Nitrogen-containing heterocyclic derivative inhibitors, their preparation method and application

Abstract

Nitrogen-containing heterocyclic derivative inhibitors, their preparation and application are disclosed, and compounds as shown in general formula (I), their preparation and their use as EGFR inhibitors in the treatment of cancer are disclosed. [Case 1] TIFF2024532835000245.tif30170

Description

[Technical field]

[0001] The present invention relates to the field of biopharmaceuticals, specifically to nitrogen-containing heterocyclic derivative inhibitors and their preparation methods and applications. [Background technology]

[0002] EGFR (Epidermal Growth Factor Receptor) is a member of the transmembrane receptor tyrosine kinase ErbB family and is activated by binding to its ligand epidermal growth factor (EGF) or transforming growth factor alpha (TGFα). Activated EGFR forms a homodimer on the cell membrane or a heterodimer with other receptors in the family (e.g., ErbB-2, ErbB-3, or ErbB-4), causing phosphorylation of important tyrosine residues in EGFR, thereby activating downstream signal pathways in the cell and playing an important role in cell proliferation, survival, and anti-apoptosis. EGFR activating mutations, overexpression, or gene amplification, etc., cause overactivation of EGFR, promoting the transformation of cells into tumor cells, playing an important role in tumor cell proliferation, invasion, metastasis, and angiogenesis, and is an important target for the development of anticancer drugs, especially lung cancer drugs.

[0003] First-generation EGFR small molecule inhibitors, including gefitinib (Iressa) and erlotinib (Tarceva), have shown good therapeutic effects in the treatment of lung cancer and are used as first-line drugs in the treatment of non-small cell lung cancer (NSCLC) with EGFR activating mutations (including L858R and delE746_A750). However, after 10-12 months of treatment with first-generation small molecule EGFR inhibitors, most NSCLC patients show drug resistance to the first-generation small molecule inhibitors, and more than half of the drug resistance mechanisms are due to secondary mutations of the EGFR gatekeeper gene residue, T790M.

[0004] Osimertinib (AZD9291) is a third-generation EGFR TKI inhibitor with a high response rate and good therapeutic effect against drug resistance caused by EGFR T790M mutation. It was approved by the US FDA in November 2015 and launched. In clinical trials, it can effectively treat patients with late-stage non-small cell lung cancer with EGFR T790M drug resistance mutation. Although osimertinib has brought great success in the clinical treatment of non-small cell lung cancer with EGFR T790M mutation, patients could not avoid the phenomenon of drug resistance after 9 to 14 months of treatment. According to research, the drug resistance of up to 20 to 40% of drug-resistant patients is due to EGFR C797S mutation. EGFR C797S mutation causes drug resistance by converting cysteine ​​at position 797 to serine, preventing osimertinib from forming a covalent bond with EGFR protein. Currently, there is still no effective inhibitor against EGFR C797S drug resistance mutation in clinical trials. Therefore, there is an urgent need to develop novel, highly active EGFR inhibitors to solve the drug resistance problem caused by the EGFR C797S mutation.

[0005] Novartis reported the compound EAI0450 against EGFR C797S drug resistance, which belongs to EGFR allosteric inhibitors and showed better antitumor effect in L858R / T790M / C797S mutated mouse in vivo pharmacodynamic model after being combined with EGFR monoclonal antibody drugs such as cetuximab; however, the single agent of the compound was ineffective and could not inhibit the C797S drug resistance mutation containing deIE746_A750, and could not proceed to clinical research. In 2017, Ken Uchibori et al. reported that the combination of Brigatinib (AP26113) and EGFR monoclonal antibodies (e.g., cetuximab) could overcome drug resistance to third-generation EGFR inhibitors due to the C797S mutation, and showed good antitumor effects in the PC9 (EGFR-C797S / T790M / de119) mouse pharmacodynamic model. However, Brigatinib has problems in that it has low activity as a single agent in vitro and no significant antitumor activity in vivo, and no further clinical studies have been conducted.

[0006] Lung cancer is a serious disease that threatens human health, and its mortality rate ranks first among all malignant tumors. In China, the incidence rate of lung cancer is increasing year by year, with around 700,000 new cases occurring each year. In China, lung cancer with EGFR activating mutations accounts for about 35% of all NSCLC cases, and the use of first-generation or third-generation EGFR inhibitors can achieve good therapeutic effects, but new drug-resistant mutations occur in the later stages, so the development of next-generation drug-resistant EGFR inhibitors has great clinical and market value. Summary of the Invention

[0007] The object of the present invention is to provide a compound represented by general formula (I), a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, wherein the structure of the compound represented by general formula (I) is as follows: [ka] Where: Ring A, Ring B, Ring C and Ring D are each independently selected from a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group; L1, L2 and L3 each independently represent a bond, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, -(CH2) n -, -(CH2) n C(O)(CR aa R bb ) n1 -, -(CH2) n C(O)NR aa (CH2) n1 -, -(CH2) n (CR aa R bb ) n2 -, -(CR aa R bb ) n O(CH2) n1 -, -(CH2) n O(CR aa R bb ) n1 -, -(CR aa R bb ) n3 S(CH2) n4 -, -(CH2) n S(CR aa R bb ) n3 -, -(CR aa R bb ) n3 (CH2) n NR cc -, -(CH2) n NR aa (CR bb R cc ) n -, -(CH2) n NR aa C(O)-, -(CH2) n P(O) p R aa -, -(CH2) n S(O) m -, -(CH2) n S(O) m NR aa -or-(CH2) n NR aa S(O) m- selected from R1 is independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -OR a , -P(O) p (R a ) n5 , -S(O) m R a Or -C(O)R a wherein the amino group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, halogenated alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may be optionally further substituted, or two of R1's connected to the atom between them form a cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, wherein the cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may be optionally further substituted; R2 independently represents hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -OR a , -P(O) p (R a ) n5 , -S(O) m R a Or -C(O)R a wherein the amino, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; R3 independently represents hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -OR a , -P(O) p (R a ) n5 , -S(O) m R a Or -C(O)R a wherein the amino, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; R4 is independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -OR a , -P(O) p (R a ) n5 , -S(O) m R a Or -C(O)R a wherein the amino, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; or one R2 and one R4, joined to the atom between them, form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, which cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may optionally be further substituted; R ais selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups, which amino, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; R aa , R bb and R cc are each independently selected from hydrogen, deuterium, a halogen, an amino group, a hydroxy group, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, which amino groups, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups may optionally be further substituted; x is 0, 1, 2, 3, 4, 5 or 6; y is 0, 1, 2, 3, 4, 5 or 6; z is 0, 1, 2, 3, 4, 5 or 6; w is 0, 1, 2, 3, 4, 5 or 6; p, m, n, n1, n2, n3, n4, and n5 are each independently 0, 1, 2, or 3.

[0008] In some embodiments of the present invention, the compound of formula (I) is further represented by the general formula (I-1): [ka] Where: M1 is N, CH; M 1-1 is N, CH, M3 is N, CH, M5 is N, CH, Ring D is selected from heteroaryl groups; Ring A is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group; R1 is independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -OR a , -P(O) p (R a ) n5 , -S(O) m R a Or -C(O)R a wherein the amino group, alkyl group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may be optionally further substituted; or wherein two R1 are linked to the atom between them to form a cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, wherein the cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may be optionally further substituted; R2 independently represents hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -OR a , -P(O) p (R a ) n5 , -S(O) m R a Or -C(O)R a wherein the amino, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; R3 is independently selected from hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, halogenated alkyl group, deuterated alkyl group, alkenyl group, alkynyl group, alkoxy group, deuterated alkoxy group, halogenated alkoxy group or hydroxyalkyl group, preferably hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-3 Alkyl groups, halogenated C 1-3 Alkyl groups, deuterated C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Alkoxy group, deuterated C 1-3 Alkoxy groups, halogenated C 1-3 Alkoxy group or C 1-3 is a hydroxyalkyl group, R4 is independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -OR a , -P(O) p (R a ) n5 , -S(O) m R a Or -C(O)R a wherein the amino, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; R a are each independently selected from hydrogen, deuterium, a halogen, an amino group, a hydroxy group, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, which amino groups, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups may optionally be further substituted; x is 0, 1, 2, 3, 4, 5 or 6; y is 0, 1, 2, 3, 4, 5 or 6; z is 0, 1, 2 or 3; w is 0, 1, 2, 3, 4, 5 or 6; p, m and n5 are each independently 0, 1, 2 or 3.

[0009] In some embodiments of the present invention, the compound of formula (I) is further as shown in general formula (II-A), (II-B), (II-C), (II-D), (II-E) or (II-F): [ka] Where: [ka] represents a saturated, unsaturated or partially saturated ring, [ka] is a single bond or a double bond, M1 is C, N, or CH; M2 is N, NH, CH, CH2, O or S; M3 is N, CH, M4 is N, NH, CH, CH2, O or S; M5 is N, CH, M9 is N, CH; M 10 is N, CH, and m1 is 0, 1, 2, 3 or 4.

[0010] In some embodiments of the present invention, ring A is C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14aryl group or 5-14 membered heteroaryl group, wherein the heteroatoms in the 3-12 membered heterocyclyl group and the 5-14 membered heteroaryl group are independently selected from nitrogen, oxygen, sulfur and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4; or ring A is absent, and L1 and R1 are directly linked; Preferably, ring A is C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5-14 membered heteroaryl group, wherein the heteroatoms in the 3-12 membered heterocyclyl group and the 5-14 membered heteroaryl group are independently selected from nitrogen, oxygen, sulfur and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4, and is preferably a 4-10 membered heterocyclyl group, and more preferably a 4-6 membered monocyclic heterocyclyl group, a 7-9 membered spirocyclic heterocyclyl group or an 8-10 membered fused ring heterocyclyl group; Specifically, preferably, [ka] and more preferably [ka] and More preferably, [ka] and Even more preferably, ring A is [ka] It is.

[0011] In some embodiments of the present invention, ring B is C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14an aryl group or a 5-14 membered heteroaryl group, wherein the heteroatoms in the 3-12 membered heterocyclyl group and the 5-14 membered heteroaryl group are independently selected from nitrogen, oxygen, sulfur and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4, and is preferably a 5-14 membered heteroaryl group, and the heteroaryl group is a monocyclic or condensed ring, and is preferably an 8-14 membered heteroaryl group; Preferably, ring B is [ka] and More preferably, ring B is [ka] and More preferably, ring B is [ka] It is.

[0012] In some embodiments of the present invention, ring C is 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 aryl group or 5-14 membered heteroaryl group, wherein the heteroatoms in the 3-12 membered heterocyclyl group and the 5-14 membered heteroaryl group are independently selected from nitrogen, oxygen, sulfur and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4, preferably a 5-6 membered heteroaryl group; More preferably, ring C is [ka] and Even more preferably, ring C is [ka] It is.

[0013] In some embodiments of the present invention, ring D is C 3-12Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 aryl or 5-14 membered heteroaryl groups, wherein the heteroatoms in the 3-12 membered heterocyclyl and 5-14 membered heteroaryl groups are independently selected from nitrogen, oxygen, sulfur and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4, and preferably 3-6 a cycloalkyl group, a 5- to 8-membered heterocyclyl group, or a 5- to 8-membered heteroaryl group; More preferably, C 3-6 a cycloalkyl group, a 5- to 8-membered heterocyclyl group, or a 5- to 6-membered heteroaryl group, the 5- to 8-membered heterocyclyl group being selected from a 5- to 6-membered monocyclic heterocyclyl group, a 7- to 8-membered spirocyclic heterocyclyl group, or a 7- to 8-membered fused ring heterocyclyl group; More preferably, it is a 5-membered heteroaryl group, a 6-membered heteroaryl group, a 5- to 6-membered monocyclic heterocyclyl group, a 7- to 8-membered spirocyclic heterocyclyl group, or a 7- to 8-membered fused ring heterocyclyl group. Preferably, ring D is [ka] and More preferably, ring D is [ka] It is.

[0014] In some embodiments of the present invention, the compound of formula (I) is further as shown in general formula (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X): [ka] Where: [ka] is a single bond or a double bond, M1 is C, N, or CH; M2 is N, NH, CH, CH2, O or S; M3 is N, CH, M4 is N, NH, CH, CH2, O or S; M5 is N, CH, M6 is S, CH=CH; M7 is a bond, N, NH, or CH; M8 is NH, CH2, O or S; M9 is N, CH; M 10 is N, CH, Ring E is a 4- to 10-membered heterocyclyl group, preferably a 4- to 10-membered heterocyclyl group containing 1 to 4 N, O, S or P; m1 is 0, 1, 2, 3 or 4; m2 is 1, 2 or 3; m3 is 1, 2, 3, 4, 5 or 6.

[0015] In some embodiments of the present invention, for general formula (VI), when M6 is CH=CH and M7 is CH, R1 is a substituted or unsubstituted -CH2S(O)2R a isn't it.

[0016] In some embodiments of the present invention, for general formula (VI), when M6 is CH=CH and M7 is CH, R1 is -CH2S(O)2R a isn't it.

[0017] In some embodiments of the present invention, for general formula (VI), when M6 is CH=CH and M7 is CH, R1 is not -CH2S(O)2CH3, -CHCH3S(O)2CH3, -CH2S(O)2CH2CH3.

[0018] In some embodiments of the present invention, Ring E is selected from a 4-6 membered monocyclic heterocyclyl group, a 7-9 membered spirocyclic heterocyclyl group, or an 8-10 membered fused ring heterocyclyl group, preferably [ka] and Preferably, [ka] and more preferably [ka] This is the base.

[0019] In some embodiments of the present invention, the compound is further represented by general formula (VII-1) or (VIII-1): [ka] where R5, R6, R7, and R8 are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 hydroxyalkyl groups, and preferably R5, R6, R7 and R8 are independently selected from hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Halogenated alkoxy groups, C 1-6 hydroxyalkyl groups, n6 is 0, 1 or 2.

[0020] In some embodiments of the present invention, R5 and R7 are independently a methyl group, an ethyl group, an n-propyl group, or an isopropyl group, preferably an isopropyl group.

[0021] In some embodiments of the invention, R8 is -OCH2CF3, -OCH2CHF2, -OCH2CH2F, -OCHFCF3, -OCF2CF3, preferably -OCH2CF3.

[0022] In some embodiments of the present invention, n6 is 0.

[0023] In some embodiments of the invention, L is a bond, substituted or unsubstituted C 2-6 Alkenyl group, substituted or unsubstituted C 2-6 Alkynyl group, -(CH2) n -, -(CH2) n C(O)(CR aa R bb ) n1 -, -(CH2) n C(O)NR aa (CH2) n1 -, -(CH2) n (CR aa R bb ) n2 -, -(CR aa R bb ) n O(CH2) n1 -, -(CH2) n O(CR aa R bb ) n1 -, -(CR aa R bb ) n3 S(CH2) n4 -, -(CH2) n S(CR aa R bb ) n3 -, -(CR aa R bb ) n3 (CH2) n NR cc -, -(CH2) n NR aa (CR bb R cc ) n -, -(CH2) n NR aa C(O)-, -(CH2) n P(O) p Raa -, -(CH2) n S(O) m -, -(CH2) n S(O) m NR aa - and - (CH2) n NR aa S(O) m -, preferably a bond.

[0024] In some embodiments of the present invention, R1 is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 Aryl group, 5-14 membered heteroaryl group, -OR a , -P(O) p (R a ) n5 , -S(O) m R a Or -C(O)R a wherein the amino group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy groups, halogenated C 1-6 Alkoxy group, C 1-6Hydroxyalkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-12 Aryl group, 5-12 membered heteroaryl group, -OR aa , -P(O) p (R aa ) n5 , -S(O) m R aa , -Se(O) m R aa Or -C(O)R aa or two of R1 may be linked to the atom between them and further substituted with one or more of 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 An aryl group and a 5- to 14-membered heteroaryl group are formed, 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 may be further substituted with one or more hydroxyalkyl groups; Preferably, R1 is independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 Aryl group, 5-14 membered heteroaryl group, -OR a , -P(O) p (R a ) n5 , -S(O) m R a Or -C(O)R a wherein the amino group, C1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy groups, halogenated C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-12 Aryl group, 5-12 membered heteroaryl group, -OR aa , -P(O) p (R aa ) n5 , -S(O) m R aa Or -C(O)R aa may be further substituted with one or more of Preferably, R1 is independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C 6-10 Aryl group, 5-12 membered heteroaryl group, -OR a , -P(O) p (R a ) n5 , -S(O) m R a Or -C(O)R awherein the amino group, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C 6-10 The aryl and 5- to 12-membered heteroaryl groups are optionally substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy groups, halogenated C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -OR aa , -P(O) p (R aa ) n5 , -S(O) m R aa Or -C(O)R aa may be further substituted with one or more of Or, two of R1 are linked to the atom between them to form C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 An aryl group or a 5- to 14-membered heteroaryl group is formed, 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6It may be further substituted with one or more hydroxyalkyl groups.

[0025] Preferably, two of R1 are linked to the atom between them and are C 3-10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C 6-12 An aryl group or a 5- to 12-membered heteroaryl group is formed, 3-10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Alkoxy group, C 1-3 It may be further substituted with one or more hydroxyalkyl groups.

[0026] In some embodiments of the invention, R1 is independently selected from -NHS(O)2CH3, -NCH3S(O)2CH3, -CH2S(O)2N(CH3)2, -CH2Se(O)2CH3, -CH2S(O)2CH3, -CH2SOCH3, -CH2NO2, a methyl group, hydrogen, [ka] , methoxy group, cyano group, -CH2OCH3, -CH2CN, -CH(CN)2, -S(O)2CH3, oxo, hydroxy group, -CH2COCH3, -COCH3, -CH2P(O)(CH3)2, [ka] is selected from.

[0027] In some embodiments of the invention, R1 is independently selected from -CH2S(O)2N(CH3)2, -CH2Se(O)2CH3, -CH2S(O)2CH3, a methyl group, hydrogen, [ka] , a methoxy group, a cyano group, -CH2OCH3, -CH2CN, -CH(CN)2, -S(O)2CH3, oxo, a hydroxy group, -CH2COCH3, -COCH3, or -CH2P(O)(CH3)2, or two R1's are linked to the atom between them to form a 3- to 12-membered heterocyclyl group, preferably [ka] It is.

[0028] In some embodiments of the present invention, R1 is independently -CH2S(O)2CH3, a methyl group, hydrogen, [ka] , a methoxy group, a cyano group, -CH2OCH3, -CH2CN, -S(O)2CH3, oxo, a hydroxy group, -CH2COCH3, -COCH3, or -CH2P(O)(CH3)2, or two of R1 are linked to the atom between them to form a 3- to 12-membered heterocyclyl group, preferably [ka] It is.

[0029] In some embodiments of the present invention, R1 is independently -CH2S(O)2CH3, a methyl group, hydrogen, [ka] , a methoxy group, a cyano group, -CH2OCH3, -CH2CN, -S(O)2CH3, oxo, a hydroxy group, -COCH3, or -CH2P(O)(CH3)2, or two of R1 are linked to the atom between them to form a 3- to 12-membered heterocyclyl group, preferably [ka] It is.

[0030] In some embodiments of the invention, L2 is a bond, substituted or unsubstituted C 2-6 Alkenyl group, substituted or unsubstituted C 2-6 Alkynyl group, -(CH2) n -, -(CH2) n C(O)(CR aa R bb ) n1 -, -(CH2) n C(O)NR aa (CH2) n1 -, -(CH2) n (CR aa R bb ) n2 -, -(CR aa R bb ) n O(CH2) n1 -, -(CH2) n O(CR aa R bb ) n1 -, -(CR aa R bb ) n3 S(CH2) n4 -, -(CH2) n S(CR aa R bb ) n3 -, -(CR aa R bb ) n3 (CH2) n NR cc -, -(CH2) n NR aa (CR bb R cc ) n -, -(CH2) n NR aa C(O)-, -(CH2) n P(O) p R aa -, -(CH2) n S(O) m -, -(CH2) n S(O) m NR aa - and - (CH2) n NR aa S(O) m -, preferably -NH-.

[0031] In some embodiments of the present invention, R2 is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 Aryl group, 5-14 membered heteroaryl group, -OR a , -P(O) p (R a ) n5 , -S(O) m R a Or -C(O)R a wherein the amino group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy groups, halogenated C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy groups, halogenated C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-12 Aryl group, 5-12 membered heteroaryl group, -OR aa , -P(O) p (R aa )n5 , -S(O) m R aa Or -C(O)R aa Preferably, R2 is independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C 6-12 Aryl group, 5-12 membered heteroaryl group, -OR a , -P(O) p (R a ) n5 , -S(O) m R a Or -C(O)R a wherein the amino group, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C 6-12 The aryl and 5- to 12-membered heteroaryl groups are optionally substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C 1-2 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy groups, halogenated C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -OR aa , -P(O) p (R aa ) n5, -S(O) m R aa Or -C(O)R aa More preferably, R2 is independently an isopropyl group, a cyano group, a trifluoromethyl group, or -OCH2CF3, and even more preferably, R2 is independently an isopropyl group, or -OCH2CF3.

[0032] In some embodiments of the invention, R2 is independently oxo, fluorine, an isopropyl group, a cyano group, a trifluoromethyl group, -NHCH(CH)3, or -OCH2CF3.

[0033] In some embodiments of the invention, L3 is a bond, substituted or unsubstituted C 2-6 Alkenyl group, substituted or unsubstituted C 2-6 Alkynyl group, -(CH2) n -, -(CH2) n C(O)(CR aa R bb ) n1 -, -(CH2) n C(O)NR aa (CH2) n1 -, -(CH2) n (CR aa R bb ) n2 -, -(CR aa R bb ) n O(CH2) n1 -, -(CH2) n O(CR aa R bb ) n1 -, -(CR aa R bb ) n3 S(CH2) n4 -, -(CH2) n S(CR aa R bb ) n3 -, -(CR aa R bb ) n3 (CH2) n NR cc -, -(CH2) n NR aa(CR bb R cc ) n -, -(CH2) n NR aa C(O)-, -(CH2) n P(O) p R aa -, -(CH2) n S(O) m -, -(CH2) n S(O) m NR aa - and - (CH2) n NR aa S(O) m -, preferably a bond.

[0034] In some embodiments of the present invention, R3 is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 Aryl group, 5-14 membered heteroaryl group, -OR a , -P(O) p (R a ) n5 , -S(O) m R a Or -C(O)R a wherein the amino group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy groups, halogenated C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy groups, halogenated C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-12 Aryl group, 5-12 membered heteroaryl group, -OR aa , -P(O) p (R aa ) n5 , -S(O) m R aa Or -C(O)R aa Preferably, R3 is hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C 6-12 Aryl group, 5-12 membered heteroaryl group, -OR a , -P(O) p (R a ) n5 , -S(O) m R a Or -C(O)R a wherein the amino group, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C 6-12The aryl and 5- to 12-membered heteroaryl groups are optionally substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy groups, halogenated C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -OR aa , -P(O) p (R aa ) n5 , -S(O) m R aa Or -C(O)R aa and more preferably, R3 is hydrogen.

[0035] In some embodiments of the present invention, R3 is independently selected from hydrogen, a methoxy group, a methyl group, fluorine, chlorine, bromine, a trifluoromethyl group, a cyano group, a cyclopropyl group, or -COCH3.

[0036] In some embodiments of the present invention, R4 is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 Aryl group, 5-14 membered heteroaryl group, -OR a , -P(O) p (R a ) n5 , -S(O) m R aOr -C(O)R a wherein the amino group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl and 5- to 14-membered heteroaryl groups may optionally be one or more R 4-1 may be further substituted with R 4-1 are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy groups, halogenated C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-12 Aryl group, 5-12 membered heteroaryl group, -OR aa , -P(O) p (R aa ) n5 , -S(O) m R aa Or -C(O)R aa and optionally R 4-1 is hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy groups, halogenated C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-12aryl group, 5-12 membered heteroaryl group, 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy groups, halogenated C 1-6 Alkoxy group, C 1-6 The hydroxyalkyl group may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy groups, halogenated C 1-6 Alkoxy group, C 1-6 It is substituted with one or more of the hydroxyalkyl groups.

[0037] In some embodiments of the present invention, R4 is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C 6-12 Aryl group, 5-12 membered heteroaryl group, -OR a , -P(O) p (R a ) n5 , -S(O) m R a Or -C(O)R a wherein the amino group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkoxy group, C 1-3Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C 6-12 The aryl and 5- to 12-membered heteroaryl groups may optionally be one or more R 4-1 may be further substituted with R 4-1 are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy groups, halogenated C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C 6-12 Aryl group, 5-12 membered heteroaryl group, -OR aa , -P(O) p (R aa ) n5 , -S(O) m R aa Or -C(O)R aa and optionally R 4-1 is hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy groups, halogenated C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C 6-12 aryl group, 5-12 membered heteroaryl group, 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C1-3 Halogenated alkyl groups, C 1-3 Alkoxy groups, halogenated C 1-3 Alkoxy group, C 1-3 The hydroxyalkyl group may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy groups, halogenated C 1-3 Alkoxy group, C 1-3 It is substituted with one or more of the hydroxyalkyl groups.

[0038] In some embodiments of the present invention, R4 is independently selected from fluorine, a methyl group, a hydroxy group, a methoxy group, -OCD3, -CH2F, -CHF2, CH2CF3, -CH2CH2F, hydrogen, -CH2OCH3, -CF3, an amino group, oxo, -COCH3, [ka] It is.

[0039] In some embodiments of the present invention, R4 is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 Aryl group, 5-14 membered heteroaryl group, -OR a , -P(O) p (R a ) n5 , -S(O) m R a Or -C(O)R a wherein the amino group, C 1-6Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy groups, halogenated C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy groups, halogenated C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-12 Aryl group, 5-12 membered heteroaryl group, -OR aa , -P(O) p (R aa ) n5 , -S(O) m R aa Or -C(O)R aa may be further substituted with one or more of Preferably, R4 is independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C 6-12 Aryl group, 5-12 membered heteroaryl group, -OR a , -P(O) p (R a ) n5, -S(O) m R a Or -C(O)R a wherein the amino group, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C 6-12 The aryl and 5- to 12-membered heteroaryl groups are optionally substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy groups, halogenated C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -OR aa , -P(O) p (R aa ) n5 , -S(O) m R aa Or -C(O)R aa More preferably, R4 is fluorine, a methyl group, a hydroxy group, a methoxy group, -OCD3, hydrogen, [ka] More preferably, R4 is fluorine, a methyl group, a hydroxy group, a methoxy group, -OCD3, hydrogen, [ka] It is.

[0040] In some embodiments of the present invention, R4 is independently selected from the group consisting of fluorine, chlorine, cyano, trifluoromethyl, methyl, ethyl, nitro, hydroxy, methoxy, -OCD3, hydrogen, [ka] A cyclopropyl group, [ka] Difluoromethyl group, [ka] is selected from.

[0041] In some embodiments of the present invention, one of R2 and one of R4 are linked to the atom between them and are C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 An aryl group or a 5- to 14-membered heteroaryl group is formed, 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy groups, halogenated C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-12 It may be further substituted with one or more of an aryl group, a 5-12 membered heteroaryl group, preferably, where -R2-R4- is [ka] It is.

[0042] In some embodiments of the present invention, R a are independently hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 aryl group, and 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy groups, halogenated C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-12 It may be further substituted with one or more of an aryl group, a 5- to 12-membered heteroaryl group. a are independently hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C 6-12aryl group, and 5- to 12-membered heteroaryl group, 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C 6-12 The aryl group and the 5- to 12-membered heteroaryl group may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy groups, halogenated C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C 6-10 It may be further substituted with one or more of an aryl group and a 5- to 10-membered heteroaryl group.

[0043] In some embodiments of the present invention, R aa , R bb and R cc are each independently hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 aryl group, and 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-12Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy groups, halogenated C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-12 It may be further substituted with one or more of an aryl group, a 5- to 12-membered heteroaryl group. aa , R bb are independently hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C 6-12 aryl group, and 5- to 12-membered heteroaryl group, 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C 6-12 The aryl group and the 5- to 12-membered heteroaryl group may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3Alkoxy groups, halogenated C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C 6-10 It may be further substituted with one or more of an aryl group and a 5- to 10-membered heteroaryl group.

[0044] In some embodiments of the present invention, the compound is further represented by the general formula (VII-2): [ka] Where: M 11 is CH or N, R 1-1 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, a methyl group, an ethyl group, a halogenated methyl group, and a halogenated ethyl group; R 1-2 is an amino group, a hydroxyl group, a cyano group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 3-6 cycloalkyl group, and 3- to 8-membered heterocyclyl group, 1-3 Alkoxy group, C 1-3 Alkyl group, C 3-6 The cycloalkyl group and the 3- to 8-membered heterocyclyl group may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy groups, halogenated C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, -C(O)R ee , -OR ee , -P(O) p (R ee ) n5 , -S(O) m R ee , -S(O)2N(R ee )2 and -S(=O)(=NCN)R eeand preferably, R 1-2 are -NHS(O)2CH3, -NCH3S(O)2CH3, -CH2S(O)2N(CH3)2, -CH2S(O)2CH3, -CH2SOCH3, -CH2NO2, methyl group, hydrogen, [ka] Methoxy group, cyano group, -CH2OCH3, -CH2CN, -CH(CN)2, hydroxy group, -CH2COCH3, [ka] is selected from R2 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, a methyl group, an ethyl group, a halogenated methyl group, and a halogenated ethyl group; R 2-1 is an amino group, C 1-3 Alkyl groups, halogenated C 1-3 Alkyl group or deuterated C 1-3 alkyl group, the amino group, C 1-3 Alkyl groups, halogenated C 1-3 Alkyl groups and deuterated C 1-3 The alkyl group may optionally be substituted with deuterium, a halogen, a cyano group, a hydroxy group, a nitro group, 1-3 Alkyl groups, halogenated C 1-3 Alkyl group or deuterated C 1-3 may be further substituted with one or more alkyl groups; R4 is a halogen, an amino group, a hydroxyl group, a cyano group, a nitro group, or C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-8 membered heterocyclyl groups, -S(O) m R d Or -C(O)R d wherein the amino group, C 1-3 Alkyl group, C 1-3Alkoxy group, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 The cycloalkyl and 3- to 8-membered heterocyclyl groups may optionally be represented by one or more R 4-1 may be further substituted with R 4-1 are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy groups, halogenated C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-6 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-12 aryl group or a 5- to 12-membered heteroaryl group, optionally R 4-1 is hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy groups, halogenated C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-6 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-12 aryl group, 5-12 membered heteroaryl group, 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy groups, halogenated C 1-3 Alkoxy group, C 1-3The hydroxyalkyl group may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy groups, halogenated C 1-3 Alkoxy group, C 1-3 Preferably, R4 is fluorine, chlorine, a cyano group, a trifluoromethyl group, a methyl group, an ethyl group, a nitro group, a hydroxyl group, a methoxy group, -OCD3, hydrogen, [ka] A cyclopropyl group, [ka] Difluoromethyl group, [ka] is selected from R 6-1 is hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl group, C 1-3 Halogenated alkyl groups, C 1-3 Deuterated alkyl groups, C 1-3 Alkoxy group, C 1-3 hydroxyalkyl groups, R 6-2 is hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclyl groups, -S(O) m R e Or -C(O)R e wherein the amino group, C 1-3Alkyl group, C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-6 The cycloalkyl and 3- to 6-membered heterocyclyl groups are optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, and C 1-3 may be further substituted with one or more alkyl groups; R d are independently hydrogen, deuterium, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclyl groups, C 1-3 Halogenated alkyl group or C 1-3 deuterated alkyl groups, R e are independently hydrogen, deuterium, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclyl groups, C 1-3 Halogenated alkyl group or C 1-3 deuterated alkyl groups, R ee are independently hydrogen, deuterium, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclyl groups, C 1-3 Halogenated alkyl group or C 1-3 deuterated alkyl groups, m is 0, 1 or 2; p is 0, 1 or 2; n5 is 0, 1 or 2; y is 0, 1, 2, 3 or 4.

[0045] In some embodiments of the present invention, the compound is further represented by the general formula (VII-3): [ka] Where: M 12 is a bond, NR9 or CR 10 R 11 is selected from R9 is selected from hydrogen, deuterium, a methyl group, an ethyl group, a monofluoromethyl group, a difluoromethyl group, or a trifluoromethyl group; R 10 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, a methyl group, an ethyl group, a monofluoromethyl group, a difluoromethyl group or a trifluoromethyl group; R 11 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, a methyl group, an ethyl group, a monofluoromethyl group, a difluoromethyl group or a trifluoromethyl group; R 1-1 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, a methyl group, an ethyl group, a monofluoromethyl group, a difluoromethyl group or a trifluoromethyl group; R2 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, monofluoromethyl, difluoromethyl, or trifluoromethyl; R 2-1 is an amino group, C 1-3 Alkyl groups, halogenated C 1-3 Alkyl group or deuterated C 1-3 alkyl group, the amino group, C 1-3 Alkyl groups, halogenated C 1-3 Alkyl group or deuterated C 1-3 The alkyl group may optionally be substituted with deuterium, a halogen, a cyano group, a hydroxy group, a nitro group, 1-3 Alkyl groups, halogenated C 1-3 Alkyl groups and deuterated C 1-3 may be further substituted with one or more alkyl groups; Preferably, R 2-1is selected from an isopropyl group, -CH(Me)OMe, or -N(Me)2; R4 is a halogen, an amino group, a hydroxyl group, a cyano group, a nitro group, or C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-8 membered heterocyclyl groups, -S(O) m R d Or -C(O)R d wherein the amino group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 The cycloalkyl and 3- to 8-membered heterocyclyl groups may optionally be represented by one or more R 4-1 may be further substituted with R 4-1 are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy groups, halogenated C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-6 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-12 aryl group or a 5- to 12-membered heteroaryl group, optionally R 4-1 is hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3Alkoxy groups, halogenated C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-6 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-12 aryl group, 5-12 membered heteroaryl group, 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy groups, halogenated C 1-3 Alkoxy group, C 1-3 The hydroxyalkyl group may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy groups, halogenated C 1-3 Alkoxy group, C 1-3 hydroxyalkyl group, and preferably, R4 is independently selected from fluorine, chlorine, cyano, trifluoromethyl, methyl, ethyl, nitro, hydroxy, methoxy, -OCD3, hydrogen, [ka] A cyclopropyl group, [ka] Difluoromethyl group, [ka] is selected from R 6-1 is hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C1-3 hydroxyalkyl groups, R 6-2 is hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclyl groups, -S(O) m R e Or -C(O)R e wherein the amino group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-6 The cycloalkyl and 3- to 8-membered heterocyclyl groups may optionally be substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 may be further substituted with one or more alkyl groups; R d are independently hydrogen, deuterium, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclyl groups, C 1-3 Halogenated alkyl groups, C 1-3 deuterated alkyl groups, R e are independently hydrogen, deuterium, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclyl groups, C 1-3 Halogenated alkyl groups, C 1-3 deuterated alkyl groups, m is 0, 1 or 2; y is 0, 1, 2, 3 or 4.

[0046] The present invention further relates to the application of the compounds of the above general formulas, their stereoisomers or their pharma- ceutically acceptable salts in the preparation of EGFR inhibitor medicines.

[0047] The present invention further relates to the application of the compound of each of the above general formulas, its stereoisomers or its pharma- ceutically acceptable salts in the manufacture of a medicament for treating cancer, wherein said cancer is non-small cell lung cancer.

[0048] The present invention further relates to a method for preventing and / or treating an EGFR-related disease, which comprises administering to a patient a therapeutically effective amount of a compound of each general formula, its stereoisomer or its pharma- ceutically acceptable salt, wherein the EGFR-related disease is non-small cell lung cancer.

[0049] In some embodiments of the invention, the EGFR is a mutated EGFR, preferably one or more of the following mutations: Del19, L858R, T790M or C797S, more preferably Del19, L858R, L858R / T790M, Del19 / T790M, Del19 / C797S, L858R / C797S, Del19 / T790M / C797S or L858R / T790M / C797S mutant EGFR.

[0050] In some embodiments of the invention, the cancer is an EGFR Del19, L858R, L858R / T790M, Del19 / T790M, Del19 / C797S, L858R / C797S, Del19 / T790M / C797S or L858R / T790M / C797S mutant cancer.

[0051] Unless stated to the contrary, terms used in the specification and claims have the following meanings.

[0052] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include 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, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, and 5-methylhexyl. , 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof.More preferred are lower alkyl groups containing 1 to 6 carbon atoms, and non-limiting examples include 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, and 2,3-dimethylbutyl. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available binding site, and said substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups, and in the present invention is preferably methyl, ethyl, isopropyl, tert-butyl, halogenated alkyl, deuterated alkyl, alkyl substituted with alkoxy and alkyl substituted with hydroxy.

[0053] The term "alkylene group" refers to an alkyl group in which one hydrogen atom is further substituted, e.g., a "methylene group" refers to -CH2-, an "ethylene group" refers to -(CH2)2-, a "propylene group" refers to -(CH2)3-, a "butylene group" refers to -(CH2)4-, etc. The term "alkenyl group" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, e.g., vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. An alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0054] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the ring of the cycloalkyl group containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., and polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.

[0055] The term "spirocycloalkyl group" refers to a 5-20 membered polycyclic group in which the monocyclic rings share one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. It is preferably 6-14 membered, more preferably 7-10 membered. Depending on the number of shared spiro atoms between the rings, spirocycloalkyl groups are divided into monospirocycloalkyl groups, bisspirocycloalkyl groups or polyspirocycloalkyl groups, preferably monospirocycloalkyl groups and bisspirocycloalkyl groups. More preferably, they are 3-membered / 6-membered, 3-membered / 5-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups are: [ka] Including, Also included are spirocycloalkyl groups in which the monospirocycloalkyl group and the heterocycloalkyl group share a spiro atom, non-limiting examples of which are: [ka] etc.

[0056] The term "fused cycloalkyl group" refers to an all-carbon polycyclic group having 5 to 20 members, in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, where one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings that it comprises, it may be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic cycloalkyl groups. Non-limiting examples of fused cycloalkyl groups are: [ka] etc.

[0057] "Bridged cycloalkyl group" refers to a 5-20 member all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly linked, which may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. It is preferably 6-14 membered, more preferably 7-10 membered. Depending on the number of rings that it comprises, it may be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include the following: [ka]

[0058] The ring of the cycloalkyl group can be fused onto the ring of an aryl group, a heteroaryl group, or a heterocycloalkyl group, where the ring connected to the base skeleton is a cycloalkyl group, non-limiting examples include an indanyl group, a tetrahydronaphthyl group, a benzocycloheptyl group, etc. The cycloalkyl group can be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an alkylamino group, a halogen, a mercapto group, a hydroxy group, a nitro group, a cyano group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a cycloalkoxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an oxo group, a carboxyl group, or a carboxylate group.

[0059] The term "heterocyclyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, where one or more of the ring atoms is nitrogen, oxygen, P(O), pp Or S(O) mm(wherein pp and mm are integers of 0 to 2), but does not include the ring moiety of -OO-, -OS- or -SS-, and the other ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, more preferably contains 3 to 8 ring atoms or 4 to 10 ring atoms, most preferably contains 3 to 8 ring atoms, and even more preferably contains 1 to 3 nitrogen atoms. The 3-8 membered heterocyclyl group is optionally substituted with 1 to 2 oxygen atoms, sulfur atoms or oxo groups, and includes a nitrogen-containing monocyclic heterocyclyl group, a nitrogen-containing spiroheterocyclyl group or a nitrogen-containing fused heterocyclyl group.

[0060] Non-limiting examples of monocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepanyl, 1,4-diazacycloheptyl, pyranyl, and the like, preferably pyrrolidinyl, morpholinyl, piperidinyl, azepanyl, 1,4-diazacycloheptyl, and piperazinyl. Polycyclic heterocyclyl groups include spirocyclic, fused ring, and bridged ring heterocyclyl groups, where such spirocyclic, fused ring, and bridged ring heterocyclyl groups are optionally linked to other groups via single bonds or further tandemly linked to other cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups via any two or more atoms on the ring.

[0061] The term "spiroheterocyclyl group" refers to a 5- to 20-membered polycyclic heterocyclyl group in which the monocyclic rings share one atom (called a spiro atom), where one or more of the ring atoms is nitrogen, oxygen, P(O) pp Or S(O) mm(where pp, mm are integers from 0 to 2), and the other ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. It is preferably 6-14 membered, more preferably 7-10 membered. Depending on the number of shared spiro atoms between the rings, the spiroheterocyclyl group is divided into a monospiroheterocyclyl group, a bisspiroheterocyclyl group or a polyspiroheterocyclyl group, preferably a monospiroheterocyclyl group and a bisspiroheterocyclyl group. More preferably, it is a 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclyl group. Non-limiting examples of spiroheterocyclyl groups are: [ka] etc.

[0062] The term "fused heterocyclyl group" refers to a 5- to 20-membered polycyclic heterocyclyl group in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, one or more of the rings may contain one or more double bonds, but no ring has a completely conjugated pi-electron system, and wherein one or more of the ring atoms is nitrogen, oxygen, P(O) pp Or S(O) mm (wherein pp and mm are integers of 0 to 2), and the other ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of constituting rings, it may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl group, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl group. Non-limiting examples of fused heterocyclyl groups are: [ka] etc.

[0063] The term "bridged heterocyclyl group" refers to a 5-14 membered polycyclic heterocyclyl group in which any two rings share two atoms that are not directly linked, which may contain one or more double bonds, but in which no ring has a completely conjugated pi-electron system, and in which one or more of the ring atoms is not nitrogen, oxygen, P(O) pp Or S(O) mm (wherein pp and mm are integers of 0 to 2), and the other ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of rings constituting it, it may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclyl groups are: [ka] etc.

[0064] The ring of the heterocyclyl group may be fused onto the ring of an aryl group, a heteroaryl group, or a cycloalkyl group, where the ring connected to the base skeleton is a heterocyclyl group, non-limiting examples of which are: [ka] etc.

[0065] Heterocyclyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylate groups.

[0066] The term "aryl group" refers to a 6-14 membered all carbon monocyclic or fused polycyclic (i.e. rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6-12 membered, such as phenyl and naphthyl groups. More preferably, it is a phenyl group. The ring of the aryl group may be fused onto a ring of a heteroaryl group, a heterocyclyl group or a cycloalkyl group, including a 5-10 membered benzoheteroaryl group, a 3-8 membered benzocycloalkyl group and a 3-8 membered benzoheteroalkyl group, preferably a 5-6 membered benzoheteroaryl group, a 3-6 membered benzocycloalkyl group and a 3-6 membered benzoheteroalkyl group, where the heterocyclyl group is a heterocyclyl group containing 1-3 nitrogen atoms, oxygen atoms, sulfur atoms, or further containing a three membered nitrogen-containing fused ring containing a benzene ring.

[0067] Here, the ring connected to the basic skeleton is an aryl group ring, and non-limiting examples thereof include: [ka] etc.

[0068] The aryl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0069] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 12 membered, more preferably 8 to 11 membered, 5 or 6 membered, such as imidazolyl group, furyl group, thienyl group, thiazolyl group, pyrazolyl group, oxazolyl group, pyrrolyl group, triazolyl group, tetrazolyl group, pyridyl group, pyrimidinyl group, thiadiazole, pyridinyl group, etc., preferably triazolyl group, thienyl group, imidazolyl group, pyrazolyl group, oxazolyl group, pyrimidinyl group or thiazolyl group, more preferably pyrazolyl group, pyrrolyl group and oxazolyl group. The ring of the heteroaryl group may be condensed onto the ring of an aryl group, a heterocyclyl group, or a cycloalkyl group, where the ring connected to the base skeleton is the ring of the heteroaryl group, non-limiting examples of which are: [ka] etc.

[0070] Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0071] The term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), where the definition of alkyl group is as described above, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy groups. An alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0072] "Halogenated alkyl group" refers to an alkyl group that is substituted with one or more halogens, where the alkyl group is as defined above.

[0073] A "halogenated alkoxy group" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.

[0074] "Hydroxyalkyl group" refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.

[0075] The term "alkenyl group" refers to a chain-like alkenyl group, also called an olefin group, and is preferably an alkyl group containing 2 to 8 carbon atoms, more preferably an alkyl group containing 2 to 6 carbon atoms, and most preferably an alkyl group containing 2 to 3 carbon atoms. Here, the alkenyl group may be further substituted with other related groups, such as an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an alkylamino group, a halogen, a mercapto group, a hydroxy group, a nitro group, a cyano group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a cycloalkoxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, a carboxyl group, or a carboxylate group.

[0076] "Alkynyl group" refers to (CH≡C-), preferably an alkyl group containing 2 to 8 carbon atoms, more preferably an alkyl group containing 2 to 6 carbon atoms, and most preferably an alkyl group containing 2 to 3 carbon atoms, wherein the alkynyl group may be further substituted with other related groups, such as an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an alkylamino group, a halogen, a mercapto group, a hydroxy group, a nitro group, a cyano group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a cycloalkoxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, a carboxyl group, or a carboxylate group.

[0077] The term "alkenylcarbonyl group" refers to -C(O)-(alkenyl group), where the definition of alkenyl group is as set forth above. Non-limiting examples of alkenylcarbonyl groups include vinylcarbonyl, propenylcarbonyl, and butenylcarbonyl groups. An alkenylcarbonyl group may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0078] A "hydroxy group" refers to an -OH group.

[0079] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0080] An "amino group" refers to -NH2.

[0081] A "cyano group" refers to -CN.

[0082] A "nitro group" refers to --NO.sub.2.

[0083] A "carbonyl group" refers to -C(O)-.

[0084] A "carboxyl group" refers to -C(O)OH.

[0085] "THF" refers to tetrahydrofuran.

[0086] "EtOAc" refers to ethyl acetate.

[0087] "MeOH" refers to methanol.

[0088] "DMF" refers to N,N-dimethylformamide.

[0089] "DIPEA" refers to diisopropylethylamine.

[0090] "TFA" refers to trifluoroacetic acid.

[0091] "MeCN" refers to acetonitrile.

[0092] "DMA" refers to N,N-dimethylacetamide;

[0093] "Et2O" refers to ether.

[0094] "DCE" refers to 1,2 dichloroethane.

[0095] "DIPEA" refers to N,N-diisopropylethylamine.

[0096] "NBS" refers to N-bromosuccinimide.

[0097] "NIS" refers to N-iodosuccinimide.

[0098] "Cbz-Cl" refers to benzyl chloroformate;

[0099] "Pd2(dba)3" refers to tri(dibenzylideneacetone)dipalladium.

[0100] "Dppf" refers to 1,1'-bisdiphenylphosphinoferrocene.

[0101] "HATU" refers to O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0102] "KHMDS" refers to potassium hexamethyldisilazane.

[0103] "LiHMDS" refers to lithium bistrimethylsilylamide;

[0104] "MeLi" refers to methyllithium.

[0105] "n-BuLi" refers to n-butyllithium.

[0106] "NaBH(OAc)3" refers to sodium triacetoxyborohydride.

[0107] The various terms "X is selected from A, B, or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and the like all mean the same thing, i.e., X can be one or more of A, B, C.

[0108] Any hydrogen atom described in the present invention may be replaced with its isotope, deuterium, and any hydrogen atom in the compounds of the examples of the present invention may also be replaced with a deuterium atom.

[0109] "Optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and the description includes cases where the event or circumstance has occurred or not occurred. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that the alkyl group may, but need not, be present, and the description includes cases where the heterocyclyl group is substituted with an alkyl group and cases where the heterocyclyl group is not substituted with an alkyl group.

[0110] "Substituted" refers to the substitution of one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group, with the corresponding number of substituents, independently of each other. Needless to say, the substituents are only present in their possible chemical positions, and the skilled person can determine (experimentally or theoretically) possible or impossible substitutions without much effort. For example, amino or hydroxy groups with free hydrogen may be unstable if they are attached to carbon atoms with unsaturated (e.g., olefinic) bonds.

[0111] The "plurality" in "substituted by one or more of..." can mean 2, 3, 4, 5, 6, or more than 6.

[0112] In each part of the present invention, linking substituents are described.When the structure clearly requires a linking group, the Markush variable listed for the group should be understood to be the linking group.For example, when the structure requires a linking group and the Markush group definition for the variable lists "alkyl group" or "aryl group", the "alkyl group" or "aryl group" should be understood to represent the linking alkylene group or arylene group, respectively.

[0113] "Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is safe and effective when used in a mammalian body and possesses the desired biological activity. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0114] The present invention will now be further described in conjunction with the following examples, which are not intended to limit the scope of the present invention.

[0115] Working Example The structures of the compounds of the invention are established by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR assays were performed using a Bruker AVANCE-400 nuclear magnetometer, with deuterated dimethylsulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3) as solvents and tetramethylsilane (TMS) as internal standard.

[0116] The LC-MS assays were performed using an Agilent 1200 Infinity Series mass spectrometer. The HPLC assays were performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mm chromatography column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C 18 A 150 x 4.6 mm chromatography column is used.

[0117] Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate, TLC uses 0.15mm-0.20mm specifications, thin layer chromatography separation and purification of products uses 0.4mm-0.5mm specifications. Column chromatography generally uses Yantai Yellow Sea silica gel 200-300 mesh silica gel as the carrier.

[0118] The starting materials in the embodiments of the present invention are either known and commercially available, or can be synthesized using or according to methods known in the art.

[0119] Unless otherwise specified, all reactions of the present invention are carried out under a dry nitrogen or argon gas atmosphere with continuous magnetic stirring, the solvents are dry solvents, and the reaction temperatures are in degrees Celsius.

[0120] Intermediate 1 3-((Methylsulfonyl)methyl)azetidine [ka]

[0121] Step 1. Synthesis of tert-butyl 3-((methylthio)methyl)azetidine-1-carboxylate [ka]

[0122] tert-Butyl 3-(iodomethyl)azetidine-1-carboxylate (2 g, 6.73 mmol) and sodium methyl mercaptan (970 mg, 13.50 mmol) were dissolved in ACN (15 mL) and H2O (5 mL), and the temperature was raised to 60°C and reacted for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and separated by column chromatography to obtain the target compound tert-butyl 3-((methylthio)methyl)azetidine-1-carboxylate (1.30 g, 88.9%).

[0123] MS m / z(ESI):162.0[M+H-56] + .

[0124] Step 2. Synthesis of tert-butyl 3-((methylsulfonyl)methyl)azetidine-1-carboxylate [ka]

[0125] tert-Butyl 3-((methylthio)methyl)azetidine-1-carboxylate (1.30g, 5.99mmol) was dissolved in dichloromethane (15mL), metachloroperbenzoic acid (2g, 12mmol) was added, and the mixture was stirred overnight. The reaction solution was washed with saturated sodium thiosulfate solution and saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain the target compound tert-butyl 3-((methylsulfonyl)methyl)azetidine-1-carboxylate (1.30g, 87.1%).

[0126] MS m / z(ESI):194.0[M+H-56] + .

[0127] Step 3 Synthesis of 3-((methylsulfonyl)methyl)azetidine trifluoroacetate [ka]

[0128] tert-Butyl 3-((methylsulfonyl)methyl)azetidine-1-carboxylate (1.30 g, 5.22 mmol) was dissolved in dichloromethane (15 mL), TFA (3 mL) was added, and the mixture was stirred for 4 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product of the target compound, 3-((methylsulfonyl)methyl)azetidine trifluoroacetate (740 mg).

[0129] MS m / z(ESI): 150.0[M+H] + .

[0130] Intermediate 2 (2S,3R)-2-Methyl-3-((methylsulfonyl)methyl)azetidine [ka]

[0131] Step 1. Synthesis of (2S,3R)-1-diphenylmethyl-2-methylazetidin-3-yl methanesulfonate [ka]

[0132] (2S,3R)-1-diphenylmethyl-2-methylazetidin-3-ol (10g, 39.50mmol) was dissolved in dichloromethane (100mL), triethylamine (4.80g, 47.30mmol) was added, the reaction solution was cooled to 0°C, methylsulfonyl chloride (5g, 43.40mmol) was slowly added dropwise, the temperature was raised to room temperature, and the reaction was allowed to proceed overnight. The reaction was quenched by adding water, and the mixture was separated from water with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the target compound (2S,3R)-1-diphenylmethyl-2-methylazetidin-3-yl methanesulfonate crude product (13g).

[0133] MS m / z(ESI):332.2[M+H] + .

[0134] Step 2. Synthesis of methyl (R)-2-((2S,3R)-1-diphenylmethyl-2-methylazetidin-3-yl)-2-(methylsulfonyl)acetate [ka]

[0135] (2S,3R)-1-diphenylmethyl-2-methylazetidin-3-yl methanesulfonate (13g, 39.20mmol) and methyl 2-(methylsulfonyl)acetate (7.70g, 50.60mmol) were dissolved in DMF (100mL), sodium hydride (2.20g, 60% in mineral oil, 55.50mmol) was added little by little, and the mixture was reacted at room temperature for 15 minutes, then heated to 80°C and reacted overnight. The reaction solution was cooled to room temperature, quenched with saturated ammonium chloride solution, and separated into ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain the target compound methyl (R)-2-((2S,3R)-1-diphenylmethyl-2-methylazetidin-3-yl)-2-(methylsulfonyl)acetate (12g, 79.0%).

[0136] MS m / z(ESI):388.2[M+H] + .

[0137] Step 3. Synthesis of (2S,3R)-1-diphenylmethyl-2-methyl-3-((methylsulfonyl)methyl)azetidine [ka]

[0138] Methyl (R)-2-((2S,3R)-1-diphenylmethyl-2-methylazetidin-3-yl)-2-(methylsulfonyl)acetate (12g, 30.97mmol) was dissolved in DMA (120mL), lithium chloride (10.50g, 247.50mmol) was added, the mixture was heated to 150°C, and reacted for 2 hours. The mixture was cooled to room temperature, and ethyl acetate and water were separated. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain the target compound (2S,3R)-1-diphenylmethyl-2-methyl-3-((methylsulfonyl)methyl)azetidine (9.50g, 93.1%).

[0139] MS m / z(ESI):330.0[M+H] + .

[0140] Step 4. Synthesis of (2S,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidine [ka]

[0141] (2S,3R)-1-diphenylmethyl-2-methyl-3-((methylsulfonyl)methyl)azetidine (9.50g, 28.60mmol) was dissolved in methanol (120mL), TFA (5mL) and palladium hydroxide (2.80g) were added, the mixture was evacuated, hydrogen gas was introduced, and the operation was repeated three times, and the mixture was reacted overnight under a hydrogen gas atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (2S,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidine crude product (4.30g).

[0142] MS m / z(ESI):164.0[M+H] + .

[0143] Intermediate 3 (3S,4R)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol [ka]

[0144] Step 1. Synthesis of tert-butyl 5-methyl-4-((trimethylsilyl)oxo)-3,6-dihydropyridine-1(2H)-carboxylate [ka]

[0145] tert-Butyl 3-methyl-4-carbonylpiperidine-1-carboxylate (10g, 46.90mmol) was dissolved in toluene (100mL), TEA (11.90g, 117.30mmol) was added, the reaction solution was cooled to 0°C, TMSOTf (12.50g, 56.30mmol) was slowly added dropwise, and the mixture was reacted at 0°C for 6 hours. Ethyl acetate and water were separated, the organic phase was dried over anhydrous sodium sulfate, and the target compound tert-butyl 5-methyl-4-((trimethylsilyl)oxo)-3,6-dihydropyridine-1(2H)-carboxylate crude product (10.70g) was obtained after concentration under reduced pressure.

[0146] Step 2 Synthesis of tert-butyl 3-fluoro-3-methyl-4-carbonylpiperidine-1-carboxylate [ka]

[0147] Tert-butyl 5-methyl-4-((trimethylsilyl)oxo)-3,6-dihydropyridine-1(2H)-carboxylate (10.70 g, 37.50 mmol) was dissolved in acetonitrile (100 mL), the reaction solution was cooled to 0 ° C., selectFluor (14.60 g, 41.30 mmol) was slowly added, and the mixture was reacted at 0 ° C. for 2 hours. Ethyl acetate and water were separated, and the organic phase was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the target compound tert-butyl 3-fluoro-3-methyl-4-carbonylpiperidine-1-carboxylate crude product (7.50 g) was obtained.

[0148] Step 3 Synthesis of tert-butyl 3-fluoro-4-hydroxy-3-methylpiperidine-1-carboxylate [ka]

[0149] tert-Butyl 3-fluoro-3-methyl-4-carbonylpiperidine-1-carboxylate (7.50 g, 32.40 mmol) was dissolved in methanol (75 mL), the reaction solution was cooled to 0°C, NaBH4 (1.50 g, 38.90 mmol) was slowly added, the temperature was raised to room temperature, and the reaction was allowed to proceed for 4 hours. Ethyl acetate and water were separated, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain the target compound tert-butyl 3-fluoro-4-hydroxy-3-methylpiperidine-1-carboxylate (6.80 g, 90.0%).

[0150] MS m / z(ESI):178.0[M+H-56] + .

[0151] Step 4 Synthesis of 3-fluoro-3-methylpiperidin-4-ol [ka]

[0152] tert-Butyl 3-fluoro-4-hydroxy-3-methylpiperidine-1-carboxylate (6.80 g, 29.20 mmol) was dissolved in dioxane (70 mL), and a solution of 4 M hydrochloric acid in dioxane (10 mL) was added and reacted for 4 hours. The reaction solution was concentrated under reduced pressure to obtain the target product 3-fluoro-3-methylpiperidin-4-ol crude product (4.60 g).

[0153] MS m / z(ESI):134.0[M+H] + .

[0154] Step 5 Synthesis of 1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol [ka]

[0155] 4-Chloro-1,3,5-triazin-2-amine (4g, 30.80mmol) and 3-fluoro-3-methylpiperidin-4-ol hydrochloride (5.70g, 33.60mmol) were dissolved in isopropyl alcohol (100mL), triethylamine (9.30g, 92.40mmol) was added, the temperature was raised to 130°C, sealed and reacted for 6 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain the target compound 1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (6g, 85.7%).

[0156] MS m / z(ESI):228.0[M+H] + .

[0157] Step 6. Preparation of (3S,4R)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol [ka]

[0158] The purified product 1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol was purified by reverse phase column to obtain two components, which were then concentrated and lyophilized to obtain cis racemate (3S,4R)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (2.20g) and trans racemate (3R,4R)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (1.40g).

[0159] The cis racemate (3S,4R)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (2.20 g) obtained by reverse phase purification was subjected to chiral resolution to obtain (3S,4R)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (850 mg) and (3R,4S)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (760 mg).

[0160] MS m / z(ESI):228.0[M+H] + .

[0161] Intermediate 4 (2R,3S)-2-Methyl-3-((methylsulfonyl)methyl)azetidine [ka]

[0162] Step 1. Synthesis of (2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl methanesulfonate [ka]

[0163] (2R,3S)-1-diphenylmethyl-2-methylazetidin-3-ol (10g, 39.50mmol) was dissolved in dichloromethane (100mL), triethylamine (4.80g, 47.30mmol) was added, the reaction solution was cooled to 0°C, methylsulfonyl chloride (5g, 43.40mmol) was slowly added dropwise, and the reaction was allowed to proceed at room temperature overnight. The reaction was quenched by adding water, and the mixture was separated with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the target compound (2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl methanesulfonate crude product (12.80g).

[0164] MS m / z(ESI):332.2[M+H] + .

[0165] Step 2. Synthesis of methyl (S)-2-((2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl)-2-(methylsulfonyl)acetate [ka]

[0166] (2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl methanesulfonate (12.80g, 38.62mmol) and methyl 2-(methylsulfonyl)acetate (7.70g, 50.60mmol) were dissolved in DMF (100mL), sodium hydride (2.20g, 60% in mineral oil, 55.50mmol) was added little by little, and the mixture was reacted at room temperature for 15 minutes, then heated to 80°C and reacted overnight. The reaction solution was cooled to room temperature, quenched with saturated ammonium chloride solution, and separated into ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target compound methyl (S)-2-((2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl)-2-(methylsulfonyl)acetate (11.60g, 77.5%).

[0167] MS m / z(ESI):388.2[M+H] + .

[0168] Step 3. Synthesis of (2R,3S)-1-diphenylmethyl-2-methyl-3-((methylsulfonyl)methyl)azetidine [ka]

[0169] Methyl (S)-2-((2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl)-2-(methylsulfonyl)acetate (11.60g, 29.94mmol) was dissolved in DMA (120mL), lithium chloride (10.50g, 247.50mmol) was added, the mixture was heated to 150°C, and reacted for 2 hours. The mixture was cooled to room temperature, and ethyl acetate and water were separated. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain the target compound (2R,3S)-1-diphenylmethyl-2-methyl-3-((methylsulfonyl)methyl)azetidine (9.20g, 93.3%).

[0170] MS m / z(ESI):330.0[M+H] + .

[0171] Step 4. Synthesis of (2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine [ka]

[0172] (2R,3S)-1-diphenylmethyl-2-methyl-3-((methylsulfonyl)methyl)azetidine (9.20g, 27.92mmol) was dissolved in methanol (120mL), TFA (5mL) and palladium hydroxide (2.80g) were added, the mixture was evacuated, hydrogen gas was introduced, and the operation was repeated three times, and the mixture was reacted overnight under a hydrogen gas atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine crude product (4g).

[0173] MS m / z(ESI):164.0[M+H] + .

[0174] Intermediate 5 8-Bromo-3-chloro-6-fluoro-5-isopropylisoquinoline [ka]

[0175] Step 1 Synthesis of 3-chloro-6-fluoroisoquinoline [ka]

[0176] 1,3-Dichloro-6-fluoroisoquinoline (7.50g, 34.72mmol) was dissolved in glacial acetic acid (40mL) and hydroiodic acid (20mL, 45% aqueous solution), heated to 100°C, and reacted for 4 hours. The reaction solution was cooled to room temperature, concentrated, diluted with dichloromethane (100mL), washed with saturated aqueous sodium carbonate solution, the organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure and separated by column chromatography to obtain the target compound 3-chloro-6-fluoroisoquinoline (4.90g, 77.8%).

[0177] MS m / z(ESI):182.0[M+H] + .

[0178] Step 2 Synthesis of 5-bromo-3-chloro-6-fluoroisoquinoline [ka]

[0179] 3-Chloro-6-fluoroisoquinoline (3.20g, 17.62mmol) was dissolved in concentrated sulfuric acid (20mL), NBS (3.45g, 19.38mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was slowly added to ice water, and the mixture was separated from water with ethyl acetate. The organic phase was separated and dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure after filtration. The target compound 5-bromo-3-chloro-6-fluoroisoquinoline (4.0g, 87.1%) was obtained by separation using column chromatography.

[0180] MS m / z(ESI):260.0[M+H] + .

[0181] Step 3 Synthesis of 3-chloro-6-fluoro-5-(prop-1-en-2-yl)isoquinoline [ka]

[0182] 5-Bromo-3-chloro-6-fluoroisoquinoline (4.0g, 15.36mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (2.71g, 16.13mmol) were dissolved in 1,4-dioxane (20mL) and water (3mL), 1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (562mg, 0.77mmol) and cesium carbonate (10.01g, 30.71mmol) were added, the temperature was raised to 80°C, and the reaction was carried out for 2 hours. The reaction solution was cooled to room temperature, and the reaction solution was concentrated under reduced pressure and then separated by column chromatography to obtain the target compound 3-chloro-6-fluoro-5-(prop-1-en-2-yl)isoquinoline (3.0g, 88.1%).

[0183] MS m / z(ESI):222.0[M+H] + Step 4 Synthesis of 3-chloro-6-fluoro-5-isopropylisoquinoline [ka]

[0184] 3-Chloro-6-fluoro-5-(prop-1-en-2-yl)isoquinoline (3.0 g, 13.53 mmol) was dissolved in ethyl acetate (20 mL), platinum dioxide (615 mg, 2.71 mmol) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and then separated by column chromatography to obtain the target compound 3-chloro-6-fluoro-5-isopropylisoquinoline (2.10 g, 69.4%).

[0185] MS m / z(ESI):224.1[M+H]+ .

[0186] Step 5 Synthesis of 8-bromo-3-chloro-6-fluoro-5-isopropylisoquinoline [ka]

[0187] In an ice bath, dibromohydantoin (1.12 g, 3.93 mmol) was slowly added little by little to a solution of 3-chloro-6-fluoro-5-isopropylisoquinoline (800 mg, 3.58 mmol) in concentrated sulfuric acid (5 mL), and the mixture was stirred for 0.5 hours in an ice bath. The reaction solution was carefully added to ice water, separated from water with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure after filtration, and separated by column chromatography to obtain the target compound 8-bromo-3-chloro-6-fluoro-5-isopropylisoquinoline (320 mg, 29.6%).

[0188] MS m / z(ESI):302.0[M+H] + .

[0189] Reference Example 1 (3S,4R)-3-Fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol [ka]

[0190] Step 1 Synthesis of 8-bromo-3-chloroisoquinolin-5-yl trifluoromethanesulfonic acid [ka]

[0191] 8-Bromo-3-chloroisoquinolin-5-ol (5g, 19.50mmol) was dissolved in dichloromethane (50mL), TEA (7.90g, 78mmol) was added, the reaction solution was cooled to -60℃, (TfO)2O (16.50g, 58.50mmol) was slowly added dropwise, the temperature was raised to room temperature, and the reaction was carried out for 4 hours. The reaction solution was concentrated under reduced pressure and then separated by column chromatography to obtain the target compound 8-bromo-3-chloroisoquinolin-5-yl trifluoromethanesulfonic acid (6.50g, 85.3%).

[0192] MS m / z(ESI):390.0[M+H] + .

[0193] Step 2 Synthesis of 8-bromo-3-chloro-5-(prop-1-en-2-yl)isoquinoline [ka]

[0194] 8-Bromo-3-chloroisoquinolin-5-yl trifluoromethanesulfonic acid (6.50 g, 16.64 mmol) was dissolved in dioxane (60 mL) and H2O (6 mL), and isopropenylboronic acid pinacol ester (4.20 g, 25 mmol), potassium carbonate (4.60 g, 33.40 mmol), and PdCl2(dppf) (610 mg, 0.84 mmol) were added, and the mixture was heated to 100 ° C. and reacted for 4 hours. The reaction solution was cooled to room temperature, concentrated, and separated from water with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then separated by column chromatography to obtain the target compound 8-bromo-3-chloro-5-(prop-1-en-2-yl)isoquinoline (2.90 g, 61.7%).

[0195] MS m / z(ESI):282.0[M+H] + .

[0196] Step 3 Synthesis of 8-bromo-3-chloro-5-isopropylisoquinoline [ka]

[0197] 8-Bromo-3-chloro-5-(prop-1-en-2-yl)isoquinoline (2.90 g, 10.26 mmol) was dissolved in ethyl acetate (100 mL), PtO2 (700 mg, 3.10 mmol) was added, the mixture was evacuated, hydrogen gas was added, and the operation was repeated three times, and the mixture was stirred for 12 hours under a hydrogen gas atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and then separated by column chromatography to obtain the target compound 8-bromo-3-chloro-5-isopropylisoquinoline (2.70 g, 92.5%).

[0198] MS m / z(ESI):284.0[M+H] + .

[0199] Step 4 Synthesis of 3-chloro-5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline [ka]

[0200] 8-Bromo-3-chloro-5-isopropylisoquinoline (500mg, 1.76mmol) and 3-((methylsulfonyl)methyl)azetidine trifluoroacetate (435mg, 1.77mmol) were dissolved in dioxane (10mL), cesium carbonate (1.15g, 3.54mmol) and Xantphos Pd G4 (164mg, 0.17mmol) were added, the temperature was raised to 100°C, and the mixture was stirred for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and separated from water with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain the target compound 3-chloro-5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline (286mg, 46.0%).

[0201] MS m / z(ESI):353.0[M+H]+ .

[0202] Step 5. Synthesis of (3S,4R)-3-fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol [ka]

[0203] 3-Chloro-5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline (100 mg, 0.28 mmol) and (3S, 4R)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (64 mg, 0.28 mmol) were dissolved in dioxane (5 mL), and cesium carbonate (274 mg, 0.84 mmol) and BrettPhos Pd G3 (24 mg, 27 μmol) were added, and the temperature was raised to 100 ° C. and stirred for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and separated from water with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then separated by column chromatography to obtain the target compound (3S,4R)-3-fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (23 mg, 15.1%).

[0204] 1H NMR(400MHz,DMSO-d6)δ 9.93(s,1H),9.08(s,1H),8.33(s,1H),7.44(d,J=8.0Hz,1H),6.45(d,J=8.1Hz,1H),5.47(s,1H),4.40(t,J=7.7Hz,2H),4.25(s,1 H),3.97(t,J=6.9Hz,2H),3.76(s,2H),3.69(s,1H),3.59(d,J=7.4Hz,3H),3.01(d,J=4.8Hz,3H),1.35(s,2H),1.33-1.27(m,12H); MS m / z(ESI):544.2[M+H] + .

[0205] Example 1 N-(2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0206] See Example 1 for the preparation of N-(2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine.

[0207] Or synthesize it by following these steps: Step 1 Synthesis of 1-(cyclopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka]

[0208] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.02 g, 5.26 mmol) was dissolved in DMF (15 mL), cooled to 0 ° C., NaH (60%, 0.32 g, 8 mmol) and cyclopropanesulfonyl chloride (0.8 g, 5.78 mmol) were added, and the mixture was reacted at room temperature for 5 hours. The mixture was separated from the saturated sodium chloride solution with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure, and then separated by column chromatography to obtain the target compound 1-(cyclopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (787.4 mg, 50.2%).

[0209] MS m / z(ESI):299.1[M+H] + .

[0210] Step 2 Synthesis of 2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-amine [ka]

[0211] 2-Chloropyrimidin-4-amine (323 mg, 2.49 mmol), 1-(cyclopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (787.4 mg, 2.64 mmol) and potassium carbonate (691 mg, 5 mmol) were mixed with dioxane (5 mL) and water (1 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (247.4 mg, 0.3 mmol) was added, the temperature was raised to 100°C, and the mixture was stirred for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and separated from water with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure, followed by separation by column chromatography to obtain the target compound, 2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (500 mg, 75.7%).

[0212] MS m / z(ESI):266.1[M+H] + .

[0213] Step 3. Synthesis of N-(2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0214] 3-Chloro-5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline (100 mg, 0.28 mmol) and 2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (74.3 mg, 0.28 mmol) were dissolved in dioxane (5 mL), and cesium carbonate (274 mg, 0.84 mmol) and BrettPhos Pd G3 (24 mg, 27 μmol) were added, and the mixture was heated to 105° C. and stirred for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and separated from water with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then separated by column chromatography to obtain the target compound N-(2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine (31.2 mg, 19.2%).

[0215] 1H NMR(400MHz,DMSO-d6)δ 10.37(s,1H),9.10(s,1H),8.80-8.74(m,1H),8.69(s,1H),8.51(s,1H),8 .43(d,J=5.9Hz,1H),7.45(d,J=8.0Hz,1H),7.29-7.20(m,1H),6.45(d,J=8 .0Hz,1H),4.41(t,J=7.6Hz,2H),3.98(t,J=6.9Hz,2H),3.60(d,J=7.4Hz, 3H),3.30-3.25(m,2H),3.02(s,3H),1.39-1.34(m,8H),1.29-1.26(m,2H); MS m / z(ESI):582.2[M+H] + .

[0216] Example 2 N-(2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2S,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0217] For the preparation of N-(2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2S,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, see Reference Example 1 or Example 1.

[0218] MS m / z(ESI):596.2[M+H] + .

[0219] Example 3 Preparation of N-(2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)-2,7-naphthyridin-3-amine [ka]

[0220] For the preparation of N-(2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)-2,7-naphthyridin-3-amine, see Reference Example 1 or Example 1.

[0221] 1 H NMR(400MHz,DMSO-d6)δ 10.56(s,1H),9.08(s,1H),8.70(s,1H),8.69-8.63(m,1H),8.52-8.47(m,2H),8.01(s,1H),4.62-4.55(m,2H),4.27-4.2 1(m2H),3.60(d,J=7.5Hz,2H),3.44-3.39(m,1H),3.31-3.27(m,2H),3.01(s,3H),1.41-1.34(m,8H),1.30-1.25(m,2H); MS m / z(ESI):583.1[M+H] + .

[0222] Example 4 Preparation of N-(2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2S,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-2,7-naphthyridin-3-amine [ka]

[0223] For the preparation of N-(2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2S,3R)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-2,7-naphthyridin-3-amine, see Reference Example 1 or Example 1.

[0224] MS m / z(ESI):597.1[M+H] + .

[0225] Example 5 Preparation of N-(2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0226] For the preparation of N-(2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, see Reference Example 1 or Example 1.

[0227] MS m / z(ESI):596.1[M+H] + .

[0228] Example 6 Preparation of N-(2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-2,7-naphthyridin-3-amine [ka]

[0229] For the preparation of N-(2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-2,7-naphthyridin-3-amine, see Reference Example 1 or Example 1.

[0230] MS m / z(ESI):597.1[M+H] + .

[0231] Example 7 Preparation of N-(2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)-2,6-naphthyridin-3-amine [ka]

[0232] For the preparation of N-(2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)-2,6-naphthyridin-3-amine, see Reference Example 1 or Example 1.

[0233] MS m / z(ESI):583.1[M+H] + .

[0234] Example 8 Preparation of N-(2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-2,6-naphthyridin-3-amine [ka]

[0235] For the preparation of N-(2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-2,6-naphthyridin-3-amine, see Reference Example 1 or Example 1.

[0236] MS m / z(ESI):597.1[M+H] + .

[0237] Example 9 Preparation of cyclopropyl(4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)methanone [ka]

[0238] For the preparation of cyclopropyl(4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)methanone, see Reference Example 1.

[0239] MS m / z(ESI):560.1[M+H] + .

[0240] Example 10 Preparation of N-(2-(3-chloro-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0241] Step 1. Synthesis of 4-bromo-3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole [ka]

[0242] 4-Bromo-3-chloro-1H-pyrazole (1.09 g, 6 mmol) and potassium carbonate (2.49 g, 18 mmol) were mixed with acetonitrile (20 mL), 2-(trimethylsilyl)ethoxymethyl chloride (1.50 g, 9 mmol) was added dropwise, and the mixture was reacted at room temperature for 3 hours. The reaction solution was diluted with dichloromethane and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent, and the residue was separated by silica gel column chromatography to obtain the title compound 4-bromo-3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.59 g, 85.0%).

[0243] MS m / z(ESI):311.0[M+H] + .

[0244] Step 2. Synthesis of 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole [ka]

[0245] 4-Bromo-3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.59 g, 5.1 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.59 g, 10.2 mmol) were dissolved in dioxane (30 mL), potassium phosphate (3.18 g, 15 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (412.4 mg, 0.5 mmol) were added, and the mixture was heated to 95° C. and stirred for 12 hours. The mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, dichloromethane was added and the mixture was separated from water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the title compound 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.22 g, 66.7%).

[0246] MS m / z(ESI):359.2[M+H] + .

[0247] Step 3: Synthesis of 2-(3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-amine [ka]

[0248] 2-Chloropyrimidin-4-amine (388.6 mg, 3 mmol), 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.22 g, 3.4 mmol) and potassium carbonate (1.38 g, 10 mmol) were added to a mixed solvent of dioxane (10 mL) and water (2 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (247.4 mg, 0.3 mmol) was added, and the reaction solution was heated to 100°C and stirred for 12 hours. Cool to room temperature, concentrate under reduced pressure to remove the solvent, and separate the residue by silica gel column chromatography to obtain the title compound 2-(3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (490 mg, 50.1%).

[0249] MS m / z(ESI):326.1[M+H] + .

[0250] Step 4. Synthesis of N-(2-(3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0251] 3-Chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline (100mg, 0.27mmol) and 2-(3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (88mg, 0.27mmol) were dissolved in dioxane (3mL), cesium carbonate (274mg, 0.84mmol) and BrettPhos Pd G3 (24mg, 27μmol) were added, and the temperature was raised to 105℃ and stirred for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and separated from water with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure, followed by separation by column chromatography to obtain the target compound N-(2-(3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine (81 mg, 45.7%).

[0252] MS m / z(ESI):656.3[M+H] + .

[0253] Step 5. Synthesis of N-(2-(3-chloro-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0254] N-(2-(3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine (81 mg, 0.12 mmol) was dissolved in THF (2 mL), 1 M TBAF solution (2 mL, 2 mmol) was added, the temperature was raised to reflux, and the mixture was stirred for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and separated from water with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure, followed by separation by column chromatography to obtain the target compound N-(2-(3-chloro-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine (31 mg, 49.1%).

[0255] 1 H NMR (400MHz, DMSO-d6) δ 13.50(s,1H),10.22(s,1H),9.09(s,1H),8.68(s,1H),8.41(d,J=6.0Hz,1H), 8.35(s,1H),7.44(d,J=8.0Hz,1H),7.25-7.18(m,1H),6.58(d,J=8.2Hz,1H),4 .68(t,J=7.6Hz,1H),4.25-4.15(m,1H),3.65(t,J=7.1Hz,1H),3.61-3.49(m, 3H),3.00(s,3H),2.95-2.84(m,1H),1.43(d,J=6.0Hz,3H),1.36-1.26(m,6H); MS m / z(ESI):526.2[M+H] + .

[0256] Example 11 Preparation of 2-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)ethanol [ka]

[0257] N-(2-(3-chloro-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine (57.9 mg, 0.11 mmol) was dissolved in DMF (2 mL), cesium carbonate (107.5 mg, 0.33 mmol) was added, the temperature was raised to 40° C., and the reaction was carried out for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and separated from water with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure, followed by separation by column chromatography to obtain the target compound, 2-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)ethanol (21.1 mg, 33.6%).

[0258] 1 H NMR(400MHz,DMSO-d6)δ 10.19(s,1H),9.10(s,1H),8.53(s,1H),8.41(d,J=6.0Hz,1H),8.32(s,1H),7.43( d,J=7.8Hz,1H),7.32-7.25(m,1H),6.58(d,J=8.0Hz,1H),5.03(t,J=5.2Hz,1H),4. 72-4.64(m,1H),4.24-4.15(m,3H),3.82-3.75(m,2H),3.68-3.63(m,1H),3.60-3.5 1(m,3H),3.00(s,3H),2.96-2.86(m,1H),1.43(d,J=6.0Hz,3H),1.35-1.27(m,6H); MS m / z(ESI):570.2[M+H] + .

[0259] Example 12 Preparation of N-(2-(1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0260] See Example 11 for the preparation of N-(2-(1-(2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine.

[0261] 1 H NMR(400MHz,DMSO-d6)δ 10.27(s,1H),9.10(s,1H),8.81(s,1H),8.45(s,1H),8.37(d,J=5.8Hz,1H),8.16(s ,1H),7.46(d,J=7.9Hz,1H),7.13(d,J=5.2Hz,1H),6.59(d,J=8.1Hz,1H),4.68(t,J =7.4Hz,2H),4.21(t,J=6.3Hz,1H),3.68-3.49(m,4H),3.00(s,3H),2.93-2.86(m,1 H),2.63-2.55(m,1H),2.43-2.35(m,1H),1.43(d,J=6.0Hz,3H),1.40-1.33(m,6H); MS m / z(ESI):568.2[M+H] + .

[0262] Example 13 1-(4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)cyclopropane-1-carbonitrile [ka] See Example 11 for the preparation of 1-(4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)cyclopropane-1-carbonitrile.

[0263] 1 H NMR(400MHz,DMSO-d6)δ 10.25(s,1H),9.10(s,1H),8.77(s,1H),8.49(s,1H),8.36(d,J=5.9Hz,1H),8.11(s,1H),7.4 6(d,J=8.0Hz,1H),7.14(d,J=5.8Hz,1H),6.59(d,J=8.1Hz,1H),4.72-4.63(m,2H),4.21(t,J= 6.2Hz,1H),3.68-3.50(m,4H),3.00(s,3H),2.92-2.85(m,1H),2.56-2.52(m,1H),2.09-2.02 (m,1H),1.87-1.80(m,1H),1.43(d,J=6.0Hz,3H),1.40-1.34(m,6H);MSm / z(ESI):557.2[M+H] + .

[0264] Example 14 5-Isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)isoquinolin-3-amine [ka]

[0265] See Example 11 for the preparation of 5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)isoquinolin-3-amine.

[0266] 1 H NMR (400MHz, DMSO-d6) δ 10.13(s,1H),9.03(s,1H),8.70(brs,1H),8.30-8.25(m,2H),8.03(s,1H), 7.39(d,J=8.0Hz,1H),7.06-7.03(m,1H),6.52(d,J=8.0Hz,1H),4.63-4.60( m,1H),4.14-4.11(m,2H),3.60-3.45(m,4H),2.93(s,3H),2.85-2.81(m,3H ),2.15(s,3H),1.99-1.92(m,6H),1.36(d,J=6.0Hz,3H),1.31-1.27(m,6H); MS m / z(ESI):589.3[M+H] + .

[0267] Example 15 N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0268] Step 1. Synthesis of 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline [ka]

[0269] 8-Bromo-3-chloro-5-isopropylisoquinoline (500 mg, 1.76 mmol) and (2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine (462 mg, 2.83 mmol) were dissolved in dioxane (10 mL), and cesium carbonate (1.15 g, 3.54 mmol) and Xantphos Pd G4 (164 mg, 0.17 mmol) were added, and the mixture was heated to 100° C. and stirred for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and separated from water with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure, followed by separation by column chromatography to obtain the target compound, 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline (318 mg, 49.2%).

[0270] MS m / z(ESI):367.1[M+H] + .

[0271] Step 2 Synthesis of 2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-amine [ka]

[0272] 2-Chloropyrimidin-4-amine (1.29 g, 10 mmol), 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.58 g, 11 mmol) and potassium carbonate (3.46 g, 25 mmol) were mixed in dioxane (20 mL) and water (2 mL), bistriphenylphosphine palladium dichloride (702 mg, 1 mmol) was added, the mixture was heated to 100 ° C., and stirred for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and separated from water with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure, followed by separation by column chromatography to obtain the target compound 2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-amine (1.05 g, 52.2%).

[0273] MS m / z(ESI):202.1[M+H] + .

[0274] Step 3. Synthesis of N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0275] 3-Chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline (100mg, 0.27mmol) and 2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-amine (54mg, 0.27mmol) were dissolved in dioxane (5mL), cesium carbonate (274mg, 0.84mmol) and BrettPhos Pd G3 (24mg, 27μmol) were added, and the mixture was heated to 100℃ and stirred for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and separated from water with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure, followed by separation by column chromatography to obtain the target compound N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine (31 mg, 21.6%).

[0276] 1H NMR(400MHz,DMSO-d6)δ 10.22(s,1H),9.09(s,1H),8.82(s,1H),8.36-8.32(m,2H),8.05(s,1H),7.46(d,J=7 .9Hz,1H),7.15-7.05(m,1H),6.59(d,J=8.1Hz,1H),4.68(t,J=7.5Hz,1H),4.25-4.1 6(m,1H),3.87-3.80(m,1H),3.68-3.51(m,4H),3.00(s,3H),2.95-2.85(m,1H),1.43 (d,J=6.0Hz,3H),1.38(dd,J=6.8,3.9Hz,6H),1.17-1.11(m,2H),1.06-1.00(m,2H); MS m / z(ESI):532.2[M+H] + .

[0277] Example 16 5-Isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)isoquinolin-3-amine [ka]

[0278] For the preparation of 5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)isoquinolin-3-amine, see Example 15 or 11.

[0279] MS m / z(ESI):576.2[M+H] + .

[0280] Example 17 N-(2-(1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0281] For the preparation of N-(2-(1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, see Example 15 or 10.

[0282] MS m / z(ESI):492.2[M+H] + .

[0283] Example 18 2-(1-((4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)methyl)cyclopropyl)acetonitrile [ka]

[0284] For the preparation of 2-(1-((4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)methyl)cyclopropyl)acetonitrile, see Example 15 or 11.

[0285] MS m / z(ESI):585.2[M+H] + .

[0286] Example 19 1-((4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)methyl)cyclopropane-1-carbonitrile [ka]

[0287] For the preparation of 1-((4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)methyl)cyclopropane-1-carbonitrile, see Example 15 or 11.

[0288] MS m / z(ESI):571.2[M+H] + .

[0289] Example 20 5-Isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)isoquinolin-3-amine [ka]

[0290] For the preparation of 5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)isoquinolin-3-amine, see Example 15 or 11.

[0291] MS m / z(ESI):548.2[M+H] + .

[0292] Example 21 5-Isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(1-(oxetan-2-ylmethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)isoquinolin-3-amine [ka]

[0293] For the preparation of 5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(1-(oxetan-2-ylmethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)isoquinolin-3-amine, see Example 15 or 11.

[0294] 1 H NMR(400MHz,DMSO-d6)δ 10.23(s,1H),9.09(s,1H),8.78(s,1H),8.38-8.28(m,2H),8.12(s,1H),7.45(d,J=8.0Hz,1 H),7.13(d,J=5.4Hz,1H),6.58(d,J=8.1Hz,1H),5.11-5.02(m,1H),4.68(t,J=7.5Hz,1H),4. 53-4.39(m,3H),4.34-4.25(m,1H),4.23-4.16(m,1H),3.67-3.49(m,4H),3.00(s,3H),2.92- 2.86(m,1H),2.72-2.64(m,1H),2.47-2.40(m,1H),1.43(d,J=6.0Hz,3H),1.39-1.33(m,6H); MS m / z(ESI):562.2[M+H] + .

[0295] Example 22A 5-Isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(1-((S)-1,1,1-trifluoropropan-2-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)isoquinolin-3-amine [ka]

[0296] For the preparation of 5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(1-((S)-1,1,1-trifluoropropan-2-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)isoquinolin-3-amine, see Example 15 or 11.

[0297] MS m / z(ESI):588.2[M+H] + .

[0298] Example 22 5-Isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(1-((S)-1,1,1-trifluoropropan-2-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)isoquinolin-3-amine [ka]

[0299] For the preparation of 5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(1-((S)-1,1,1-trifluoropropan-2-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)isoquinolin-3-amine, see Example 15 or 11.

[0300] 1H NMR(400MHz,DMSO-d6)δ 10.26(s,1H),9.11(s,1H),8.69(s,1H),8.49(s,1H),8.38(d,J=5.9Hz,1H),8.20(s ,1H),7.45(d,J=8.0Hz,1H),7.21(d,J=5.8Hz,1H),6.59(d,J=8.1Hz,1H),5.53(p,J =7.2Hz,1H),4.69(t,J=7.5Hz,1H),4.21(p,J=6.1Hz,1H),3.70-3.47(m,4H),3.00( s,3H),2.94-2.86(m,1H),1.76(d,J=7.0Hz,3H),1.44(d,J=6.0Hz,3H),1.35(m,6H); MS m / z(ESI):588.2[M+H] + .

[0301] Example 23 5-Isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(1-((R)-1,1,1-trifluoropropan-2-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)isoquinolin-3-amine [ka]

[0302] For the preparation of 5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(1-((R)-1,1,1-trifluoropropan-2-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)isoquinolin-3-amine, see Example 15 or 11.

[0303] 1H NMR(400MHz,DMSO-d6)δ 10.26(s,1H),9.11(s,1H),8.69(s,1H),8.49(s,1H),8.38(d,J=5.9Hz,1H),8.20(s ,1H),7.45(d,J=8.0Hz,1H),7.21(d,J=5.8Hz,1H),6.59(d,J=8.1Hz,1H),5.53(p,J =7.2Hz,1H),4.69(t,J=7.5Hz,1H),4.21(p,J=6.1Hz,1H),3.70-3.47(m,4H),3.00( s,3H),2.94-2.86(m,1H),1.76(d,J=7.0Hz,3H),1.44(d,J=6.0Hz,3H),1.35(m,6H); MS m / z(ESI):588.2[M+H] + .

[0304] Example 24 5-Isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0305] See Example 15 for the preparation of 5-isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine.

[0306] 1H NMR (400MHz, DMSO-d6) δ 10.21(s,1H),9.10(s,1H),8.82(s,1H),8.34(d,J=5.9Hz,1H),8.28(s,1H) ,8.07(s,1H),7.46(d,J=8.0Hz,1H),7.10(d,J=5.8Hz,1H),6.59(d,J=8.0Hz ,1H),4.68(t,J=7.5Hz,1H),4.34-4.18(m,1H),3.94(s,3H),3.70-3.44(m, 4H),3.00(s,3H),2.90(q,J=7.3Hz,1H),1.43(d,J=6.0Hz,3H),1.37(m,6H); MS m / z(ESI):506.2[M+H] + .

[0307] Example 25 N-(2-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0308] For the preparation of N-(2-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, see Example 15 or 11.

[0309] 1H NMR (400MHz, DMSO-d6) δ 10.35(s,1H),9.11(s,1H),8.79(brs,1H),8.73(s,1H),8.42(d,J=8.0Hz,1H) ,8.36(s,1H),7.94(t,J=60Hz,1H),7.46(d,J=8.0Hz,1H),7.21(s,1H),6.60(d ,J=8.0Hz,1H),4.69(t,J=7.6Hz,1H),4.21(t,J=7.6Hz,1H),3.69-3.40(m,4H) ,3.00(s,3H),2.92-2.87(m,1H),1.44(d,J=8.0Hz,3H),1.35(d,J=8.0Hz,6H); MS m / z(ESI):542.2[M+H] + .

[0310] Example 26 5-Isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)isoquinolin-3-amine [ka]

[0311] For the preparation of 5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)isoquinolin-3-amine, see Example 15 or 11.

[0312] 1H NMR(400MHz,DMSO-d6)δ 10.26(s,1H),9.10(s,1H),8.70(brs,1H),8.44(s,1H),8.37(d,J=7.2 Hz,1H),8.20(s,1H),7.46(d,J=8.0Hz,1H),7.20(s,1H),6.60(d,J=8.0 Hz,1H),5.32-5.25(m,2H),4.68(t,J=7.6Hz,1H),4.21(t,J=7.6Hz,1H) ,3.68-3.34(m,4H),3.00(s,3H),2.92-2.87(m,1H),1.44-1.31(m,9H); MS m / z(ESI):574.2[M+H] + .

[0313] Example 27 N-(2-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0314] For the preparation of N-(2-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, see Example 15 or 11.

[0315] 1H NMR(400MHz,DMSO-d6)δ 10.26(s,1H),9.10(s,1H),8.79(brs,1H),8.37-8.35m,2H),8.14(s,1H),7.46(d,J=8.0Hz,1H),7.13(s,1H),6.60(d,J=8.0Hz,1H),4.89(m, 1H),4.78(m,1H),4.68(m,1H),4.57(m,1H),4.50(m,1H),4.21(m,1H), 3.67-3.31(m,4H),3.00(s,3H),2.92-2.88(m,1H),1.44-1.33(m,9H); MS m / z(ESI):538.2[M+H] + .

[0316] Example 28 N-(2-(1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0317] For the preparation of N-(2-(1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, see Example 15 or 11.

[0318] MS m / z(ESI):578.2[M+H] + .

[0319] Example 29 N-(2-(1-(1-(fluoromethyl)cyclopropyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0320] For the preparation of N-(2-(1-(1-(fluoromethyl)cyclopropyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, see Example 15 or 11.

[0321] 1 H NMR(400MHz,DMSO-d6)δ 10.25(s,1H),9.10(s,1H),8.81(s,1H),8.38-8.32(m,2H),8.13(s,1H) ,7.46(d,J=8.0Hz,1H),7.09(s,1H),6.59(d,J=8.1Hz,1H),4.74(s,1H), 4.68(t,J=7.6Hz,1H),4.62(s,1H),4.24-4.17(m,1H),3.68-3.51(m,4H) ,3.00(s,3H),2.93-2.85(m,1H),1.46-1.36(m,11H),1.31-1.26(m,2H); MS m / z(ESI):564.2[M+H] + .

[0322] Example 30 N-(2-(1-((1-fluorocyclopropyl)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0323] For the preparation of N-(2-(1-((1-fluorocyclopropyl)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, see Example 15 or 11.

[0324] MS m / z(ESI):564.2[M+H] + .

[0325] Example 31 N-(2-(3-(cyclopropylsulfonyl)-1-methyl-1H-pyrazol-5-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0326] See Example 15 for the preparation of N-(2-(3-(cyclopropylsulfonyl)-1-methyl-1H-pyrazol-5-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine.

[0327] MS m / z(ESI):610.2[M+H] + .

[0328] Example 32 Preparation of 5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(5-(trifluoromethyl)thiophen-3-yl)pyrimidin-4-yl)isoquinolin-3-amine [ka]

[0329] See Example 15 for the preparation of 5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(5-(trifluoromethyl)thiophen-3-yl)pyrimidin-4-yl)isoquinolin-3-amine.

[0330] MS m / z(ESI):576.2[M+H] + .

[0331] Example 33 Preparation of 1-(4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)thiophen-2-yl)ethan-1-one [ka]

[0332] See Example 15 for a method for preparing 1-(4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)thiophen-2-yl)ethan-1-one.

[0333] 1 H NMR(400MHz,DMSO-d6)δ 10.36(s,1H),9.12(s,1H),8.64(s,1H),8.60(s,1H),8.52-8.40(m,2H) ,7.43(d,J=8.0Hz,1H),7.40-7.34(m,1H),6.58(d,J=8.0Hz,1H),4.69( t,J=7.5Hz,1H),4.23-4.19(m,1H),3.66(t,J=7.2Hz,1H),3.58-3.51(m ,2H),3.01(s,3H),2.90-2.85(m,1H),2.62(s,3H),1.52-1.22(m,10H); MS m / z(ESI):550.2[M+H] + .

[0334] Example 34 Preparation of 5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(5-(trifluoromethyl)furan-3-yl)pyrimidin-4-yl)isoquinolin-3-amine [ka]

[0335] See Example 15 for the preparation of 5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(5-(trifluoromethyl)furan-3-yl)pyrimidin-4-yl)isoquinolin-3-amine.

[0336] MS m / z(ESI):560.2[M+H] + .

[0337] Example 35 Preparation of 1-(4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)furan-2-yl)ethan-1-one [ka]

[0338] See Example 15 for a method for preparing 1-(4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)furan-2-yl)ethan-1-one.

[0339] 1H NMR(400MHz,DMSO-d6)δ 10.31(d,J=2.6Hz,1H),9.04(d,J=2.6Hz,1H),8.67(s,1H),8.54(d,J=2.7Hz,1H),8.38-8.33(m,1H),7.82(d,J=2.6Hz,1H),7.43-7.35(m,1H) ,7.19(s,1H),6.55-6.50(m,1H),4.63(d,J=8.6Hz,1H),4.14(s,1H),3. 62-3.41(m,7H),2.93(d,J=2.6Hz,3H),1.40-1.25(m,9H),1.17(s,1H); MS m / z(ESI):534.2[M+H] + .

[0340] Example 36 Preparation of N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-7-fluoro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0341] See Example 15 for the preparation of N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-7-fluoro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine.

[0342] MS m / z(ESI):550.2[M+H] + .

[0343] Example 37 Preparation of N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0344] See Example 15 for the preparation of N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine.

[0345] MS m / z(ESI):550.2[M+H] + .

[0346] Example 38 Preparation of 7-fluoro-5-isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0347] See Example 15 for the preparation of 7-fluoro-5-isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine.

[0348] MS m / z(ESI):524.2[M+H] + .

[0349] Example 39 Preparation of 6-fluoro-5-isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0350] See Example 15 for the preparation of 6-fluoro-5-isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine.

[0351] 1 H NMR(400MHz,DMSO-d6)δ 10.24(s,1H),9.03(s,1H),8.85(s,1H),8.36(d,J=5.8Hz,1H),8.26(s,1 H),8.04(d,J=0.8Hz,1H),7.10(d,J=5.8Hz,1H),6.35(d,J=14.4Hz,1H),4 .73(t,J=7.8Hz,1H),4.31-4.20(m,1H),3.93(s,3H),3.76(t,J=7.2Hz,1 H),3.63-3.48(m,3H),3.00(s,3H),2.96-2.82(m,1H),1.49-1.39(m,9H); MS m / z(ESI):524.2[M+H] + .

[0352] Example 40 Preparation of 2-(1-(3-((2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)acetonitrile [ka]

[0353] See Example 15 or 1 for the preparation of 2-(1-(3-((2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)acetonitrile.

[0354] 1H NMR(400MHz,DMSO-d6)δ 10.38(s,1H),9.12(s,1H),8.81-8.74(m,1H),8.70(s,1H),8.52(s,1H), 8.44(d,J=5.8Hz,1H),7.46(d,J=7.8Hz,1H),7.28-7.22(m,1H),6.47(d,J =8.0Hz,1H),4.39-4.33(m,2H),3.96-3.89(m,2H),3.63-3.56(m,1H),3. 16-3.07(m,1H),3.01-2.94(m,2H),1.42-1.33(m,7H),1.32-1.21(m,4H); MS m / z(ESI):529.2[M+H] + .

[0355] Example 41 Preparation of 1-(3-((2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidine-3-carbonitrile [ka]

[0356] For the preparation of 1-(3-((2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidine-3-carbonitrile, see Example 15 or 1.

[0357] MS m / z(ESI):515.2[M+H] + .

[0358] Example 42 Preparation of 2-((2R,3S)-1-(3-((2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)acetonitrile [ka]

[0359] For the preparation of 2-((2R,3S)-1-(3-((2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)acetonitrile, see Example 15 or 1.

[0360] MS m / z(ESI):543.2[M+H] + .

[0361] Example 43 Preparation of (2R,3S)-1-(3-((2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidine-3-carbonitrile [ka]

[0362] For the preparation of (2R,3S)-1-(3-((2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidine-3-carbonitrile, see Example 15 or 1.

[0363] MS m / z(ESI):529.2[M+H] + .

[0364] Example 44 Preparation of 2-(1-(5-isopropyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)azetidin-3-yl)acetonitrile [ka]

[0365] See Example 15 for the preparation of 2-(1-(5-isopropyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)azetidin-3-yl)acetonitrile.

[0366] 1 H NMR(400MHz,DMSO-d6)δ 10.19(s,1H),9.10(s,1H),8.81(s,1H),8.34(d,J=5.8Hz,1H),8.28(s,1H),8.07(s,1H),7.46(d,J=8.0Hz,1H),7.14-7.08(m,1H),6.45(d, J=8.0Hz,1H),4.34(t,J=7.8Hz,2H),3.98-3.87(m,5H),3.65-3.60(m,1H),3.15-3.04(m,1H),2.97(d,J=6.8Hz,2H),1.36(d,J=6.8Hz,6H); MS m / z(ESI):439.2[M+H] + .

[0367] Example 45 Preparation of 2-((2R,3S)-1-(5-isopropyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)-2-methylazetidin-3-yl)acetonitrile [ka]

[0368] See Example 15 for the preparation of 2-((2R,3S)-1-(5-isopropyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)-2-methylazetidin-3-yl)acetonitrile.

[0369] MS m / z(ESI):453.2[M+H] + .

[0370] Example 46 Preparation of 2-(1-(3-((2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)acetonitrile [ka]

[0371] See Example 15 for the preparation of 2-(1-(3-((2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)acetonitrile.

[0372] MS m / z(ESI):465.2[M+H] + .

[0373] Example 47 Preparation of 2-((2R,3S)-1-(3-((2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)acetonitrile [ka]

[0374] See Example 15 for the preparation of 2-((2R,3S)-1-(3-((2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)acetonitrile.

[0375] MS m / z(ESI):479.2[M+H] + .

[0376] Example 48 Preparation of 2-(4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)ethan-1-ol [ka]

[0377] For the preparation of 2-(4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, see Example 11 or 15.

[0378] 1 H NMR(400MHz,DMSO-d6)δ 10.22(s,1H),9.10(s,1H),8.80(s,1H),8.35(d,J=7.2Hz,1H),8.29(s,1H),8.09(s,1H),7.46(d,J=7.2Hz,1H),7.11(brs,1H),6.59(d,J=7. 2Hz,1H),4.70-4.66(m,1H),4.23-4.19(m,3H),3.87-3.51(m,6H),3.0 0(s,3H),2.91-2.88(m,1H),1.43(d,J=6.4Hz,3H),1.31-1.26(m,6H); MS m / z(ESI):536.2[M+H] + .

[0379] Example 49 Preparation of 5-isopropyl-N-(2-(1-(1-methoxycyclopropyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0380] For the preparation of 5-isopropyl-N-(2-(1-(1-methoxycyclopropyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, see Example 11 or 15.

[0381] 1 H NMR (400MHz, DMSO-d6) δ 10.21(s,1H),9.03(s,1H),8.79(s,1H),8.41(s,1H),8.30(d,J=6.0Hz,1H ),8.10(s,1H),7.40(d,J=8.0Hz,1H),7.06-7.02(m,1H),6.53(d,J=8.2Hz, 1H),4.61(t,J=7.6Hz,1H),4.18-4.12(m,1H),3.62-3.54(m,2H),3.55-3.4 4(m,3H),3.20(s,3H),2.93(s,3H),2.87-2.78(m,1H),1.37-1.31(m,12H); MS m / z(ESI):562.3[M+H] + .

[0382] Example 50 Preparation of 2-(1-(4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)cyclopropyl)acetonitrile [ka]

[0383] For the preparation of 2-(1-(4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)cyclopropyl)acetonitrile, see Example 11 or 15.

[0384] 1 H NMR (400MHz, DMSO-d6) δ 10.18(s,1H),9.03(s,1H),8.70(s,1H),8.33(s,1H),8.29(d,J=6.0Hz,1H),8. 09(s,1H),7.40(d,J=7.8Hz,1H),7.08-7.04(m,1H),6.53(d,J=8.0Hz,1H),4.61 (t,J=7.6Hz,1H),4.18-4.11(m,1H),3.61-3.56(m,1H),3.52-3.45(m,3H),3.17 (s,2H),2.93(s,3H),2.86-2.79(m,1H),1.38-1.30(m,10H),1.19-1.13(m,3H); MS m / z(ESI):571.3[M+H] + .

[0385] Example 51 Preparation of N-(2-(1-allyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0386] For the preparation of N-(2-(1-allyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, see Example 11 or 15.

[0387] 1H NMR(400MHz,DMSO-d6)δ 10.23(s,1H),9.10(s,1H),8.79(brs,1H),8.37-8.30(m,2H),8.11(s,1H),7.46( d,J=7.2Hz,1H),7.15(brs,1H),6.59(d,J=7.2Hz,1H),5.34-5.15(m,3H),4.86(d, J=7.2Hz,2H),4.70-4.66(m,1H),4.22-4.19(m,1H),3.66-3.52(m,3H),3.00(s,3H) ),2.90-2.87(m,1H),2.01-1.99(m,1H),1.43(d,J=6.4Hz,3H),1.39-1.36(m,6H); MS m / z(ESI):532.2[M+H] + .

[0388] Example 52 Preparation of N-(2-(1-(but-2-yn-1-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0389] For the preparation of N-(2-(1-(but-2-yn-1-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, see Example 11 or 15.

[0390] 1H NMR (400MHz, DMSO-d6) δ 10.22(s,1H),9.10(s,1H),8.79(s,1H),8.37-8.35(m,2H),8.09(s,1H),7.46 (d,J=7.2Hz,1H),7.13(brs,1H),6.59(d,J=7.2Hz,1H),5.08(s,2H),4.70-4. 66(m,1H),4.25-4.19(m,1H),3.66-3.51(m,3H),3.00(s,3H),2.91-2.87(m,1 H),2.01-1.99(m,1H),1.86(s,3H),1.43(d,J=6.4Hz,3H),1.39-1.36(m,6H); MS m / z(ESI):544.2[M+H] + .

[0391] Example 53 Preparation of 5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(1-(prop-2-yn-1-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)isoquinolin-3-amine [ka]

[0392] For the preparation of 5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(1-(prop-2-yn-1-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)isoquinolin-3-amine, see Example 11 or 15.

[0393] 1H NMR(400MHz,DMSO-d6)δ 10.23(s,1H),9.10(s,1H),8.77(s,1H),8.37-8.35(m,2H),8.11(s,1H),7 .46(d,J=7.2Hz,1H),7.15(brs,1H),6.59(d,J=7.2Hz,1H),5.15(s,2H),4 .70-4.66(m,1H),4.22-4.19(m,1H),3.66-3.52(m,4H),3.00(s,3H),2.90 -2.87(m,1H),2.01-1.99(m,1H),1.43(d,J=6.4Hz,3H),1.39-1.36(m,6H); MS m / z(ESI):530.2[M+H] + .

[0394] Example 54 Preparation of 5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(thiazol-5-yl)pyrimidin-4-yl)isoquinolin-3-amine [ka]

[0395] See Example 15 for the preparation of 5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(thiazol-5-yl)pyrimidin-4-yl)isoquinolin-3-amine.

[0396] 1H NMR(400MHz,DMSO-d6)δ 10.46(s,1H),9.29(s,1H),9.12(s,1H),8.76(s,1H),8.66(s,1H),8.43(d ,J=5.8Hz,1H),7.48(d,J=8.0Hz,1H),7.26(s,1H),6.61(d,J=8.0Hz,1H),4 .69-4.67(m,1H),4.21-4.20(m,1H),3.70-3.68(m,2H),3.63-3.45(m,2H) ,3.00(s,3H),2.90-2.89(m,1H),1.44(d,J=6.0Hz,3H),1.38-1.35(m,6H); MS m / z(ESI):509.2[M+H] + .

[0397] Example 55 Preparation of 4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1-methyl-1H-pyrazole-3-carbonitrile [ka]

[0398] See Example 15 for the preparation of 4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1-methyl-1H-pyrazole-3-carbonitrile.

[0399] 1H NMR(400MHz,DMSO-d6)δ 10.30(s,1H),9.11(s,1H),8.58(s,1H),8.48-8.44(m,2H),7.44(d,J=8.0Hz,1H),7.34(s,1H),6.59(d,J=8.1Hz,1H),4.69(t,J=7.5 Hz,1H),4.23-4.17(m,1H),4.05(s,3H),3.68-3.49(m,4H),3.00(s,3H),2.93-2.85(m,1H),1.43(d,J=6.1Hz,3H),1.35-1.29(m,6H); MS m / z(ESI):531.2[M+H] + .

[0400] Example 56 Preparation of 5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)isoquinolin-3-amine [ka]

[0401] See Example 15 for the preparation of 5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)isoquinolin-3-amine.

[0402] 1H NMR(400MHz,DMSO-d6)δ 10.21(s,1H),9.10(s,1H),8.59(s,1H),8.50-8.33(m,2H),7.44(d,J=7. 6Hz,1H),7.31(d,J=5.8Hz,1H),6.58(d,J=8.0Hz,1H),4.69-4.67(m,1H) ,4.21-4.19(m,1H),4.02(s,3H),3.69-3.59(m,1H),3.59-3.48(m,3H),3 .00(s,3H),2.89-2.86(m,1H),1.43(d,J=6.0Hz,3H),1.36-1.32(m,6H); MS m / z(ESI):574.2[M+H] + .

[0403] Example 57 Preparation of N-(2-(3-ethyl-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0404] See Example 15 for the preparation of N-(2-(3-ethyl-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine.

[0405] 1H NMR(400MHz,DMSO-d6)δ 10.08(s,1H),9.10(s,1H),8.58(s,1H),8.36(d,J=5.8Hz,1H),8.18(s,1H),7.44(d,J =8.0Hz,1H),7.17(d,J=5.6Hz,1H),6.58(d,J=8.0Hz,1H),4.68(t,J=7.4Hz,1H),4.21 (t,J=6.2Hz,1H),3.86(s,3H),3.65(t,J=7.1Hz,1H),3.59-3.49(m,3H),3.04-2.99(m ,5H),2.93-2.86(m,1H),1.43(d,J=6.0Hz,3H),1.36-1.32(m,6H),1.22-1.17(m,3H); MS m / z(ESI):534.3[M+H] + .

[0406] Example 58 Preparation of 2-(4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methyl-1H-pyrazol-1-yl)ethan-1-ol [ka]

[0407] For the preparation of 2-(4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methyl-1H-pyrazol-1-yl)ethan-1-ol, see Example 11 or 15.

[0408] 1H NMR (400MHz, DMSO-d6) δ 10.23(s,1H),9.11(s,1H),8.60(s,1H),8.37(d,J=7.2Hz,1H),8.13(s,1H) ,7.46(d,J=7.2Hz,1H),7.21(brs,1H),6.59(d,J=7.2Hz,1H),4.99-4.91(m ,1H),4.71-4.67(m,1H),4.23-4.12(m,3H),3.82-3.49(m,6H),3.00(s,3H) ,2.90-2.87(m,1H),2.52(s,3H),1.43(d,J=6.4Hz,3H),1.39-1.36(m,6H); MS m / z(ESI):550.3[M+H] + .

[0409] Example 59 Preparation of 2-(4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-ol [ka]

[0410] For the preparation of 2-(4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-ol, see Example 11 or 15.

[0411] 1H NMR(400MHz,DMSO-d6)δ 10.20(s,1H),9.11(s,1H),8.49(s,1H),8.43(d,J=6.2Hz,2H),7.44(d,J= 8.0Hz,1H),7.36(s,1H),6.58(d,J=8.0Hz,1H),5.08(s,1H),4.68-4.66(m, 1H),4.30-4.26(m,2H),4.23-4.21(m,2H),3.82(s,2H),3.65-3.63(m,1H) ,3.58-3.43(m,3H),3.00(s,3H),1.43(d,J=6.0Hz,3H),1.36-1.32(m,6H); MS m / z(ESI):604.2[M+H] + .

[0412] Example 60 Preparation of N-(1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methanesulfonamide [ka]

[0413] See Example 15 for the preparation of N-(1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methanesulfonamide.

[0414] 1H NMR(400MHz,DMSO-d6)δ 10.07(s,1H),9.08(s,1H),8.54(s,1H),8.37(d,J=5.8Hz,1H),8.18(s,1H) ),7.84(s,1H),7.44(d,J=8.0Hz,1H),7.21(d,J=5.8Hz,1H),6.46(d,J=8. 0Hz,1H),4.54(t,J=7.4Hz,2H),4.37-4.33(m,1H),3.92-3.89(m,2H),3.8 5(s,3H),3.56-3.53(m,1H),2.97(s,3H),2.53(s,3H),1.37-1.33(m,6H); MS m / z(ESI):507.2[M+H] + .

[0415] Example 61 Preparation of 1-((2R,3S)-1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N,N-dimethylmethanesulfonamide [ka]

[0416] See Example 15 for the preparation of 1-((2R,3S)-1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N,N-dimethylmethanesulfonamide.

[0417] 1H NMR(400MHz,DMSO-d6)δ 10.09(s,1H),9.10(s,1H),8.57(s,1H),8.36(d,J=5.8Hz,1H),8.19(s,1H),7.44(d, J=8.0Hz,1H),7.18(d,J=6.0Hz,1H),6.57(d,J=8.0Hz,1H),4.66-4.63(m,1H),4.20- 4.15(m,1H),3.85(s,3H),3.64-3.61(m,1H),3.57-3.55(m,1H),3.52-3.39(m,2H),2 .88-2.80(m,1H),2.77(s,6H),2.53(s,3H),1.44(d,J=6.0Hz,3H),1.37-1.33(m,6H); MS m / z(ESI):549.3[M+H] + .

[0418] Example 62 Preparation of N-(2-(3-fluoro-1-methyl-1H-pyrazolyl-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine [ka]

[0419] See Example 15 for the preparation of N-(2-(3-fluoro-1-methyl-1H-pyrazolyl-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine.

[0420] 1H NMR(400MHz,DMSO-d6)δ 10.20(s,1H),9.09(s,1H),8.66(s,1H),8.35(d,J=5.9Hz,1H),8.21(s,1H),7.44(d,J=8.0Hz,1H),7.15(s,1H),6.58(d,J=8.2Hz,1H),4.67( t,J=7.4Hz,1H),4.24-4.14(m,1H),3.82(s,3H),3.66-3.50(m,4H),3. 00(s,3H),2.92-2.86(m,1H),1.43(d,J=6.0Hz,3H),1.33-1.26(m,6H); MS m / z(ESI):524.2[M+H] + .

[0421] Example 63 Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-((methylsulfonyl)methyl)cyclobutyl)isoquinolin-3-amine [ka]

[0422] See Example 15 for the preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-((methylsulfonyl)methyl)cyclobutyl)isoquinolin-3-amine.

[0423] 1H NMR (400MHz, DMSO-d6) δ 10.24(d,J=5.9Hz,1H),9.17(d,J=24.3Hz,1H),8.71(s,1H),8.41(d,J=5.9Hz, 1H),8.35(s,1H),7.60-7.55(m,1H),7.41-7.22(m,2H),4.51-4.08(m,1H),3.91 (s,3H),3.73-3.64(m,1H),3.58(d,J=7.5Hz,1H),3.31-3.27(m,3H),2.97(d,J= 10.9Hz,3H),2.87-2.74(m,2H),2.15-2.05(m,1H),1.34(dd,J=6.7,3.5Hz,6H); MS m / z(ESI):525.2[M+H] + .

[0424] Example 64 Preparation of 5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(1-(methyl-d3)-3-nitro-1H-pyrazol-4-yl)pyrimidin-4-yl)isoquinolin-3-amine [ka]

[0425] See Example 15 for the preparation of 5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(1-(methyl-d3)-3-nitro-1H-pyrazol-4-yl)pyrimidin-4-yl)isoquinolin-3-amine.

[0426] MS m / z(ESI):554.2[M+H] + .

[0427] Example 65 Preparation of N-(2-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine [ka]

[0428] See Example 15 for the preparation of N-(2-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine.

[0429] 1 H NMR (400MHz, DMSO-d6) δ 10.20(s,1H),9.09(s,1H),8.66(s,1H),8.35(d,J=5.9Hz,1H),8.21(d,J=1.9 Hz,1H),7.44(d,J=8.0Hz,1H),7.16(d,J=5.8Hz,1H),6.58(d,J=8.1Hz,1H),4. 67(t,J=7.4Hz,1H),4.20(t,J=6.3Hz,1H),3.71-3.48(m,4H),3.00(s,3H),2. 89(dd,J=14.3,7.2Hz,1H),1.43(d,J=6.0Hz,3H),1.31(dd,J=6.5,5.0Hz,6H); MS m / z(ESI):527.2[M+H] + .

[0430] Example 66 Preparation of 5-isopropyl-N-(2-(1-((1-(methoxymethyl)cyclopropyl)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0431] For the preparation of 5-isopropyl-N-(2-(1-((1-(methoxymethyl)cyclopropyl)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, see Example 11 or 15.

[0432] 1 H NMR(400MHz,DMSO-d6)δ 10.21(s,1H),9.10(s,1H),8.76(s,1H),8.35(d,J=5.8Hz,1H),8.25(s,1H),8.09(s,1H) ,7.45(d,J=8.0Hz,1H),7.19-7.13(m,1H),6.58(d,J=8.0Hz,1H),4.69(t,J=7.6Hz,1H), 4.27-4.09(m,3H),3.68-3.51(m,4H),3.23(s,3H),3.09(s,2H),3.00(s,3H),2.93-2.86 (m,1H),1.43(d,J=6.2Hz,3H),1.40-1.33(m,6H),0.74-0.65(m,2H),0.61-0.48(m,2H); MS m / z(ESI):590.3[M+H] + .

[0433] Example 67 Preparation of 3-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)propionitrile [ka]

[0434] For the preparation of 3-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)propionitrile, see Example 11 or 15.

[0435] 1 H NMR(400MHz,DMSO-d6)δ 10.20(s,1H),9.10(s,1H),8.60-8.37(m,3H),7.51-7.30(m,2H),6.58(s,1H),4.75-4.64(m,1H),4.45-4.39(m,2H),4.2 5-4.12(m,1H),3.69-3.54(m,4H),3.17(s,2H),3.00(s,3H),2.92-2.85(m,1H),1.43(d,J=6.0Hz,3H),1.35-1.19(m,6H); MS m / z(ESI):579.2[M+H] + .

[0436] Example 68 Preparation of 2-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)isothiazolidine 1,1-dioxide [ka]

[0437] See Example 15 for the preparation of 2-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)isothiazolidine 1,1-dioxide.

[0438] 1H NMR(400MHz,DMSO-d6)δ 10.18(s,1H),9.10(s,1H),8.57(s,1H),8.41(d,J=5.9Hz,1H),8.34(s, 1H),7.43(d,J=8.0Hz,1H),7.28(s,1H),6.47(d,J=8.1Hz,1H),4.46-4.3 1(m,3H),4.29-4.20(m,2H),3.90(s,3H),3.65-3.52(m,1H),3.43(t,J= 6.6Hz,2H),3.33-3.23(m,2H),2.30-2.25(m,2H),1.30(d,J=6.8Hz,6H); MS m / z(ESI):553.2[M+H] + .

[0439] Example 69 Preparation of 2-(1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)isothiazolidine 1,1-dioxide [ka]

[0440] See Example 15 for the preparation of 2-(1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)isothiazolidine 1,1-dioxide.

[0441] 1H NMR (400MHz, DMSO-d6) δ 10.08(s,1H),9.10(s,1H),8.55(s,1H),8.37(d,J=5.9Hz,1H),8.19(s,1H),7. 44(d,J=8.0Hz,1H),7.22(d,J=5.6Hz,1H),6.47(d,J=8.0Hz,1H),4.41-4.30(m, 3H),4.26-4.22(m,2H),3.85(s,3H),3.62-3.50(m,1H),3.43(t,J=6.6Hz,2H), 3.32-3.24(m,3H),2.48-2.44(m,2H),2.34-2.24(m,2H),1.33(d,J=6.8Hz,6H); MS m / z(ESI):533.2[M+H] + .

[0442] Example 70 Preparation of N-(2-(3-chloro-1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0443] See Example 15 for the preparation of N-(2-(3-chloro-1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine.

[0444] 1H NMR(400MHz,DMSO-d6)δ 10.21(s,1H),9.09(s,1H),8.62(s,1H),8.41(d,J=5.1Hz,2H),7.44(d,J=8.0Hz ,1H),7.23(d,J=4.5Hz,1H),6.58(d,J=8.1Hz,1H),4.68(s,1H),4.23-4.15(m,1H ),3.86-3.80(m,1H),3.66-3.48(m,4H),3.00(s,3H),2.93-2.84(m,1H),1.43(d, J=6.1Hz,3H),1.32(dd,J=6.7,4.9Hz,6H),1.18-1.12(m,2H),1.06-1.00(m,2H); MS m / z(ESI):566.2[M+H] + .

[0445] Example 71 Preparation of N-(2-(1-(2-aminoethyl)-3-chloro-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0446] For the preparation of N-(2-(1-(2-aminoethyl)-3-chloro-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, see Example 11 or 15.

[0447] MS m / z(ESI):569.2[M+H] + .

[0448] Example 72 Preparation of methyl (1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)carbamate [ka]

[0449] See Example 15 for the preparation of methyl (1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)carbamate.

[0450] 1 H NMR(400MHz,DMSO-d6)δ 10.17(s,1H),9.08(s,1H),8.58(s,1H),8.40(d,J=5.8Hz,1H),8.33(s,1H),7.85(d,J=7.2Hz,1H),7.43(d,J=8.0Hz,1 H),7.28-7.23(m,1H),6.44(d,J=8.0Hz,1H),4.57-4.42(m,4H),3.90(s,3H),3.63-3.54(m,5H),1.30(d,J=6.8Hz,6H); MS m / z(ESI):507.2[M+H] + .

[0451] Example 73 Preparation of N-(2-(3-chloro-1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0452] For the preparation of N-(2-(3-chloro-1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, see Example 11 or 15.

[0453] 1 H NMR(400MHz,DMSO-d6)δ 10.19(s,1H),9.10(s,1H),8.53(s,1H),8.41(d,J=5.8Hz,1H),8.33(s,1H),7.43(d,J= 8.0Hz,1H),7.32-7.28(m,1H),6.58(d,J=8.1Hz,1H),4.68(t,J=7.4Hz,1H),4.36-4.28 (m,2H),4.24-4.18(m,1H),3.73(t,J=5.2Hz,2H),3.68-3.62(m,1H),3.61-3.50(m,3H) ,3.25(s,3H),3.00(s,3H),2.94-2.85(m,1H),1.43(d,J=6.0Hz,3H),1.33-1.27(m,6H); MS m / z(ESI):584.2[M+H] + .

[0454] Example 74 Preparation of 3-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)oxazolidin-2-one [ka]

[0455] See Example 15 for the preparation of 3-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)oxazolidin-2-one.

[0456] 1H NMR(400MHz,DMSO-d6)δ 10.26(s,1H),9.08(s,1H),8.52(s,1H),8.35(d,J=6.0Hz,1H),8.28(s,1H),7.40 (d,J=8.0Hz,1H),7.20(d,J=5.2Hz,1H),6.60(d,J=8.1Hz,1H),4.58(t,J=7.5Hz, 1H),4.40-4.36(m,1H),4.30-4.18(m,2H),3.84(s,3H),3.79(t,J=7.2Hz,1H),3. 68-3.58(m,2H),3.55-3.48(m,2H),1.34(d,J=6.0Hz,3H),1.24(t,J=6.0Hz,6H); MS m / z(ESI):533.2[M+H] + .

[0457] Example 75 Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0458] See Example 15 for the preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine.

[0459] MS m / z(ESI):493.2[M+H] + .

[0460] Example 76 Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-((methylsulfinyl<sulfinyl>)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0461] See Example 15 for the preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-((methylsulfinyl<sulfinyl>)methyl)azetidin-1-yl)isoquinolin-3-amine.

[0462] MS m / z(ESI):510.2[M+H] + .

[0463] Example 77 Preparation of N-(2-(5-fluoro-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0464] See Example 15 for the preparation of N-(2-(5-fluoro-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine.

[0465] 1H NMR (400MHz, DMSO-d6) δ 10.12(s,1H),9.09(s,1H),8.50(s,1H),8.39(d,J=5.9Hz,1H),7.44(d,J=8.0H z,1H),7.26-7.18(m,1H),6.58(d,J=8.1Hz,1H),4.67(t,J=7.6Hz,1H),4.20(t, J=6.2Hz,1H),3.71(s,3H),3.65(t,J=7.1Hz,1H),3.58-3.49(m,3H),3.00(s,3H) ),2.93-2.85(m,1H),2.45(s,3H),1.43(d,J=6.0Hz,3H),1.29(t,J=6.1Hz,6H); MS m / z(ESI):538.2[M+H] + .

[0466] Example 78 Preparation of N-(2-(3-chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0467] For the preparation of N-(2-(3-chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, see Example 11 or 15.

[0468] 1H NMR (400MHz, DMSO-d6) δ 10.19(s,1H),9.10(s,1H),8.52(s,1H),8.42-8.40(m,2H),7.43(d,J=7.2Hz ,1H),7.28(brs,1H),6.59(d,J=7.2Hz,1H),4.71-4.67(m,1H),4.48-4.44(m, 1H),4.23-4.20(m,1H),4.02-3.99(m,2H),3.65-3.43(m,6H),3.00(s,3H),2. 90-2.87(m,1H),2.01-1.96(m,4H),1.43(d,J=6.4Hz,3H),1.39-1.36(m,6H); MS m / z(ESI):610.2[M+H] + .

[0469] Example 79 Preparation of N-(1-(3-((2-(3-chloro-1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide [ka]

[0470] For the preparation of N-(1-(3-((2-(3-chloro-1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide, see Example 11 or 15.

[0471] 1H NMR(400MHz,DMSO-d6)δ 10.15(s,1H),9.13(s,1H),8.50(s,1H),8.41(d,J=5.8Hz,1H),8.32(s,1 H),7.44(d,J=8.0Hz,1H),7.34(s,1H),6.47(d,J=7.6Hz,1H),5.06-4.99 (m,1H),4.72-4.62(m,1H),4.47-4.36(m,2H),4.28-4.15(m,4H),3.84-3 .75(m,2H),3.60-3.53(m,1H),2.99-2.91(m,6H),1.31(d,J=6.6Hz,6H); MS m / z(ESI):571.2[M+H] + .

[0472] Example 80 Preparation of 1-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)propan-2-ol [ka]

[0473] For the preparation of 1-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)propan-2-ol, see Example 11 or 15.

[0474] 1H NMR(400MHz,DMSO-d6)δ 10.19(s,1H),9.10(s,1H),8.53(s,1H),8.41(d,J=5.8Hz,1H),8.30(s,1H),7.43(d,J=8.0Hz, 1H),7.28(s,1H),6.58(d,J=8.2Hz,1H),5.10-5.03(m,1H),4.68(t,J=7.6Hz,1H),4.24-4.17( t,J=6.4Hz,1H),4.15-4.07(m,1H),4.05-3.96(m,2H),3.67-3.62(m,1H),3.60-3.49(m,3H),3 .00(s,3H),2.93-2.86(m,1H),1.43(d,J=6.0Hz,3H),1.36-1.28(m,6H),1.10(d,J=5.8Hz,3H); MS m / z(ESI):584.2[M+H] + .

[0475] Example 81 Preparation of N-(2-(3-chloro-1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0476] For the preparation of N-(2-(3-chloro-1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, see Example 11 or 15.

[0477] 1H NMR (400MHz, DMSO-d6) δ 10.13(s,1H),9.03(s,1H),8.45(s,1H),8.41(s,1H),8.35(d,J=5.8Hz,1H),7. 36(d,J=8.0Hz,1H),7.24(d,J=5.8Hz,1H),6.51(d,J=8.0Hz,1H),5.61-5.50(m, 1H),4.93-4.82(m,4H),4.61(t,J=7.6Hz,1H),4.17-4.10(m,1H),3.62-3.39(m ,4H),2.93(s,3H),2.87-2.77(m,1H),1.36(d,J=6.0Hz,3H),1.25-1.14(m,6H); MS m / z(ESI):582.2[M+H] + .

[0478] Example 82 Preparation of 1-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)-3-fluoropropan-2-ol [ka]

[0479] See Example 11 for the preparation of 1-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)-3-fluoropropan-2-ol.

[0480] 1H NMR (400MHz, DMSO-d6) δ 10.20(s,1H),9.10(s,1H),8.53(s,1H),8.42(d,J=5.8Hz,1H),8.32(s,1H) ,7.44(d,J=8.0Hz,1H),7.29(s,1H),6.58(d,J=7.8Hz,1H),5.62(s,1H),4. 67(d,J=7.6Hz,1H),4.49-4.11(m,6H),3.69-3.63(m,1H),3.60-3.51(m,3H ),3.00(s,3H),2.92-2.87(m,1H),1.43(d,J=6.0Hz,3H),1.35-1.27(m,6H); MS m / z(ESI):602.2[M+H] + .

[0481] Example 83 Preparation of N-(((1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methyl)(methyl)(carbonyl)-16-sulfanylidene)cyanoamide [ka]

[0482] See Example 15 for the preparation of N-(((1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methyl)(methyl)(carbonyl)-16-sulfanylidene)cyanoamide.

[0483] 1H NMR(400MHz,DMSO-d6)δ 10.07(s,1H),9.09(s,1H),8.54(s,1H),8.37(d,J=5.8Hz,1H),8.18(s,1H) ),7.44(d,J=8.0Hz,1H),7.21(d,J=5.5Hz,1H),6.44(d,J=8.1Hz,1H),4.47 -4.37(m,2H),4.13(d,J=7.2Hz,2H),4.06-3.98(m,2H),3.85(s,3H),3.58 -3.50(m,4H),3.43-3.38(m,1H),2.49-2.45(m,3H),1.33(d,J=6.8Hz,6H); MS m / z(ESI):530.2[M+H] + .

[0484] Example 84 Preparation of (R)-3-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-5-methyloxazolidin-2-one [ka]

[0485] See Example 15 for the preparation of (R)-3-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-5-methyloxazolidin-2-one.

[0486] 1H NMR(400MHz,DMSO-d6)δ 10.10(s,1H),9.06(s,1H),8.50(s,1H),8.34(d,J=5.9Hz,1H),8.26(s,1H),7.37( d,J=8.0Hz,1H),7.21(d,J=5.7Hz,1H),6.41(d,J=8.0Hz,1H),4.74-4.57(m,2H),4. 32(dd,J=16.5,8.2Hz,2H),4.25-4.12(m,2H),3.87(t,J=8.4Hz,1H),3.84(s,3H), 3.54-3.47(m,1H),1.96-1.90(m,1H),1.29(d,J=6.2Hz,3H),1.23(d,J=6.8Hz,6H); MS m / z(ESI):533.2[M+H] + .

[0487] Example 85 N-(2-(6-(fluoromethyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine (including epimeric pair) [ka]

[0488] See Example 15 for the preparation of N-(2-(6-(fluoromethyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine.

[0489] MS m / z(ESI):564.2[M+H] + .

[0490] Example 86 N-(2-(6-(difluoromethyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine (including epimeric pair) [ka]

[0491] See Example 15 for the preparation of N-(2-(6-(difluoromethyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine.

[0492] MS m / z(ESI):582.2[M+H] + .

[0493] Example 87 5-Isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(6-(trifluoromethyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrimidin-4-yl)isoquinolin-3-amine (including epimeric pair) [ka]

[0494] See Example 15 for the preparation of 5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(6-(trifluoromethyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrimidin-4-yl)isoquinolin-3-amine.

[0495] MS m / z(ESI):600.2[M+H] +.

[0496] Example 88 5-Isopropyl-N-(2-(6-(methoxymethyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine (including epimeric pair) [ka]

[0497] See Example 15 for the preparation of 5-isopropyl-N-(2-(6-(methoxymethyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine.

[0498] MS m / z(ESI):576.2[M+H] + .

[0499] Example 89 Preparation of N-(2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyridin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0500] For the preparation of N-(2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyridin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, see Example 1 or 15.

[0501] MS m / z(ESI):595.2[M+H] + .

[0502] Example 90 Preparation of 2-(1-(3-((2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyridin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)acetonitrile [ka]

[0503] For the preparation of 2-(1-(3-((2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyridin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)acetonitrile, see Example 1 or 15.

[0504] MS m / z(ESI):528.2[M+H] + .

[0505] Example 91 Preparation of N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0506] See Example 15 for the preparation of N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine.

[0507] MS m / z(ESI):531.2[M+H] + .

[0508] Example 92 Preparation of 5-isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0509] See Example 15 for the preparation of 5-isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine.

[0510] MS m / z(ESI):505.2[M+H] + .

[0511] Example 93 Preparation of 2-(1-(5-isopropyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)amino)isoquinolin-8-yl)azetidin-3-yl)acetonitrile [ka]

[0512] See Example 15 for the preparation of 2-(1-(5-isopropyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)amino)isoquinolin-8-yl)azetidin-3-yl)acetonitrile.

[0513] MS m / z(ESI):438.2[M+H] + .

[0514] Example 94 Preparation of 2-((2R,3S)-1-(5-isopropyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)amino)isoquinolin-8-yl)-2-methylazetidin-3-yl)acetonitrile [ka]

[0515] See Example 15 for the preparation of 2-((2R,3S)-1-(5-isopropyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)amino)isoquinolin-8-yl)-2-methylazetidin-3-yl)acetonitrile.

[0516] MS m / z(ESI):452.2[M+H] + .

[0517] Example 95 Preparation of N-(2-(3-chloro-1-(2,2-difluorocyclobutyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0518] See Example 11 for the preparation of N-(2-(3-chloro-1-(2,2-difluorocyclobutyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine.

[0519] MS m / z(ESI):616.2[M+H] + .

[0520] Example 96 Preparation of 4-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)cyclohexan-1-one [ka]

[0521] See Example 11 for the preparation of 4-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)cyclohexan-1-one.

[0522] MS m / z(ESI):622.2[M+H] + .

[0523] Example 97 Preparation of 2-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)-1-(fluoromethyl)cyclobutan-1-ol [ka]

[0524] See Example 11 for the preparation of 2-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)-1-(fluoromethyl)cyclobutan-1-ol.

[0525] MS m / z(ESI):628.2[M+H] + .

[0526] Example 98 Preparation of N-(2-(3-chloro-1-(2-methoxy-2-methylcyclobutyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka]

[0527] See Example 11 for the preparation of N-(2-(3-chloro-1-(2-methoxy-2-methylcyclobutyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine.

[0528] MS m / z(ESI):624.2[M+H] + .

[0529] Example 99 Preparation of 2-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)-1-methylcyclobutane-1-carbonitrile [ka]

[0530] See Example 11 for the preparation of 2-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)-1-methylcyclobutane-1-carbonitrile.

[0531] MS m / z(ESI):619.2[M+H] + .

[0532] Example 100 Preparation of N-((2R,3S)-1-(3-((2-(3-chloro-1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide [ka]

[0533] See Example 15 for the preparation of N-((2R,3S)-1-(3-((2-(3-chloro-1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide.

[0534] MS m / z(ESI):585.2[M+H] + .

[0535] Example 101 Preparation of N-((2R,3S)-1-(3-((2-(3-chloro-1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide [ka]

[0536] See Example 15 for the preparation of N-((2R,3S)-1-(3-((2-(3-chloro-1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide.

[0537] MS m / z(ESI):571.2[M+H] + .

[0538] Example 102 Preparation of N-((2R,3S)-1-(3-((2-(3-chloro-1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-(1-methoxyethyl)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide [ka]

[0539] See Example 15 for the preparation of N-((2R,3S)-1-(3-((2-(3-chloro-1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-(1-methoxyethyl)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide.

[0540] MS m / z(ESI):601.2[M+H] + .

[0541] Example 103 Preparation of N-((2R,3S)-1-(3-((2-(3-chloro-1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-(dimethylamino)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide [ka]

[0542] See Example 15 for the preparation of N-((2R,3S)-1-(3-((2-(3-chloro-1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-(dimethylamino)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide.

[0543] MS m / z(ESI):586.2[M+H] + . Biological Test Evaluation

[0544] The present invention will be further described below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0545] Test Example 1: Assay of the inhibitory effect of the compounds of the present invention on the kinase activity of EGFR del19 / T790M / C797S and EGFR L858R / T790M / C797S mutations Experimental Objective: The objective of this experimental example is to test the activity of compounds to inhibit the kinase activity of EGFR del19 / T790M / C797S and EGFR L858R / T790M / C797S mutations.

[0546] Experimental equipment: Centrifuge (5810R) was purchased from Eppendorf, pipette was purchased from Eppendorf or Rainin, microplate reader was purchased from BioTek, USA, full-function microplate reader with model number SynergyH1.

[0547] Experimental method: This experiment used Cisbio's HTRF kinase assay method (Cisbio #62TK0PEB) to catalyze the substrate polypeptide TK and ATP in the presence of tyrosine kinase EGFR del19 / T790M / C797S or EGFR L858R / T790M / C797S mutation, phosphorylate the substrate, and characterize the kinase activity by measuring the content of phosphorylated substrate produced during the reaction. The half-inhibitory concentration IC of the compound for kinase activity inhibition against EGFR del19 / T790M / C797S or EGFR L858R / T790M / C797S mutation was calculated. 50 obtained.

[0548] The specific experimental procedures are as follows.

[0549] Kinase reactions were performed in white 384-well plates (Perkin Elmer #6008280), adding 1-5 μL of different concentrations of compounds diluted in ddH2O containing 1% DMSO to each well, adding 1-5 μL of ddH2O containing 1% DMSO to the positive control wells, and adding 1-5 μL of 0.5-5 nM 4× EGFR del19 / T790M / C797S or EGFR L858R / T790M / C797S mutant kinase solution diluted in Dilution buffer (5× kinase buffer, MgCl2 6.65 mM, MnCl2 1.33 mM, DTT 1.33 mM) to each well, adding 1-5 μL of Dilution buffer to the negative control wells, adding 1-5 μL of 4 μM 4× substrate TK solution prepared in 10× Dilution buffer to all wells, and finally adding 1-5 μL of Dilution buffer to the negative control wells. The reaction was initiated by adding 1 to 5 μL of 24 μM 4xATP solution diluted with buffer, and allowed to react for 120 minutes at room temperature. After that, 10 μL of detection solution (TK antibody 16 nM, XL665 0.5 μM) was added to each well, and the reaction was allowed to continue for 20 minutes at room temperature in the dark. The chemiluminescence values ​​were then detected using a BioTek Synergy H1 microplate reader.

[0550] How to process experimental data: Percent inhibition data for compound treated wells across positive control wells (DMSO control wells) and negative control wells (no kinase added) on the plate

number

[0551] [Table 1]

[0552] [Table 2] The above data demonstrate that the examples of the present invention have good inhibitory effects against EGFR L858R / T790M / C797S and EGFR del19 / T790M / C797S drug-resistant mutant kinases.

[0553] Test Example 2: Cell proliferation inhibition experiment Experimental Objective: The objective of this experiment is to test the proliferation inhibitory activity of compounds against different EGFR C797S drug-resistant mutant cell lines Ba / F3 EGFR Del19 / T790M / C797S, Ba / F3 EGFR L858R / T790M / C797S and Ba / F3 EGFR Del19 / C797S.

[0554] Experimental equipment: Centrifuge (Eppendorf 5810R) Microplate reader (BioTek Synergy H1) Pipette (Eppendorf or Rainin) Carbon dioxide incubator (Thermo 311) Cytometer (Life Countess II)

[0555] Experimental Reagents and Consumables: Ba / F3 EGFR Del19 / T790M / C797S cells purchased from Beijing Hongyuan Bochuang Biological Technology Co., Ltd. Ba / F3 EGFR Del19 / C797S cells purchased from Nanjing Kebai Biotechnology Co., Ltd. Ba / F3 EGFR L858R / T790M / C797S cells purchased from Nanjing Kebai Biotechnology Co., Ltd. Cell Titer-Glo was purchased from Promega and has the catalog number G7573. RPMI 1640, purchased from Gibco, catalog number 22400089; FBS, purchased from Gibco, catalog number 10091148; Cell culture plates purchased from Corning, catalog number 3610

[0556] Testing Method: The Cell Titer-Glo method was used to detect the growth inhibitory activity of compounds against different EGFR C797S drug-resistant mutant cell lines. Different cell lines were cultured in RPMI 1640 complete medium containing 10% FBS at 37℃, 5% CO2, respectively, and grown to a certain density, then centrifuged to collect the cells, counted and adjusted to the appropriate cell density, seeded into a white 96-well plate at 90μL per well, cultured overnight in an incubator at 37℃, 5% CO2, added with 10μL per well of the prepared compound solutions with different concentrations, and set up the corresponding solvent controls, then cultured in an incubator at 37℃, 5% CO2 for 72 hours, after which 50μL of CellTiter-Glo solution was added to each well, shaken to mix evenly, incubated in the dark for 10 minutes, and read on a BioTek Synergy H1 microplate reader.

[0557] How to process experimental data: The luminescence signal values ​​were used to calculate the inhibition rate, and nonlinear regression curve fitting was performed for the concentration and inhibition rate using Graphpad Prism software to obtain the IC 50 The values ​​obtained are specifically as shown in Tables 3 and 4 below:

[0558] [Table 3]

[0559] [Table 4-1] [Table 4-2] The above data demonstrate that the compounds of the examples have excellent proliferation inhibitory activity against any of Ba / F3 EGFR Del19 / T790M / C797S, Ba / F3 EGFR L858R / T790M / C797S, and Ba / F3 EGFR Del19 / C797S.

Claims

1. A compound represented by general formula (II-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 【Chemical 1】 where: M １ is N, CH, M ３ is N, CH, Ring D is selected from heteroaryl groups; Ring A is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group; R １ are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -OR ａ , -P(O) ｐ (R ａ ) ｎ５ , -S(O) ｍ R ａ or -C(O)R ａ wherein the amino group, alkyl group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted, or two of them may be selected from R １ are linked to the atoms therebetween to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, which cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups may optionally be further substituted; R ２ are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -OR ａ , -P(O) ｐ (R ａ ) ｎ５ , -S(O) ｍ R ａ or -C(O)R ａ wherein the amino group, alkyl group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted; R ４ are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -OR ａ , -P(O) ｐ (R ａ ) ｎ５ , -S(O) ｍ R ａ or -C(O)R ａ wherein the amino, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; R ａ are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, which amino, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may optionally be further substituted; x is 0, 1, 2, 3, 4, 5 or 6; y is 0, 1, 2, 3, 4, 5 or 6; w is 0, 1, 2, 3, 4, 5, or 6; p, m and n5 are each independently 0, 1, 2 or 3, a compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

2. Ring A is C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl groups or 5- to 14-membered heteroaryl groups, wherein the heteroatoms in the 3- to 12-membered heterocyclyl groups and the 5- to 14-membered heteroaryl groups are independently selected from nitrogen, oxygen, sulfur and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4; Preferably, it is a 4- to 10-membered heterocyclyl group, more preferably a 4- to 6-membered monocyclic heterocyclyl group, a 7- to 9-membered spirocyclic heterocyclyl group, or an 8- to 10-membered fused-ring heterocyclyl group; Specifically, preferably, 【Chemistry 2】 and More preferably, 【Chemistry 3】 and More preferably, 【Chemistry 4】 and Even more preferably, ring A is 【Chemistry 5】 2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

3. Ring D is selected from 5- to 8-membered heteroaryl groups, more preferably 5-membered heteroaryl groups; More preferably, ring D is 【Chemistry 6】 and Even more preferably, ring D is 【Chemistry 7】 2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

4. A compound represented by general formula (VII), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 【Chemistry 8】 where: M ３ is N, CH, M ５ is N, CH, Ring E is a 4- to 10-membered heterocyclyl group, preferably a 4- to 10-membered heterocyclyl group containing 1 to 4 N, O, S or P; R １ are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -OR ａ , -P(O) ｐ (R ａ ) ｎ５ , -S(O) ｍ R ａ or -C(O)R ａ wherein the amino group, alkyl group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted, or two of them may be selected from R １ are linked to the atoms therebetween to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, which cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups may optionally be further substituted; R ２ are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -OR ａ , -P(O) ｐ (R ａ ) ｎ５ , -S(O) ｍ R ａ or -C(O)R ａ wherein the amino group, alkyl group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted; R ４ are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -OR ａ , -P(O) ｐ (R ａ ) ｎ５ , -S(O) ｍ R ａ or -C(O)R ａ wherein the amino, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; R ａ are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, which amino, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may optionally be further substituted; x is 0, 1, 2, 3, 4, 5 or 6; y is 0, 1, 2, 3, 4, 5 or 6; w is 0, 1, 2, 3, 4, 5, or 6; p, m and n5 are each independently 0, 1, 2 or 3, a compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

5. Ring E is selected from a 4- to 6-membered monocyclic heterocyclyl group, a 7- to 9-membered spirocyclic heterocyclyl group, or an 8- to 10-membered fused-ring heterocyclyl group; Preferably, 【Chemistry 9】 and Preferably, 【Chemistry 10】 and More preferably, 【Chemistry 11】 5. The compound according to claim 4, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

6. Furthermore, it is as shown in general formula (VII-1), 【Chemistry 12】 where: R ５ represents hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group or C １－６ hydroxyalkyl groups, Preferably, R ５ represents hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Alkoxy group, C １－３ Halogenated alkoxy group or C １－６ hydroxyalkyl groups, R ６ are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group or C １－６ hydroxyalkyl groups, Preferably, R ６ are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Alkoxy group, C １－３ Halogenated alkoxy group or C １－６ hydroxyalkyl groups, The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 4, wherein n6 is 0, 1 or 2.

7. R １ are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ an aryl group, a 5- to 14-membered heteroaryl group, —OR ａ , -P(O) ｐ (R ａ ) ｎ５ , -S(O) ｍ R ａ or -C(O)R ａ wherein the amino group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１２ an aryl group, a 5- to 12-membered heteroaryl group, —OR ａａ , -P(O) ｐ (R ａａ ) ｎ５ , -S(O) ｍ R ａａ , -Se(O) ｍ R ａａ or -C(O)R ａａ may be further substituted with one or more of Or two of them １ are connected to the atoms between them, and C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ forming an aryl group or a 5- to 14-membered heteroaryl group, ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ may be further substituted with one or more hydroxyalkyl groups; Preferably, R １ are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ an aryl group, a 5- to 14-membered heteroaryl group, —OR ａ , -P(O) ｐ (R ａ ) ｎ５ , -S(O) ｍ R ａ or -C(O)R ａ wherein the amino group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１２ an aryl group, a 5- to 12-membered heteroaryl group, —OR ａａ , -P(O) ｐ (R ａａ ) ｎ５ , -S(O) ｍ R ａａ or -C(O)R ａａ may be further substituted with one or more of Or two of them １ are connected to the atoms between them, and C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group and 5- to 14-membered heteroaryl group, ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ may be further substituted with one or more hydroxyalkyl groups; More preferably, R １ are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 3- to 10-membered heterocyclyl group, C ６－１０ an aryl group, a 5- to 12-membered heteroaryl group, —OR ａ , -P(O) ｐ (R ａ ) ｎ５ , -S(O) ｍ R ａ or -C(O)R ａ wherein the amino group, C １－３ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 3- to 10-membered heterocyclyl group, C ６－１０ The aryl and 5- to 12-membered heteroaryl groups may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C １－３ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ an aryl group, a 5- to 10-membered heteroaryl group, —OR ａａ , -P(O) ｐ (R ａａ ) ｎ５ , -S(O) ｍ R ａａ or -C(O)R ａａ may be further substituted with one or more of Even more preferably, R １ are independently -NHS(O) ２ CH ３ , -NCH ３ S (O) ２ CH ３ , -CH ２ S (O) ２ N (CH ３ ) ２ , -CH ２ Se(O) ２ CH ３ , -CH ２ S (O) ２ CH ３ , -CH ２ SOCH ３ , -CH ２ NO ２ , methyl group, hydrogen, 【Chemistry 13】 Methoxy group, cyano group, -CH ２ OCH ３ , -CH ２ CN, -CH (CN) ２ , -S(O) ２ CH ３ , oxo, hydroxy group, -CH ２ COCH ３ , -COCH ３ , -CH ２ P(O)(CH ３ ) ２ , 【Chemistry 14】 is selected from R ａａ are each independently hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ an aryl group, a 5- to 14-membered heteroaryl group, and the amino group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl group, the 5- to 14-membered heteroaryl group, may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１２ aryl groups, 5- to 12-membered heteroaryl groups, Preferably, R ａａ are each independently hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－１０ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１２ an aryl group, a 5- to 12-membered heteroaryl group, and the amino group, C １－３ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 3- to 10-membered heterocyclyl group, C ６－１２ The aryl group, the 5- to 12-membered heteroaryl group, may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ The compound of each general formula according to claim 1 or 4, its stereoisomer or pharmaceutically acceptable salt thereof, which may be further substituted with one or more of an aryl group, a 5- to 10-membered heteroaryl group.

8. R ２ are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ an aryl group, a 5- to 14-membered heteroaryl group, —OR ａ , -P(O) ｐ (R ａ ) ｎ５ , -S(O) ｍ R ａ or -C(O)R ａ wherein the amino group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１２ an aryl group, a 5- to 12-membered heteroaryl group, —OR ａａ , -P(O) ｐ (R ａａ ) ｎ５ , -S(O) ｍ R ａａ or -C(O)R ａａ may be further substituted with one or more of Preferably, R ２ are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－１０ Cycloalkyl group, 3- to 10-membered heterocyclyl group, C ６－１２ an aryl group, a 5- to 12-membered heteroaryl group, —OR ａ , -P(O) ｐ (R ａ ) ｎ５ , -S(O) ｍ R ａ or -C(O)R ａ wherein the amino group, C １－３ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－１０ Cycloalkyl group, 3- to 10-membered heterocyclyl group, C ６－１２ The aryl and 5- to 12-membered heteroaryl groups may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C １－２ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－１０ Cycloalkyl group, 3- to 10-membered heterocyclyl group, C ６－１０ an aryl group, a 5- to 10-membered heteroaryl group, —OR ａａ , -P(O) ｐ (R ａａ ) ｎ５ , -S(O) ｍ R ａａ or -C(O)R ａａ may be further substituted with one or more of R ａａ are each independently hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ an aryl group, a 5- to 14-membered heteroaryl group, and the amino group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl group, the 5- to 14-membered heteroaryl group, may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１２ aryl groups, 5- to 12-membered heteroaryl groups, Preferably, R ａａ are each independently hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１２ an aryl group, a 5- to 12-membered heteroaryl group, and the amino group, C １－３ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１２ The aryl group, the 5- to 12-membered heteroaryl group, may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ The compound of each general formula according to claim 1 or 4, its stereoisomer or pharmaceutically acceptable salt thereof, which may be further substituted with one or more of an aryl group, a 5- to 10-membered heteroaryl group.

9. R ４ are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ an aryl group, a 5- to 14-membered heteroaryl group, —OR ａ , -P(O) ｐ (R ａ ) ｎ５ , -S(O) ｍ R ａ or -C(O)R ａ wherein the amino group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be one or more R ４－１ may be further substituted with R ４－１ are each independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１２ an aryl group, a 5- to 12-membered heteroaryl group, —OR ａａ , -P(O) ｐ (R ａａ ) ｎ５ , -S(O) ｍ R ａａ or -C(O)R ａａ and optionally R ４－１ represents hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１２ aryl group, 5- to 12-membered heteroaryl group, wherein the amino group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, C １－６ The hydroxyalkyl group may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, C １－６ substituted with one or more of hydroxyalkyl groups; Preferably, R ４ are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－１０ Cycloalkyl group, 3- to 10-membered heterocyclyl group, C ６－１２ an aryl group, a 5- to 12-membered heteroaryl group, —OR ａ , -P(O) ｐ (R ａ ) ｎ５ , -S(O) ｍ R ａ or -C(O)R ａ wherein the amino group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－１０ Cycloalkyl group, 3- to 10-membered heterocyclyl group, C ６－１２ The aryl and 5- to 12-membered heteroaryl groups may optionally be one or more R ４－１ may be further substituted with R ４－１ are each independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－１０ Cycloalkyl group, 3- to 10-membered heterocyclyl group, C ６－１２ an aryl group, a 5- to 12-membered heteroaryl group, —OR ａａ , -P(O) ｐ (R ａａ ) ｎ５ , -S(O) ｍ R ａａ or -C(O)R ａａ and optionally R ４－１ represents hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－１０ Cycloalkyl group, 3- to 10-membered heterocyclyl group, C ６－１２ aryl group, 5- to 12-membered heteroaryl group, wherein the amino group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ The hydroxyalkyl group may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ substituted with one or more of hydroxyalkyl groups; Or, R ４ are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ an aryl group, a 5- to 14-membered heteroaryl group, —OR ａ , -P(O) ｐ (R ａ ) ｎ５ , -S(O) ｍ R ａ or -C(O)R ａ wherein the amino group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１２ an aryl group, a 5- to 12-membered heteroaryl group, —OR ａａ , -P(O) ｐ (R ａａ ) ｎ５ , -S(O) ｍ R ａａ or -C(O)R ａａ may be further substituted with one or more of R ａａ are each independently hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ an aryl group, a 5- to 14-membered heteroaryl group, and the amino group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl group, the 5- to 14-membered heteroaryl group, may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１２ aryl groups, 5- to 12-membered heteroaryl groups, Preferably, R ａａ are each independently hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１２ an aryl group, a 5- to 12-membered heteroaryl group, and the amino group, C １－３ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１２ The aryl group, the 5- to 12-membered heteroaryl group, may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more of an aryl group, a 5- to 10-membered heteroaryl group, Even more preferably, R ４ are independently fluorine, chlorine, cyano group, trifluoromethyl group, methyl group, ethyl group, nitro group, hydroxy group, methoxy group, -OCD ３ ,hydrogen, 【Chemistry 15】 a cyclopropyl group, 【Chemistry 16】 difluoromethyl group, 【Chemistry 17】 5. A compound of any of the general formulae according to claim 1 or 4, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

10. R ａ are each independently hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ an aryl group, a 5- to 14-membered heteroaryl group, and the amino group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl group, the 5- to 14-membered heteroaryl group, may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１２ aryl groups, 5- to 12-membered heteroaryl groups, Preferably, R ａ are each independently hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－１０ Cycloalkyl group, 3- to 10-membered heterocyclyl group, C ６－１２ an aryl group, a 5- to 12-membered heteroaryl group, and the amino group, C １－３ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－１０ Cycloalkyl group, 3- to 10-membered heterocyclyl group, C ６－１２ The aryl group, the 5- to 12-membered heteroaryl group, may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－１０ Cycloalkyl group, 3- to 10-membered heterocyclyl group, C ６－１０ The compound of each general formula according to claim 1 or 4, its stereoisomer or pharmaceutically acceptable salt thereof, which may be further substituted with one or more of an aryl group, a 5- to 10-membered heteroaryl group.

11. Furthermore, it is as shown in general formula (VII-2), 【Chemistry 18】 where: M １１ is CH or N, R １－１ is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, halogenated methyl, and halogenated ethyl; R １－２ represents an amino group, a hydroxy group, a cyano group, C １－３ Alkoxy group, C １－３ Alkyl group, C ３－６ a cycloalkyl group, a 3- to 8-membered heterocyclyl group, and １－３ Alkoxy group, C １－３ Alkyl group, C ３－６ The cycloalkyl group and the 3- to 8-membered heterocyclyl group may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, —C(O)R ｅｅ , -OR ｅｅ , -P(O) ｐ (R ｅｅ ) ｎ５ , -S(O) ｍ R ｅｅ , -S(O) ２ N (R ｅｅ ) ２ and -S(=O)(=NCN)R ｅｅ and preferably R １－２ is -NHS(O) ２ CH ３ , -NCH ３ S (O) ２ CH ３ , -CH ２ S (O) ２ N (CH ３ ) ２ , -CH ２ S (O) ２ CH ３ , -CH ２ SOCH ３ , -CH ２ NO ２ , methyl group, hydrogen, 【Chemistry 19】 Methoxy group, cyano group, -CH ２ OCH ３ , -CH ２ CN, -CH (CN) ２ , hydroxy group, —CH ２ COCH ３ , 【Chemistry 20】 is selected from R ２ are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, halogenated methyl, and halogenated ethyl; R ２－１ is an amino group, C １－３ Alkyl group, halogenated C １－３ Alkyl group or deuterated C １－３ alkyl group, the amino group, C １－３ Alkyl group, halogenated C １－３ Alkyl groups and deuterated C １－３ The alkyl group may optionally contain deuterium, halogen, cyano, hydroxy, nitro, C １－３ Alkyl group, halogenated C １－３ Alkyl group or deuterated C １－３ may be further substituted with one or more alkyl groups; R ４ is a halogen, an amino group, a hydroxy group, a cyano group, a nitro group, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－６ Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, —S(O) ｍ R ｄ or -C(O)R ｄ wherein the amino group, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－６ The cycloalkyl and 3- to 8-membered heterocyclyl groups may optionally be one or more R ４－１ may be further substituted with R ４－１ are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１２ aryl group or 5- to 12-membered heteroaryl group, and optionally R ４－１ represents hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１２ aryl group, 5- to 12-membered heteroaryl group, wherein the amino group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ The hydroxyalkyl group may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ hydroxyalkyl groups, preferably R ４ represents fluorine, chlorine, cyano group, trifluoromethyl group, methyl group, ethyl group, nitro group, hydroxy group, methoxy group, -OCD ３ ,hydrogen, 【Chemical 21】 a cyclopropyl group, 【Chemical 22】 difluoromethyl group, 【Chemical 23】 is selected from R ６－１ represents hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C １－３ Halogenated alkyl group, C １－３ Deuterated alkyl groups, C １－３ Alkoxy group, C １－３ hydroxyalkyl groups, R ６－２ represents hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl groups, 3- to 6-membered heterocyclyl groups, —S(O) ｍ R ｅ or -C(O)R ｅ wherein the amino group, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ The cycloalkyl and 3- to 6-membered heterocyclyl groups may optionally be substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, and C １－３ may be further substituted with one or more alkyl groups; R ｄ are independently hydrogen, deuterium, an amino group, a hydroxy group, a cyano group, a nitro group, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl group, 3- to 6-membered heterocyclyl group, C １－３ Halogenated alkyl group or C １－３ deuterated alkyl groups, R ｅ are independently hydrogen, deuterium, an amino group, a hydroxy group, a cyano group, a nitro group, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl group, 3- to 6-membered heterocyclyl group, C １－３ Halogenated alkyl group or C １－３ deuterated alkyl groups, R ｅｅ are independently hydrogen, deuterium, an amino group, a hydroxy group, a cyano group, a nitro group, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl group, 3- to 6-membered heterocyclyl group, C １－３ Halogenated alkyl group or C １－３ deuterated alkyl groups, m is 0, 1 or 2; p is 0, 1 or 2; n5 is 0, 1 or 2; 2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein y is 0, 1, 2, 3 or 4.

12. Furthermore, it is as shown in general formula (VII-3), 【Chemistry 24】 where: M １２ is a bond, NR ９ or CR １０ R １１ is selected from R ９ is selected from hydrogen, deuterium, a methyl group, an ethyl group, a monofluoromethyl group, a difluoromethyl group, or a trifluoromethyl group; R １０ is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, monofluoromethyl, difluoromethyl or trifluoromethyl; R １１ is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, monofluoromethyl, difluoromethyl or trifluoromethyl; R １－１ is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, monofluoromethyl, difluoromethyl or trifluoromethyl; R ２ are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, monofluoromethyl, difluoromethyl, or trifluoromethyl; R ２－１ is an amino group, C １－３ Alkyl group, halogenated C １－３ Alkyl group or deuterated C １－３ alkyl group, the amino group, C １－３ Alkyl group, halogenated C １－３ Alkyl group or deuterated C １－３ The alkyl group may optionally contain deuterium, halogen, cyano, hydroxy, nitro, C １－３ Alkyl group, halogenated C １－３ Alkyl groups and deuterated C １－３ may be further substituted with one or more alkyl groups; Preferably, R ２－１ is an isopropyl group, —CH(Me)OMe, or —N(Me) ２ is selected from R ４ is a halogen, an amino group, a hydroxy group, a cyano group, a nitro group, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－６ Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, —S(O) ｍ R ｄ or -C(O)R ｄ wherein the amino group, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－６ The cycloalkyl and 3- to 8-membered heterocyclyl groups may optionally be one or more R ４－１ may be further substituted with R ４－１ are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１２ aryl group or 5- to 12-membered heteroaryl group, and optionally R ４－１ represents hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１２ aryl group, 5- to 12-membered heteroaryl group, wherein the amino group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ The hydroxyalkyl group may optionally be substituted with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ hydroxyalkyl groups, preferably R ４ are independently fluorine, chlorine, cyano group, trifluoromethyl group, methyl group, ethyl group, nitro group, hydroxy group, methoxy group, -OCD ３ ,hydrogen, 【Chemistry 25】 a cyclopropyl group, 【Chemical 26】 difluoromethyl group, 【Chemical 27】 is selected from R ６－１ represents hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ hydroxyalkyl groups, R ６－２ represents hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl groups, 3- to 6-membered heterocyclyl groups, —S(O) ｍ R ｅ or -C(O)R ｅ wherein the amino group, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ The cycloalkyl and 3- to 8-membered heterocyclyl groups may optionally be substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C １－３ may be further substituted with one or more alkyl groups; R ｄ are independently hydrogen, deuterium, an amino group, a hydroxy group, a cyano group, a nitro group, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl group, 3- to 6-membered heterocyclyl group, C １－３ Halogenated alkyl group, C １－３ deuterated alkyl groups, R ｅ are independently hydrogen, deuterium, an amino group, a hydroxy group, a cyano group, a nitro group, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl group, 3- to 6-membered heterocyclyl group, C １－３ Halogenated alkyl group, C １－３ deuterated alkyl groups, m is 0, 1 or 2; 12. The compound of each of the general formulae according to claim 11, its stereoisomers or pharmaceutically acceptable salts thereof, wherein y is 0, 1, 2, 3 or 4.

13. Specific compounds include: 【Chemical formula 28】 【Chemical formula 29】 【Chemistry 30】 【Chemical 31】 【Chemical 32】 2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

14. 10. Use of the compound according to claim 1 or 4, its stereoisomer or a pharmaceutically acceptable salt thereof in the manufacture of an EGFR inhibitor pharmaceutical.

15. The application of claim 14, wherein the EGFR is a mutated EGFR, preferably one or more mutations of Del19, L858R, T790M or C797S, more preferably L858R / T790M, Del19 / T790M, Del19 / C797S, L858R / C797S, Del19 / T790M / C797S or L858R / T790M / C797S mutant EGFR.

16. 10. The use of the compound according to claim 1 or 4, its stereoisomer or its pharmaceutically acceptable salt in the manufacture of a medicament for treating cancer, wherein preferably, the cancer is non-small cell lung cancer.

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