, 3-b] tetrahydrofuranyl, furanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridyl, indolenyl, indolyl, Indolyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoindolyl, iso Quinolinyl, isothiazolyl, isothiazolopyridyl, isoxazolyl, isoxazolopyridyl, methylenedioxyphenyl, morpholinyl, naphthyl, octahydroisoquinoline base, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl , oxazolidinyl, oxazolyl, oxazolopyridyl, oxazolidinyl, rylene, oxindole, pyrimidinyl, phenanthridine, phenanthroline, phenazinyl , phenothiazinyl, phenoxthiyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidinone, 4-piperidinone, piperonyl, pteridyl, purinyl, Pyranyl, pyrazinyl, pyrazolidine, pyrazolinyl, pyrazolopyridyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridyl , pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidone, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinuclidine, quinoxalinyl, quinuclidinyl, Tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4- Thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthyl, thiazolyl, thienyl, thiazolopyridyl, thienothiazolyl, thienooxa azolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4 - Triazolyl and xanthyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indoline, 1H-indazolyl, benzo Imidazolyl, 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" may also include biaryl structures formed by the above-defined "aryl" and a monocyclic "heteroaryl", such as, but not limited to, "-phenylbipyridyl-", "- Phenylbipyrimidinyl", "-pyridylbiphenyl", "-pyridylbipyrimidinyl-", "-pyrimidinylbiphenyl-"; wherein the present invention also includes fused rings containing, for example, the above heterocycles and Spiro compounds.

The term "heterocycloalkyl" as used herein refers to a monocyclic heterocycloalkyl system, or a bicyclic heterocycloalkyl system, and also includes spiroheterocycles or bridged heterocycloalkyls. Monocyclic heterocycloalkyl refers to a 3-8 membered cyclic alkyl system containing at least one saturated or unsaturated but non-aromatic alkyl group selected from O, N, S, P. A bicyclic heterocycloalkyl system refers to a heterocycloalkyl group fused to a phenyl group, or a cycloalkyl group, or a cycloalkenyl group, or a heterocycloalkyl group, or a heteroaryl group.

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

The term "spirocycloalkyl" as used herein refers to polycyclic hydrocarbons in which a single carbon atom (called a spiro atom) is shared between the monocyclic rings.

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

The term "heterospirocyclyl" as used herein refers to polycyclic hydrocarbons in which a single carbon atom (called a spiro atom) is shared between single rings, and the ring contains at least one atom selected from O, N and S.

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

Where nitrogen atoms (eg, amines) are present on the compounds of the present invention, these nitrogen atoms can be converted to N-oxides by treatment with oxidizing agents (eg, mCPBA and/or hydrogen peroxide) to obtain other compounds of the present invention . Accordingly, both shown and claimed nitrogen atoms are considered to encompass both the shown nitrogen and its N-oxides to obtain the derivatives of the present invention.

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

The term "patient" as used herein refers to an organism treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (eg, murine, simian/monkey, equine, bovine, porcine, canine, feline, etc.) and most preferably refer to humans.

As used herein, the term "effective amount" means the amount of a drug or agent (ie, a compound of the invention) that will elicit the biological or medical response of a tissue, system, animal or human, eg, sought by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means an amount that results in improved treatment, cure, prevention or alleviation of a disease, disorder or side effect, or a reduction in the incidence of a disease, as compared to a corresponding subject not receiving such amounts or the rate of progression of the disease. An effective amount can be administered in one or more administrations, administrations or doses and is not intended to be limited by a particular formulation or route of administration. The term also includes within its scope an amount effective to enhance normal physiology.

As used herein, the term "treating" includes any effect that results in amelioration of a condition, disease, disorder, etc., eg, alleviation, reduction, modulation, amelioration or elimination, or amelioration of symptoms thereof.

The term "pharmaceutically acceptable" is used herein to refer to those compounds, substances, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without unduly toxic, irritating sexual, allergic reactions and/or other problems or complications and are commensurate with a reasonable benefit/risk ratio.

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

The term "pharmaceutical composition" means a composition comprising a compound of the present invention and at least one other pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering a biologically active agent to an animal, particularly a mammal, including (ie) adjuvants, excipients or vehicles such as diluents, preservatives , fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating and dispersing agents, depending on The mode of administration and the nature of the dosage form.

Certain Pharmacy and Medical Terms

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

The term "cancer", as used herein, refers to an abnormal growth of cells that is uncontrollable and, under certain conditions, is capable of metastasizing (spreading). Cancers of this type include, but are not limited to, solid tumors (eg, bladder, bowel, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (eg, thyroid), prostate , skin (melanoma), or blood tumor (eg, nonleukemic leukemia).

The term "co-administration" or similar terms, as used herein, refers to the administration of several selected therapeutic agents to a patient, administered in the same or different administrations at the same or different times.

The term "enhancing" or "enhancing", as used herein, refers to the ability of a desired result to be increased or prolonged, either in potency or duration. Thus, in enhancing the therapeutic effect of a drug, the term "enhancer" refers to the drug's ability to increase or prolong the potency or duration of the drug in the system. As used herein, "potentiation value" refers to the ability to maximize the ability of another therapeutic agent in an ideal system.

The term "immune disease" refers to a disease or condition of an adverse or deleterious response to an endogenous or exogenous antigen. The result is usually the dysfunction of cells, or the destruction and dysfunction of the cells, or the destruction of organs or tissues that may produce immune symptoms.

The terms "kit" and "product packaging" are synonymous.

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

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

As used herein, a compound or pharmaceutical composition, when administered, results in amelioration, especially improvement in severity, delay in onset, slow progression, or reduction in duration of a disease, symptom or condition. Whether fixed or temporary, continuous or intermittent, conditions may be attributable to or associated with the administration.

Route of administration

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

In one aspect, the compounds described herein are administered locally rather than systemically. In certain specific embodiments, the depot formulation is administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in another embodiment, the drug is administered by a targeted drug delivery system. For example, liposomes encapsulated by organ-specific antibodies. In this particular embodiment, the liposomes are selectively targeted to specific organs and absorbed.

Pharmaceutical composition and dosage

The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of the present invention formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents, and optionally a one or more of the other therapeutic agents described above. The compounds of the present invention may be administered for any of the above uses by any suitable means, eg orally, such as tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups and emulsions; sublingual; buccal; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (eg, in sterile injectable aqueous or non-aqueous solutions or suspensions liquid); nasally, including administration to nasal membranes, such as by inhalation spray; topically, such as in cream or ointment; or rectally, such as in suppository; or by intratumoral injection. They can be administered alone, but are usually administered using a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

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

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

Of course, dosage regimens for the compounds of the present invention will vary depending on known factors, such as the pharmacodynamic properties of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition and weight of the recipient. nature and extent of symptoms; type of concomitant treatment; frequency of treatment; route of administration, renal and hepatic function of the patient, and desired effect. According to general guidance, the daily oral dose of each active ingredient should 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, when used for the indicated effect Typically from about 0.1 mg/day to about 250 mg/day. During constant rate infusion, the most preferred intravenous dose should be from about 0.01 mg/kg/minute to about 10 mg/kg/minute. The compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily.

The compounds are usually in the form of suitable pharmaceutical diluents, excipients or carriers (herein) appropriately selected according to the intended form of administration (eg, oral tablets, capsules, elixirs and syrups) and consistent with conventional pharmaceutical practice. are administered in the form of a mixture of drug carriers).

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

A typical capsule for oral administration contains at least one compound of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture was passed through a 60 mesh screen and packaged into size 1 gelatin capsules.

A typical injectable formulation can be prepared by aseptically placing at least one compound of the invention (250 mg) in a vial, aseptically lyophilizing and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline to produce an injectable formulation.

Within the scope of the present invention are pharmaceutical compositions comprising, either alone or in combination with a pharmaceutical carrier, a therapeutically effective amount of at least one compound of the present invention as an active ingredient. Optionally, the compounds of the present invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more other therapeutic agents (eg, anticancer agents or other pharmaceutically active substances).

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

The actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention can be varied to obtain an amount of active ingredient that is effective in achieving the desired therapeutic response, composition, and mode of administration for a particular patient, without being toxic to the patient.

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

A physician or veterinarian having ordinary skill in the art can readily determine and prescribe an effective amount of the desired pharmaceutical composition. For example, to achieve the desired therapeutic effect, a physician or veterinarian may initiate a dose of a compound of the present invention used in a pharmaceutical composition at a level below that required and gradually increase the dose until the desired effect is achieved. In general, a suitable daily dose of a compound of the present invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend on the factors discussed above. Typically, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of the invention for patients will range from about 0.01 to about 50 mg/kg body weight/day. If desired, an effective daily dose of the active compound may be administered separately in two, three, four, five, six or more sub-doses at appropriate intervals throughout the day, optionally in unit dosage form. In certain aspects of the invention, the dosing is once a day.

Although the compounds of the present invention may be administered alone, it is preferred to administer the compounds in the form of a pharmaceutical formulation (composition). Kit/Product Packaging

Kits/product packaging are also described herein for use in the treatment of the above-mentioned indications. These kits may consist of a transporter, a pack, or a case of containers, which may be divided into compartments to accommodate one or more containers, such as vials, test tubes, and the like, each container containing the a single component of the method described above. Suitable containers include bottles, vials, syringes and test tubes, among others. Containers are made of acceptable materials such as glass or plastic.

For example, the container may contain one or more of the compounds described herein, which may be present as pharmaceutical components or in admixture with other ingredients described herein. The container may have a sterile outlet (eg, the container may be an IV pack or bottle, the stopper being pierced by a hypodermic needle). Such kits may carry a compound, along with instructions for use, labels, or instructions for use as described herein.

A typical kit may include one or more containers, each containing one or more materials (such as reagents, or concentrated stock solutions, and/ or equipment). These materials include, but are not limited to, buffers, diluents, filters, needles, syringes, dispensers, bags, containers, vials and/or tubes, with a list of contents and/or instructions for use, as well as instructions for the inner packaging. The entire set of instructions is to be included.

Labels can be displayed on or closely associated with the container. The presence of a label on a container means that the letters, numbers or other features of the label are affixed, molded, or engraved on the container; the label can also appear in a container box or shipping box containing a variety of containers, such as in product inserts. A label may be used to indicate a specific therapeutic use of the contents. The label may also indicate instructions for use of the contents, such as described in the above method.

All features described in this specification (including any stated claims, abstract and figures), and/or all steps involved in any method or process, may be present in any combination, unless certain features Or steps are mutually exclusive in the same combination.

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

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions or in accordance with the conditions suggested by the manufacturer. All percentages, ratios, ratios, or parts are by weight unless otherwise indicated.

The unit in the weight volume percentage in the present invention is well known to those skilled in the art, for example, it refers to the weight of the solute in 100 ml of the solution. Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the methods of the present invention. Methods and materials for preferred embodiments described herein are provided for illustrative purposes only.

Example

Generic process

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

Room temperature refers to 20-30°C.

Unless otherwise specified in the reaction examples, the reactions were all carried out under nitrogen atmosphere. Nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1 L.

The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times. Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L.

microwave reaction use

Initiator + microwave reactor.

The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<" ⁶ > (ppm). NMR was measured using a (Bruker Ascend ^TM 500 type) nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and internal standard. For tetramethylsilane (TMS). The following abbreviations are used for the multiplicity of NMR signals: s=singlet, brs=broad, d=doublet, t=triplet, m=multiplet. Coupling constants are listed in J values, measured in Hz.

The measurement of LC-MS was performed using a Thermo liquid mass spectrometer (UltiMate 3000+MSQ PLUS). For the HPLC measurement, a Thermo high pressure liquid chromatograph (UltiMate 3000) was used. Preparative Reversed Phase Chromatography A Thermo (UltiMate 3000) Preparative Reversed Phase Chromatograph was used. Fast column chromatography uses AIJER (FS-9200T) automatic column passing machine, and silica gel prepacked column uses Santai

Prepacked columns. The thin layer chromatography silica gel plate is made of Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specifications of the thin layer chromatography separation and purification products are 0.4mm ~ 0.5mm.

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

Intermediate 1

Intermediate 1 was prepared by the following steps:

The first step: 1-methyl-3,5-dinitropyridin-2-one Int-1a (1.0 g, 5.02 mmol) was dissolved in methanol (50 mL), followed by adding ammonia methanol solution (7 mol/L, 8.61 mL, 60.27 mmol) and 1-methylpiperidin-4-one Int-1b (625 mg, 5.52 mmol). 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, the reaction solution was concentrated under reduced pressure, and the residue was added with ethyl acetate (50 mL), followed by filtration. The filtrate was concentrated under reduced pressure to obtain Int-1c (1.0 g) as a red solid, which was directly used in the next reaction. ESI-MS (m/z): 194.4 [M+H] ⁺ ; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.14 (d, J=2.5 Hz, 1 H), 8.36 (d, J=2.5 Hz) , 1H), 3.64(s, 2H), 3.02(t, J=6.0Hz, 2H), 2.74(t, J=6.0Hz, 2H), 2.39(s, 3H).

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

The third step: 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. Saturated aqueous sodium bicarbonate solution was added to quench the reaction until no bubbles were generated, the aqueous phase was extracted with methanol/dichloromethane (1/20, 50 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound Int-1e (38 mg, 25% yield). ESI-MS (m/z): 242.3 [M+H] ⁺ ; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 6.77 (s, 1H), 5.25 (s, 2H), 3.37 (s, 2H) , 2.69(t, J=6.0Hz, 2H), 2.60(t, J=6.0Hz, 2H), 2.32(s, 3H).

The fourth step: Compound Int-1e (37mg, 0.15mmol) was dissolved in methanol (1mL), cuprous iodide (3mg, 0.015mmol), 1,10-phenanthroline (3mg, 0.03mmol) and carbonic acid were added. Cesium (99 mg, 0.30 mmol). The reaction mixture was replaced with nitrogen and heated to 100°C with microwave and stirred for 2 hours. The reaction was cooled to room temperature, the reaction solution was concentrated, and the residue was purified by preparative thin layer chromatography (methanol/dichloromethane/triethylamine=1/10/0.1) to obtain a yellow solid Int-1 (20 mg, yield 67%) . ESI-MS (m/z): 194.5 [M+H] ⁺ ; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 6.54 (s, 1H), 4.68 (s, 2H), 3.80 (s, 3H) , 3.30(s, 2H), 2.64(t, J=5.6Hz, 2H), 2.59(t, J=5.7Hz, 2H), 2.31(s, 3H).

Intermediate 2

Intermediate 2 was prepared by the following steps:

The first step: Compound Int-1e (230mg, 0.94mmol) was dissolved in ethanol (2mL), cuprous iodide (18mg, 0.095mmol), 1,10-phenanthroline (34mg, 0.18mmol) and carbonic acid were added Cesium (619 mg, 1.90 mmol). The reaction mixture was heated to 100°C by microwave and stirred for 5 hours after displacing nitrogen. The reaction 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 yellow solid Int-2 (113 mg, yield 57%). ESI-MS (m/z): 208.5 [M+H] ⁺ .

Intermediate 3

Intermediate 3 was prepared by the following steps:

The first step: N-tert-butoxycarbonyl-4-piperidinone Int-3a (4.4 g, 22.1 mmol) and 1-methyl-3,5-dinitro-2-pyridinone Int-1a (4.0 g, 20.1 mmol) was dissolved in methanol (150 mL) and ammonia in methanol (7N, 34.4 mL, 240.8 mmol) was added. Stir at 60°C for 6 hours under nitrogen protection. The reaction solution was cooled to room temperature, and stirring was continued for 2 days. The reaction was monitored by LCMS, the reaction solution was concentrated, ethyl acetate (150 mL) was added, stirred for half an hour, filtered, and the filtrate was concentrated to obtain yellow solid Int-3b (5.1 g, yield 91%). ESI-MS (m/z): 280.1 [M+H] ⁺ .

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

The third step: Compound Int-3c (3.7 g, 14.8 mmol) was dissolved in DMF (20 mL), and 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 and completed by LCMS. Water (100 mL) was added, the aqueous phase (150 mL*3) was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by silica gel column chromatography to obtain a yellow solid Int- 3d (3.6 g, 74% yield). ESI-MS (m/z): 328.2 [M+H] ⁺ .

The fourth step: Compound Int-3d (500 mg, 1.53 mmol) was dissolved in methanol (5 mL), and sodium methoxide methanol solution (5N, 0.33 mL, 1.65 mmol) was added. The reaction mixture was heated to 100°C with microwave and stirred for 3 hours. The reaction was cooled to room temperature, the reaction solution was concentrated, and the residue was separated by silica gel column chromatography to obtain Int-3 as a yellow solid (330 mg, yield 77%). ESI-MS (m/z): 280.2 [M+H] ⁺ .

Intermediate 4

Intermediate 4 was prepared by the following steps:

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

The second step: Compound Int-4b (1.1 g, 3.41 mmol) was dissolved in DMF (20 mL), and cesium carbonate (1.67 g, 5.12 mmol) and methyl iodide (484 mg, 3.41 mol) were successively added under ice bath at 0°C. . The mixture was warmed to room temperature and stirred for 1 hour. After the reaction was complete, water was added to quench the reaction, and 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 to obtain a yellow oily liquid compound Int-4c (1.1 g, yield 95%). ESI-MS (m/z): 337.3 [M+H] ⁺ ; ¹ H NMR (500 MHz, DMSO-d6) δ 7.84 (s, 1H), 4.28 (s, 2H), 4.19 (q, J=7.1 Hz, 2H), 3.57(t, J=5.9Hz, 2H), 3.40(s, 3H), 2.80(t, J=5.9Hz, 2H), 1.41(s, 9H), 1.24(t, J=7.1 Hz, 3H).

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

The fourth step: Compound Int-4d (830mg, 2.69mmol) was dissolved in toluene (10mL), diphenylphosphoryl azide (2.22g, 8.08mmol), benzyl alcohol (873mg, 8.08mmol) and N,N were added - Diisopropylethylamine (1.39 mg, 10.77 mmol), the reaction mixture was heated to 120°C and stirred for 16 hours. The reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain yellow solid compound Int-4e (930 mg, yield 83%). ESI-MS(m/z): 414.3[M+H] ⁺ ; ¹ H NMR(500MHz, methanol-d4)δ7.84(s,1H),7.48-7.31(m,6H),5.21(s,2H) ), 4.36(s, 2H), 3.71(t, J=6.3Hz, 2H), 3.56(s, 3H), 2.80-2.77(m, 2H), 1.50(s, 9H).

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

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

Intermediate 5

Intermediate 5 was prepared by the following steps:

The first step: Compound Int-4b (520 mg, 1.61 mmol) was dissolved in DMF (5 mL), and lithium bistrimethylsilylamide (1N solution in tetrahydrofuran, 1.77 mL) was added dropwise at 0°C under ice bath, The mixture was stirred at 0°C for 30 minutes. Then bromomethylcyclopropane (240 mg, 1.77 mmol) was added and stirring was continued at room temperature for 2 hours. After the reaction was complete, water was added to quench the reaction, and 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 and purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain yellow oily liquid compound Int-5a (410 mg, yield 67%). ESI-MS (m/z): 377.4 [M+H] ⁺ ; ¹ H NMR (500 MHz, DMSO-d6) δ 7.84 (s, 1H), 4.30 (s, 2H), 4.20 (q, J=7.1 Hz, 2H), 3.93(d, J＝6.9Hz, 2H), 3.59(t, J＝5.8Hz, 2H), 2.90(t, J＝5.5Hz, 2H), 1.43(s, 9H), 1.26( t, J=7.1 Hz, 3H), 1.18-1.13 (m, 1H), 0.47-0.43 (m, 2H), 0.41-0.37 (m, 2H).

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

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

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

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

Intermediate 6

Intermediate 6 was prepared by the following steps:

The first step: Compound Int-4b (1.28 g, 3.97 mmol) was dissolved in DMF (15 mL), and bistrimethylsilyl amide lithium (1 mol/L in THF, 4.76 mL) was added dropwise at 0 °C in an ice bath. ), the mixture was stirred at 0 °C for 30 min. Then 1-iodo-2-methoxyethane (739 mg, 3.97 mmol) was added and the temperature was raised to 50°C and stirring was continued for 16 hours. After the reaction was complete, water was added to quench the reaction, and 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 column chromatography (PE/EA=1/2) to obtain compound Int-6a (600 mg, 1.58 mmol), yield 39.7%, pale yellow solid. ESI-MS (m/z): 381.6 [M+H] ⁺ .

The second step: Compound Int-6a (850 mg, 2.23 mmol) was dissolved in ethanol (10 mL), 1N aqueous sodium hydroxide solution (6.7 mL) was added, and the mixture was stirred at room temperature for 2 hours. The pH was adjusted to 6 with 6N aqueous hydrochloric acid and diluted with additional water (60 mL). The precipitate was filtered, the filter cake was washed with water, and dried to obtain a yellow solid compound Int-6b (700 mg, 1.99 mmol), yield 88.9%, pale yellow solid. ESI-MS (m/z): 353.3 [M+H] ⁺ .

The third step: Compound Int-6b (700mg, 1.99mmol) was dissolved in toluene (10mL), diphenylphosphoryl azide (1.64g, 5.96mmol), benzyl alcohol (644mg, 5.96mmol) and N,N were added - Diisopropylethylamine (1.03 g, 7.95 mmol), the mixture was heated to 120°C and stirred for 16 hours. The reaction solution was concentrated, and the residue was separated by column chromatography (PE/EA=2/3) to obtain yellow solid compound Int-6c (650 mg, 1.42 mmol), yield 71.5%, pale yellow solid. ESI-MS (m/z): 458.4 [M+H] ⁺ .

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

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

Example 1

3-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-6-methyl-5,6,7,8-tetrahydro -1,6-Naphthyridine-2(1H)-one

Compound 1 was prepared by the following steps:

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

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

Example 2

3-((5-Chloro-4-((2-(methylthio)phenyl)amino)pyrimidin-2-yl)amino)-6-methyl-5,6,7,8-tetrahydro-1 ,6-Naphthyridine-2(1H)-one

Example 3

3-((5-Chloro-4-((2-(methylsulfinyl<sulfinyl>)phenyl)amino)pyrimidin-2-yl)amino)-6-methyl-5,6,7 ,8-Tetrahydro-1,6-naphthalen-2(1H)-one

Compounds 2 and 3 were prepared by the following steps:

Step 1: Dissolve 2-(methylthio)aniline 2a (1.0 g, 7.18 mmol) and 2,4,5-trichloropyrimidine 2b (1.45 g, 7.90 mmol) in isopropanol (10 mL), add N,N-diisopropylethylamine (1.21 g, 9.34 mmol, 0.90 mL), the reaction solution was heated to 85°C and stirred for 40 hours. After the reaction solution was cooled to room temperature, isopropanol (50 mL) was added to dilute, the reaction mixture was filtered, the filter cake was washed with isopropanol (10 mL), and dried under reduced pressure to obtain white solid compound 2c (1.72 g, yield 83%). ESI-MS (m/z): 286.1 [M+H] ⁺ .

The second step: Compound 2c (300mg, 1.05mmol) was dissolved in dichloromethane (5mL), m-chloroperoxybenzoic acid (223mg, content 85%, 1.10mmol) was added under ice bath, and the reaction solution was at 0°C Stir for 1 hour. Water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, the obtained suspension was filtered, and the filter cake was dried under reduced pressure to obtain white solid 2d (217 mg, yield 68%). ESI-MS (m/z): 302.1 [M+H] ⁺ .

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

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

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

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

Example 4

3-((5-Chloro-4-((2-(methylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-6-methyl-5,6,7,8-tetrahydro-1 ,6-Naphthyridine-2(1H)-one

Compound 4 was prepared by the following steps:

The first step: Compound 2c (182 mg, 0.63 mmol) was dissolved in a mixture of acetic acid (1.19 g, 1.13 mL) and water (0.1 mL), sodium tungstate dihydrate (10 mg, 0.031 mmol) was added, and the reaction solution was After stirring at room temperature for 30 minutes, hydrogen peroxide (1.44 g, 30% content, 12.73 mmol, 1.31 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight. The reaction solution was diluted with water (30 mL), the obtained suspension was filtered, the filter cake was dried under reduced pressure to obtain and ethyl acetate (10 mL), the obtained suspension was filtered, and the filter cake was dried under reduced pressure to obtain a mixture of compounds 4a and 2d (200 mg , the ratio of 8/2), directly used in the next reaction.

The second step: The mixture of 4a and 2d obtained in the previous step (39 mg) and Int-1 (20 mg, 0.10 mmol) were dissolved in 1,4-dioxane (3 mL), and BrettPhos Pd G3 (9 mg, 10 umol) was added. ), BrettPhos (11 mg, 20 umol) and cesium carbonate (67 mg, 0.20 mmol). After the reaction system was replaced with nitrogen, it was heated to 100°C and stirred for 18 hours. After the reaction solution was cooled to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated. The residue was purified by reverse preparative HPLC to give 4b (10 mg) as a white solid. ESI-MS (m/z): 475.1 [M+H] ⁺ ; ¹ H NMR (500 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.39-8.28 (m, 2H), 8.25 (s, 1H) ),7.92(dd,J=8.0,1.5Hz,1H),7.71-7.62(m,2H),7.40(t,J=7.6Hz,1H),3.84(s,3H),3.28(s,2H) , 3.25(s, 3H), 2.76(t, J=6.0Hz, 2H), 2.65(t, J=5.9Hz, 2H), 2.35(s, 3H).

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

Example 5

3-((5-Chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-6-methyl-5,6,7,8-tetrahydro -1,6-Naphthyridine-2(1H)-one

Compound 5 was prepared by the following steps:

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

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

Example 6

6-Methyl-3-((4-((2-(methylthio)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5,6,7,8 -Tetrahydro-1,6-naphthalen-2(1H)-one

Compound 6 was prepared by the following steps:

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

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

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

Example 7

3-((4-((2-(Dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6-methyl-5,6,7 ,8-Tetrahydro-1,6-naphthalen-2(1H)-one

Substituting 2-(dimethyloxyphosphoryl)aniline for 2-(methylthio)aniline in the first step of Example 6, and using a similar method and reaction procedure, compound 7 can be obtained. ESI-MS (m/z): 493.1 [M+H] ⁺ ; ¹ H NMR (500 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.93-7.78 (m, 3H), 7.73 (t, J =7.2Hz,1H),7.54-7.50(m,1H),2.98(br s,2H),2.70-2.64(m,4H),2.45(s,3H),1.79(s,3H),1.77(s , 3H).

Example 8

3-((5-Chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-1,6-dimethyl-5,6,7,8 -Tetrahydro-1,6-naphthalen-2(1H)-one

Compound 8 was prepared by the following steps:

The first step: Compound 5a (52 mg, 0.16 mmol) and Int-4 (32 mg, 0.16 mmol) were dissolved in 1,4-dioxane (5 mL), followed by adding BrettPhos G3 Pd (15 mg, 0.016 mmol), BrettPhos (17 mg, 0.033 mmol) and cesium carbonate (107 mg, 0.33 mmol). After the reaction mixture was purged with nitrogen, it was stirred at 100°C overnight. The complete reaction of compound 5a was detected by LCMS. The reaction solution was cooled to room temperature, filtered through celite, the filtrate was concentrated, and the residue was purified by reverse preparative HPLC to obtain compound 8 (30 mg, yield 38%). ESI-MS (m/z): 473.1[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO-d6) δ 11.00(s, 1H), 8.30(br s, 1H), 8.25(s, 1H) ,8.25(s,1H),8.06(s,1H),7.81(s,1H),7.69-7.59(m,2H),7.26(t,J＝7.4Hz,1H),3.48(s,3H), 3.12(s, 2H), 2.72(t, J=5.8Hz, 2H), 2.60(t, J=5.8Hz, 2H), 2.32(s, 3H), 1.78(s, 3H), 1.75(s, 3H ).

Example 9

2-((5-Chloro-2-((6-methyl-2-carbonyl-1,2,5,6,7,8-hexahydro-1,6-naphthalen-3-yl)amino )pyrimidin-4-yl)amino)benzoic acid

Compound 9 was prepared by the following steps:

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

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

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

Example 10

3-((4-((2-(isopropylsulfonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6-methyl-5,6,7 ,8-Tetrahydro-1,6-naphthalen-2(1H)-one

Compound 10 was prepared by the following steps:

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

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

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

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

Example 11

3-((5-Chloro-4-((2-(isopropylthio)phenyl)amino)pyrimidin-2-yl)amino)-6-methyl-5,6,7,8-tetrahydro -1,6-Naphthyridine-2(1H)-one

Compound 11 was prepared by the following steps:

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

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

The third step: Compound 11b (120 mg, 0.36 mmol) and intermediate Int-2 (75 mg, 0.36 mmol) were dissolved in dioxane (6 mL), and BrettPhos G3 Pd (32 mg, 0.036 mmol), BrettPhos ( 19 mg, 0.036 mmol) and cesium carbonate (236 mg, 0.72 mmol). After the reaction mixture was replaced with nitrogen, it was stirred at 100°C overnight. The complete reaction of compound 11b was detected by LCMS. The reaction solution was cooled to room temperature, filtered through celite, the filtrate was concentrated, and the residue was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate=1/1) to obtain a crude product of compound 11c. The crude fraction 11c was purified by reverse preparative HPLC to give compound 11c (8 mg). ESI-MS (m/z): 500.4[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO-d6) δ 9.70(s, 1H), 8.18(s, 1H), 7.81(s, 1H), 7.78(d,J＝7.7Hz,1H),7.65(d,J＝7.7Hz,1H),7.60-7.54(m,2H),7.48(t,J＝7.6Hz,1H),4.28(q,J ＝7.0Hz, 2H), 3.11-2.98(m, 3H), 2.68(t, J＝5.2Hz, 2H), 2.63-2.58(m, 2H), 2.35(s, 3H), 1.28(t, J＝ 7.0Hz, 3H), 1.10 (d, J=7.0Hz, 3H), 0.98 (d, J=6.7Hz, 3H).

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

Example 12

3-((5-Chloro-4-((2-(ethylthio)phenyl)amino)pyrimidin-2-yl)amino)-6-methyl-5,6,7,8-tetrahydro-1 ,6-Naphthyridine-2(1H)-one

Compound 12 was prepared by the following steps:

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

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

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

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

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

The fourth step: The crude compound 12e (50 mg) obtained in the previous step was dissolved in a hydrochloric acid dioxane solution (2N, 5 mL), and the reaction solution was heated to 100° C. and stirred for 6 hours. The reaction solution was concentrated, and the residue was purified by reverse preparative HPLC to give compound 12 (4 mg). ESI-MS(m/z): 443.1[M+H] ⁺ ; 1HNMR(500MHz, DMSO-d6)δ11.72(s,1H), 8.93(s,1H), 8.15(s,1H), 7.78( s, 1H), 7.58-7.49(m, 2H), 7.42-7.29(m, 3H), 2.89(q, J=7.3Hz, 2H), 2.83(br s, 2H), 2.50-2.45(m, 2H) ), 2.32(s, 3H), 1.14(t, J=7.3Hz, 3H).

Example 13

3-((5-Chloro-4-((2-(ethylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-6-methyl-5,6,7,8-tetrahydro- 1,6-Naphthyridine-2(1H)-one

Compound 13 was prepared by the following steps:

The first step: Compound 12d (50 mg, 0.15 mmol) and intermediate Int-2 (31 mg, 0.15 mmol) were dissolved in 1,4-dioxane (5 mL), followed by adding BrettPhos G3 Pd (13 mg, 0.015 mmol) ), BrettPhos (8 mg, 0.015 mmol) and cesium carbonate (98 mg, 0.030 mmol). After the reaction mixture was replaced with nitrogen, it was stirred at 100°C overnight. The reaction of compound 12d was completed by LCMS. The reaction solution was cooled to room temperature, filtered through Celite, and the filtrate was concentrated. The residue was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate=1/1) to obtain a crude product of compound 13a (75 mg), which was directly used in the next reaction.

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

Example 14

3-((5-Chloro-4-((2-(hydroxymethyl)phenyl)amino)pyrimidin-2-yl)amino)-6-methyl-5,6,7,8-tetrahydro-1 ,6-Naphthyridine-2(1H)-one

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

Example 15

3-((5-Chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-1-(cyclopropylmethyl)-6-methyl- 5,6,7,8-Tetrahydro-1,6-naphthalen-2(1H)-one

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

Example 16

3-((5-Chloro-4-((2-(methylsulfinyl<sulfinyl>)phenyl)amino)pyrimidin-2-yl)amino)-1,6-dimethyl-5, 6,7,8-Tetrahydro-1,6-naphthalen-2(1H)-one

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

Example 17

3-((5-Chloro-4-((2-(methylthio)phenyl)amino)pyrimidin-2-yl)amino)-1,6-dimethyl-5,6,7,8-tetra Hydro-1,6-naphthyridine-2(1H)-one

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

Example 18

3-((4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-1,6-dimethyl-5,6,7,8-tetrahydro- 1,6-Naphthyridine-2(1H)-one

Example 19

3-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-1,6-dimethyl-5,6,7,8 -Tetrahydro-1,6-naphthalen-2(1H)-one

Compounds 18 and 19 were prepared by the following steps:

The first step: Compound Int-4 (20 mg, 0.10 mmol) and compound 1a (35 mg, 0.10 mmol) were dissolved in 1,4-dioxane (5 mL), cesium carbonate (67 mg, 0.20 mmol) was added, BrettPhos (11 mg, 0.020 mmol) and BrettPhos Pd G3 (9 mg, 0.010 mmol). The reaction mixture was replaced with nitrogen and then heated to 100°C with stirring for 18 hours. The reaction solution was cooled to room temperature, filtered through Celite, and the filtrate was concentrated. The residue was purified by preparative thin layer chromatography (dichloromethane/methanol=10/1) to obtain the crude product, which was then separated by reverse-phase preparative HPLC to obtain compound 18 (5 mg, yield 11%) and compound 19 (12 mg, yield twenty three%).

Compound 18: ESI-MS (m/z): 468.5 [M+H] ⁺ ; ¹ H NMR (500 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.12 (d, J=5.7 Hz, 1H) ,7.95-7.90(m,2H),7.89-7.79(m,2H),7.62(br s,1H),7.51(t,J＝7.7Hz,1H),6.47(d,J＝5.8Hz,1H) ,3.45(s,3H),3.35-3.33(m,1H),2.89(br s,2H),2.68(t,J＝6.9Hz,2H),2.58-2.54(m,2H),2.31(s, 3H), 1.09 (d, J=6.9Hz, 6H).

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

Example 20

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

Example 21

3-((5-Chloro-4-((2-(ethylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-1,6-dimethyl-5,6,7,8- Tetrahydro-1,6-naphthalen-2(1H)-one

Substituting 11c for 1a in the first step of Examples 18/19, and using a similar method and reaction procedure, compounds 20 and 21 can be obtained.

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

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

Example 22

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

Example 23

3-((5-Chloro-4-((2-(methylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-1,6-dimethyl-5,6,7,8-tetra Hydro-1,6-naphthyridine-2(1H)-one

Substituting 4b for 1a in the first step of Examples 18/19, and using a similar method and reaction procedure, compounds 22 and 23 can be obtained.

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

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

Example 24

3-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-1-(cyclopropylmethyl)-6-methyl- 5,6,7,8-Tetrahydro-1,6-naphthalen-2(1H)-one

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

Example 25

3-((5-Chloro-4-((2-(difluoromethoxy)phenyl)amino)pyrimidin-2-yl)amino)-6-methyl-5,6,7,8-tetrahydro -1,6-Naphthyridine-2(1H)-one

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

Example 26

3-((5-Chloro-4-((2-ethoxyphenyl)amino)pyrimidin-2-yl)amino)-6-methyl-5,6,7,8-tetrahydro-1,6- Naphthalene-2(1H)-one

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

Example 27

3-((5-Chloro-4-((2-ethylphenyl)amino)pyrimidin-2-yl)amino)-6-methyl-5,6,7,8-tetrahydro-1,6- Naphthalene-2(1H)-one

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

Example 28

3-((5-Chloro-4-((2-(cyclopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-6-methyl-5,6,7,8-tetrahydro -1,6-Naphthyridine-2(1H)-one

Compound 28 was prepared by the following steps:

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

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

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

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

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

Example 29

3-((5-Chloro-4-((2-(cyclopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-1,6-dimethyl-5,6,7,8 -Tetrahydro-1,6-naphthalen-2(1H)-one

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

Example 30

3-((5-Chloro-4-((2-(ethylsulfinyl<sulfinyl>)phenyl)amino)pyrimidin-2-yl)amino)-1,6-dimethyl-5, 6,7,8-Tetrahydro-1,6-naphthalen-2(1H)-one

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

Compounds 31-60 were prepared according to the synthetic routes and the synthetic methods of the intermediates described in the above examples. The analytical data of Examples 31-42 are shown in the following table.

Comparative Example 1 and Comparative Example 2

Comparative Example 1

and control 2

According to the methods and intermediates described in Method A in WO2018102366, compounds I-5 and I-2 in the patent were obtained, which were used as Comparative Example 1 and Comparative Example 2, respectively.

Biological Screening and Results of HPK1 Inhibitors

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

The required reagents are as follows

Experimental procedure

The specific operations are as follows: configure the enzymatic reaction system buffer (10mM MOPS, pH 7.2, 5mM β-glycerol-phosphate, 10mM MgCl2, 0.8mM EDTA, 2mM EGTA, 0.1mM DTT); test compounds (prepared in 1mM DMSO) Compound stock solution) was diluted with buffer to a maximum concentration of 60uM (containing 6% DMSO), and formulated at a concentration of 60 μM starting with a 5-fold dilution with a buffer containing 6% DMSO for a total of 8 point gradient concentrations; subsequently used Buffer diluted HPK1 kinase to 30 nM. Add 2 μl of HPK1 kinase dilution to each well of a Greiner 384-well microplate (Cat. No. 784075), and add 2 μl of buffer to control wells; add 1 μl of diluted compound to reaction wells after brief centrifugation, and add 1 μl of control wells containing 6% DMSO buffer; briefly centrifuged and then placed in a 25°C constant temperature incubator (Shanghai Yiheng Scientific Instrument Co., Ltd., product number: LRH-150) for 20 min. Add 3 μl of reaction substrate (10 μM MBP and 20 μM ATP dissolved in distilled water) to each well, centrifuge briefly and then incubate in a constant temperature incubator at 25 °C for 60 min. The enzymatic reaction activity was detected by ADP-Glo Kinase Assay Kit, ADP - Glo Kinase Assay Kit assays are performed according to the kit's operating instructions. Data are described using the compound's median inhibitory concentration _IC50 .

化合物编号Compound number	IC ₅₀(nM) _IC50 (nM)	化合物编号Compound number	IC ₅₀(nM) _IC50 (nM)
对照例1Comparative Example 1	0.70.7	对照例2Comparative Example 2	0.1650.165
11	<0.1<0.1	22	2.412.41
33	<0.1<0.1	44	0.210.21
55	0.760.76	77	3.343.34
88	6.576.57	99	<0.1<0.1
1212	2.922.92	1313	<0.1<0.1
1414	<0.1<0.1	1515	0.170.17
1616	0.90.9	1717	<0.1<0.1
1919	0.440.44	2020	89.389.3
21twenty one	<0.1<0.1	23twenty three	<0.1<0.1
24twenty four	0.210.21	2525	<0.1<0.1
2626	40.4940.49	2727	1.641.64
2828	2.252.25	2929	<0.1<0.1
3030	5.115.11	3131	<0.1<0.1
3232	<0.1<0.1	3333	1.141.14
3434	6.846.84	3535	3.283.28
3636	53.5053.50	3838	14.7114.71
3939	5.535.53	4040	3.773.77
4141	6.156.15	4242	0.540.54

From the HPK1 kinase inhibitory data in the table above, the compounds of the present invention have comparable or better kinase inhibitory ability to the compounds of the control examples, and have unique structure-activity relationship characteristics.

Test Example 2: Detection of the agonistic ability of the compound to secrete cytokine interleukin-2 (IL-2) by Jurkat cells and the effect of the compound on the viability of Jurkat cells (Method 2)

The required reagents and cells are as follows

Experimental reagents:

Experimental cells:

细胞cell	细胞类型cell type	品牌brand
Jurkat E6-1Jurkat E6-1	人T淋巴细胞白血病细胞human T-lymphocytic leukemia cells	中科院细胞库Chinese Academy of Sciences Cell Bank

Experimental procedure

The specific operations are as follows: dissolve the compound powder to 10 mM with DMSO, add 2 μl of the compound to 998 μl of RPMI 1640 medium (both in this test containing 10% FBS), and vortex to mix the highest concentration point. The compound solution was gradually diluted 3-fold with 0.2% DMSO medium for a total of 8 concentration points. The control was treated with RPMI 1640 medium solution containing 0.1% DMSO. 1×105 Jurkat E6-1 cells were added to each well of a Corning 96-well cell culture plate (Cat. No. 3599), followed by an equal volume of compound dilutions. The control group was added with RPMI 1640 medium containing 0.2% DMSO and placed in Incubate for 1 h at 37°C in a cell incubator (Thermo Fisher Scientific, model: 3111). Subsequently, Anti-human CD3 Antibody and 1 μg/ml Anti-human CD28 Antibody at a final concentration of 1 μg/ml were added and incubated in a 37°C cell incubator for 24 hours. The culture supernatant was collected and the cells were detected by Human IL-2 DuoSet ELISA KIT. The IL-2 content in the supernatant was detected by Human IL-2 DuoSet ELISA according to the operating instructions of the kit. IL-2 secretion data are described as the highest fold ratio of the stimulation signal of the compound to the signal of 0.1% DMSO; cells were harvested, using

Cell viability was detected by the Luminescent Cell Viability Assay Kit, and the cell viability data were described by the compound's median inhibitory concentration _IC50 .

It can be seen from the above experiment that the Jurkat cells stimulate the release of IL2, the compounds of the present invention have a lower degree of inhibition on the viability of Jurkat cells compared with the control.

Test Example 3: Detection of agonistic ability of compounds on human PBMC cells to secrete cytokine interleukin-2 (IL-2) Effects of compounds on viability of human PBMC cells (Method 3)

The required reagents are as follows

Experimental cell source information:

Experimental procedure

The specific operations are as follows: human PBMCs are taken out from liquid nitrogen according to standard operations, thawed and thawed in a 37°C water bath, resuspended in RPMI 1640 medium (both containing 10% FBS in this test), and washed twice by centrifugation. ; Human PBMC cells were then resuspended in RPMI 1640 medium for use. Compound powder was dissolved to 10 mM with DMSO, 2 μl of compound was added to 998 μl of RPMI 1640 medium, and the highest concentration point was obtained after vortexing and mixing. The compound solution was gradually diluted 3-fold with 0.2% DMSO medium for a total of 8 concentration points. The control was treated with RPMI 1640 medium solution containing 0.1% DMSO. 1×105 human PBMC cells were added to each well of a Corning 96-well cell culture plate (Cat. No. 3599), followed by an equal volume of compound dilutions. For the control group, RPMI 1640 medium containing 0.2% DMSO was added, and the cells were placed at 37°C. The cells were incubated in a cell incubator (Thermo Fisher Scientific, model: 3111) for 1 h. Subsequently, Anti-human CD3 Antibody and 1 μg/ml Anti-human CD28 Antibody were added at a final concentration of 0.01 μg/ml, and incubated in a 37°C cell incubator for 24 h. Human IL-2 DuoSet ELISA KIT was used to detect the IL-2 content in the cell supernatant, and Human IL-2 DuoSet ELISA was performed according to the operating instructions of the kit. Data are described as the highest fold ratio of the stimulation signal of the compound to the signal of 0.1% DMSO. cells were collected, using

The Luminescent Cell Viability Assay Kit detects cell viability, and the cell viability data is described by the half inhibitory concentration IC50 of the compound.

As can be seen from the above table Human PBMC cells stimulated and released IL2 experiments, the compounds of the present invention have a lower degree of inhibition on PBMC cell viability compared with the control.

Claims

A compound of formula I or formula II or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof:

in,

R 1 represents hydrogen, (C 1 -C 6 )alkyl, halogen, (C 1 -C 6 )alkoxy, OR a , NR a R b , cyano or (C 3 -C 6 )cycloalkyl;

R 2 represents hydrogen, halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, -(C 1 -C 6 alkylene)-OR a , -O-(C 1 -C6 )alkyl, -S-( C1 - C6 )alkyl, -S(O)-( C1 - C6 )alkyl, -S(O) 2- ( C1 - C6 ) Alkyl, -S(O) 2 -(C 3 -C 8 )cycloalkyl, -S-(C 1 -C 6 )alkylene-COOR a , -S(O)-(C 1 -C 6 ) alkylene-COOR a , -S(O) 2 -(C 1 -C 6 )alkylene-COOR a , -S-(C 1 -C 6 )alkylene-C(O)NR a R b , -NR a R b , -COOR a , -CONR a R b , -OCONR a R b , -NR a COR b , -P(O)R a R b , -S(O) 2 NR a R b or -NR a S(O) 2 R b ;

R 3 represents hydrogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, -(C 1 -C 6 alkylene)hydroxy, -(C 0 -C 6 alkylene) )OR a , -(C 0 -C 6 alkylene)(C 3 -C 8 )cycloalkyl, -(C 0 -C 6 alkylene)(4-10 membered) heterocycloalkyl, -( C 0 -C 6 alkylene) COOR a , -(C 0 -C 6 alkylene) CONR a R b , -(C 0 -C 6 alkylene) P(O)R a R b , -( C 0 -C 6 alkylene)S(O) 2 NR a R b , -(C 0 -C 6 alkylene)SR a , -(C 0 -C 6 alkylene)S(O)R a or -(C 0 -C 6 alkylene)S(O) 2 R a ;

R 4 and R 4 ′ each independently represent hydrogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl or halogen;

Or R 4 and R 4' together form a 3-6-membered ring with the carbon atom connected to it, and the ring can optionally contain 0, 1 or 2 heteroatoms selected from N, O, and S;

R 5 represents hydrogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl or (4-8 membered)heterocycloalkyl;

R 6 and R 6' each independently represent hydrogen, (C 1 -C 6 )alkyl, -(C 1 -C 6 alkylene)hydroxy or halogen;

Or R 6 and R 6' together form a 3-6 membered ring with the carbon atom connected to it, and the ring can also optionally contain 0, 1 or 2 heteroatoms selected from N, O, and S;

R 7 and R 7' each independently represent hydrogen, (C 1 -C 6 )alkyl or halogen;

Or R 7 and R 7' together form a 3-6 membered ring with the carbon atom connected to it, and the ring can also optionally contain 0, 1 or 2 heteroatoms selected from N, O, and S;

W 1 means CR W1 or N;

W 2 means CR W2 or N;

wherein, R W1 and R W2 each independently represent hydrogen, halogen, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, -OR a , - NR a R b , cyano, -COOR a , -CONR a R b , -OCONR a R b , -NR a COR b , -P(O)R a R b , -S(O) 2 NR a R b , -NR a S(O) 2 R b , -SR a , -S(O) R a , -S(O) 2 R a ;

For alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl as defined above, it may be optionally substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, -(C 1 -C 6 -idene Alkyl)-O-( C1 - C6 )alkyl, (C3 - C8 )cycloalkyl, halo(C3 - C8 )cycloalkyl, halogen, -CN, oxo, -NR a R b , -OR a , -SR a , -(C 1 -C 6 alkylene)hydroxyl, -C(O)R a , -N(R a )C(O)R a , -NR a C (O)OR a , -NR a SO 2 R a , -C(O)OR a , -C(O)NR a R b , -S(O) 2 NR a R b , -S(O)R a , -S(O) 2 R a , -P(O)R a R b ;

Wherein, R a and R b each independently represent hydrogen, (C 1 -C 6 )alkyl or halogenated (C 1 -C 6 )alkyl; or R a and R b together with the adjacent atoms A 3-8 membered ring is formed, and the ring can optionally contain 0, 1 or 2 heteroatoms selected from N, O, and S;

m, n, o, and r each independently represent 0, 1, 2, or 3.
The compound of claim 1 or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof, wherein R 1 represents hydrogen, (C 1 -C 6 )alkyl, halogen or halogenated (C 1 ) -C 6 ) alkyl.
The compound of claim 1 or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof, wherein R 2 represents hydrogen, halogen, (C 1 -C 6 )alkyl, halogenated (C 1 ) -C 6 )alkyl, -(C 1 -C 6 alkylene)-OR a , -O-(C 1 -C 6 )alkyl, -S-(C 1 -C 6 )alkyl, -S (O)-(C 1 -C 6 )alkyl, -S(O) 2 -(C 1 -C 6 )alkyl, -S(O) 2 -(C 3 -C 8 )cycloalkyl, - S-(C 1 -C 6 )alkylene-COOR a , -S(O)-(C 1 -C 6 )alkylene-COOR a , -S(O) 2 -(C 1 -C 6 ) Alkylene-COOR a , -S-(C 1 -C 6 )alkylene-C(O)NR a R b , -CONR a R b , -P(O)R a R b or -S(O ) 2 NR a R b ; wherein, R a , R b independently represent hydrogen, (C 1 -C 6 )alkyl or halogenated (C 1 -C 6 ) alkyl; or R a , R b together with The adjacent atoms together form a 3-8 membered ring, and the ring can optionally contain 0, 1 or 2 heteroatoms selected from N, O and S.
The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof, wherein R 3 represents hydrogen, (C 1 -C 6 )alkyl, halogenated (C 1 -C 6 )alkyl, -(C 1 -C 6 alkylene)hydroxy, -(C 0 -C 6 alkylene)OR a , -(C 0 -C 6 alkylene)(C 3 - C8 )cycloalkyl, -( C0 - C6alkylene )(4-10 membered)heterocycloalkyl.
The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof, wherein R 4 and R 4 ' each independently represent hydrogen.
The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof, wherein R 5 represents hydrogen, (C 1 -C 6 )alkyl, halogenated (C 1 -C 6 )alkyl.
The compound of any one of claims 1-6, wherein R 6 and R 6' each independently represent hydrogen, (C 1 -C 6 )alkyl or halogen;

Or R 6 and R 6' together form a 3-6 membered ring with the carbon atom connected to it, and the ring can optionally contain 0, 1 or 2 heteroatoms selected from N, O, and S.
The compound of any one of claims 1-7, wherein R 7 and R 7' each independently represent hydrogen
The compound of any one of claims 1-8, wherein R W1 and R W2 each independently represent hydrogen, halogen, (C 1 -C 6 )alkyl.
A compound with the following structure:
A pharmaceutical composition comprising the compound of any one of claims 1-10 and a pharmaceutically acceptable carrier.
The compound of any one of claims 1-10 or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof or the pharmaceutical composition of claim 11 is prepared for the prevention and/or treatment of cancer, Use in the medicament of tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.