Pyridine derivatives and preparation methods and uses thereof

Abstract

The present invention relates to pyridine derivatives, preparation methods and pharmaceutical applications thereof. Specifically, the present invention relates to a pyridine derivative represented by general formula (I), preparation methods and pharmaceutically acceptable salts thereof, and their use as therapeutic agents, especially as tyrosine kinase 2 (TYK2) inhibitors, wherein the definitions of the substituents in the general formula (I) are the same as those in the specification. #imgabs0#

Description

Technical Field

[0001] The present invention relates to a novel pyridine derivative, a preparation method thereof, a pharmaceutical composition containing the derivative, and the use of the derivative as a therapeutic agent, in particular as a tyrosine kinase 2 (TYK2) inhibitor. Background Art

[0002] Tyrosine kinase 2 (TYK2) is a non-receptor tyrosine kinase belonging to the Janus kinase family (JAKS). JAKS includes JAK1, JAK2, JAK3 and TYK2 subtypes. These four family members consist of 1,100 amino acids, have high homology, and can be divided into 7 homology domains (JH): JH1 is a highly conserved kinase region with catalytic activity; JH2 is a kinase-like region, which is the unique feature of JAK kinases that is different from other tyrosine kinases. This region does not have catalytic activity, but can regulate the activity of JH1; JH3-JH4 is an SH2 domain that can specifically recognize and bind to activated tyrosine residues; JH5-JH7 is a FERM domain, which is relatively conservative and regulates the binding of JAK to receptors. JAK1, JAK2 and TYK2 are widely present in the human body, while JAK3 is only present in hematopoietic tissues such as bone marrow and lymph.

[0003] The Janus kinase / signal transducer and activator of transcription (JAK / STAT) signaling pathway mediates a variety of cytokine signal transductions, including interleukins, interferons, erythropoietin, granulocyte and macrophage colony stimulating factor, etc. After cytokines bind to their receptors, they cause the dimerization of receptor molecules, allowing the JAK kinases coupled to the receptors to approach each other and become activated through interactive tyrosine phosphorylation. The activated JAK catalyzes the phosphorylation of the receptor itself and forms the corresponding STAT docking site, allowing STAT to achieve its phosphorylation. Then STAT forms homologous or heterologous dimers and enters the cell nucleus, binding to the corresponding target gene promoter to activate gene transcription and expression. Therefore, the JAK kinase-mediated signaling pathway plays an important role in various life processes such as cell proliferation, differentiation, apoptosis, and inflammatory response. However, in the pathological process, excessive secretion of cytokines leads to excessive activation of the JAK / STAT pathway, causing the occurrence of autoimmune diseases, inflammatory diseases and cancers; wherein the autoimmune diseases include asthma, psoriasis, systemic lupus erythematosus, multiple sclerosis, allergic rhinitis, atopic dermatitis, contact dermatitis and delayed allergic reaction; wherein the inflammatory diseases include inflammatory bowel disease and rheumatoid arthritis, and the inflammatory bowel disease includes Crohn's syndrome and ulcerative colitis; wherein the cancer includes non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, gastric cancer, liver cancer, gastrointestinal stromal tumors, thyroid cancer, leukemia, non-Hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumor, lymphoma, multiple myeloma, bile duct cancer and solid tumors, wherein the leukemia is selected from chronic myeloid leukemia and acute myeloid leukemia.

[0004] JAK kinases participate in the signal transduction of cytokines and regulate immune responses. Therefore, JAK kinases can be used as targets for the treatment of autoimmune diseases such as psoriasis and rheumatoid arthritis. At present, tofacitinib developed by Pfizer has been successfully launched on the market, which can effectively inhibit JAK1, JAK2, and JAK3, and is therefore used to treat rheumatoid arthritis; baricitinib, a JAK1 and JAK2 kinase inhibitor developed by Eli Lilly, has also been launched as a drug for the treatment of rheumatoid arthritis. Upadacitinib, a JAK1 kinase inhibitor developed by AbbVie, was launched in the United States in 2019, also for the treatment of rheumatoid arthritis. The continuous impressive achievements in the development of other members of the JAK kinase family have made TYK2 a research hotspot. Although there are currently no drugs for this target on the market, several compounds are already in the clinical stage, and TYK2 has finally made its debut in the history of protein kinases. Most notably, the TYK2 inhibitor BMS-986165 developed by BMS is used to treat psoriasis and is currently in Phase 3 clinical trials. It has achieved the primary efficacy endpoint in Phase 2 clinical trials for patients with moderate to severe plaque psoriasis, with few side effects and high safety and effectiveness. However, there is still a huge room for improvement, and it is still necessary to continue researching and developing new TYK2 inhibitors. I believe that in the near future, TYK2 inhibitors will bring good news to psoriasis patients. Summary of the invention

[0005] The object of the present invention is to provide a new type of pyridine derivatives represented by general formula (I), or its stereoisomers, tautomers or pharmaceutically acceptable salts:

[0006]

[0007] in:

[0008] W and Y are each independently selected from CR n or N, and W and Y contain at most one N;

[0009] X is selected from C, S, S═O or S═NH, X is preferably C;

[0010] R 1 is selected from alkyl, cycloalkyl, alkynyl or heterocyclyl, wherein the alkyl, cycloalkyl, alkynyl or heterocyclyl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent;

[0011] R 2 Selected from 5-10 membered heteroaryl or -C(O)R a wherein the heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 8 、-S(O) n NR 9 R 10 or -NR 9 C(O)R 10 wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl groups are optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent;

[0012] R a is selected from alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more R g substituted by a substituent;

[0013] R g is selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl groups are optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent;

[0014] R 3 is selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-S(O) n R 8 、-S(O) n NR 9 R 10 or -NR 9 C(O)R 10 wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent;

[0015] R 4 is selected from hydrogen, hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-S(O) n NR 9 R 10 or -NR 9 C(O)R 10 wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, alkyl, nitro, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 Preferably, R 4 is selected from a hydrogen atom or a heteroaryl group;

[0016] R n , R 5 , R 6 and R 7 are the same or different and are each independently selected from hydrogen, hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-S(O) n NR 9 R 10 or -NR 9 C(O)R 10wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, alkyl, nitro, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 Preferably, R n , R 5 , R 6 and R 7 are each independently selected from a hydrogen atom, an alkyl group or a halogen;

[0017] R 8 , R 9 and R 10 Each is independently selected from hydrogen, hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 11 、-C(O)OR 11 、-OC(O)R 11 、-NR 12 R 13 、-C(O)NR 12 R 13 、-SO2NR 12 R 13 or -NR 12 C(O)R 13 substituted by a substituent;

[0018] Or, R 9 and R 10 Together with the connected nitrogen atom, it forms a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic ring contains one or more N, O or S(O) n , and the 4- to 8-membered heterocyclic ring is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R 11 、-C(O)OR 11 、-OC(O)R 11 、-NR12 R 13 、-C(O)NR 12 R 13 、-SO2NR 12 R 13 or -NR 12 C(O)R 13 substituted by a substituent;

[0019] R 11 , R 12 and R 13 Each is independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl or carboxylate;

[0020] n is selected from 0, 1 or 2.

[0021] In some preferred embodiments of the present invention, the compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt is a compound of general formula (II) or its stereoisomer, tautomer or pharmaceutically acceptable salt,

[0022]

[0023] in:

[0024] Ring A is selected from cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is preferably C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, more preferably cyclopropyl, cyclobutyl or tetrahydropyranyl;

[0025] R b are the same or different and are each independently selected from hydrogen, hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl groups are optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent;

[0026] m is selected from 0, 1, 2, 3, 4 or 5;

[0027] R 1 , R 3 ~R 7 , X, W and Y are as defined in the general formula (I).

[0028] In some preferred embodiments of the present invention, the compound described by general formula (I) or (II) or its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein:

[0029] R 1 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkynyl or 3-6 membered heterocyclic group, wherein the alkyl, cycloalkyl, alkynyl or heterocyclic group is optionally further substituted by one or more selected from halogen, C 1-4 Alkyl or C 1-6 The alkoxy group is substituted with an alkoxy substituent.

[0030] In some preferred embodiments of the present invention, the compound described by general formula (I) or (II) or its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein:

[0031] R 1 It is selected from methyl, ethyl, isopropyl, ethynyl, 1-propynyl, 2-propynyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl or cyclopentyl, preferably methyl, ethyl or cyclopropyl.

[0032] In some preferred embodiments of the present invention, the compound described by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein:

[0033] R 2 Selected from -C(O)R a ;

[0034] R a Selected from C 1-4 Alkyl, C 3-6Cycloalkyl or 3-6 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group is optionally further substituted by one or more selected from hydroxyl, C 1-4 Alkyl, C 1-6 The group may be substituted with an alkoxy group or a halogen group.

[0035] In some preferred embodiments of the present invention, the compound described by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein:

[0036] R a R is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or tetrahydropyranyl, wherein the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or tetrahydropyranyl is optionally further substituted with one or more hydroxyl or halogen, wherein the halogen is preferably fluorine; a Preferred is cyclopropyl.

[0037] In some preferred embodiments of the present invention, the compound described by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein:

[0038] R 2 The invention is selected from 5-10 membered heteroaryl groups, wherein the heteroaryl groups are optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl groups, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl groups are optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl groups.

[0039] In some preferred embodiments of the present invention, the compound described by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein:

[0040] R 2 is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, thiazolyl, quinolyl or isoquinolyl, wherein the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, thiazolyl, quinolyl or isoquinolyl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, amino, cyano, C 1-4 Alkyl, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl, a 3- to 6-membered heterocyclic group, a 5- to 10-membered aryl or a 5- to 10-membered heteroaryl substituent, wherein the C 1-4 Alkyl, C 1-6 Alkoxy, C 3-6Cycloalkyl, 3-6 membered heterocyclic, 5-10 membered aryl or 5-10 membered heteroaryl may be further substituted with one or more selected from hydroxy, halogen, nitro, amino, cyano, C 1-4 Alkyl, C 1-6 Alkoxy, C 3-6 Substituted by a cycloalkyl or 3- to 6-membered heterocyclic group; wherein R 2 Preferably it is pyridyl, more preferably

[0041] In some preferred embodiments of the present invention, the compound described by general formula (I) or (II) or its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein:

[0042] R 3 Selected from C 1-4 Alkyl, C 1-6 Alkoxy or -S(O)2R 8 ; R 3 Preferably C 1-6 Alkoxy, more preferably methoxy;

[0043] R 8 Selected from C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally further substituted with one or more selected from halogen, C 1-4 Alkyl, C 1-6 Alkoxy is substituted by a substituent; R 8 Preferred is methyl.

[0044] In some preferred embodiments of the present invention, the compound described by general formula (I) or (II) or its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein:

[0045] R 4 Selected from hydrogen atom, 5-10 membered heteroaryl or -C(O)NR 9 R 10 wherein the heteroaryl is optionally further substituted by one or more selected from halogen, C 1-4 Alkyl or C 1-6 substituted by an alkoxy substituent;

[0046] R 9 and R 10 are independently selected from hydrogen atoms, C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally further substituted with one or more selected from halogen, C 1-4 Alkyl or C 1-6 Alkoxy is substituted by a substituent; R 9 and R 10 Preferred is a hydrogen atom.

[0047] In some preferred embodiments of the present invention, the compound described by general formula (I) or (II) or its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein:

[0048] R 4 is selected from triazolyl, pyrazolyl, thiazolyl, pyrimidinyl or oxadiazolyl, wherein the triazolyl, pyrazolyl, thiazolyl, pyrimidinyl or oxadiazolyl is optionally further substituted by one or more C 1-4 is substituted by an alkyl or halogen substituent; R 4 Preferably it is triazole, more preferably

[0049] In some preferred embodiments of the present invention, the compound of formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R 5 , R 6 or R 7 Selected from hydrogen atoms.

[0050] In some preferred embodiments of the present invention, the compound described by general formula (I) or (II) or its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein:

[0051] W and Y are selected from CR n ;

[0052] R n Selected from hydrogen atoms, halogens, C 1-4 Alkyl, C 1-6 The alkoxy group is preferably a hydrogen atom, a fluorine atom or a methyl group, and more preferably a hydrogen atom.

[0053] Typical compounds of the present invention include, but are not limited to:

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060] or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

[0061] Note: If there is a discrepancy between a drawn structure and the name given for that structure, the drawn structure will be given greater weight.

[0062] Furthermore, the present invention provides a method for preparing a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, the method comprising:

[0063]

[0064] The compound of formula (IA) is reacted with the compound of formula (IB), optionally further oxidized, to obtain the compound of formula (I);

[0065] in:

[0066] X 1 is a leaving group, wherein the leaving group is preferably a halogen, more preferably chlorine;

[0067] X, W, Y, R 1 ~R 7 The definition of is as described in the general formula (I).

[0068] Furthermore, the present invention provides a method for preparing a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, the method comprising:

[0069]

[0070] The compound of general formula (IC) reacts with the compound of general formula (IB) to obtain the compound of general formula (ID); the compound of general formula (ID) reacts with the compound of general formula (IE) to obtain the compound of general formula (I);

[0071] in:

[0072] X 1 is a leaving group, wherein the leaving group is preferably a halogen, more preferably chlorine;

[0073] X is a carbon atom;

[0074] W, Y, R 1 ~R 7 The definition of is as described in the general formula (I).

[0075] The present invention also provides a compound represented by general formula (IA) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

[0076]

[0077] in:

[0078] X 1 is a leaving group, wherein the leaving group is preferably a halogen, more preferably chlorine;

[0079] X, W, Y, R 1 , R3 ~R 7 The definition of is as described in the general formula (I).

[0080] The compounds of the general formula (IA) of the present invention include, but are not limited to:

[0081]

[0082]

[0083]

[0084]

[0085] or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

[0086] Note: If there is a discrepancy between a drawn structure and the name given for that structure, the drawn structure will be given greater weight.

[0087] The present invention further provides a compound represented by the general formula (ID) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

[0088]

[0089] in:

[0090] X, W, Y, R 2 ~R 7 The definition of is as described in the general formula (I).

[0091] The compounds of the general formula (ID) of the present invention include, but are not limited to:

[0092]

[0093] In another aspect, the present invention provides a pharmaceutical composition comprising an effective dose of a compound of formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

[0094] In another aspect, the present invention provides a pharmaceutical composition, which further contains at least one anti-inflammatory drug selected from non-steroidal anti-inflammatory drugs, non-specific cyclooxygenase-2 inhibitors, specific cyclooxygenase-2 inhibitors, corticosteroids, tumor necrosis factor receptor antagonists, salicylate or salt, immunosuppressant or methotrexate.

[0095] In another aspect, the present invention provides a method for inhibiting TYK2 kinase, wherein the method comprises administering to a patient a pharmaceutical composition comprising an effective dose of a compound of formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

[0096] In another aspect, the present invention provides a use of a compound of formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof in the preparation of a TYK2 kinase inhibitor.

[0097] In another aspect, the present invention provides a use of a compound of formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof, in the preparation of a medicament for treating a disease mediated by TYK2 kinase, preferably in the preparation of a medicament for treating a disease mediated by TYK2 kinase, wherein the disease mediated by TYK2 kinase includes autoimmune diseases, inflammatory diseases and cancer; wherein the autoimmune diseases include asthma, psoriasis, systemic lupus erythematosus, multiple sclerosis, allergic rhinitis, atopic dermatitis, contact dermatitis and delayed hypersensitivity reaction; wherein The inflammatory diseases include inflammatory bowel disease and rheumatoid arthritis, and the inflammatory bowel disease includes Crohn's syndrome and ulcerative colitis; wherein the cancer includes non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, leukemia, non-Hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumor, lymphoma, multiple myeloma, bile duct cancer and solid tumors; the leukemia is further preferably selected from chronic myeloid leukemia and acute myeloid leukemia.

[0098] In another aspect, the present invention provides a use of a compound of general formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof, in the preparation of drugs for treating autoimmune diseases, inflammatory diseases and cancer; wherein the autoimmune diseases include asthma, psoriasis, systemic lupus erythematosus, multiple sclerosis, allergic rhinitis, atopic dermatitis, contact dermatitis and delayed hypersensitivity reaction; wherein the inflammatory diseases include inflammatory bowel disease and rheumatoid arthritis, and the inflammatory bowel disease includes Crohn's syndrome and ulcerative colitis; wherein the cancers include non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, gastric cancer, liver cancer, gastrointestinal stromal tumors, thyroid cancer, leukemia, non-Hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumor, lymphoma, multiple myeloma, bile duct cancer and solid tumors.

[0099] Detailed description of the invention

[0100] Unless otherwise stated, some of the terms used in the specification and claims of the present invention are defined as follows:

[0101] "Alkyl" as a group or a part of a group refers to a group consisting of C1-C 20 A straight chain or branched aliphatic hydrocarbon group. Preferably C1-C 10 Alkyl, more preferably C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl can be substituted or unsubstituted.

[0102] "Alkylene" is a divalent alkyl group. Preferably, it is C1-C 10 Alkylene, more preferably C1-C6 alkylene, particularly preferably C1-C4 alkylene. Examples of alkylene groups include, but are not limited to, methylene, ethylene, -C(CH3)2-, n-propylene, etc. Alkylene may be substituted or unsubstituted.

[0103] "Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, representative examples include but are not limited to ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. Alkenyl groups may be optionally substituted or unsubstituted.

[0104] "Alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be straight chain or branched. 10 The alkynyl group of any of the preceding claims may be substituted or unsubstituted.

[0105] "Cycloalkyl" refers to a saturated or partially saturated monocyclic, fused, bridged or spirocyclic carbon ring. 12 Cycloalkyl, more preferably C3-C8 cycloalkyl, most preferably C3-C6 cycloalkyl. Examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., preferably cyclopropyl and cyclohexenyl.

[0106] "Spirocycloalkyl" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and one carbon atom (called spiro atom) shared between the monocyclic rings, containing one or more double bonds in the ring, but no ring has a completely conjugated π-electron aromatic system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of spiro atoms shared between the rings, the spirocycloalkyl is divided into single spiro, double spiro or multiple spirocycloalkyl, preferably single spiro and double spirocycloalkyl, preferably 4 / 5 members, 4 / 6 members, 5 / 5 members or 5 / 6 members. Non-limiting examples of "spirocycloalkyl" include, but are not limited to, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.

[0107] "Fused cycloalkyl" refers to a 5 to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl or tetradecahydrophenanthryl.

[0108] "Bridged cycloalkyl" refers to a 5-18 membered, all-carbon polycyclic group containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron aromatic system, preferably 6-12 members, more preferably 7-10 members. Preferably 6-14 members, more preferably 7-10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s, 4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s, 5s)-bicycloo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r, 5r)-bicyclo[3.3.2]decyl.

[0109] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl may be optionally substituted or unsubstituted.

[0110] "Heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably in this application and all refer to non-aromatic heterocyclic groups, wherein one or more of the atoms forming the ring is a heteroatom, such as oxygen, nitrogen, sulfur atoms, etc., including monocyclic, fused, bridged and spirocyclic rings. Preferably, it has a 5-7 membered monocyclic ring or a 7-10 membered bi- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and piperazinyl. The heterocyclyl group may be substituted or unsubstituted.

[0111] "Spiro heterocyclyl" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and the single rings share one atom with each other, containing one or more double bonds in the ring, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) n(wherein n is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of shared spiral atoms between rings, the spirocycloalkyl is divided into a monospiro heterocyclic group, a bispiro heterocyclic group or a polyspiro heterocyclic group, preferably a monospiro heterocyclic group and a bispiro heterocyclic group. More preferably, it is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiro heterocyclic group. Non-limiting examples of "spiro heterocyclic group" include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl and 5-oxaspiro[2.4]heptyl.

[0112] "Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more ring structures that share a pair of atoms with each other, one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) n (wherein n is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic group, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of "fused heterocyclic group" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxin (dioxine).

[0113] "Bridged heterocyclic group" refers to a 5- to 14-membered, 5- to 18-membered polycyclic group containing two or more cyclic structures, sharing two atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) n (wherein n is selected from 0, 1 or 2) heteroatom, and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.

[0114] Non-limiting examples of "fused heterocyclyl" include, but are not limited to, 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl and 2-azabicyclo[3.3.2]decyl.

[0115] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is the heterocyclyl. The heterocyclyl may be optionally substituted or unsubstituted.

[0116] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl. Preferably, aryl is C6-C 10 Aryl, more preferably phenyl and naphthyl, most preferably phenyl. Aryl can be substituted or unsubstituted. The "aryl" can be fused with heteroaryl, heterocyclic or cycloalkyl, wherein the aryl ring is connected to the parent structure, non-limiting examples include but are not limited to:

[0117]

[0118] "Heteroaryl" refers to an aromatic 5 to 6-membered monocyclic or 8 to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur. The embodiment of "heteroaryl" includes, but is not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolyl, isoquinolyl, indazolyl, benzisothiazolyl, benzoxazolyl and benzisoxazolyl. Heteroaryl may be substituted or unsubstituted. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include but are not limited to:

[0119]

[0120] "Alkoxy" refers to a group of (alkyl-O-). Wherein, alkyl is as defined herein. C1-C6 alkoxy is preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0121] "Aryloxy" refers to a group of (aryl-O-). Wherein, aryl is as defined herein. 10 Aryloxy is preferred, and examples thereof include, but are not limited to, phenoxy, naphthoxy, etc., and phenoxy is most preferred.

[0122] "Hydroxy" refers to an -OH group.

[0123] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0124] "Amino" refers to -NH2.

[0125] "Cyano" refers to -CN.

[0126] "Nitro" refers to -NO2.

[0127] "Benzyl" refers to -CH2-phenyl.

[0128] "Carboxy" refers to -C(O)OH.

[0129] "Carboxylate" refers to -C(O)O-alkyl or -C(O)O-cycloalkyl, wherein alkyl and cycloalkyl are as defined above.

[0130] "DMSO" refers to dimethyl sulfoxide.

[0131] "BOC" refers to tert-butoxycarbonyl.

[0132] "Ts" refers to p-toluenesulfonyl.

[0133] "Leaving group", or leaving group, is an atom or functional group that detaches from a larger molecule in a chemical reaction. It is a term used in nucleophilic substitution reactions and elimination reactions. In nucleophilic substitution reactions, the reactant attacked by the nucleophile is called a substrate, and the atom or group of atoms that breaks away from the substrate molecule with a pair of electrons is called a leaving group. Groups that are easy to accept electrons and have a strong ability to bear negative charges are good leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to detach from other molecules. The reason is that when the pKa of its conjugate acid is smaller, the corresponding leaving group does not need to combine with other atoms, and the tendency to exist in the form of anions (or electrically neutral leaving groups) is enhanced. Common leaving groups include but are not limited to halogens, -OTs or -OH.

[0134] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

[0135] The term "substituted" or "substituted" as used herein, unless otherwise specified, means that a group may be substituted by one or more groups selected from the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 ;

[0136] R 8 , R 9 and R 10 Each is independently selected from a hydrogen atom, a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more hydroxyl groups, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -C(O)R 11 、-C(O)OR 11 、-OC(O)R 11 、-NR 12 R 13 、-C(O)NR 12 R 13 、-SO2NR 12 R 13 or -NR 12 C(O)R 13 substituted by a substituent;

[0137] Or, R 9 and R 10 Together with the connected nitrogen atom, it forms a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic ring contains one or more N, O or S(O) n , and the 4- to 8-membered heterocyclic ring is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R 11 、-C(O)OR 11 、-OC(O)R 11 、-NR 12 R 13 、-C(O)NR 12 R 13 、-SO2NR 12 R 13 or -NR 12 C(O)R 13 substituted by a substituent;

[0138] R 11 , R 12 and R 13Each is independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl or carboxylate;

[0139] n is selected from 0, 1 or 2.

[0140] "Pharmaceutically acceptable salts" refer to certain salts of the above compounds that can maintain the original biological activity and are suitable for medical use. The pharmaceutically acceptable salts of the compounds represented by formula (I) can be metal salts or amine salts formed with suitable acids.

[0141] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity. DETAILED DESCRIPTION

[0142] The present invention is further described below with reference to the embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0143] Example

[0144] The examples provide the preparation of representative compounds represented by formula (I) and related structural identification data. It must be noted that the following examples are used to illustrate the present invention rather than to limit the present invention. 1 H NMR spectra were measured using a Bruker instrument (400 MHz), and chemical shifts were expressed in ppm using tetramethylsilane as an internal standard (0.00 ppm). 1 H NMR notation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are given in Hz.

[0145] The mass spectrum is obtained by LC / MS, and the ionization method can be ESI or APCI.

[0146] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0147] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0148] In the following examples, unless otherwise specified, all temperatures are in degrees Celsius. Unless otherwise specified, various starting materials and reagents are commercially available or synthesized according to known methods (1b is synthesized according to the document J.Med.Chem.2019,62,20,8973-8995; 22a is prepared according to the patent publication WO2018183649A1). Commercially available raw materials and reagents are used directly without further purification. Unless otherwise specified, commercial manufacturers include but are not limited to Shanghai Bid Pharmaceutical Technology Co., Ltd., Shanghai Shaoyuan Reagent Co., Ltd. and San Chemical Technology (Shanghai) Co., Ltd.

[0149] CD3OD: deuterated methanol.

[0150] CDCl3: deuterated chloroform.

[0151] DMSO-d6: deuterated dimethyl sulfoxide.

[0152] Argon atmosphere means that the reaction bottle is connected to an argon balloon with a capacity of about 1L.

[0153] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0154] The compound is purified using a silica gel column chromatography eluent system and thin layer chromatography, wherein the eluent system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane and ethyl acetate; wherein the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagents, such as acetic acid or triethylamine, may also be added for adjustment.

[0155] Example 1

[0156] N-(5-Acetyl-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide

[0157]

[0158] first step

[0159] 6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)nicotinic acid

[0160] Dissolve 4,6-dichloronicotinic acid 1a (6.0 g, 31.25 mmol) and 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline 1b (5.80 g, 28.41 mmol, synthesized according to J.Med.Chem.2019,62,20,8973-8995) in 50 mL of N,N-dimethylacetamide, cool in an ice-water bath, and slowly add lithium bistrimethylsilylamide solution (1.0 M / THF, 60 mL). After addition, naturally warm to room temperature and react for 4 hours. The mixture was quenched with water and concentrated under reduced pressure to remove most of tetrahydrofuran and water. Hydrochloric acid (6.0 M) was added dropwise to the remaining solution until the pH value was 1-2. A large amount of white solid precipitated. The solid was filtered and the filter cake was washed with water several times. The filter cake was dried to give 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)nicotinic acid 1c (8.5 g). Yield: 83%.

[0161] MS m / z(ESI):360.1[M+1]

[0162] Step 2

[0163] 6-Chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylnicotinamide

[0164] 6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)nicotinic acid 1c (7.0 g, 19.46 mmol) was dissolved in 80 mL of tetrahydrofuran, and N,N'-carbonyldiimidazole (9.46 g, 58.37 mmol), N,N-diisopropylethylamine (12.57 g, 97.29 mmol) and N,O-dimethylhydroxylamine hydrochloride (3.80 g, 38.91 mmol) were added in sequence at room temperature, and the mixture was reacted at room temperature for 24 hours. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (100 mL×2), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylnicotinamide 1d (8.5 g), which was used directly in the next step without purification.

[0165] MS m / z(ESI):403.1[M+1]

[0166] Step 3

[0167] 1-(6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)ethan-1-one

[0168] Under nitrogen protection, 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylnicotinamide 1d (1.30 g, 3.23 mmol) was dissolved in 20 mL of tetrahydrofuran, cooled in an ice-water bath, methylmagnesium bromide solution (1.0 M / THF, 1.6 mL) was slowly added, and the temperature was raised to room temperature for reaction for 2 hours. The reaction mixture was cooled in an ice-water bath, quenched with water, extracted with ethyl acetate (20 mL×3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give 1-(6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)ethan-1-one 1e (0.60 g) in a yield of 52%.

[0169] MS m / z(ESI):358.1[M+1]

[0170] Step 4

[0171] N-(5-Acetyl-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide

[0172] 1-(6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)ethan-1-one 1e (0.50 g, 1.40 mmol) was dissolved in 20 mL of 1,4-dioxane, and cyclopropylcarboxamide (0.36 g, 4.19 mmol), tris(dibenzylideneacetone)dipalladium (0.26 g, 0.28 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.16 g, 0.28 mmol) and cesium carbonate (0.91 g, 2.80 mmol) were added in sequence, and the reaction mixture was reacted under microwave heating at 130 °C for 30 min. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (20 mL), extracted with an organic mixed solvent (dichloromethane / methanol=10 / 1, 20 mL×3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: B system) to obtain N-(5-acetyl-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide 1 (0.20 g), with a yield of 35%.

[0173] MS m / z(ESI):407.2[M+1]

[0174] 1 H NMR (400MHz, DMSO-d6) δ11.05(s,1H),10.94(s,1H),8.84(s,1H),8.56(s,1H),8.04(s,1H),7.65(d,J=7.7Hz,1H),7. 52(d,J=7.9Hz,1H),7.23-7.28(m,1H),3.94(s,3H),3.70(s,3H),2.65(s,3H),1.95-2.05(m,1H),0.77-0.80(m,4H).

[0175] Example 2

[0176] N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide

[0177]

[0178] first step

[0179] 1-(6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)propan-1-one

[0180] Under nitrogen protection, 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylnicotinamide 1d (3.0 g, 7.45 mmol) was dissolved in 75 mL of tetrahydrofuran, cooled in an ice-water bath, ethylmagnesium bromide solution (1.0 M / THF, 22 mL) was slowly added, and the mixture was heated to room temperature for 2 hours. After the reaction, the mixture was cooled in an ice-water bath, water was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to obtain 1-(6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)propan-1-one 2a (2.20 g), yield: 79%. MS m / z (ESI): 372.2 [M+1]

[0181] Step 2

[0182] N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide

[0183] 1-(6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)propan-1-one 2a (0.30 g, 0.81 mmol) was dissolved in 20 mL of 1,4-dioxane, and cyclopropylcarboxamide (0.14 g, 1.61 mmol), tris(dibenzylideneacetone)dipalladium (0.15 g, 0.16 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.093 g, 0.16 mmol) and cesium carbonate (0.53 g, 1.61 mmol) were added in sequence, and the reaction mixture was heated in a microwave at 130 ° C for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, water (20 mL) was added to dilute the reaction solution, and the mixture was extracted with an organic mixed solvent (dichloromethane / methanol=10 / 1, 20 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide 2 (90 mg), with a yield of 27%.

[0184] MS m / z(ESI):421.2[M+1]

[0185] 1 H NMR (400MHz, DMSO-d6) δ11.04(s,1H),10.90(s,1H),8.88(s,1H),8.56(s,1H),8.03(s,1H),7.64(d,J=7.7Hz,1H),7.52(d,J=7.9Hz, 1H),7.23-7.28(m,1H),3.95(s,3H),3.71(s,3H),3.12(q,J=7.0Hz,2H),1.98-2.01(m,1H),1.12(t,J=7.0Hz,3H),0.77-0.80(m,4H).

[0186] Example 3

[0187] N-(5-(Cyclopropanecarbonyl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide

[0188]

[0189] first step

[0190] (6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)(cyclopropyl)methanone

[0191] Under nitrogen protection, 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylnicotinamide 1d (1.0 g, 2.48 mmol) was dissolved in 20 mL of tetrahydrofuran and cooled in an ice-water bath. Cyclopropylmagnesium bromide solution (1.0 M / THF, 7.5 mL) was slowly added and the mixture was heated to room temperature for 3 hours. After the reaction, the mixture was cooled in an ice-water bath, water was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to obtain (6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)(cyclopropyl)methanone 3a (0.90 g), yield: 94%. MS m / z (ESI): 384.1 [M+1]

[0192] Step 2

[0193] N-(5-(Cyclopropanecarbonyl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide

[0194] (6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)(cyclopropyl)methanone 3a (0.90 g, 2.34 mmol) was dissolved in 20 mL of 1,4-dioxane, and cyclopropylcarboxamide (0.60 g, 7.03 mmol), tris(dibenzylideneacetone)dipalladium (0.43 g, 0.47 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.27 g, 0.47 mmol) and cesium carbonate (1.53 g, 4.69 mmol) were added in sequence, and the reaction mixture was heated in a microwave at 130 ° C for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (20 mL), extracted with an organic mixed solvent (dichloromethane / methanol=10 / 1, 20 mL×3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to obtain N-(5-(cyclopropanecarbonyl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide 3 (0.30 g) with a yield of 30%.

[0195] MS m / z(ESI):433.2[M+1]

[0196] 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),10.94(s,1H),9.13(s,1H),8.56(s,1H),8.03(s,1H),7.63(d,J=7.8Hz,1H),7.51(d,J=7.9 Hz,1H),7.22-7.27(m,1H),3.94(s,3H),3.68(s,3H),2.98-3.00(m,1H),1.97-2.03(m,1H),1.02-1.10(m,4H),0.76-0.80(m,4H).

[0197] Example 4

[0198] N-(5-isobutyryl-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide

[0199]

[0200] first step

[0201] 1-(6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)-2-methylpropan-1-one Under nitrogen protection, 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylnicotinamide 1d (1.0 g, 2.48 mmol) was dissolved in 20 mL of tetrahydrofuran, cooled in an ice-water bath, and isopropylmagnesium bromide solution (1.0 M / THF, 7.5 mL) was slowly added, and the temperature was raised to room temperature for reaction for 4 hours. The reaction mixture was cooled in an ice-water bath, quenched with water, extracted with ethyl acetate (20 mL×3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give 1-(6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)-2-methylpropan-1-one 4a (0.30 g) in a yield of 31%.

[0202] MS m / z(ESI):386.1[M+1]

[0203] Step 2

[0204] N-(5-isobutyryl-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide

[0205] 1-(6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)-2-methylpropan-1-one 4a (0.30 g, 0.78 mmol) was dissolved in 20 mL of 1,4-dioxane, and cyclopropylcarboxamide (0.20 g, 2.33 mmol), tris(dibenzylideneacetone)dipalladium (0.14 g, 0.16 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.090 g, 0.16 mmol) and cesium carbonate (0.51 g, 1.56 mmol) were added in sequence, and the reaction mixture was reacted under microwave heating at 130 °C for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (20 mL), extracted with an organic mixed solvent (dichloromethane / methanol=10 / 1, 20 mL×3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: B system) to give N-(5-isobutyryl-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide 4 (60 mg), yield: 18%.

[0206] MS m / z(ESI):435.2[M+1]

[0207] 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),10.92(s,1H),8.91(s,1H),8.56(s,1H),8.03(s,1H),7.64(d,J=7.8Hz,1H),7.53(d ,J=8.0Hz,1H),7.23-7.28(m,1H),3.94(s,3H),3.70(s,3H),1.98-2.03(m,2H),1.16(d,J=6.7Hz,6H),0.77-0.84(m,4H).

[0208] Example 5

[0209] N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(3-methylbutanoyl)pyridin-2-yl)cyclopropanecarboxamide

[0210]

[0211] first step

[0212] 1-(6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)-3-methylbutan-1-one Under nitrogen protection, 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylnicotinamide 1d (0.5 g, 1.24 mmol) was dissolved in 10 mL of tetrahydrofuran, cooled in an ice-water bath, and isobutylmagnesium chloride solution (2.0 M / THF, 7.0 mL) was slowly added, and the temperature was raised to room temperature for reaction for 4 hours. After the reaction was completed, the mixture was cooled in an ice-water bath, water was added to the reaction solution to quench it, and it was extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give 1-(6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)-3-methylbutan-1-one 5a (0.20 g) in a yield of 40%.

[0213] MS m / z(ESI):400.2[M+1]

[0214] Step 2

[0215] N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(3-methylbutanoyl)pyridin-2-yl)cyclopropanecarboxamide

[0216] 1-(6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)-3-methylbutan-1-one 5a (0.20 g, 0.50 mmol) was dissolved in 10 mL of 1,4-dioxane, and cyclopropylcarboxamide (0.13 g, 1.50 mmol), tris(dibenzylideneacetone)dipalladium (0.092 g, 0.10 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.058 g, 0.10 mmol) and cesium carbonate (0.33 g, 1.0 mmol) were added in sequence, and the reaction mixture was reacted under microwave heating at 130 °C for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (20 mL), extracted with an organic mixed solvent (dichloromethane / methanol=10 / 1, 20 mL×3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: B system) to give N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(3-methylbutanoyl)pyridin-2-yl)cyclopropanecarboxamide 5 (74 mg) in a yield of 33%.

[0217] MS m / z(ESI):449.3[M+1]

[0218] 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),10.91(s,1H),8.87(s,1H),8.56(s,1H),8.03(s,1H),7.65(d,J=7.7Hz,1H),7.52(d,J=7.6Hz,1H),7.23 -7.28(m,1H),3.94(s,3H),3.69(s,3H),2.95(d,J=6.6Hz,2H),2.17-2. 21(m,1H),2.01-2.03(m,1H),0.97(d,J=6.4Hz,6H),0.76-0.79(m,4H).

[0219] Example 6

[0220] N-(5-(Cyclopentanecarbonyl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide

[0221]

[0222]

[0223] first step

[0224] (6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)(cyclopentyl)methanone

[0225] Under nitrogen protection, 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylnicotinamide 1d (0.5 g, 1.24 mmol) was dissolved in 10 mL of tetrahydrofuran, cooled in an ice-water bath, cyclopentylmagnesium bromide solution (1.0 M / THF, 6.5 mL) was slowly added, and the temperature was raised to room temperature for reaction for 4 hours. After the reaction, the mixture was cooled in an ice-water bath, water was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to obtain (6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)(cyclopentyl)methanone 6a (0.20 g), yield: 39%. MS m / z (ESI): 412.2 [M+1] +

[0226] Step 2

[0227] N-(5-(Cyclopentanecarbonyl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide

[0228] (6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)(cyclopentyl)methanone 6a (0.16 g, 0.39 mmol) was dissolved in 6 mL of 1,4-dioxane, and cyclopropylcarboxamide (0.10 g, 1.17 mmol), tris(dibenzylideneacetone)dipalladium (0.071 g, 0.078 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.045 g, 0.078 mmol) and cesium carbonate (0.25 g, 0.78 mmol) were added in sequence, and the reaction mixture was heated in a microwave at 130 ° C for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, and water (20 mL) was added to dilute the reaction solution, and the mixture was extracted with an organic mixed solvent (dichloromethane / methanol=10 / 1, 20 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give N-(5-(cyclopentanecarbonyl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide 6 (55 mg) in a yield of 31%.

[0229] MS m / z(ESI):461.3[M+1]

[0230] 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),10.90(s,1H),8.91(s,1H),8.56(s,1H),8.02(s,1H),7.64(d,J=7.8Hz,1H),7.52(d,J=8.0Hz, 1H),7.22-7.28(m,1H),3.93-3.95(m,4H),3.70(s,3H),1.91-2.03(m,3H),1.80-1.82(m,2H),1.63-1.66(m,4H),0.76-0.79(m,4H).

[0231] Example 7

[0232] N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyridin-2-yl)cyclobutylcarboxamide

[0233]

[0234] first step

[0235] N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyridin-2-yl)cyclobutylcarboxamide

[0236] 1-(6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)propan-1-one 2a (0.40 g, 1.08 mmol) was dissolved in 20 mL of 1,4-dioxane, and cyclobutylcarboxamide (0.21 g, 2.15 mmol), tris(dibenzylideneacetone)dipalladium (0.20 g, 0.22 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.12 g, 0.22 mmol) and cesium carbonate (0.70 g, 2.20 mmol) were added in sequence, and the reaction mixture was reacted under microwave heating at 130 ° C for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, and water (20 mL) was added to dilute the reaction solution, and the mixture was extracted with an organic mixed solvent (dichloromethane / methanol=10 / 1, 20 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to obtain N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyridin-2-yl)cyclobutylcarboxamide 7 (0.13 g) in a yield of 28%.

[0237] MS m / z(ESI):435.3[M+1]

[0238] 1 H NMR (400MHz, DMSO-d6) δ11.05(s,1H),10.42(s,1H),8.85(s,1H),8.57(s,1H),8.08(s,1H),7.67(d,J=6.8Hz,1H),7.56 (d,J=7.5Hz,1H),7.27-7.32(m,1H),3.95(s,3H),3.72(s,3H),3.09-3.13(m,2H),1.75-2.18(m,7H),1.09-1.14(m,3H).

[0239] Example 8

[0240] N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide

[0241]

[0242] first step

[0243] N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide

[0244] 1-(6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)propan-1-one 2a (0.40 g, 1.08 mmol) was dissolved in 20 mL of 1,4-dioxane, and tetrahydro-2H-pyran-4-carboxamide (0.42 g, 3.23 mmol), tris(dibenzylideneacetone)dipalladium (0.20 g, 0.22 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.12 g, 0.22 mmol) and cesium carbonate (0.70 g, 2.20 mmol) were added in sequence, and the reaction mixture was heated in a microwave at 130 ° C for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, and the reaction solution was diluted with water (20 mL), extracted with an organic mixed solvent (dichloromethane / methanol=10 / 1, 20 mL×3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: B system) to obtain N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide 8 (0.15 g), with a yield of 30%.

[0245] MS m / z(ESI):465.3[M+1]

[0246] 1 H NMR(400MHz,DMSO-d6)δ11.05(s,1H),10.58(s,1H),8.87(s,1H),8.57(s,1 H),8.05(s,1H),7.66(d,J=8.0Hz,1H),7.55(d,J=7.7Hz,1H),7.26-7.32(m, 1H),3.95(s,3H),3.84-3.88(m,2H),3.72(s,3H),3.25-3.32(m,2H),3.12(q ,J=7.2Hz,2H),2.66-2.77(m,1H),1.52-1.67(m,4H),1.12(t,J=7.2Hz,3H).

[0247] Example 9

[0248] N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyridin-2-yl)isobutyramide

[0249]

[0250] first step

[0251] N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyridin-2-yl)isobutyramide

[0252] 1-(6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)propan-1-one 2a (0.40 g, 1.08 mmol) was dissolved in 20 mL of 1,4-dioxane, and isobutyramide (0.28 g, 3.23 mmol), tris(dibenzylideneacetone)dipalladium (0.20 g, 0.22 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.12 g, 0.22 mmol) and cesium carbonate (0.70 g, 2.20 mmol) were added in sequence, and the reaction mixture was heated in a microwave at 130 ° C for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (20 mL), extracted with an organic mixed solvent (dichloromethane / methanol=10 / 1, 20 mL×3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: B system) to give N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyridin-2-yl)isobutyramide 9 (0.14 g), yield: 31%.

[0253] MS m / z(ESI):423.2[M+1]

[0254] 1 H NMR (400MHz, DMSO-d6) δ11.05(s,1H),10.54(s,1H),8.87(s,1H),8.57(s,1H),8.07(s,1H),7.66(d,J=8.0Hz,1H),7.55 (d,J=7.8Hz,1H),7.26-7.32(m,1H),3.95(s,3H),3.72(s,3H),3.10-3.14(m,2H),2.72-2.76(m,1H),0.85-1.15(m,9H).

[0255] Example 10

[0256] 6-((5-acetyl-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-2-yl)amino)nicotinonitrile

[0257]

[0258] first step

[0259] 6-((5-acetyl-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-2-yl)amino)nicotinonitrile

[0260] 1-(6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)ethan-1-one 1e (0.15 g, 0.42 mmol) was dissolved in 10 mL of 1,4-dioxane, and 6-aminonicotinonitrile (0.050 g, 0.42 mmol), tris(dibenzylideneacetone)dipalladium (0.077 g, 0.083 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (0.15 g, 0.25 mmol) and cesium carbonate (0.27 g, 0.84 mmol) were added in sequence, and the reaction mixture was reacted under microwave heating at 130 ° C for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, and the reaction solution was diluted with water (20 mL), extracted with an organic mixed solvent (dichloromethane / methanol=10 / 1, 20 mL×3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: B system) to obtain 6-((5-acetyl-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-2-yl)amino)nicotinonitrile 10 (50 mg), with a yield of 27%.

[0261] MS m / z(ESI):441.2[M+1]

[0262] 1 H NMR (400MHz, DMSO-d6) δ11.10(s,1H),10.54(s,1H),8.87(s,1H),8.64(s,1H),8.56(s,1H),8.08(d,J=7.2Hz,1H) ,7.86(s,1H),7.81(d,J=8.8Hz,1H),7.63-7.68(m,2H),7.33-7.39(m,1H),3.95(s,3H),3.73(s,3H),2.65(s,3H).

[0263] Embodiment 11

[0264] 1-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-((5-(trifluoromethyl)pyridin-2-yl)amino)pyridin-3-yl)ethan-1-one

[0265]

[0266] first step

[0267] 1-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-((5-(trifluoromethyl)pyridin-2-yl)amino)pyridin-3-yl)ethan-1-one

[0268] 1-(6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)ethan-1-one 1e (0.20 g, 0.56 mmol) was dissolved in 15 mL of 1,4-dioxane, and 2-amino-5-trifluoromethylpyridine (0.091 g, 0.56 mmol), tris(dibenzylideneacetone)dipalladium (0.10 g, 0.11 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.19 g, 0.34 mmol) and cesium carbonate (0.36 g, 1.12 mmol) were added in sequence, and the reaction mixture was reacted under microwave heating at 130 ° C for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, and the reaction solution was diluted with water (20 mL), extracted with an organic mixed solvent (dichloromethane / methanol=10 / 1, 20 mL×3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give 1-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-((5-(trifluoromethyl)pyridin-2-yl)amino)pyridin-3-yl)ethan-1-one 11 (80 mg) in a yield of 30%.

[0269] MS m / z(ESI):484.2[M+1]

[0270] 1H NMR (400MHz, DMSO-d6) δ11.10(s,1H),10.45(s,1H),8.86(s,1H),8.56(s,1H),8.52(s,1H),8.03(d,J=8. 5Hz,1H),7.83-7.87(m,2H),7.62-7.69(m,2H),7.32-7.37(m,1H),3.95(s,3H),3.73(s,3H),2.64(s,3H).

[0271] Example 12

[0272] N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(methylsulfinyl)pyridin-2-yl)cyclopropanecarboxamide

[0273]

[0274] first step

[0275] 2,4-Dichloro-5-(methylthio)pyridine

[0276] Tert-butyl nitrite (1.90 g, 18.40 mmol) and dimethyl disulfide (2.31 g, 24.54 mmol) were dissolved in 30 mL of dichloromethane, and the mixture was cooled in an ice-water bath. A dichloromethane solution (10 mL) of 4,6-dichloropyridin-3-amine 12a (2.0 g, 12.27 mmol) was slowly added dropwise to the above-mentioned coolant, and after the addition was completed, the mixture was moved to room temperature for reaction for 30 minutes. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: A system) to obtain 2,4-dichloro-5-(methylthio)pyridine 12b (0.35 g), with a yield of 15%.

[0277] 1 H NMR (400MHz, CDCl3) δ8.16(s,1H),7.36(s,1H),2.55(s,3H).

[0278] Step 2

[0279] 2,4-Dichloro-5-(methylsulfinyl)pyridine

[0280] 2,4-dichloro-5-(methylthio)pyridine 12b (0.25 g, 1.29 mmol) was dissolved in 10 mL of dichloromethane, and silica (0.23 g, 2.86 mmol), acetic anhydride (0.14 g, 1.42 mmol) and hydrogen peroxide (30% aqueous solution, 0.6 mL) were added, and the mixture was reacted at room temperature for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to obtain 2,4-dichloro-5-(methylsulfinyl)pyridine 12c (0.24 g) with a yield of 89%.

[0281] MS m / z(ESI):210.0[M+1]

[0282] Step 3

[0283] 2-Chloro-N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-(methylsulfinyl)pyridin-4-amine

[0284] Dissolve 2,4-dichloro-5-(methylsulfinyl)pyridine 12c (0.21 g, 0.98 mmol) and 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline 1b (0.20 g, 0.98 mmol) in 20 mL of tetrahydrofuran, cool in an ice-water bath, and slowly add lithium bistrimethylsilylamide solution (1.0 M / THF, 4.0 mL). After addition, react at room temperature for 2 hours. After the reaction was completed, water was added under ice-water bath to quench, and the mixture was extracted with an organic mixed solvent (dichloromethane / methanol=10 / 1, 20 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: B system) to give 2-chloro-N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-(methylsulfinyl)pyridin-4-amine 12d (0.10 g) in a yield of 27%.

[0285] MS m / z(ESI):378.1[M+1]

[0286] Step 4

[0287] N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(methylsulfinyl)pyridin-2-yl)cyclopropanecarboxamide

[0288] 2-Chloro-N-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5-(methylsulfinyl)pyridin-4-amine 12d (0.15 g, 0.40 mmol) was dissolved in 6 mL of 1,4-dioxane, and cyclopropylcarboxamide (0.10 g, 1.19 mmol), tris(dibenzylideneacetone)dipalladium (0.073 g, 0.079 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (0.046 g, 0.079 mmol) and cesium carbonate (0.26 g, 0.79 mmol) were added in sequence, and the reaction mixture was reacted under microwave heating at 130 °C for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, and water (20 mL) was added to dilute the reaction solution, and the mixture was extracted with an organic mixed solvent (dichloromethane / methanol=10 / 1, 20 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(methylsulfinyl)pyridin-2-yl)cyclopropanecarboxamide 12 (60 mg) in a yield of 35%.

[0289] MS m / z(ESI):427.1[M+1]

[0290] 1 H NMR (400MHz, DMSO-d6) δ9.44(s,1H),9.14(s,1H),8.23(s,1H),8.11(s,1H),8.03(s,1H),7.73(d,J=7.8Hz,1H),7.59(d,J=7. 9Hz,1H),7.23-7.28(m,1H),3.98(s,3H),3.76(s,3H),3.02(s,3H),1.57-1.59(m,1H),1.04-1.06(m,2H),0.83-0.86(m,2H).

[0291] Embodiment 13

[0292] N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(S-methylsulfonylimino)pyridin-2-yl)cyclopropanecarboxamide

[0293]

[0294]

[0295] first step

[0296] (4,6-Dichloropyridin-3-yl)(Imino)(methyl)-λ 6 -Sulfone

[0297] 2,4-dichloro-5-(methylthio)pyridine 12b (0.5 g, 2.58 mmol) was dissolved in 20 mL of methanol, and ammonium carbonate (0.37 g, 3.86 mmol) and iodobenzene acetate (1.91 g, 5.93 mmol) were added and reacted at room temperature for 3 hours. After the reaction was completed, the product was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: B system) to obtain (4,6-dichloropyridin-3-yl)(imino)(methyl)-λ 6 -sulfone 13a (0.50 g), yield: 86%.

[0298] MS m / z(ESI):225.0[M+1]

[0299] Step 2

[0300] (6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)(imino)(methyl)-λ 6 -Sulfone

[0301] (4,6-dichloropyridin-3-yl)(imino)(methyl)-λ 6 -sulfone 13a (0.45 g, 2.0 mmol) and 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline 1b (0.41 g, 2.0 mmol) were dissolved in 30 mL of tetrahydrofuran, cooled in an ice-water bath, and lithium bistrimethylsilylamide solution (1.0 M / THF, 8.0 mL) was slowly added. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 hour. After the reaction was completed, water was added to quench the reaction under an ice-water bath, and the mixture was extracted with an organic mixed solvent (dichloromethane / methanol=10 / 1, 20 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: B system) to obtain (6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)(imino)(methyl)-λ 6 -sulfone 13b (0.12 g), yield: 15%.

[0302] MS m / z(ESI):393.1[M+1]

[0303] Step 3

[0304] N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(S-methylsulfonylimino)pyridin-2-yl)cyclopropanecarboxamide

[0305] (6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)(imino)(methyl)-λ 6 -sulfone 13b (0.20 g, 0.51 mmol) was dissolved in 6 mL of 1,4-dioxane, and cyclopropylcarboxamide (0.13 g, 1.53 mmol), tris(dibenzylideneacetone)dipalladium (0.093 g, 0.10 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.059 g, 0.10 mmol) and cesium carbonate (0.33 g, 1.0 mmol) were added in sequence, and the reaction mixture was heated in a microwave at 130 ° C for 0.5 h. After the reaction was completed, the mixture was cooled to room temperature, and water (20 mL) was added to dilute the reaction solution, and the mixture was extracted with an organic mixed solvent (dichloromethane / methanol=10 / 1, 20 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(S-methylsulfonylimino)pyridin-2-yl)cyclopropanecarboxamide 13 (16 mg) in a yield of 7%.

[0306] MS m / z(ESI):442.2[M+1]

[0307] 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),9.84(s,1H),8.55(s,1H),8.48(s,1H),8.09(s,1H),7.63(d,J=6.7Hz,1H),7.54(d,J =6.8Hz,1H),7.24-7.28(m,1H),4.95(s,1H),3.94(s,3H),3.68(s,3H),3.17(s,3H),1.97-1.99(m,1H),0.77-0.79(m,4H).

[0308] Embodiment 14

[0309] N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(methylsulfonyl)pyridin-2-yl)cyclopropanecarboxamide

[0310]

[0311] first step

[0312] N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(methylsulfonyl)pyridin-2-yl)cyclopropanecarboxamide

[0313] N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(methylsulfinyl)pyridin-2-yl)cyclopropanecarboxamide 12 (0.090 g, 0.21 mmol) was dissolved in 10 mL of dichloromethane, and m-chloroperbenzoic acid (0.051 g, 0.25 mmol) was added and reacted at room temperature for 1 hour. After the reaction was completed, 5 mL of dilute sodium hydroxide solution was added dropwise to quench the reaction, and the mixture was extracted with an organic mixed solvent (dichloromethane / methanol=10 / 1, 20 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(methylsulfonyl)pyridin-2-yl)cyclopropanecarboxamide 14 (36 mg) in a yield of 39%.

[0314] MS m / z(ESI):443.2[M+1]

[0315] 1 H NMR (400MHz, DMSO-d6) δ11.04(s,1H),8.63(s,1H),8.56(s,1H),8.47(s,1H),8.02(s,1H),7.69(d,J=7.8Hz,1H),7. 51(d,J=7.9Hz,1H),7.25-7.31(m,1H),3.94(s,3H),3.69(s,3H),3.33(s,3H),1.97-1.99(m,1H),0.76-0.79(m,4H).

[0316] Embodiment 15

[0317] 3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxybenzamide

[0318]

[0319] first step

[0320] 3-((5-acetyl-2-chloropyridin-4-yl)amino)-2-methoxybenzamide

[0321] 1-(4,6-dichloropyridin-3-yl)ethan-1-one 15a (0.50 g, 2.63 mmol) and 3-amino-2-methoxybenzamide 15b (0.44 g, 2.63 mmol) were dissolved in 15 mL of anhydrous ethanol, 2 drops of concentrated hydrochloric acid were added, and the mixture was heated to 100°C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with 15 mL of dilute sodium hydroxide aqueous solution, extracted with an organic mixed solvent (dichloromethane / methanol = 10 / 1, 20 mL × 3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: B system) to obtain 3-((5-acetyl-2-chloropyridin-4-yl)amino)-2-methoxybenzamide 15c (0.60 g), with a yield of 71%.

[0322] MS m / z(ESI):320.1[M+1]

[0323] Step 2

[0324] 3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxybenzamide

[0325] 3-((5-acetyl-2-chloropyridin-4-yl)amino)-2-methoxybenzamide 15c (0.20 g, 0.63 mmol) was dissolved in 10 mL of 1,4-dioxane, and cyclopropylcarboxamide (0.11 g, 1.25 mmol), tris(dibenzylideneacetone)dipalladium (0.11 g, 0.13 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.24 g, 0.41 mmol) and cesium carbonate (0.413 g, 1.25 mmol) were added in sequence, and the reaction mixture was heated in a microwave at 130 ° C for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, and water (20 mL) was added to dilute the reaction solution, and the mixture was extracted with an organic mixed solvent (dichloromethane / methanol=10 / 1, 20 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give 3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxybenzamide 15 (60 mg) in a yield of 26%.

[0326] MS m / z(ESI):369.1[M+1]

[0327] 1H NMR(400MHz,DMSO-d6)δ10.97(s,1H),10.93(s,1H),8.84(s,1H),7.98(s,1H),7.74(s,1H),7.52-7.57(m,2H ),7.38(d,J=7.6Hz,1H),7.20-7.26(m,1H),3.71(s,3H),2.65(s,3H),1.98-2.03(m,1H),0.77-0.80(m,4H).

[0328] Example 16

[0329] N-(5-Acetyl-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidin-2-yl)cyclopropanecarboxamide

[0330]

[0331] first step

[0332] 1-(2-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidin-5-yl)ethan-1-one

[0333] 1-(2,4-Dichloropyrimidin-5-yl)ethan-1-one 16a (0.60 g, 3.14 mmol) and 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline 1b (0.64 g, 3.14 mmol) were dissolved in 50 mL of 1,4-dioxane, 2 drops of concentrated hydrochloric acid were added, and the mixture was heated to 90 °C and reacted for 2 hours. After the reaction, the mixture was cooled to room temperature, diluted with 30 mL of dilute sodium hydroxide aqueous solution, extracted with an organic mixed solvent (dichloromethane / methanol=10 / 1, 20 mL×3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give 1-(2-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidin-5-yl)ethan-1-one 16b (0.42 g) in a yield of 37%.

[0334] MS m / z(ESI):359.1[M+1]

[0335] Step 2

[0336] N-(5-Acetyl-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidin-2-yl)cyclopropanecarboxamide

[0337] 1-(2-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidin-5-yl)ethan-1-one 16b (0.40 g, 1.11 mmol) was dissolved in 5 mL of 1,4-dioxane, and cyclopropylcarboxamide (0.095 g, 1.11 mmol), tris(dibenzylideneacetone)dipalladium (0.10 g, 0.11 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.13 g, 0.22 mmol) and cesium carbonate (1.09 g, 3.34 mmol) were added in sequence, and the reaction mixture was reacted under microwave heating at 130 °C for 0.5 h. After the reaction was completed, the mixture was cooled to room temperature, and water (20 mL) was added to dilute the reaction solution, and the mixture was extracted with an organic mixed solvent (dichloromethane / methanol=10 / 1, 20 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give N-(5-acetyl-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidin-2-yl)cyclopropanecarboxamide 16 (100 mg) in a yield of 22%.

[0338] MS m / z(ESI):408.2[M+1]

[0339] 1 H NMR (400MHz, DMSO-d6) δ11.99(s,1H),11.13(s,1H),9.36(d,J=8.1Hz,1H),9.05(s,1H),8.56(s,1H),7.55(d, J=7.6Hz,1H),7.15-7.21(m,1H),3.96(s,3H),3.83(s,3H),2.63(s,3H),2.18-2.20(m,1H),0.85-0.91(m,4H).

[0340] Embodiment 17

[0341] (1R,2R)-2-Fluoro-N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyridin-2-yl)cyclopropane-1-carboxamide

[0342]

[0343] 1-(6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)propan-1-one 2a (0.15 g, 0.40 mmol) was dissolved in 10 mL of 1,4-dioxane, and (1R,2R)-2-fluorocyclopropane-1-carboxamide (0.12 g, 1.21 mmol), tris(dibenzylideneacetone)dipalladium (0.074 g, 0.081 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.047 g, 0.081 mmol) and cesium carbonate (0.26 g, 0.81 mmol) were added in sequence, and the reaction mixture was heated in a microwave at 130 ° C for 1 hour. After the reaction, water (20 mL) was added for dilution, and the mixture was extracted with an organic solvent (dichloromethane / methanol = 10 / 1, 20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: B system) to obtain (1R,2R)-2-fluoro-N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyridin-2-yl)cyclopropane-1-carboxamide 17 (40 mg), yield: 19%. MS m / z (ESI): 439.2 [M+1]

[0344] 1 H NMR (400MHz, DMSO-d6) δ11.06(s,1H),10.95(s,1H),8.89(s,1H),8.56(s,1H),8.02(s,1H),7.66(d,J=7.2Hz,1H),7.54(d,J=7.1Hz,1H),7 .25-7.30(m,1H),4.80-4.99(m,1H),3.95(s,3H),3.72(s,3H),3.11- 3.14(m,2H),2.19-2.21(m,1H),1.55-1.63(m,1H),1.11-1.24(m,4H).

[0345] Embodiment 18

[0346] 2,2-Difluoro-N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyridin-2-yl)cyclopropane-1-carboxamide

[0347]

[0348] 1-(6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)propan-1-one 2a (0.20 g, 0.54 mmol) was dissolved in 10 mL 1,4-dioxane, and 2,2-difluorocyclopropane-1-carboxamide (0.20 g, 1.61 mmol), tris(dibenzylideneacetone)dipalladium (0.099 g, 0.11 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.062 g, 0.11 mmol) and cesium carbonate (0.35 g, 1.10 mmol) were added in sequence, and the reaction mixture was heated in a microwave at 130 ° C for 1 hour. After the reaction, water (20 mL) was added for dilution, and the mixture was extracted with an organic solvent (dichloromethane / methanol=10 / 1, 20 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System B) to give 2,2-difluoro-N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyridin-2-yl)cyclopropane-1-carboxamide 18 (75 mg) with a yield of 30%.

[0349] MS m / z(ESI):457.2[M+1]

[0350] 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),11.06(s,1H),8.91(s,1H),8.57(s,1H),7.97(s,1H),7.67(d,J=7.7Hz,1H),7.54(d,J=7.8Hz, 1H),7.25-7.30(m,1H),3.95(s,3H),3.72(s,3H),3.14(q,J=7.0Hz,2H),2.88-3.01(m,1H),1.90-2.10(m,2H),1.13(t,J=7.0Hz,3H).

[0351] Embodiment 19

[0352] N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-methyl-5-propionylpyridin-2-yl)cyclopropanecarboxamide

[0353]

[0354] first step

[0355] 6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-methylnicotinic acid

[0356] 4,6-Dichloro-2-methylnicotinic acid 19a (1.0 g, 4.85 mmol) and 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline 1b (0.90 g, 4.41 mmol) were dissolved in 20 mL of N,N-dimethylacetamide and cooled in an ice-water bath. A tetrahydrofuran solution of lithium bistrimethylsilylamide (1.0 M, 13 mL) was slowly added. After the addition was complete, the mixture was naturally heated to room temperature and reacted for 2 hours. The reaction mixture was quenched with water and concentrated under reduced pressure to remove most of tetrahydrofuran and water. Hydrochloric acid (6.0 M) was added dropwise to the remaining solution until the pH value was 1-2, and the mixture was extracted with n-butanol (20 mL×2). The organic phases were combined and concentrated under reduced pressure to give a crude product, 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-methylnicotinic acid 19b, which was directly used for the next step without purification.

[0357] MS m / z(ESI):374.1[M+1]

[0358] Step 2

[0359] 6-Chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N,2-dimethylnicotinamide

[0360] 6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-methylnicotinic acid 19b (crude product) was dissolved in 20 mL of tetrahydrofuran, and N,N'-carbonyldiimidazole (2.36 g, 14.55 mmol), N,N-diisopropylethylamine (3.13 g, 24.25 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.95 g, 9.70 mmol) were added at room temperature, and the mixture was reacted at room temperature for 24 hours. After the reaction, the reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL×3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System B) to give 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N,2-dimethylnicotinamide 19c (0.60 g). The total yield of the two steps was 30%.

[0361] MS m / z(ESI):417.2[M+1]

[0362] Step 3

[0363] 1-(6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-methylpyridin-3-yl)propan-1-one

[0364] Under nitrogen protection, 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N,2-dimethylnicotinamide 19c (0.60 g, 1.44 mmol) was dissolved in 10 mL of tetrahydrofuran and cooled in an ice-water bath. A solution of ethylmagnesium bromide in tetrahydrofuran (2.0 M, 2.0 mL) was slowly added and the mixture was heated to room temperature for 4 hours. Under ice-water cooling, the reaction solution was quenched with water and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System B) to give 1-(6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-methylpyridin-3-yl)propan-1-one 19d (0.15 g) in a yield of 27%.

[0365] MS m / z(ESI):386.1[M+1]

[0366] Step 4

[0367] N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-methyl-5-propionylpyridin-2-yl)cyclopropanecarboxamide

[0368] 1-(6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-methylpyridin-3-yl)propan-1-one 19d (0.15 g, 0.39 mmol) was dissolved in 5 mL of 1,4-dioxane, and cyclopropylcarboxamide (0.099 g, 1.17 mmol), tris(dibenzylideneacetone)dipalladium (0.071 g, 0.077 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (0.045 g, 0.077 mmol) and cesium carbonate (0.25 g, 0.77 mmol) were added in sequence, and the reaction mixture was reacted under microwave heating at 130 ° C for 30 minutes. After the reaction, water (20 mL) was added for dilution, and the mixture was extracted with an organic solvent (dichloromethane / methanol=10 / 1, 20 mL×3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System B) to give N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-methyl-5-propionylpyridin-2-yl)cyclopropanecarboxamide 19 (40 mg) in a yield of 24%.

[0369] MS m / z(ESI):435.3[M+1]

[0370] 1 H NMR (400MHz, DMSO-d6) δ10.66(s,1H),8.54(s,1H),8.53(s,1H),7.71(s,1H),7.58(d,J=7.6Hz,1H),7.33(d,J=7.8Hz,1H),7.16-7.2 1(m,1H),3.94(s,3H),3.67(s,3H),2.90(q,J=7.2Hz,2H),2.40(s,3H),1.94-1.99(m,1H),1.08(t,J=7.2Hz,3H),0.71-0.74(m,4H).

[0371] Embodiment 20

[0372] N-(3-Fluoro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide

[0373]

[0374] first step

[0375] 6-Chloro-5-fluoro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)nicotinic acid

[0376] 4,6-Dichloro-5-fluoronicotinic acid 20a (0.5 g, 2.38 mmol) and 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline 1b (0.48 g, 2.38 mmol) were dissolved in 10 mL of N,N-dimethylacetamide, cooled in an ice-water bath, and a tetrahydrofuran solution of lithium bistrimethylsilylamide (1.0 M, 7 mL) was slowly added. After the addition was complete, the temperature was naturally raised to room temperature and reacted for 2 hours. The mixture was quenched with water and concentrated under reduced pressure to remove most of tetrahydrofuran and water. Hydrochloric acid (6.0 M) was added dropwise to the remaining solution until the pH value was 1-2. A large amount of white solid precipitated. The solid was filtered, washed with water, and the filter cake was dried to give 6-chloro-5-fluoro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)nicotinic acid 20b (0.8 g). Yield: 89%.

[0377] MS m / z(ESI):378.1[M+1]

[0378] Step 2

[0379] 6-Chloro-5-fluoro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylnicotinamide

[0380] 6-Chloro-5-fluoro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)nicotinic acid 20b (0.8 g, 2.12 mmol) was dissolved in 20 mL of tetrahydrofuran, and N,N'-carbonyldiimidazole (0.91 g, 6.35 mmol), N,N-diisopropylethylamine (1.37 g, 10.6 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.26 g, 2.65 mmol) were added at room temperature respectively, and the mixture was reacted at room temperature for 24 hours. After the reaction was completed, water (20 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, 6-chloro-5-fluoro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylnicotinamide 20c (0.92 g), which was used for the next step without purification.

[0381] MS m / z(ESI):421.1[M+1]

[0382] Step 3

[0383] 1-(6-Chloro-5-fluoro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)propan-1-one

[0384] Under nitrogen protection, 6-chloro-5-fluoro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylnicotinamide 20c (0.92 g, 2.19 mmol) was dissolved in 20 mL of tetrahydrofuran and cooled in an ice-water bath. A solution of ethylmagnesium bromide in tetrahydrofuran (2.0 M, 3.3 mL) was slowly added and the mixture was heated to room temperature for 4 hours. The reaction mixture was cooled in an ice-water bath, quenched with water, extracted with ethyl acetate (20 mL×3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System B) to give 1-(6-chloro-5-fluoro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)propan-1-one 20d (0.5 g). The total yield of the two steps was 60%.

[0385] MS m / z(ESI):390.1[M+1]

[0386] Step 4

[0387] N-(3-Fluoro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide

[0388] 1-(6-chloro-5-fluoro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)propan-1-one 20d (0.25 g, 0.64 mmol) was dissolved in 5 mL of 1,4-dioxane, and cyclopropylcarboxamide (0.16 g, 1.92 mmol), tris(dibenzylideneacetone)dipalladium (0.12 g, 0.13 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.074 g, 0.13 mmol) and cesium carbonate (0.42 g, 1.28 mmol) were added in sequence, and the reaction mixture was reacted at 130 ° C for 30 minutes under microwave heating. After the reaction, water (20 mL) was added for dilution, and the mixture was extracted with an organic solvent (dichloromethane / methanol=10 / 1, 20 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: B system) to obtain N-(3-fluoro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide 20 (0.1 g), with a yield of 35%.

[0389] MS m / z(ESI):439.2[M+1]

[0390] 1 H NMR (400MHz, DMSO-d6) δ10.67(s,1H),10.51(s,1H),8.80(s,1H),8.55(s,1H),7.54(d,J=7.6Hz,1H),7.05-7.16(m ,2H),3.95(s,3H),3.75(s,3H),3.16(q,J=6.8Hz,2H),1.92-1.94(m,1H),1.09(t,J=6.8Hz,3H),0.80-0.81(m,4H).

[0391] Embodiment 21

[0392] N-(4-((2-(methylsulfonyl)phenyl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide

[0393]

[0394]

[0395] first step

[0396] 6-Chloro-4-((2-(methylthio)phenyl)amino)nicotinic acid

[0397] 4,6-Dichloronicotinic acid 1a (1.65 g, 8.62 mmol) and 2-(methylthio)aniline 21a (1.0 g, 7.18 mmol) were dissolved in 20 mL of tetrahydrofuran, cooled in an ice-water bath, and a tetrahydrofuran solution of lithium bistrimethylsilylamide (1.0 M, 14 mL) was slowly added. After the addition was complete, the mixture was naturally warmed to room temperature and reacted for 2 hours. Water was added to quench the mixture, and most of the tetrahydrofuran and water were removed by concentration under reduced pressure. Hydrochloric acid (6.0 M) was added dropwise to the remaining solution until the pH value was 1-2, and the mixture was extracted with n-butanol (20 mL×2), and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: B system) to obtain 6-chloro-4-((2-(methylthio)phenyl)amino)nicotinic acid 21b (1.0 g) with a yield of 47%.

[0398] MS m / z(ESI):295.1[M+1]

[0399] Step 2

[0400] 6-Chloro-N-methoxy-N-methyl-4-((2-(methylthio)phenyl)amino)nicotinamide

[0401] 6-Chloro-4-((2-(methylthio)phenyl)amino)nicotinic acid 21b (1.0 g, 3.39 mmol) was dissolved in 20 mL of dichloromethane, and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.58 g, 6.79 mmol), N,N-diisopropylethylamine (0.88 g, 6.79 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.66 g, 6.79 mmol) were added at room temperature and reacted at room temperature for 24 hours. The reaction solution was diluted with water (20 mL), extracted with dichloromethane (20 mL×3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System B) to obtain 6-chloro-N-methoxy-N-methyl-4-((2-(methylthio)phenyl)amino)nicotinamide 21c (1.1 g), yield: 88%

[0402] MS m / z(ESI):338.1[M+1]

[0403] Step 3

[0404] 1-(6-Chloro-4-((2-(methylthio)phenyl)amino)pyridin-3-yl)propan-1-one

[0405] Under nitrogen protection, 6-chloro-N-methoxy-N-methyl-4-((2-(methylthio)phenyl)amino)nicotinamide 21c (0.90 g, 2.66 mmol) was dissolved in 15 mL of tetrahydrofuran, cooled in an ice-water bath, and a tetrahydrofuran solution of ethylmagnesium bromide (2.0 M, 5 mL) was slowly added, and the mixture was heated to room temperature for 4 hours. After cooling in an ice-water bath, the reaction solution was quenched with water, extracted with ethyl acetate (20 mL×3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: B system) to obtain 1-(6-chloro-4-((2-(methylthio)phenyl)amino)pyridin-3-yl)propan-1-one 21d (0.7 g), with a yield of 86%.

[0406] MS m / z(ESI):307.1[M+1]

[0407] Step 4

[0408] N-(4-((2-(methylthio)phenyl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide

[0409] 1-(6-Chloro-4-((2-(methylthio)phenyl)amino)pyridin-3-yl)propan-1-one 21d (0.30 g, 0.98 mmol) was dissolved in 15 mL of 1,4-dioxane, and cyclopropylcarboxamide (0.17 g, 1.96 mmol), tris(dibenzylideneacetone)dipalladium (0.075 g, 0.08 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.15 g, 0.26 mmol) and cesium carbonate (0.64 g, 1.96 mmol) were added in sequence, and the reaction mixture was heated in a microwave at 130 ° C for 30 minutes. The reaction solution was diluted with water (20 mL), extracted with an organic solvent (dichloromethane / methanol=10 / 1, 20 mL×3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System B) to give N-(4-((2-(methylthio)phenyl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide 21e (0.2 g), yield: 57%.

[0410] MS m / z(ESI):356.2[M+1]

[0411] Step 5

[0412] N-(4-((2-(methylsulfonyl)phenyl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide

[0413] N-(4-((2-(methylthio)phenyl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide 21e (0.15 g, 0.42 mmol) was dissolved in 10 mL of dichloromethane, and m-chloroperbenzoic acid (0.15 g, 0.84 mmol) was added, and the reaction was stirred at room temperature for 24 hours. Water was added to quench, and the mixture was extracted with an organic solvent (dichloromethane / methanol=10 / 1, 20 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: B system) to obtain N-(4-((2-(methylsulfonyl)phenyl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide 21 (0.04 g), with a yield of 24%.

[0414] MS m / z(ESI):388.1[M+1]

[0415] 1 H NMR(400MHz,DMSO-d6)δ11.19(s,1H),10.98(s,1H),8.92(s,1H),7.96-7.98(m,2H),7.73-7.78(m,1H),7.67-7 .71(m,1H),7.42-7.48(m,1H),3.09-3.16(m,5H),1.98-2.00(m,1H),1.11(t,J=7.0Hz,3H),0.75-0.79(m,4H).

[0416] Embodiment 22

[0417] N-(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-propionylpyridazin-3-yl)cyclopropanecarboxamide

[0418]

[0419]

[0420] first step

[0421] 6-Chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide

[0422] 6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxylic acid 22a (1.0 g, 2.77 mmol, prepared according to patent WO2018183649A1) was dissolved in 30 mL of dichloromethane, and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.11 g, 5.54 mmol), N,N-diisopropylethylamine (0.72 g, 5.54 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.54 g, 5.54 mmol) were added at room temperature, and the reaction was carried out at room temperature for 24 hours. The reaction solution was diluted with water (20 mL), extracted with dichloromethane (20 mL×3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System B) to give 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide 22b (1.0 g), yield: 89%.

[0423] MS m / z(ESI):404.1[M+1]

[0424] Step 2

[0425] 1-(6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-yl)propan-1-one

[0426] Under nitrogen protection, 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide 22b (1.0 g, 2.48 mmol) was dissolved in 15 mL of tetrahydrofuran and cooled in an ice-water bath. A solution of ethylmagnesium bromide in tetrahydrofuran (2.0 M, 5.0 mL) was slowly added and the mixture was heated to room temperature for 4 hours. The reaction mixture was cooled in an ice-water bath, quenched with water, extracted with dichloromethane (20 mL×3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System B) to give 1-(6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-yl)propan-1-one 22c (0.7 g) in a yield of 76%.

[0427] MS m / z(ESI):373.1[M+1]

[0428] Step 3

[0429] N-(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-propionylpyridazin-3-yl)cyclopropanecarboxamide

[0430] 1-(6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-yl)propan-1-one 22c (0.3 g, 0.80 mmol) was dissolved in 15 mL of 1,4-dioxane, and cyclopropylcarboxamide (0.14 g, 1.61 mmol), tris(dibenzylideneacetone)dipalladium (0.20 g, 0.22 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (0.15 g, 0.26 mmol) and cesium carbonate (0.52 g, 1.61 mmol) were added in sequence, and the reaction mixture was heated in a microwave at 130 ° C for 30 minutes. The reaction solution was diluted with water (20 mL), extracted with an organic solvent (dichloromethane / methanol=10 / 1, 20 mL×3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System B) to give N-(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-propionylpyridazin-3-yl)cyclopropanecarboxamide 22 (0.15 g), yield: 44%.

[0431] MS m / z(ESI):422.2[M+1]

[0432] 1 H NMR (400MHz, DMSO-d6) δ11.48(s,1H),10.54(s,1H),8.57(s,1H),8.10(s,1H),7.71(d,J=7.5Hz,1H),7.51(d,J=7.8Hz,1H), 7.26-7.31(m,1H),3.95(s,3H),3.71(s,3H),3.32-3.37(m,2H),2.00-2.08(m,1H),1.16(t,J=7.2Hz,3H),0.81-0.84(m,4H).

[0433] Implementation 23

[0434] (1R,2R)-2-Fluoro-N-(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-propionylpyridazin-3-yl)cyclopropane-1-carboxamide

[0435]

[0436] 1-(6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-yl)propan-1-one 22c (0.3 g, 0.80 mmol) was dissolved in 15 mL 1,4-dioxane, and (1R,2R)-2-fluorocyclopropane-1-carboxamide (0.17 g, 1.61 mmol), tris(dibenzylideneacetone)dipalladium (0.075 g, 0.08 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.20 g, 0.35 mmol) and cesium carbonate (0.52 g, 1.61 mmol) were added in sequence. The reaction mixture was heated in a microwave at 130 °C for 30 min. The reaction solution was diluted with water (20 mL), extracted with an organic solvent (dichloromethane / methanol=10 / 1, 20 mL×3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System B) to give (1R,2R)-2-fluoro-N-(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-propionylpyridazin-3-yl)cyclopropane-1-carboxamide 23 (0.20 g), yield: 56%.

[0437] MS m / z(ESI):440.2[M+1]

[0438] 1 H NMR (400MHz, DMSO-d6) δ11.54(s,1H),10.57(s,1H),8.58(s,1H),8.10(s,1H),7.73(d,J=7.7Hz,1H),7.53(d,J=7.8Hz,1H),7.28-7. 34(m,1H),4.86-5.05(m,1H),3.95(s,3H),3.73(s,3H),3.33-3.38(m,2H),2.28-2.29(m,1H),1.58-1.65(m,1H),1.15-1.23(m,4H).

[0439] Embodiment 24

[0440] N-(6-(Cyclopropylcarbonyl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-yl)cyclopropylcarboxamide

[0441]

[0442] first step

[0443] 6-(Cyclopropylcarboxamido)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylnicotinamide

[0444] 6-Chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide 22b (0.5 g, 1.24 mmol) was dissolved in 20 mL of 1,4-dioxane, and cyclopropylcarboxamide (0.21 g, 2.48 mmol), tris(dibenzylideneacetone)dipalladium (0.13 g, 0.14 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.35 g, 0.60 mmol) and cesium carbonate (0.81 g, 2.48 mmol) were added in sequence, and the reaction mixture was heated in a microwave at 130 ° C for 1 hour. The reaction solution was diluted with water (20 mL), extracted with an organic solvent (dichloromethane / methanol=10 / 1, 20 mL×3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System B) to give 6-(cyclopropylcarboxamido)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylnicotinamide 24a (0.38 g), yield: 67%.

[0445] MS m / z(ESI):453.2[M+1]

[0446] Step 2

[0447] N-(6-(Cyclopropylcarbonyl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-yl)cyclopropylcarboxamide

[0448] 6-(Cyclopropylcarboxamido)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylnicotinamide 24a (0.2 g, 0.44 mmol) was dissolved in 10 mL of tetrahydrofuran, cooled in an ice-water bath, and a tetrahydrofuran solution of cyclopropylmagnesium bromide (1.0 M, 1.0 mL) was slowly added, and the temperature was raised to room temperature for reaction for 3 hours. The reaction mixture was cooled in an ice-water bath, quenched with water, extracted with dichloromethane (20 mL×3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System B) to give N-(6-(cyclopropylcarbonyl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-yl)cyclopropanecarboxamide 24 (0.15 g) in a yield of 78%.

[0449] MS m / z(ESI):434.2[M+1]

[0450] 1 H NMR (400MHz, DMSO-d6) δ11.54(s,1H),10.61(s,1H),8.57(s,1H),8.11(s,1H),7.71(d,J=7.7Hz,1H),7.52(d,J=7.7Hz,1H),7 .26-7.31(m,1H),3.95(s,3H),3.67-3.69(m,4H),3.36-3.38(m,1H),1.98-2.10(m,1H),1.44-1.49(m,2H),0.81-0.84(m,5H).

[0451] Embodiment 25

[0452] 2,2-Difluoro-N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyridin-2-yl)acetamide

[0453]

[0454] 1-(6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)propan-1-one 2a (0.30 g, 0.81 mmol) was dissolved in 20 mL of 1,4-dioxane, and 2,2-difluoroacetamide (0.23 g, 2.42 mmol), tris(dibenzylideneacetone)dipalladium (0.15 g, 0.16 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.093 g, 0.16 mmol) and cesium carbonate (0.53 g, 1.61 mmol) were added in sequence, and the reaction mixture was heated in a microwave at 130 ° C for 1 hour. The reaction solution was diluted with water (20 mL), extracted with an organic solvent (dichloromethane / methanol=10 / 1, 20 mL×3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System B) to give 2,2-difluoro-N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyridin-2-yl)acetamide 25 (30 mg), yield: 9%.

[0455] MS m / z(ESI):431.1[M+1]

[0456] 1 H NMR (400MHz, DMSO-d6) δ11.44(s,1H),11.06(s,1H),8.94(s,1H),8.57(s,1H),7.94(s,1H),7.69(d,J=7.7Hz,1H),7.55(d,J= 7.9Hz,1H),7.26-7.32(m,1H),6.36(t,J=53.4Hz,1H),3.95(s,3H),3.72(s,3H),3.16(q,J=7.1Hz,2H),1.13(t,J=7.0Hz,3H).

[0457] Embodiment 26

[0458] (1S,2S)-2-Fluoro-N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyridin-2-yl)cyclopropane-1-carboxamide

[0459]

[0460] 1-(6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)propan-1-one 2a (0.20 g, 0.54 mmol) was dissolved in 10 mL 1,4-dioxane, and (1S,2S)-2-fluorocyclopropane-1-carboxamide (0.11 g, 1.08 mmol), tris(dibenzylideneacetone)dipalladium (0.098 g, 0.11 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.062 g, 0.11 mmol) and cesium carbonate (0.35 g, 1.08 mmol) were added in sequence, and the reaction mixture was heated in a microwave at 130 ° C for 1 hour. The reaction solution was diluted with water (20 mL), extracted with an organic solvent (dichloromethane / methanol=10 / 1, 20 mL×3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System B) to give (1S,2S)-2-fluoro-N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyridin-2-yl)cyclopropane-1-carboxamide 26 (30 mg), yield: 13%.

[0461] MS m / z(ESI):439.2[M+1]

[0462] 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),10.95(s,1H),8.89(s,1H),8.56(s,1H),8.03(s,1H),7.66(d,J=7.6Hz,1H),7.54(d,J=7.6Hz,1H),7.2 5-7.31(m,1H),4.79-4.99(m,1H),3.95(s,3H),3.72(s,3H),3.14(q,J =7.2Hz,2H),2.19-2.21(m,1H),1.55-1.63(m,1H),1.11-1.21(m,4H).

[0463] Embodiment 27

[0464] 2-Hydroxy-N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyridin-2-yl)acetamide

[0465]

[0466] 1-(6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)propan-1-one 2a (0.30 g, 0.81 mmol) was dissolved in 10 mL of 1,4-dioxane, and 2-hydroxyacetamide (0.12 g, 1.61 mmol), tris(dibenzylideneacetone)dipalladium (0.15 g, 0.16 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.093 g, 0.16 mmol) and cesium carbonate (0.53 g, 1.61 mmol) were added in sequence, and the reaction mixture was reacted under microwave heating at 130 °C for 1 hour. The reaction solution was diluted with water (20 mL), extracted with an organic solvent (dichloromethane / methanol=10 / 1, 20 mL×3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System B) to give 2-hydroxy-N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyridin-2-yl)acetamide 27 (30 mg), yield: 9%.

[0467] MS m / z(ESI):411.2[M+1]

[0468] 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),9.82(s,1H),8.89(s,1H),8.57(s,1H),8.04(s,1H),7.67(d,J=7.7Hz,1H),7.56(d,J=7.6Hz, 1H),7.25-7.30(m,1H),5.67(s,1H),4.02(d,J=4.2Hz,2H),3.96(s,3H),3.73(s,3H),3.13(q,J=7.2Hz,2H),1.13(t,J=7.0Hz,3H).

[0469] Embodiment 28

[0470] (1R,2R)-N-(5-(cyclopropanecarbonyl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-2-yl)-2-fluorocyclopropane-1-carboxamide

[0471]

[0472] (6-Chloro-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)(cyclopropyl)methanone 3a (0.30 g, 0.78 mmol) was dissolved in 20 mL of 1,4-dioxane, and (1R,2R)-2-fluorocyclopropane-1-carboxamide (0.24 g, 2.34 mmol), tris(dibenzylideneacetone)dipalladium (0.14 g, 0.16 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.090 g, 0.16 mmol) and cesium carbonate (0.51 g, 1.56 mmol) were added in sequence, and the reaction mixture was heated in a microwave at 130°C for 1 hour. The reaction solution was diluted with water (20 mL), extracted with an organic solvent (dichloromethane / methanol=10 / 1, 20 mL×3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System B) to give (1R,2R)-N-(5-(cyclopropanecarbonyl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-2-yl)-2-fluorocyclopropane-1-carboxamide 28 (90 mg), yield: 26%.

[0473] MS m / z(ESI):451.2[M+1]

[0474] 1 H NMR (400MHz, DMSO-d6) δ11.04(s,1H),10.99(s,1H),9.14(s,1H),8.56(s,1H),8.03(s,1H),7.65(d,J=7.8Hz,1H),7.53(d,J=7.9Hz,1H),7 .25-7.30(m,1H),4.82-5.00(m,1H),3.95(s,3H),3.70(s,3H),2.99- 3.02(m,1H),2.20-2.22(m,1H),1.57-1.64(m,1H),1.04-1.18(m,5H).

[0475] Embodiment 29

[0476] N-(5-(But-2-ynyl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide

[0477]

[0478]

[0479] first step

[0480] 1-(6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)but-2-yn-1-one

[0481] Under nitrogen protection, 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylnicotinamide 1d (0.5 g, 1.24 mmol) was dissolved in 10 mL of tetrahydrofuran and cooled in an ice-water bath. A solution of 1-propynylmagnesium bromide in tetrahydrofuran (1.0 M, 7.4 mL) was slowly added and the mixture was heated to room temperature for 4 hours. The reaction mixture was cooled in an ice-water bath, quenched with water, extracted with ethyl acetate (15 mL × 3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System B) to obtain 1-(6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)but-2-yn-1-one 29a (0.20 g), yield: 42%. MS m / z (ESI): 381.2 [M+1]

[0482] Step 2

[0483] N-(5-(But-2-ynyl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide

[0484] 1-(6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)but-2-yn-1-one 29a (0.20 g, 0.52 mmol) was dissolved in 6 mL of 1,4-dioxane, and cyclopropylcarboxamide (0.13 g, 1.57 mmol), tris(dibenzylideneacetone)dipalladium (0.096 g, 0.10 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.061 g, 0.10 mmol) and cesium carbonate (0.34 g, 1.05 mmol) were added in sequence, and the reaction mixture was reacted under microwave heating at 130 °C for 1 hour. The reaction solution was diluted with water (20 mL), extracted with an organic solvent (dichloromethane / methanol=10 / 1, 20 mL×3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System B) to give N-(5-(but-2-ynyl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide 29 (30 mg), yield: 13%.

[0485] MS m / z(ESI):431.2[M+1]

[0486] 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),9.05(s,1H),8.61(s,1H),8.14(d,J=7.7Hz,1H),7.55-7.58(m,2H),7 .45-7.51(m,1H),6.28(s,1H),3.94(s,3H),3.40(s,3H),2.01(s,3H),1.93-1.96(m,1H),0.69-0.73(m,4H).

[0487] Embodiment 30

[0488] (1R,2R)-N-(5-acetyl-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidin-2-yl)-2-fluorocyclopropane-1-carboxamide

[0489]

[0490] 1-(2-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidin-5-yl)ethan-1-one 16b (0.10 g, 0.28 mmol) was dissolved in 5 mL of 1,4-dioxane, and (1R,2R)-2-fluorocyclopropane-1-carboxamide (0.057 g, 0.56 mmol), tris(dibenzylideneacetone)dipalladium (0.051 g, 0.056 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.032 g, 0.056 mmol) and cesium carbonate (0.18 g, 0.56 mmol) were added in sequence, and the reaction mixture was reacted under microwave heating at 130°C for 0.5 h. The reaction solution was diluted with water (20 mL), extracted with an organic solvent (dichloromethane / methanol=10 / 1, 20 mL×3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System B) to give (1R,2R)-N-(5-acetyl-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidin-2-yl)-2-fluorocyclopropane-1-carboxamide 30 (21 mg), yield: 18%.

[0491] MS m / z(ESI):426.2[M+1]

[0492] 1 H NMR (400MHz, DMSO-d6) δ12.0(s,1H),11.19(s,1H),9.34(d,J=8.2Hz,1H),9.07(s,1H),8.57(s,1H),7.57(d,J=7.8Hz,1H),7.18- 7.23(m,1H),4.86-5.04(m,1H),3.96(s,3H),3.84(s,3H),2.65(s,3H),2.38-2.40(m,1H),1.70-1.77(m,1H),1.09-1.20(m,1H).

[0493] Embodiment 31

[0494] N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyrimidin-2-yl)cyclopropanecarboxamide

[0495]

[0496]

[0497] first step

[0498] 2-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carbaldehyde

[0499] 2,4-Dichloro-5-pyrimidinecarboxaldehyde 31a (2.0 g, 11.3 mmol) and 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline 1b (2.3 g, 11.3 mmol) were dissolved in 30 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (1.46 g, 11.3 mmol) was added and stirred at room temperature for 4 hours. The mixture was diluted with water (30 mL), extracted with dichloromethane (30 mL×3), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System A) to give 2-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carbaldehyde 31b (1.3 g) in a yield of 33%.

[0500] MS m / z(ESI):345.1[M+1]

[0501] Step 2

[0502] 1-(2-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidin-5-yl)propan-1-ol

[0503] 2-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carboxaldehyde 31b (1.1 g, 3.19 mmol) was dissolved in 20 mL of tetrahydrofuran, cooled in an ice-water bath, and a tetrahydrofuran solution of methylmagnesium bromide (1.0 M, 6.4 mL) was slowly added, and the mixture was heated to room temperature for 2 hours. The mixture was cooled in an ice-water bath, quenched with water, extracted with dichloromethane (20 mL×3), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, 1-(2-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidin-5-yl)propan-1-ol 31c (1.5 g), which was directly used for the next step without purification.

[0504] MS m / z(ESI):375.2[M+1]

[0505] Step 3

[0506] 1-(2-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidin-5-yl)acetone

[0507] 1-(2-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidin-5-yl)propan-1-ol 31c (1.5 g, 4.0 mmol) was dissolved in 100 mL of acetone, and manganese dioxide (34.8 g, 400 mmol) was added. The mixture was stirred at room temperature for 20 hours, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: B system) to give 1-(2-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidin-5-yl)propanone 31d (0.7 g). The two-step yield was 59%.

[0508] MS m / z(ESI):373.2[M+1]

[0509] Step 4

[0510] N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyrimidin-2-yl)cyclopropanecarboxamide

[0511] 1-(2-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidin-5-yl)propanone 31d (0.20 g, 0.54 mmol) was dissolved in 10 mL of 1,4-dioxane, and cyclopropylcarboxamide (0.14 g, 1.61 mmol), tris(dibenzylideneacetone)dipalladium (0.049 g, 0.054 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.062 g, 0.11 mmol) and cesium carbonate (0.44 g, 1.34 mmol) were added in sequence, and the reaction mixture was heated in a microwave at 130 ° C for 1 hour. The reaction solution was diluted with water (20 mL), extracted with an organic solvent (dichloromethane / methanol=10 / 1, 20 mL×3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System B) to give N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyrimidin-2-yl)cyclopropanecarboxamide 31 (40 mg), yield: 18%.

[0512] MS m / z(ESI):422.2[M+1]

[0513] 1 H NMR (400MHz, DMSO-d6) δ12.01(s,1H),11.10(s,1H),9.34(d,J=7.1Hz,1H),9.08(s,1H),8.56(s,1H),7.54(d,J=6.6Hz,1H) ,7.17-7.20(m,1H),3.95(s,3H),3.83(s,3H),3.08-3.11(m,2H),2.18-2.20(m,1H),1.11-1.13(m,3H),0.86-0.91(m,4H).

[0514] Embodiment 32

[0515] (1R,2R)-2-Fluoro-N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyrimidin-2-yl)cyclopropane-1-carboxamide

[0516]

[0517] 1-(2-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidin-5-yl)propanone 31d (0.20 g, 0.54 mmol) was dissolved in 5 mL of 1,4-dioxane, and (1R,2R)-2-fluorocyclopropane-1-carboxamide (0.11 g, 1.10 mmol), tris(dibenzylideneacetone)dipalladium (0.098 g, 0.11 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.062 g, 0.11 mmol) and cesium carbonate (0.35 g, 1.1 mmol) were added in sequence, and the reaction mixture was reacted under microwave heating at 130 ° C for 0.5 h. The reaction solution was diluted with water (20 mL), extracted with an organic solvent (dichloromethane / methanol=10 / 1, 20 mL×3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System B) to give (1R,2R)-2-fluoro-N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-propionylpyrimidin-2-yl)cyclopropane-1-carboxamide 32 (58 mg), yield: 25%.

[0518] MS m / z(ESI):440.3[M+1]

[0519] 1H NMR (400MHz, DMSO-d6) δ12.01(s,1H),11.17(s,1H),9.32(d,J=8.3Hz,1H),9.10(s,1H),8.57(s,1H),7.56(d,J=7.8Hz,1H),7.18-7.23(m,1H),4. 84-5.06(m,1H),3.96(s,3H),3.84(s,3H),3.11(q,J=7.2Hz,2H),2.35-2 .44(m,1H),1.67-1.79(m,1H),1.20-1.23(m,1H),1.19(t,J=7.2Hz,3H).

[0520] Biological evaluation

[0521] Test Example 1: Determination of the inhibitory activity of the compounds of the present invention on p-STAT3 in Jurkat cells induced by IFN-α2b by HTRF method

[0522] The following method was used to determine the effect of the compounds of the present invention on p-STAT3 in Jurkat cells induced by IFN-α2b. Jurkat cells were purchased from the cell bank of the Committee for the Preservation of Typical Cultures of the Chinese Academy of Sciences. The cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum, 100U penicillin and 100μg / mL streptomycin; cultured in a 37°C, 5% CO2 incubator. p-STAT3 was determined by LANCE Ultra Phosphorylated STAT3 (Y705) Cellular Detection Kit (PerkinElmer, #TRF4004M).

[0523] The experimental method was performed according to the steps in the kit instructions, which are briefly described as follows: the test compound was first dissolved in DMSO to prepare a stock solution, and then gradiently diluted with the culture medium of the corresponding cells to prepare the test sample, and the final concentration of the compound ranged from 10000nM to 0.61nM. A certain number of Jurkat cells were inoculated into T25 or T75 culture flasks and starved overnight in a 37°C, 5% CO2 incubator, and then the starved cells were plated into a 384-well plate at 200,000 cells (8μl cell suspension) / well. Then, 2μl of the diluted test compound was added to each well of the 384-well plate, placed in a 37°C, 5% CO2 incubator for incubation for 30min, and then 2ul of IFN-α2b with a final concentration of 60nM was added to activate p-STAT3 for 20min. Subsequently, p-STAT3 was detected using the LANCE UltraPhosphorylated STAT3 (Y705) Cellular Detection Kit. The assay method of the kit is briefly described as follows: cells were lysed for 40 minutes using LANCE Ultra Lysis Buffer 1, and then 5ul 4X MIX Eu-labeled anti-STAT3(Y705)Antibody(0.5nM final) and ULight labeledanti-STAT3 Antibody(5nM final) were added to a 384-well plate. After incubation at room temperature for 4 hours, the fluorescence intensity of each well at an emission wavelength of 620nM and 665nM was measured in a microplate reader in TF-FRET mode at an excitation wavelength of 304nM, and the fluorescence intensity ratio of 665 / 620 of each well was calculated.

[0524] The experimental data were deducted from the cell background data, and the logarithm of the sample concentration was used as the horizontal axis and the ratio was used as the vertical axis. The nonlinear regression analysis was performed using the logarithm of the compound concentration-inhibition rate in GraphPad Prism 5 software to obtain the IC of the compound to inhibit cell p-STAT3. 50 Values ​​are shown in Table 1.

[0525] Table 1 Inhibitory activity of the compounds of the present invention on p-STAT3 in Jurkat cells induced by IFN-α2b

[0526] Compound No. <![CDATA[IC 50 (nM)]]> 1 10.0 2 17.2 10 23.7 16 17.1 17 12.1 18 27 26 5.0 31 8.8 32 24.7

[0527] Note: ND stands for not determined.

[0528] Conclusion: It can be seen from Table 1 that the compounds of the present invention have a strong inhibitory effect on p-STAT3 in Jurkat cells induced by IFN-α2b.

[0529] Test Example 2: Oral pharmacokinetics study of the compounds of the present invention in SD rats

[0530] 1. Experimental purpose

[0531] SD rats were used as test animals, and the pharmacokinetic characteristics of the compounds of the present invention in rats were studied by LC / MS / MS method, and the drug concentrations in plasma at different times were determined after intravenous injection or oral gavage.

[0532] 2. Experimental plan

[0533] 2.1 Experimental drugs and animals

[0534] Compound 2 of the present invention; BMS-986165;

[0535] Six healthy adult Sprague Dawley (SD) male rats were purchased from Weitonglihua Laboratory Animal Technology Co., Ltd., with production license number: 11400700271077.

[0536] 2.2 Drug preparation and administration

[0537] Oral gavage group:

[0538] Weigh an appropriate amount of sample, add appropriate amount of DMSO and PEG200 (v / v=12.1:87.9), and vortex to mix to prepare a 0.5 mg / mL solution.

[0539] Six healthy adult SD male rats were fasted overnight and given the drug by oral gavage (dosage 10 mg / kg), and were fed 4 hours after the drug administration.

[0540] 2.3 Sample collection

[0541] Before administration and at 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours after administration, approximately 0.2 mL of blood was collected from the jugular vein and anticoagulated with sodium heparin. After blood sample collection, it was placed on ice and centrifuged to separate plasma (centrifugation conditions: 1500g, 10 minutes). The collected plasma was stored at -40 to -20°C before analysis.

[0542] 2.4 Sample pretreatment

[0543] Take 10 μL of plasma sample, add 400 μL of acetonitrile (containing internal standard working solution, including 5 ng / mL of verapamil and 50 ng / mL of glibenclamide), vortex for 10 minutes, centrifuge at 3700 rpm for 10 minutes, take 70 μL of supernatant, add 70 μL of water, vortex for 10 minutes, and take 2 μL of the mixed solution for LC-MS / MS injection analysis.

[0544] 3. Pharmacokinetic parameter results

[0545] The pharmacokinetic parameters of the compounds of the present invention and the positive control are shown in the following table

[0546] Table 2

[0547]

[0548] Conclusion: It can be seen from Table 2 that at a dose of 10 mg / kg, compound 2 of the present invention has good pharmacokinetic properties, wherein the blood concentration and area under the curve are better than those of BMS-986165.

[0549] Note: BMS-986165 is prepared according to WO 2014074661, and its specific structure is as follows:

[0550]

Claims

1. A compound represented by general formula (I) or its stereoisomer or a pharmaceutically acceptable salt thereof: in: W is selected from CR n , Y is selected from CR n or N; X is C; R 1 Selected from C 1-6 alkyl; R 2 Selected from or -C(O)R a ; R a Selected from C 3-6 Cycloalkyl, wherein the C 3-6 The cycloalkyl group is optionally further substituted with one or more R g substituted by a substituent; R g is selected from halogen; R 3 Selected from methoxy; R 4 is selected from 5-membered heteroaryl, wherein the heteroaryl is optionally further substituted with a C 1-4 Alkyl substituted; R n , R 5 , R 6 and R 7 are each independently selected from a hydrogen atom; The condition is that the compound of general formula (I) does not include:

2. The compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is a compound according to general formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in: Ring A is selected to be cyclopropyl; R b is selected from a hydrogen atom or a halogen; m is selected from 0, 1, 2, 3, 4 or 5; R 1 , R 3 ~R 7 , X, W and Y are as defined in claim 1.

3. The compound according to claim 1 or 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from methyl or ethyl.

4. The compound according to claim 1 or 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 4 Selected from triazolyl.

5. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: R 4 for 6. The compound according to any one of claims 1 to 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: W and Y are selected from CR n ; R n Selected from hydrogen atoms.

7. The compound according to claim 1 or its stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound is selected from:

8. A method for preparing the compound of general formula (I) or its stereoisomer or pharmaceutically acceptable salt according to claim 1, the method comprising: The compound of formula (IA) is reacted with the compound of formula (IB), optionally further oxidized, to obtain the compound of formula (I); in: X 1 is the leaving group; X, W, Y, R 1 ~R 7 The definition is as stated in claim 1.

9. The preparation method according to claim 8, wherein: X 1 It is a halogen.

10. The preparation method according to claim 8, wherein: X 1 For chlorine.

11. A method for preparing the compound of general formula (I) or its stereoisomer or pharmaceutically acceptable salt according to claim 1, the method comprising: The compound of general formula (IC) reacts with the compound of general formula (IB) to obtain the compound of general formula (ID); the compound of general formula (ID) reacts with the compound of general formula (IE) to obtain the compound of general formula (I); in: X 1 is the leaving group; X is a carbon atom; W, Y, R 1 ~R 7 The definition is as stated in claim 1.

12. The preparation method according to claim 11, wherein X 1 It is a halogen.

13. The preparation method according to claim 11, wherein: X 1 For chlorine.

14. A compound represented by the general formula (IA) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof: in: X 1 , X, W, Y, R 1 , R 3 ~R 7 The definition as in claim 8; The general formula (IA) does not include:

15. The compound according to claim 14 or its stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound is selected from:

16. A pharmaceutical composition comprising an effective dose of the compound according to any one of claims 1 to 7 or its stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

17. The pharmaceutical composition according to claim 16, characterized in that The pharmaceutical composition also contains at least one anti-inflammatory drug, which is selected from non-steroidal anti-inflammatory drugs, non-specific cyclooxygenase-2 inhibitors, specific cyclooxygenase-2 inhibitors, corticosteroids, tumor necrosis factor receptor antagonists, salicylates or salts, immunosuppressants or methotrexate.

18. Use of the compound according to any one of claims 1 to 7 or its stereoisomer or pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 16 or 17 in the preparation of a TYK2 kinase inhibitory drug.

19. Use of the compound according to any one of claims 1 to 7 or its stereoisomer or pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 16 or 17 in the preparation of a medicament for treating a disease mediated by TYK2 kinase.

20. The use according to claim 19, wherein the disease mediated by TYK2 kinase is an autoimmune disease, an inflammatory disease and a cancer; wherein the autoimmune disease is asthma, psoriasis, systemic lupus erythematosus, multiple sclerosis, allergic rhinitis, atopic dermatitis, contact dermatitis and delayed hypersensitivity reaction; wherein the inflammatory disease is inflammatory bowel disease and rheumatoid arthritis, and the inflammatory bowel disease is Crohn's syndrome and ulcerative colitis; wherein the cancer is non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, leukemia, non-Hodgkin's lymphoma, nasopharyngeal carcinoma, esophageal cancer, brain tumor, lymphoma, multiple myeloma, bile duct cancer and solid tumor, wherein the leukemia is selected from chronic myeloid leukemia and acute myeloid leukemia.

21. Use of a compound according to any one of claims 1 to 7 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 16 or 17 in the preparation of a drug for treating autoimmune diseases, inflammatory diseases and cancer; wherein the autoimmune diseases are asthma, psoriasis, systemic lupus erythematosus, multiple sclerosis, allergic rhinitis, atopic dermatitis, contact dermatitis and delayed hypersensitivity reaction; wherein the inflammatory diseases are inflammatory bowel disease and rheumatoid arthritis, and the inflammatory bowel diseases are Crohn's syndrome and ulcerative colitis; wherein the cancers are non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, gastric cancer, liver cancer, gastrointestinal stromal tumors, thyroid cancer, leukemia, non-Hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumor, lymphoma, multiple myeloma, bile duct cancer and solid tumors.

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