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

Abstract

The present invention relates to nitrogen-containing heterocyclic derivative EGFR inhibitors, their preparation method and application, in particular to a compound represented by general formula (I) and its preparation, pharmaceutical composition containing said compound, and its use as an EGFR inhibitor in the treatment of cancer:

Description

[Technical Field]

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

[0002] The epidermal growth factor receptor (EGFR) is a member of the ErbB family of transmembrane receptor tyrosine kinases and is activated by binding to its ligands, epidermal growth factor (EGF) or transforming growth factor α (TGFα). Activated EGFR forms homodimers on the cell membrane or heterodimers with other receptors in the family (e.g., ErbB-2, ErbB-3, or ErbB-4), resulting in phosphorylation of key tyrosine residues within the EGFR, activating downstream signaling pathways and playing an important role in cell proliferation, survival, and anti-apoptosis. Activating mutations, overexpression, or gene amplification of EGFR cause excessive activation of EGFR, promoting its transformation into tumor cells and playing an important role in tumor cell proliferation, invasion, metastasis, and angiogenesis. EGFR is therefore an important target for the development of anticancer drugs, particularly for lung cancer.

[0003] First-generation EGFR small molecule inhibitors, including gefitinib (Iressa) and erlotinib (Tarceva), have shown favorable therapeutic effects in the treatment of lung cancer and are used as first-line drugs for 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 develop drug resistance to these inhibitors, and more than half of these drug resistance mechanisms are due to secondary mutations at the EGFR gatekeeper gene residue, T790M.

[0004] Osimertinib (AZD9291), a third-generation EGFR TKI inhibitor, has a high response rate and favorable therapeutic efficacy against drug resistance due to the EGFR T790M mutation. It was approved by the US FDA in November 2015 and is currently effective in treating patients with advanced non-small cell lung cancer (NSCLC) with the EGFR T790M drug resistance mutation. While osimertinib has shown significant success in the clinical treatment of EGFR T790M NSCLC, patients still experience drug resistance after 9–14 months of treatment. Studies have shown that 20–40% of patients with EGFR resistance experience drug resistance due to the EGFR C797S mutation. The EGFR C797S mutation converts cysteine ​​at position 797 to serine, preventing osimertinib from forming a covalent bond with the EGFR protein, resulting in drug resistance. Currently, no effective inhibitors for the EGFR C797S drug resistance mutation are available 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 has reported the compound EAI0450 for EGFR C797S drug resistance, which belongs to the EGFR allosteric inhibitor class. After being combined with an EGFR monoclonal antibody drug such as cetuximab, it showed better antitumor effects in an in vivo pharmacodynamic model of mice with the L858R / T790M / C797S mutation. However, the compound was ineffective as a single agent and was unable to inhibit the C797S drug resistance mutation containing deIE746_A750, and therefore could not proceed to clinical studies. In 2017, Ken Uchibori et al. reported that the combination of Brigatinib (AP26113) with an EGFR monoclonal antibody (e.g., cetuximab) can overcome drug resistance to third-generation EGFR inhibitors due to the C797S mutation, and demonstrated favorable antitumor effects in a PC9 (EGFR-C797S / T790M / de119) mouse pharmacodynamic model. However, Brigatinib as a single agent has problems such as low activity in vitro and no significant antitumor activity in vivo, and further clinical studies have not been conducted.

[0006] Lung cancer is a serious disease threatening human health, ranking first in mortality among all malignant tumors. In China, the incidence of lung cancer is increasing year by year, with approximately 700,000 new cases occurring each year. In China, lung cancer with EGFR-activating mutations accounts for approximately 35% of all NSCLC cases. While first- or third-generation EGFR inhibitors have demonstrated favorable therapeutic effects, new drug-resistant mutations emerge in the later stages. Therefore, the development of next-generation EGFR inhibitors that prevent drug resistance is of great clinical and commercial value. Summary of the Invention

[0007] An object of the present invention is to provide a compound represented by general formula (I), a stereoisomer thereof, or a pharmaceutically 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 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 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 optionally be further substituted, or two R groups therein may be linked to the atom between them to form a cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, wherein the cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be 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 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; 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 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; or one R2 and one R4, joined to the atom therebetween, 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, wherein said 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, 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; 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 each independently represent 0, 1, 2, or 3.

[0008] In some embodiments of the present invention, the compound of formula (I) is further represented by general formula (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), [ka] where: [ka] represents a saturated, unsaturated or partially saturated ring, [ka] is a single or 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, m1 is 0, 1, 2, 3 or 4.

[0009] In some embodiments of the present invention, ring A is C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, wherein the heteroatoms in the 3- to 12-membered heterocyclyl group and the 5- to 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 L and R are directly linked; Preferably, ring A is C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, wherein the heteroatoms in the 3- to 12-membered heterocyclyl group and the 5- to 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- 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; More preferably, [ka] and more preferably, [ka] and More preferably, [ka] and Even more preferably, ring A is [ka] is.

[0010] In some embodiments of the present invention, ring B is C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, wherein the heteroatoms in the 3- to 12-membered heterocyclyl group and the 5- to 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- to 14-membered heteroaryl group, and the heteroaryl group is a monocyclic or fused ring, and is preferably an 8- to 14-membered heteroaryl group; Preferably, ring B is [ka] and preferably, ring B is [ka] and more preferably, ring B is [ka] and more preferably, ring B is [ka] is.

[0011] In some embodiments of the present invention, ring C is C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14an aryl group or a 5- to 14-membered heteroaryl group, wherein the heteroatoms in the 3- to 12-membered heterocyclyl group and the 5- to 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- to 6-membered heteroaryl group; More preferably, ring C is [ka] and more preferably, ring C is [ka] and even more preferably, ring C is [ka] is.

[0012] In some embodiments of the present invention, ring D is C 3-12 Cycloalkyl groups, 3- to 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, and preferably C 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, wherein the 5- to 8-membered heterocyclyl group is 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, More preferably, ring D is [ka] and preferably [ka] and preferably, ring D is [ka] and more preferably, ring D is [ka] is.

[0013] 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), (X), (XI), (XII), (XIII), or (XIV): [ka] where: [ka] is a single or 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.

[0014] 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.

[0015] 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.

[0016] 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, or -CH2S(O)2CH2CH3.

[0017] In some embodiments of the present invention, 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 [ka] and more preferably, [ka] and preferably [ka] and more preferably, [ka] This is the base.

[0018] In some embodiments of the present invention, the compound is further represented by general formula (VII-1) or (VIII-1): [ka] wherein 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 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy group, 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 1-6 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 More 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.

[0019] In some embodiments of the present invention, R6 is a methyl group, a deuterated methyl group, fluorine, or chlorine.

[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 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 Aryl group, 5- to 14-membered heteroaryl group, -(CH2) n OR a , -(CH2) n P(O) p (R a ) n5 , -(CH2) n S(O)R aa N(R aa ), -(CH2) n N=S(O)(R aa )2, -(CH2) n S(O) m R a or -(CH2) n 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 1-6Alkyl 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 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, -OR aa , -S(O)R aa N(R aa ), -N=S(O)(R aa )2, -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 to form a 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 It may be further substituted with one or more hydroxyalkyl groups.

[0025] In some embodiments of the present invention, R1 is 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, C1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 Aryl group, 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 groups, 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, -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 to form C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14aryl 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; Preferably, R1 is 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 Aryl group, 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 groups, C1-6 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, -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 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- to 10-membered heterocyclyl groups, C 6-10 Aryl group, 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 groups, 3- to 10-membered heterocyclyl groups, C 6-10 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, C1-3 Alkoxy group, halogenated C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 Aryl group, 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 Or, two of the R1s are linked to the atom between them to form 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; Preferably, two of R1 are linked to the atom between them and form C 3-10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, C 6-12 An aryl group and a 5- to 12-membered heteroaryl group are formed, and 3-10 Cycloalkyl groups, 3- to 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 1-3It may be further substituted with one or more hydroxyalkyl groups.

[0026] In some embodiments of the present invention, R1 is -CH2S(O)2N(CH3)2, -CH2Se(O)2CH3, -CH2S(O)2CH3, -CH2S(O)2F, -NCH3S(O)2CH3, -NHS(O)2CH3, 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, -CH2NO2, [ka] or two R1's are linked to the atom between them to form a 3- to 12-membered heterocyclyl group, preferably [ka] is.

[0027] In some embodiments of the present invention, R1 is -CH2S(O)2N(CH3)2, -CH2Se(O)2CH3, -CH2S(O)2CH3, -CH2S(O)2F, -NHS(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, -CH2P(O)(CH3)2, or -CH2NO2, or two R1's are linked to the atom between them to form a 3- to 12-membered heterocyclyl group, preferably [ka] is.

[0028] In some embodiments of the present invention, R1 is -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 thereof are linked to the atom between them to form a 3- to 12-membered heterocyclyl group, preferably [ka] is.

[0029] In some embodiments of the present invention, R1 is -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 R1's are linked to the atom between them to form a 3- to 12-membered heterocyclyl group, preferably [ka] is.

[0030] In some embodiments of the present invention, R1 is -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 R1's are linked to the atom between them to form a 3- to 12-membered heterocyclyl group, preferably [ka] is.

[0031] 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 aaC(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-.

[0032] In some embodiments of the present invention, R2 is 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 Aryl group, 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 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, 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 6-14 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 2-6Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, 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, -OR aa , -P(O) p (R aa ) n5 , -S(O) m R aa or -C(O)R aa Preferably, R2 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- to 10-membered heterocyclyl groups, C 6-12 Aryl group, 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 groups, 3- to 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 1-2 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, halogenated C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, C 6-10 Aryl group, 5- to 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 an isopropyl group, a cyano group, a trifluoromethyl group, or —OCH2CF3, and even more preferably, R2 is an isopropyl group or —OCH2CF3.

[0033] In some embodiments of the present invention, R2 is oxo, fluorine, an isopropyl group, a cyano group, a trifluoromethyl group, -NHCH(CH)3, or -OCH2CF3.

[0034] 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 -,-(CRaa 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.

[0035] In some embodiments of the present invention, R3 is 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 Aryl group, 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, C2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, 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 6-14 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 groups, 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, -OR aa , -P(O) p (R aa ) n5 , -S(O) m R aa or -C(O)R aa and 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- to 10-membered heterocyclyl groups, C 6-12 Aryl group, 5- to 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 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3- to 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 group, halogenated C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, C 6-10 Aryl group, 5- to 10-membered heteroaryl group, -OR aa , -P(O) p (R aa ) n5 , -S(O) m R aa or -C(O)R aa or R3 and R4 may be linked to form a 5-10 membered heterocyclyl group, more preferably R3 is hydrogen.

[0036] In some embodiments of the present invention, -R3-R4- is -OCH2-.

[0037] In some embodiments of the present invention, R3 is selected from hydrogen, a methoxy group, a methyl group, fluorine, chlorine, bromine, a trifluoromethyl group, a cyano group, a cyclopropyl group, or -COCH3.

[0038] In some embodiments of the present invention, R4 is hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro 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- to 12-membered heterocyclyl groups, C 6-14 Aryl group, 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 group and the 5- to 14-membered heteroaryl group may optionally be R 4-1 and 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 groups, 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, -OR aa , -P(O) p (R aa ) n5 , -S(O) m R aa or -C(O)R aa and optionally R 4-1represents 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 groups, 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 groups, 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 groups, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 1-6 It is substituted with one or more of the hydroxyalkyl groups.

[0039] In some embodiments of the present invention, R4 is 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 groups, 3- to 10-membered heterocyclyl groups, C6-12 Aryl group, 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 groups, 3- to 10-membered heterocyclyl groups, C 6-12 The aryl group and the 5- to 10-membered heteroaryl group may optionally be R 4-1 and 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 groups, C 1-3 Alkoxy group, halogenated C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, C 6-12 Aryl group, 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 groups, C1-3 Alkoxy group, halogenated C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, 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 groups, 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 groups, C 1-3 Alkoxy group, halogenated C 1-3 Alkoxy group, C 1-3 It is substituted with one or more of the hydroxyalkyl groups.

[0040] In some embodiments of the present invention, R4 is fluorine, chlorine, a methyl group, a hydroxy group, a methoxy group, a nitro group, oxo, -CD3, -OCD3, -CH2F, -CHF2, CH2CF3, -CH2CH2F, hydrogen, -CH2OCH3, -CF3, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2CN, -CH2CH2N(CH3)2, -CH2CH2NH2, -CH2CH2NHCH3, an amino group, oxo, -COCH3, a cyclopropyl group, [ka] is.

[0041] In some embodiments of the present invention, R4 is fluorine, chlorine, a methyl group, a hydroxy group, a methoxy group, a nitro group, oxo, -OCD3, -CH2F, -CHF2, CH2CF3, -CH2CH2F, hydrogen, -CH2OCH3, -CF3, -CH2CH2OH, an amino group, oxo, -COCH3, a cyclopropyl group, [ka] is.

[0042] In some embodiments of the present invention, R4 is fluorine, a methyl group, a hydroxy group, a methoxy group, -OCD3, -CH2F, -CHF2, CH2CF3, -CH2CH2F, hydrogen, -CH2OCH3, -CF3, an amino group, oxo, -COCH3, [ka] is.

[0043] In some embodiments of the present invention, R4 is 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 Aryl group, 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 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, halogenated C 1-6Alkoxy 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 groups, 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, -OR aa , -P(O) p (R aa ) n5 , -S(O) m R aa or -C(O)R aa Preferably, R4 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- to 10-membered heterocyclyl groups, C 6-12 Aryl group, 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, C1-3 Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3- to 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 group, halogenated C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, C 6-10 Aryl group, 5- to 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, R4 is fluorine, a methyl group, a hydroxy group, a methoxy group, -OCD3, hydrogen, [ka] and more preferably, R4 is fluorine, a methyl group, a hydroxy group, a methoxy group, -OCD3, hydrogen, [ka] is.

[0044] In some embodiments of the present invention, one R2 and one R4 are linked to the atom between them and are C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 An aryl group or a 5- to 14-membered heteroaryl group is formed, and 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14The 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 groups, 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 It may be further substituted with one or more of an aryl group, a 5- to 12-membered heteroaryl group, and preferably, where -R2-R4- is [ka] and more preferably, where -R2-R4- is [ka] is.

[0045] In some embodiments of the present invention, R a represents 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 6-14The 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 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 It may be further substituted with one or more of an aryl group, a 5- to 12-membered heteroaryl group. a represents 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 groups, 3- to 10-membered heterocyclyl groups, 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 groups, 3- to 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 group, halogenated C 1-3 Alkoxy group, C 1-3Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3- to 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.

[0046] In some embodiments of the present invention, R aa , R bb and R cc 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 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 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 It may be further substituted with one or more of an aryl group, a 5- to 12-membered heteroaryl group. aa , R bb and R ccare 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 groups, 3- to 10-membered heterocyclyl groups, 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 groups, 3- to 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 group, halogenated C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3- to 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.

[0047] In some embodiments of the present invention, the compound is further represented by general formula (VII-2), (VII-3), or (VII-4): [ka] R1 independently represents hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-3 Alkyl group, C 2-3Alkenyl 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, -(CH2) n OR a , -(CH2) n P(O) p (R a ) n5 , -(CH2) n S(O)R aa N(R aa ), -(CH2) n N=S(O)(R aa )2, -(CH2) n S(O) m R a or -(CH2) n 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 The cycloalkyl group and the 3- to 10-membered heterocyclyl 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 group, halogenated C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, -OR aa , -S(O)R aa N(R aa ), -N=S(O)(R aa )2, -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 R2 independently represents hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-3 Alkyl groups, halogenated C 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 1-3 Alkoxy group, C 1-3 hydroxyalkyl groups, R4 independently 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 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, -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 The cycloalkyl group and the 3- to 10-membered heterocyclyl group are optionally R 4-1 and 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 groups, C 1-3 Alkoxy group, halogenated C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-6 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-12 aryl group or 5- to 12-membered heteroaryl group, and optionally R4-1 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 groups, C 1-3 Alkoxy group, halogenated C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-6 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, 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 groups, 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 groups, C 1-3 Alkoxy group, halogenated C 1-3 Alkoxy group, C 1-3 hydroxyalkyl groups, preferably 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 groups, C 1-3 Alkoxy group, halogenated C 1-3 Alkoxy group, C 1-3hydroxyalkyl groups, 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 groups, C 1-3 Alkoxy group, halogenated C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-10 cycloalkyl groups, 3- to 10-membered heterocyclyl groups, 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 groups, 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 groups, C 1-3 Alkoxy group, halogenated C 1-3 Alkoxy group, C 1-3 substituted with one or more of hydroxyalkyl groups; R5 independently represents hydrogen, deuterium, oxo, thio, 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, C 1-3 hydroxyalkyl groups, and the amino group, C 1-3Alkyl groups, halogenated C 1-3 Alkyl groups and deuterated C 1-3 The alkyl group may optionally be substituted with deuterium, halogen, cyano, hydroxy, nitro, C 1-3 Alkyl groups, halogenated C 1-3 Alkyl group or deuterated C 1-3 R5 may be further substituted with one or more of an alkyl group, preferably 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, R6 independently 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 a or -C(O)R a 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 R6 may be further substituted with one or more of an alkyl group, and preferably R6 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 Halogenated alkoxy groups, C 1-6 hydroxyalkyl groups, Ra are independently hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-3 Alkyl group, C 1-3 Halogenated alkyl groups, C 1-3 Deuterated 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, and 3- to 10-membered heterocyclyl groups, preferably R a represents 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 a cycloalkyl group, a 3- to 10-membered heterocyclyl group, 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 groups, x is 0, 1, 2, or 3, y is 0, 1, 2, 3, p is 0, 1, 2 or 3; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; n5 is 0, 1, 2 or 3; n6 is 0, 1 or 2.

[0048] In some embodiments of the present invention, the compound is further represented by general formula (VII-2-1), (VII-3-1), or (VII-4-1): [ka] where: M 11 are independently CH or N, R 1-1 are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, and halogenated methyl; R 1-2 are independently 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, 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 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 and preferably R 1-2 are -NHS(O)2CH3, -NCH3S(O)2CH3, -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 R 2-1are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, halogenated methyl, and halogenated ethyl; R 2-2 are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, halogenated methyl, and halogenated ethyl; R 2-3 are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, halogenated methyl, and halogenated ethyl; R 2-4 are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, halogenated methyl, and halogenated ethyl; R5 independently represents 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, halogen, cyano, hydroxy, nitro, C 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 independently represents a halogen atom, an amino group, a hydroxy 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- 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, C3-6 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 groups, C 1-3 Alkoxy group, halogenated C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-6 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, 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 groups, C 1-3 Alkoxy group, halogenated C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-6 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, 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 groups, 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 1-3Alkyl 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 group, halogenated C 1-3 Alkoxy group, C 1-3 Preferably, R4 is fluorine, chlorine, cyano, trifluoromethyl, methyl, ethyl, nitro, hydroxy, methoxy, -OCD3, hydrogen, [ka] a cyclopropyl group, [ka] difluoromethyl group, [ka] [ka] More preferably, R4 is 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 are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-3 Alkyl group, C 1-3 Halogenated alkyl groups, C 1-3 Deuterated alkyl groups, C 1-3Alkoxy group, C 1-3 hydroxyalkyl groups, R 6-2 are independently 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, 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, C 1-3 Halogenated alkyl group or C 1-3 deuterated alkyl groups; R e are independently hydrogen, deuterium, 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, C 1-3 Halogenated alkyl group or C 1-3 deuterated alkyl groups; R ee are independently hydrogen, deuterium, amino group, hydroxy group, cyano group, nitro group, C 1-3 Alkyl group, C1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclyl groups, C 1-3 Halogenated alkyl group or C 1-3 deuterated alkyl groups; m is independently 0, 1 or 2; p is independently 0, 1 or 2; n5 is independently 0, 1 or 2.

[0049] In some embodiments of the present invention, the compound is further represented by general formula (VII-2-1-1), (VII-3-1-1), or (VII-4-1-1): [ka] where: M 12 are independently a bond, NR9 or CR 10 R 11 is selected from R9 is independently selected from hydrogen, deuterium, methyl, ethyl, monofluoromethyl, difluoromethyl, or trifluoromethyl; R 10 are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, monofluoromethyl, difluoromethyl, or trifluoromethyl; R 11 are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, monofluoromethyl, difluoromethyl, or trifluoromethyl; R 1-1 are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, monofluoromethyl, difluoromethyl, or trifluoromethyl; R 2-1 are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, halogenated methyl, and halogenated ethyl; R 2-2are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, halogenated methyl, and halogenated ethyl; R 2-3 are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, halogenated methyl, and halogenated ethyl; R 2-4 are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, halogenated methyl, and halogenated ethyl; R5 independently represents 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, halogen, cyano, hydroxy, nitro, C 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, R5 is independently selected from an isopropyl group, -CH(Me)OMe, or -N(Me)2; R4 independently represents a halogen atom, an amino group, a hydroxy 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- 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 3-6The 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 groups, C 1-3 Alkoxy group, halogenated C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-6 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, 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 groups, C 1-3 Alkoxy group, halogenated C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-6 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, 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 groups, 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, C2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, halogenated C 1-3 Alkoxy group, C 1-3 Preferably, R4 is fluorine, chlorine, cyano, trifluoromethyl, methyl, ethyl, nitro, hydroxy, methoxy, -OCD3, hydrogen, [ka] a cyclopropyl group, [ka] difluoromethyl group, [ka] [ka] More preferably, R4 is selected from fluorine, chlorine, cyano, trifluoromethyl, methyl, ethyl, nitro, hydroxy, methoxy, -OCD3, hydrogen, [ka] a cyclopropyl group, [ka] difluoromethyl group, [ka] [ka] is selected from R 6-1 are independently hydrogen, deuterium, oxo, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C1-3 hydroxyalkyl groups, R 6-2 are independently 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 group and the 3- to 8-membered heterocyclyl group 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, 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, C 1-3 Halogenated alkyl groups, C 1-3 deuterated alkyl groups; R e are independently hydrogen, deuterium, 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, C 1-3 Halogenated alkyl groups, C 1-3 deuterated alkyl groups; m is independently 0, 1 or 2.

[0050] In some embodiments of the present invention, the compound is further represented by general formula (VII-2-1-2), (VII-3-1-2), or (VII-4-1-2): [ka] where: M 12 are independently a bond, NR9 or CR 10 R 11 is selected from R9 is independently selected from hydrogen, deuterium, methyl, ethyl, monofluoromethyl, difluoromethyl, or trifluoromethyl; R 10 are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, monofluoromethyl, difluoromethyl, or trifluoromethyl; R 11 are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, monofluoromethyl, difluoromethyl, or trifluoromethyl; R 1-1 are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, monofluoromethyl, difluoromethyl, or trifluoromethyl; R 2-1 are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, halogenated methyl, and halogenated ethyl; R 2-2 are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, halogenated methyl, and halogenated ethyl; R 2-3 are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, halogenated methyl, and halogenated ethyl; R 2-4 are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, halogenated methyl, and halogenated ethyl; R5 independently represents an amino group, C 1-3Alkyl 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, halogen, cyano, hydroxy, nitro, C 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, R5 is independently selected from an isopropyl group, -CH(Me)OMe, or -N(Me)2; L4 independently represents a bond, C 1-3 Alkylene group, C 2-4 Alkenylene group, C 2-4 Alkynylene group, -(CH2) n7 NH(CH2) n8 -, -(CH2) n9 O(CH2) n10 wherein C is selected from 1-3 Alkylene group, C 2-4 Alkenylene group, C 2-4 Alkynylene group, -(CH2) n7 NH(CH2) n8 -, -(CH2) n9 O(CH2) n10 - is optionally a halogen, an amino group, a hydroxy group, a cyano group, a 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 group, halogenated C 1-3 Alkoxy group, C 1-3 substituted with one or more of hydroxyalkyl groups; Ring F is independently C 3-6 Preferably, ring F is independently selected from a cycloalkyl group or a 3- to 8-membered heterocyclyl group. [ka] and more preferably, ring F is independently selected from [ka] is selected from R 12 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 groups, C 1-3 Alkoxy group, halogenated C 1-3 Alkoxy group, C 1-3 hydroxyalkyl groups, 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 group, halogenated C 1-3 Alkoxy group, C 1-3 The hydroxyalkyl group may optionally be substituted with a halogen, an amino group, a hydroxy group, a cyano group, a nitro group, a 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 group, halogenated C 1-3 Alkoxy group, C 1-3 substituted with one or more of hydroxyalkyl groups; R 6-1 are independently hydrogen, deuterium, oxo, 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 6-2are independently 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 group and the 3- to 8-membered heterocyclyl group 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, 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, C 1-3 Halogenated alkyl groups, C 1-3 deuterated alkyl groups; R e are independently hydrogen, deuterium, 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, C 1-3 Halogenated alkyl groups, C 1-3 deuterated alkyl groups; m is independently 0, 1 or 2; n7 is independently 0, 1 or 2; n8 is independently 0, 1 or 2; n9 is independently 0, 1 or 2; n10 is independently 0, 1 or 2; u is independently 0, 1 or 2.

[0051] The present invention provides a method for producing a compound represented by the above general formula (II-G), its stereoisomer, or a pharmaceutically acceptable salt thereof, which comprises the step of reacting a compound represented by formula (XV) with a compound represented by formula (XVI) to obtain a compound represented by formula (II-G): [ka] where X is a halogen, preferably chlorine; Further provided is a method, wherein R1, x, ring B, R2, y, M1, R4, and w are as described above.

[0052] The present invention provides a method for producing a compound represented by the above general formula (VII-1), its stereoisomer, or a pharmaceutically acceptable salt thereof, which comprises the steps of reacting a compound represented by formula (XV-1) with a compound represented by formula (XVI-1) to obtain a compound represented by formula (VII-1), [ka] where X is a halogen, preferably chlorine; The method is further provided, wherein R1, x, M3, M5, R5, R2, y, R6, R4 and n6 are as described above.

[0053] The present invention provides a method for producing a compound represented by the above general formula (VII-2), its stereoisomer, or a pharmaceutically acceptable salt thereof, which comprises the steps of reacting a compound represented by formula (XV-2) with a compound represented by formula (XVI-2) to obtain a compound represented by formula (VII-2), [ka] where X is a halogen, preferably chlorine; The method is further provided, wherein R1, x, R5, R2, y, R6, R4 and n6 are as described above.

[0054] The present invention provides a method for producing a compound represented by the above general formula (VII-2-1), its stereoisomer, or a pharmaceutically acceptable salt thereof, which comprises the steps of reacting a compound represented by formula (XV-3) with a compound represented by formula (XVI-3) to obtain a compound represented by formula (VII-2-1), [ka] where X is a halogen, preferably chlorine; R 1-1 , R 1-2 , M 11 , R 2-1 , R 2-2 , R 2-3 , R 2-4 , R5, R 6-1 , R 6-2 and R4 is as described above.

[0055] The present invention provides a method for producing a compound represented by the above general formula (VII-2-1-1), its stereoisomer, or a pharmaceutically acceptable salt thereof, which comprises the steps of reacting a compound represented by formula (XV-4) with a compound represented by formula (XVI-4) to obtain a compound represented by formula (VII-2-1-1), [ka] where X is a halogen, preferably chlorine; R 1-1 , M 12 , R 2-1 , R 2-2 , R 2-3 , R 2-4 , R5, R 6-1 , R 6-2 and R4 is as described above.

[0056] The present invention also relates to pharmaceutical compositions, which contain a therapeutically effective amount of each of the compounds of the general formulae set forth above, its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0057] In some embodiments of the present invention, the weight percentage of the compound, its stereoisomer, or its pharmaceutically acceptable salt in the composition is 0.1% to 95%, preferably 0.5% to 85%, more preferably 1% to 60%, even more preferably 10% to 50%, even more preferably 15 to 40%, even more preferably 20 to 30%, and even more preferably 20 to 25% (based on the total weight of the pharmaceutical composition).

[0058] In some embodiments of the invention, the dosage of the compound, its stereoisomer, or its pharmaceutically acceptable salt is 1 mg to 1000 mg, for example, 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg (or any integer therebetween).

[0059] The present invention also relates to the application of each of the compounds of the general formula described above, their stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions described above in the manufacture of EGFR inhibitor pharmaceuticals.

[0060] The present invention also relates to the application of each of the compounds of the general formulas described above, their stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions described above, in the manufacture of a medicament for treating cancer, preferably, the cancer is selected from ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, acute myeloid leukemia (AML), multiple myeloma, melanoma or mesothelioma, more preferably, the cancer is non-small cell lung cancer.

[0061] The present invention also relates to a method for preventing and / or treating EGFR-related diseases, which comprises administering to a patient a therapeutically effective amount of each of the compounds of the general formula, its stereoisomers or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, wherein the EGFR-related diseases are ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, acute myeloid leukemia (AML), multiple myeloma, melanoma, or mesothelioma, and preferably non-small cell lung cancer.

[0062] In some embodiments of the present invention, the EGFR is a mutated EGFR, preferably one or more mutations of 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.

[0063] 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.

[0064] In some embodiments of the invention, the cancer is EGFR L858R / T790M, Del19 / T790M, Del19 / C797S, L858R / C797S, Del19 / T790M / C797S or L858R / T790M / C797S mutant non-small cell lung cancer.

[0065] The present invention has obtained a series of compounds through research, which have strong inhibitory effects on EGFR, and not only have good inhibitory activity against EGFR triple mutations, but also have strong inhibitory effects against EGFR double mutations. They also have excellent drug properties and significant pharmacodynamic effects, and are expected to be in clinical development.

[0066] Unless stated to the contrary, terms used in the specification and claims have the following meanings.

[0067] 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 groups. , 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. When substituted, the substituent may be substituted at any available linkage site, and the substituent is 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, and carboxylate groups, and in the present invention, is preferably a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a halogenated alkyl group, a deuterated alkyl group, an alkyl group substituted with an alkoxy group, and an alkyl group substituted with a hydroxy group.

[0068] The term "alkylene group" refers to an alkyl group in which one hydrogen atom is further substituted, e.g., a "methylene group" refers to -CH-, an "ethylene group" refers to -(CH)-, a "propylene group" refers to -(CH)-, a "butylene group" refers to -(CH)-, 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. The 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.

[0069] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the ring of the cycloalkyl group contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms, and 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. Polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0070] The term "spirocycloalkyl group" refers to a 5- to 20-membered polycyclic group in which monocyclic rings share one carbon atom (called a spiro atom), which may contain one or more double bonds, but in which none of the rings has a completely conjugated π-electron system. It is preferably 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of shared spiro atoms between the rings, spirocycloalkyl groups are classified as monospirocycloalkyl groups, bisspirocycloalkyl groups, or polyspirocycloalkyl groups, with monospirocycloalkyl groups and bisspirocycloalkyl groups being preferred. More preferred 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 include: [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] Includes:

[0071] The term "fused cycloalkyl group" refers to a 5- to 20-membered all-carbon polycyclic group 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 no ring has a completely conjugated π-electron system. Preferably, it has 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings, fused cycloalkyl groups may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, 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] Includes:

[0072] A "bridged cycloalkyl group" refers to a 5- to 20-membered all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly linked, and it may contain one or more double bonds, but no ring has a completely conjugated π-electron system. It is preferably 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of rings, bridged cycloalkyl groups may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, and are preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include the following: [ka]

[0073] 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 of which include an indanyl group, a tetrahydronaphthyl group, a benzocycloheptyl group, etc. The cycloalkyl group can 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, and carboxylate groups.

[0074] The term "heterocyclyl group" refers to a saturated or partially unsaturated mono- or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, wherein one or more of the ring atoms is nitrogen, oxygen, P(O) pp or S(O) mm(where pp and mm are integers of 0 to 2), but does not include the ring moiety -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 3 to 8 ring atoms or 4 to 10 ring atoms, most preferably 3 to 8 ring atoms, and even more preferably 3 to 8-membered heterocyclyl groups containing 1 to 3 nitrogen atoms, optionally substituted with 1 to 2 oxygen atoms, sulfur atoms, or oxo groups, and includes nitrogen-containing monocyclic heterocyclyl groups, nitrogen-containing spiroheterocyclyl groups, and nitrogen-containing fused heterocyclyl groups.

[0075] 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, [ka] and piperazinyl groups. 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 a single bond or further tandemly linked to other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups via any two or more atoms on the ring.

[0076] The term "spiroheterocyclyl group" refers to a 5- to 20-membered polycyclic heterocyclyl group in which the monocyclic rings share one atom (called a spiroatom), where one or more of the ring atoms is nitrogen, oxygen, P(O) pp or S(O) mm(where pp and mm are integers of 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 to 14-membered, more preferably 7 to 10-membered. Depending on the number of shared spiro atoms between the rings, spiroheterocyclyl groups are classified as monospiroheterocyclyl groups, bisspiroheterocyclyl groups, or polyspiroheterocyclyl groups, and preferred are monospiroheterocyclyl groups and bisspiroheterocyclyl groups. More preferred are 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 groups. Non-limiting examples of spiroheterocyclyl groups are: [ka] Includes:

[0077] 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 rings may contain one or more double bonds, but no ring has a completely conjugated pi-electron system, and wherein one or more ring atoms are nitrogen, oxygen, P(O) pp or S(O) mm (where 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] Includes:

[0078] The term "bridged heterocyclyl group" refers to a 5- to 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 no ring has a completely conjugated pi-electron system, and in which one or more ring atoms is not nitrogen, oxygen, P(O) pp or S(O) mm (where 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] Includes:

[0079] 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 include: [ka] Includes:

[0080] Heterocyclyl groups 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, oxo groups, carboxyl groups, or carboxylate groups.

[0081] The term "aryl group" refers to a 6- to 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- to 12-membered, such as phenyl and naphthyl groups. Phenyle is more preferred. The ring of the aryl group may be fused to a heteroaryl group, heterocyclyl group, or cycloalkyl group, including 5- to 10-membered benzoheteroaryl groups, 3- to 8-membered benzocycloalkyl groups, and 3- to 8-membered benzoheteroalkyl groups, preferably 5- to 6-membered benzoheteroaryl groups, 3- to 6-membered benzocycloalkyl groups, and 3- to 6-membered benzoheteroalkyl groups, where the heterocyclyl group is a heterocyclyl group containing 1 to 3 nitrogen, oxygen, or sulfur atoms, or further containing a 3-membered nitrogen-containing fused ring containing a benzene ring.

[0082] Here, the ring connected to the basic skeleton is an aryl group ring, and non-limiting examples thereof include: [ka] Includes:

[0083] The aryl group may be 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.

[0084] 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-membered, or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, or pyridinyl, preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl, or thiazolyl, more preferably pyrazolyl, pyrrolyl, or oxazolyl. The ring of the heteroaryl group can be fused 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 include: [ka] Includes:

[0085] Heteroaryl groups 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.

[0086] The term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), where alkyl group is as defined above, and is 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. An alkoxy group may be optionally substituted or unsubstituted; if substituted, the substituents are 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, carboxyl, or carboxylate.

[0087] "Halogenated alkyl group" refers to an alkyl group that is substituted with one or more halogens, where alkyl group is as defined above.

[0088] A "halogenated alkoxy group" refers to an alkoxy group substituted with one or more halogens, where alkoxy groups are as defined above.

[0089] "Hydroxyalkyl group" refers to an alkyl group substituted with a hydroxy group, where alkyl group is as defined above.

[0090] The term "alkenyl group" refers to a chain-like alkenyl group, also known as 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 alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogen atoms, 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.

[0091] The term "alkynyl group" refers to (CH≡C-), 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 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 atom, 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.

[0092] The term "alkenylcarbonyl group" refers to -C(O)-(alkenyl group), where the definition of alkenyl group is as defined above. Non-limiting examples of alkenylcarbonyl groups include vinylcarbonyl, propenylcarbonyl, and butenylcarbonyl groups. An alkenylcarbonyl group may be optionally substituted or unsubstituted; if substituted, the substituents are 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, carboxyl, or carboxylate groups.

[0093] "Hydroxy" refers to an -OH group.

[0094] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0095] An "amino group" refers to -NH2.

[0096] A "cyano group" refers to -CN.

[0097] A "nitro group" refers to -NO2.

[0098] A "carbonyl group" refers to -C(O)-.

[0099] A "carboxyl group" refers to -C(O)OH.

[0100] "THF" refers to tetrahydrofuran.

[0101] "EtOAc" refers to ethyl acetate.

[0102] "MeOH" refers to methanol.

[0103] "DMF" refers to N,N-dimethylformamide.

[0104] "DIPEA" refers to diisopropylethylamine.

[0105] "TFA" refers to trifluoroacetic acid.

[0106] "MeCN" refers to acetonitrile.

[0107] "DMA" refers to N,N-dimethylacetamide.

[0108] "Et2O" refers to ether.

[0109] "DCE" refers to 1,2 dichloroethane.

[0110] "DIPEA" refers to N,N-diisopropylethylamine.

[0111] "NBS" refers to N-bromosuccinimide.

[0112] "NIS" refers to N-iodosuccinimide.

[0113] "Cbz-Cl" refers to benzyl chloroformate.

[0114] "Pd2(dba)3" refers to tri(dibenzylideneacetone)dipalladium.

[0115] "Dppf" refers to 1,1'-bisdiphenylphosphinoferrocene.

[0116] "HATU" refers to O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0117] "KHMDS" refers to potassium hexamethyldisilazane.

[0118] "LiHMDS" refers to lithium bistrimethylsilylamide.

[0119] "MeLi" refers to methyllithium.

[0120] "n-BuLi" refers to n-butyllithium.

[0121] "NaBH(OAc)3" refers to sodium triacetoxyborohydride.

[0122] Various terms such as "X is selected from A, B, or C," "X is selected from A, B, and C," "X is A, B, or C," and "X is A, B, and C" all mean the same thing, i.e., X can be one or more of A, B, and C.

[0123] Any hydrogen atom described in the present invention may be substituted with its isotope, deuterium, and any hydrogen atom in the compounds of the examples of the present invention may also be substituted with a deuterium atom.

[0124] "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.

[0125] "Substituted" refers to the fact that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently replaced with the corresponding number of substituents. Needless to say, substituents are present only at their possible chemical positions, and those skilled in the art can determine (experimentally or theoretically) possible or impossible substitutions without much effort. For example, an amino group or a hydroxy group having free hydrogen may be unstable if it is bound to a carbon atom having an unsaturated (e.g., olefinic) bond.

[0126] The "plurality" in "substituted by one or more of..." can mean 2, 3, 4, 5, 6 or more than 6.

[0127] In each section of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood to be the linking group. For example, when the structure requires a linking group and the Markush group definition for that variable lists an "alkyl group" or an "aryl group," it should be understood that the "alkyl group" or "aryl group" represents the linking alkylene group or arylene group, respectively.

[0128] A "pharmaceutical composition" is meant to contain a mixture of one or more compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, as well as other components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism and promote absorption of the active ingredients, thereby exerting their biological activity.

[0129] "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. MODE FOR CARRYING OUT THE INVENTION

[0130] The present invention will be further described below in conjunction with examples, but these examples are not intended to limit the scope of the present invention. Example

[0131] The structures of the compounds of the present invention are confirmed by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetometer in deuterated dimethyl sulfoxide (DMSO-d), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3). The internal standard was tetramethylsilane (TMS).

[0132] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC was 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.

[0133] Thin-layer chromatography silica gel plates are Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plates, with TLC using 0.15mm to 0.20mm specifications, and thin-layer chromatography product separation and purification using 0.4mm to 0.5mm specifications. Column chromatography generally uses Yantai Yellow Sea silica gel 200-300 mesh silica gel as the carrier.

[0134] 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.

[0135] Unless otherwise specified, all reactions of the present invention are carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, the solvents are dry solvents, and the reaction temperatures are in degrees Celsius.

[0136] Intermediate 1 3-((methylsulfonyl)methyl)azetidine [ka] Step 1. Synthesis of tert-butyl 3-((methylthio)methyl)azetidine-1-carboxylate [ka] tert-Butyl 3-(iodomethyl)azetidine-1-carboxylate (2 g, 6.73 mmol) and methyl mercaptan sodium (970 mg, 13.50 mmol) were dissolved in ACN (15 mL) and HO (5 mL), heated to 60°C, and reacted for 12 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and then separated by column chromatography to obtain the target compound, tert-butyl 3-((methylthio)methyl)azetidine-1-carboxylate (1.30 g, 88.9%). MS m / z (ESI): 162.0 [M + H-56] + . Step 2: Synthesis of tert-butyl 3-((methylsulfonyl)methyl)azetidine-1-carboxylate [ka] tert-Butyl 3-((methylthio)methyl)azetidine-1-carboxylate (1.30 g, 5.99 mmol) was dissolved in dichloromethane (15 mL), metachloroperbenzoic acid (2 g, 12 mmol) was added, and the mixture was stirred overnight. The reaction mixture was washed with saturated sodium thiosulfate solution and saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The mixture was then separated by column chromatography to obtain the target compound, tert-butyl 3-((methylsulfonyl)methyl)azetidine-1-carboxylate (1.30 g, 87.1%). MS m / z (ESI): 194.0 [M + H-56] + . Step 3: Synthesis of 3-((methylsulfonyl)methyl)azetidine trifluoroacetate [ka] tert-Butyl 3-((methylsulfonyl)methyl)azetidine-1-carboxylate (1.30 g, 5.22 mmol) was dissolved in dichloromethane (15 mL), and TFA (3 mL) was added and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure to give the crude target compound, 3-((methylsulfonyl)methyl)azetidine trifluoroacetate (740 mg). MS m / z (ESI): 150.0 [M + H] + .

[0137] Intermediate 2 1,6-Dichloro-4-isopropyl-2,7-naphthyridine [ka] Step 1 Synthesis of 6-chloro-4-iodo-2,7-naphthyridin-1(2H)-one [ka] 6-Chloro-2,7-naphthyridin-1(2H)-one (10 g, 55.37 mmol) was dissolved in DMF (60 mL), the reaction mixture was cooled to 0°C, NIS (14.80 g, 66 mmol) was added portionwise, the mixture was warmed to room temperature, and stirred for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of the target compound, 6-chloro-4-iodo-2,7-naphthyridin-1(2H)-one (12 g). MS m / z(ESI):307.1[M+H] + . Step 2 Synthesis of 1,6-dichloro-4-iodo-2,7-naphthyridine [ka] 6-Chloro-4-iodo-2,7-naphthyridin-1(2H)-one (12 g, 39.15 mmol) was dissolved in phosphorus oxychloride (80 mL), heated to 100° C., and reacted for 2 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was separated from water using 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, 1,6-dichloro-4-iodo-2,7-naphthyridine (10.60 g, 83.3%). MS m / z(ESI):325.1[M+H] + . Step 3 Synthesis of 1,6-dichloro-4-(prop-1-en-2-yl)-2,7-naphthyridine [ka] 1,6-Dichloro-4-iodo-2,7-naphthyridine (10.60 g, 32.62 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (5.50 g, 32.70 mmol) were mixed in dioxane (60 mL) and water (10 mL), and potassium carbonate (13.60 g, 98.10 mmol) and dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphorus palladium(II) (2.34 g, 3.30 mmol) were added, the mixture was heated to 50°C, and the reaction was carried out for 1 hour. The reaction mixture 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, 1,6-dichloro-4-(prop-1-en-2-yl)-2,7-naphthyridine (5 g, 64.1%). MS m / z (ESI): 239.0 [M + H] + . Step 4 Synthesis of 1,6-dichloro-4-isopropyl-2,7-naphthyridine [ka] 1,6-Dichloro-4-(prop-1-en-2-yl)-2,7-naphthyridine (5 g, 20.91 mmol) was dissolved in ethyl acetate (80 mL), platinum dioxide (5.72 g, 25.20 mmol) was added, and the mixture was evacuated and hydrogen gas was introduced. This procedure was repeated three times, and the mixture was reacted for 12 hours under a hydrogen gas atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and then separated by column chromatography to obtain the target compound, 1,6-dichloro-4-isopropyl-2,7-naphthyridine (4 g, 79.3%). MS m / z (ESI): 241.0 [M + H] + .

[0138] Intermediate 3 (2R,3S)-2-Methyl-3-((methylsulfonyl)methyl)azetidine [ka] Step 1. Synthesis of (2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl methanesulfonate [ka] (2R,3S)-1-diphenylmethyl-2-methylazetidin-3-ol (10 g, 39.50 mmol) was dissolved in dichloromethane (100 mL), triethylamine (4.80 g, 47.30 mmol) was added, the reaction mixture was cooled to 0 ° C, methylsulfonyl chloride (5 g, 43.40 mmol) was added dropwise slowly, and the mixture was allowed to react 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 (12.80 g). MS m / z(ESI):332.2[M+H] + . Step 2. Synthesis of methyl (S)-2-((2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl)-2-(methylsulfonyl)acetate [ka] (2R,3S)-1-Diphenylmethyl-2-methylazetidin-3-yl methanesulfonate (12.80 g, 38.62 mmol) and methyl 2-(methylsulfonyl)acetate (7.70 g, 50.60 mmol) were dissolved in DMF (100 mL), and sodium hydride (2.20 g, 60% in mineral oil, 55.50 mmol) was added portionwise. The mixture was reacted at room temperature for 15 minutes, then heated to 80 °C and reacted overnight. The reaction mixture was cooled to room temperature, quenched with saturated ammonium chloride solution, and separated from water with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the target compound, methyl (S)-2-((2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl)-2-(methylsulfonyl)acetate (11.60 g, 77.5%). MS m / z(ESI):388.2[M+H] + . Step 3. Synthesis of (2R,3S)-1-diphenylmethyl-2-methyl-3-((methylsulfonyl)methyl)azetidine [ka] Methyl (S)-2-((2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl)-2-(methylsulfonyl)acetate (11.60 g, 29.94 mmol) was dissolved in DMA (120 mL), lithium chloride (10.50 g, 247.50 mmol) was added, the mixture was heated to 150 ° C, and the mixture was allowed to react for 2 hours. The mixture was cooled to room temperature, separated from water with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then separated by column chromatography to obtain the target compound (2R,3S)-1-diphenylmethyl-2-methyl-3-((methylsulfonyl)methyl)azetidine (9.20 g, 93.3%). MS m / z(ESI):330.0[M+H] + . Step 4. Synthesis of (2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine [ka] (2R,3S)-1-Diphenylmethyl-2-methyl-3-((methylsulfonyl)methyl)azetidine (9.20 g, 27.92 mmol) was dissolved in methanol (120 mL), TFA (5 mL) and palladium hydroxide (2.80 g) were added, and the mixture was evacuated and hydrogen gas was introduced. This procedure was repeated three times and allowed to react overnight under a hydrogen gas atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude target compound (2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine (4 g). MS m / z (ESI): 164.0 [M + H] + .

[0139] Intermediate 4 8-Bromo-3-chloro-6-fluoro-5-isopropylisoquinoline [ka] Step 1. Synthesis of 3-chloro-6-fluoroisoquinoline [ka] 1,3-Dichloro-6-fluoroisoquinoline (7.50 g, 34.72 mmol) was dissolved in glacial acetic acid (40 mL) and hydroiodic acid (20 mL, 45% aqueous solution), red phosphorus (2.69 g, 86.8 mmol) was added, and the mixture was heated to 100 ° C. and reacted for 4 hours. The reaction solution was cooled to room temperature, concentrated, diluted with dichloromethane (100 mL), washed with saturated aqueous sodium carbonate, the organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The target compound, 3-chloro-6-fluoroisoquinoline (4.90 g, 77.8%), was obtained by column chromatography. MS m / z (ESI): 182.0 [M + H] + . Step 2 Synthesis of 5-bromo-3-chloro-6-fluoroisoquinoline [ka] 3-Chloro-6-fluoroisoquinoline (3.20 g, 17.62 mmol) was dissolved in concentrated sulfuric acid (20 mL), NBS (3.45 g, 19.38 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture 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. After filtration, the organic solvent was concentrated under reduced pressure and separated by column chromatography to obtain the target compound, 5-bromo-3-chloro-6-fluoroisoquinoline (4.0 g, 87.1%). MS m / z (ESI): 260.0 [M + H] + . Step 3 Synthesis of 3-chloro-6-fluoro-5-(prop-1-en-2-yl)isoquinoline [ka] 5-Bromo-3-chloro-6-fluoroisoquinoline (4.0 g, 15.36 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (2.71 g, 16.72 mmol) were dissolved in 1,4-dioxane (20 mL) and water (3 mL), and 1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (562 mg, 0.77 mmol) and cesium carbonate (10.01 g, 30.71 mmol) were added, heated to 80 ° C., and reacted for 2 hours. The reaction solution was cooled to room temperature, 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 (3.0 g, 88.1%). MS m / z (ESI): 222.0 [M + H] + . Step 4 Synthesis of 3-chloro-6-fluoro-5-isopropylisoquinoline [ka] 3-Chloro-6-fluoro-5-(prop-1-en-2-yl)isoquinoline (3.0 g, 13.53 mmol) was dissolved in ethyl acetate (30 mL), platinum dioxide (615 mg, 2.71 mmol) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The reaction mixture 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%). MS m / z(ESI):224.1[M+H] + . Step 5 Synthesis of 8-bromo-3-chloro-6-fluoro-5-isopropylisoquinoline [ka] In an ice bath, dibromohydantoin (1.12 g, 3.93 mmol) was slowly added in small portions 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 mixture was carefully added to ice water, separated with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the organic solvent was concentrated under reduced pressure and separated by column chromatography to obtain the target compound, 8-bromo-3-chloro-6-fluoro-5-isopropylisoquinoline (320 mg, 29.6%). MS m / z (ESI): 302.0 [M + H] + .

[0140] Intermediate 5 N-Methyl-N-((2R,3S)-2-methylazetidin-3-yl)methanesulfonamide trifluoroacetate [ka] Step 1. Synthesis of (2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl methanesulfonate [ka] (2R,3S)-1-Diphenylmethyl-2-methylazetidin-3-ol (100 g, 397 mmol), triethylamine (110 mL, 793 mmol), and anhydrous dichloromethane (1000 mL) were added to a 2 L reaction flask. The mixture was cooled to 5 °C under a nitrogen atmosphere, and methanesulfonic anhydride (138 g, 795 mmol) was added portionwise. The mixture was then warmed to room temperature and stirred for 2 h. Water and dichloromethane were added, and the mixture was separated. The organic phase was separated and washed sequentially with 5% sodium carbonate solution and saturated sodium chloride solution. The organic phase was then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl methanesulfonate (138 g). MS m / z(ESI):332.1[M+H] + . Step 2: Synthesis of N-((2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl)-N-methylmethanesulfonamide [ka] (2R,3S)-1-Diphenylmethyl-2-methylazetidin-3-yl methanesulfonate (138 g, 0.42 mol) was dissolved in MeCN (950 mL) at room temperature, and CsCO (273 g, 0.84 mol) and N-methylmethanesulfonamide (82 g, 0.75 mol) were added. The mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (0.5 L) was added, and the mixture was extracted with ethyl acetate (1 L x 2). The combined organic phases were washed with saturated aqueous sodium chloride solution, separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent. The desired product, N-((2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (110 g, 76.7%), was obtained by column chromatography. MS m / z(ESI):345.1[M+H] + . Step 3: Synthesis of N-methyl-N-((2R,3S)-2-methylazetidin-3-yl)methanesulfonamide trifluoroacetate [ka] N-((2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (85 g, 0.247 mol) was dissolved in a mixture of MeOH (850 mL) and TFA (52 mL), and 10% Pd(OH)2 / C (28 g) was added. The mixture was stirred overnight at room temperature under a H2 atmosphere. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the crude product, N-methyl-N-((2R,3S)-2-methylazetidin-3-yl)methanesulfonamide trifluoroacetate (66 g). 1H NMR(400MHz,DMSO-d6)δ 8.88(s,1H),4.62-4.56(m,1H),4.31-4.25(m,1H),4.10-4.06(m,1H),3.95-3.91(m,1H),2.95(s,3H),2.83(s,3H),1.40(d,J=6.0Hz,3H); MS m / z (ESI): 179.1 [M + H] + .

[0141] Intermediate 6 3-chloro-5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline [ka] Step 1. Synthesis of 8-bromo-3-chloroisoquinolin-5-yl trifluoromethanesulfonic acid [ka] 8-Bromo-3-chloroisoquinolin-5-ol (5 g, 19.50 mmol) was dissolved in dichloromethane (50 mL), TEA (7.90 g, 78 mmol) was added, the reaction mixture was cooled to -60 °C, (TfO)2O (16.50 g, 58.50 mmol) was added dropwise, the mixture was warmed to room temperature, and the reaction mixture was allowed to react for 4 hours. The reaction mixture was concentrated under reduced pressure and then separated by column chromatography to obtain the target compound, 8-bromo-3-chloroisoquinolin-5-yl trifluoromethanesulfonic acid (6.50 g, 85.3%). MS m / z (ESI): 390.0 [M + H] + . Step 2 Synthesis of 8-bromo-3-chloro-5-(prop-1-en-2-yl)isoquinoline [ka] 8-Bromo-3-chloroisoquinolin-5-yl trifluoromethanesulfonic acid (6.50 g, 16.64 mmol) was dissolved in dioxane (60 mL) and HO (6 mL), and isopropenylboronic acid pinacol ester (4.20 g, 25 mmol), potassium carbonate (4.60 g, 33.40 mmol), and PdCl(dppf) (610 mg, 0.84 mmol) were added. The mixture was heated to 100 °C and reacted for 4 hours. The reaction mixture was cooled to room temperature, concentrated, and separated with dichloromethane and water. 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%). MS m / z (ESI): 282.0 [M + H] + . Step 3 Synthesis of 8-bromo-3-chloro-5-isopropylisoquinoline [ka] 8-Bromo-3-chloro-5-(prop-1-en-2-yl)isoquinoline (2.90 g, 10.26 mmol) was dissolved in ethyl acetate (100 mL), PtO (700 mg, 3.10 mmol) was added, and the mixture was evacuated and hydrogen gas was introduced. This procedure was repeated three times and stirred under a hydrogen gas atmosphere for 12 hours. The reaction mixture 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%). MS m / z (ESI): 284.0 [M + H] + . Step 4: Synthesis of 3-chloro-5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline [ka] 8-Bromo-3-chloro-5-isopropylisoquinoline (500 mg, 1.76 mmol) and 3-((methylsulfonyl)methyl)azetidine trifluoroacetate (435 mg, 1.77 mmol) were dissolved in dioxane (10 mL), cesium carbonate (1.15 g, 3.54 mmol) and Xantphos Pd G4 (164 mg, 0.17 mmol) were added, the mixture was heated to 100 ° C., and stirred for 12 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and separated with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then separated by column chromatography to obtain the target compound, 3-chloro-5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline (286 mg, 46.0%). MS m / z (ESI): 353.0 [M + H] + .

[0142] Reference Example 1 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] Step 1. Synthesis of 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline [ka] 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. The mixture was heated to 100°C and stirred for 12 hours. The reaction mixture 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. The residue was then separated 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%). MS m / z(ESI):367.1[M+H] + . Step 2: Synthesis of 2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-amine [ka] 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), and bistriphenylphosphine palladium dichloride (702 mg, 1 mmol) was added. The mixture was heated to 100 ° C and stirred for 12 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and separated with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The target compound, 2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-amine (1.05 g, 52.2%), was obtained. MS m / z(ESI):202.1[M+H] + . 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] 3-Chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline (100 mg, 0.27 mmol) and 2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-amine (54 mg, 0.27 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. The mixture was heated to 100° C. and stirred for 12 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and separated with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The residue was then separated 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%). 1 H 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]+ .

[0143] Reference Example 2 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] Step 1. Synthesis of 4-bromo-3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole [ka] 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), and 2-(trimethylsilyl)ethoxymethyl chloride (1.50 g, 9 mmol) was added dropwise. The mixture was allowed to react at room temperature for 3 hours. The reaction mixture 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. The residue was purified 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%). MS m / z (ESI): 311.0 [M + H] + . 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] 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, 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%). MS m / z(ESI):359.2[M+H] + . Step 3: Synthesis of 2-(3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-amine [ka] 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). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (247.4 mg, 0.3 mmol) was added, and the reaction mixture was heated to 100°C and stirred for 12 hours. The mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and the residue was purified 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%). MS m / z(ESI):326.1[M+H] + . 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] 3-Chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline (100 mg, 0.27 mmol) and 2-(3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (88 mg, 0.27 mmol) were dissolved in dioxane (3 mL), and cesium carbonate (274 mg, 0.84 mmol) and BrettPhos Pd G3 (24 mg, 27 μmol) were added. The mixture was heated to 105° C. and stirred for 12 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and separated with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The residue was then separated 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%). MS m / z(ESI):656.3[M+H] + . 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] 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), and 1 M TBAF solution (2 mL, 2 mmol) was added. The mixture was heated to reflux and stirred for 12 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and separated with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The residue was then separated 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%). 1 H NMR (400 MHz, 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] + . Step 6: Synthesis 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] 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 mixture was heated to 40°C, and the mixture was allowed to react for 12 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and separated with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The residue was then separated 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%). 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] + . For the production method 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, reference may be made to Reference Example 1.

[0144] Example 1 Preparation of N-(2-(1,3-dimethyl-1H-pyrazolyl-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine [ka] See Reference Example 1 for the preparation of N-(2-(1,3-dimethyl-1H-pyrazolyl-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine. 1 H NMR (400 MHz, DMSO-d6) δ 10.08(s,1H),9.09(s,1H),8.56(s,1H),8.36(d,J=5.8Hz,1H),8.18(s,1H),7. 43(d,J=7.6Hz,1H),7.21-7.14(m,1H),6.56(d,J=8.0Hz,1H),4.67-4.65(m,1H) ,4.29-4.10(m,1H),3.84(s,3H),3.67-3.62(m,1H),3.60-3.51(m,3H),2.99(s ,3H),2.91-2.83(m,1H),2.49(s,3H),1.42(d,J=5.6Hz,3H),1.35-1.30(m,6H); MS m / z(ESI):520.2[M+H] + .

[0145] Example 2 Preparation of 5-isopropyl-N-(2-(3-methyl-1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka] See Reference Example 1 for the preparation of 5-isopropyl-N-(2-(3-methyl-1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine. 1 H NMR(400MHz,DMSO-d6)δ 10.09(s,1H),9.10(s,1H),8.57(s,1H),8.37(d,J=5.8Hz,1H),8.19(s, 1H),7.45(d,J=8.0Hz,1H),7.19(d,J=5.4Hz,1H),6.58(d,J=8.1Hz,1H), 4.72-4.65(m,1H),4.25-4.17(m,1H),3.68-3.51(m,4H),3.00(s,3H),2 .94-2.86(m,1H),2.50(s,3H),1.44(d,J=6.1Hz,3H),1.37-1.31(m,6H); MS m / z (ESI): 523.2 [M + H] + .

[0146] Example 3 Preparation of 5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(1-methyl-3-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-4-yl)isoquinolin-3-amine [ka] For the preparation of 5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(1-methyl-3-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-4-yl)isoquinolin-3-amine, see Reference Example 1. MS m / z (ESI): 523.2 [M + H] + .

[0147] Example 4 Preparation of N-(2-(1,3-bis(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] For the preparation of N-(2-(1,3-bis(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, see Reference Example 1. MS m / z(ESI):526.2[M+H] + .

[0148] Example 5 Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine [ka] For the preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine, see Reference Example 1.

[0149] It may be synthesized according to the following steps: Step 1. Synthesis of 4-bromo-3-chloro-1-methyl-1H-pyrazole [ka] 3-Chloro-1-methyl-1H-pyrazole (500 mg, 4.29 mmol) was dissolved in dichloromethane (10 mL), cooled to 0 ° C, NBS (764 mg, 4.29 mmol) was added portionwise, and the mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, dichloromethane was added, and the mixture was separated from water. The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The target compound, 4-bromo-3-chloro-1-methyl-1H-pyrazole (790 mg, 94.2%), was obtained by column chromatography. Step 2: Synthesis of 3-chloro-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] 4-Bromo-3-chloro-1-methyl-1H-pyrazole (790 mg, 4.04 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.23 g, 4.85 mmol) were dissolved in dioxane (15 mL), and potassium phosphate (793 mg, 8.08 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (300 mg, 0.41 mmol) were added, the mixture was heated to 95°C, and stirred for 12 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and dichloromethane was added to separate the water. The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The resulting mixture was separated by column chromatography to obtain the target compound, 3-chloro-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (590 mg, 60.2%). MS m / z(ESI):243.1[M+H] + . Step 3 Synthesis of 2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine [ka] 2-Chloropyrimidin-4-amine (259 mg, 2 mmol), 3-chloro-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (534 mg, 2.20 mmol), and potassium carbonate (829 mg, 6 mmol) were mixed in dioxane (5 mL) and water (1 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (146 mg, 0.20 mmol) was added, and the mixture was heated to 95°C and stirred for 12 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and separated with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The product was then separated by column chromatography to obtain the target compound, 2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (143 mg, 34.2%). MS m / z(ESI):210.0[M+H] + . Step 4 Synthesis of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine [ka] 3-Chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline (100 mg, 0.27 mmol) and 2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (57 mg, 0.27 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. The mixture was heated to 100° C. and stirred for 12 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and separated with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was then separated by column chromatography to obtain the target compound, N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine (44 mg, 30.5%). 1 H NMR(400MHz,DMSO-d6)δ 10.18(s,1H),9.10(s,1H),8.59(s,1H),8.40(d,J=5.9Hz,1H),8.33(s,1H) ),7.43(d,J=8.0Hz,1H),7.25(d,J=5.8Hz,1H),6.58(d,J=8.1Hz,1H),4.6 8(t,J=7.5Hz,1H),4.21(t,J=6.2Hz,1H),3.90(s,3H),3.68-3.51(m,4H), 3.00(s,3H),2.94-2.85(m,1H),1.43(d,J=6.0Hz,3H),1.34-1.26(m,6H); MS m / z(ESI):540.2[M+H] + .

[0150] Example 6 Preparation of N-(2-(3-chloro-1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka] For the preparation of N-(2-(3-chloro-1-(methyl-d3)-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. 1 H NMR(400MHz,DMSO-d6)δ 10.19(s,1H),9.10(s,1H),8.59(s,1H),8.40(d,J=5.9Hz,1H),8.33(s,1H),7.43(d,J=8.0Hz,1H),7.25(d,J=5.6Hz,1H),6.58(d,J=8.1H) z,1H),4.71-4.64(m,1H),4.24-4.16(m,1H),3.67-3.48(m,4H),3.00(s,3H),2.93-2.85(m,1H),1.43(d,J=6.1Hz,3H),1.33-1.27(m,6H); MS m / z (ESI): 543.2 [M + H] + .

[0151] Example 7 Preparation of N-(2-(1-cyclopropyl-3-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] For the preparation of N-(2-(1-cyclopropyl-3-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 Reference Example 1. MS m / z (ESI): 546.2 [M + H] + .

[0152] Example 8 Preparation of N-(2-(1-cyclopropyl-3-(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] For the preparation of N-(2-(1-cyclopropyl-3-(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, see Reference Example 1. MS m / z(ESI):549.2[M+H] + .

[0153] Example 9 Preparation of N-(2-(1-cyclopropyl-3-fluoro-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka] See Reference Example 1 for the preparation of N-(2-(1-cyclopropyl-3-fluoro-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine. MS m / z(ESI):550.2[M+H] + .

[0154] Example 10 Preparation of 2-(1-cyclopropyl-1H-pyrazol-4-yl)-N-(8-isopropyl-5-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)quinazolin-2-yl)thiazol-5-amine [ka] See Reference Example 1 for the preparation of 2-(1-cyclopropyl-1H-pyrazol-4-yl)-N-(8-isopropyl-5-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)quinazolin-2-yl)thiazol-5-amine. MS m / z(ESI):538.2[M+H] + .

[0155] Example 11 Preparation of N-(8-isopropyl-5-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)quinazolin-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)thiazol-5-amine [ka] See Reference Example 1 for the preparation of N-(8-isopropyl-5-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)quinazolin-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)thiazol-5-amine. MS m / z(ESI):512.2[M+H] + .

[0156] Example 12 Preparation of 2-(1,3-dimethyl-1H-pyrazol-4-yl)-N-(8-isopropyl-5-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)quinazolin-2-yl)thiazol-5-amine [ka] See Reference Example 1 for the preparation of 2-(1,3-dimethyl-1H-pyrazol-4-yl)-N-(8-isopropyl-5-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)quinazolin-2-yl)thiazol-5-amine. MS m / z(ESI):526.2[M+H] + .

[0157] Example 13 Preparation of 2-(3-chloro-1-methyl-1H-pyrazol-4-yl)-N-(8-isopropyl-5-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)quinazolin-2-yl)thiazol-5-amine [ka] See Reference Example 1 for the preparation of 2-(3-chloro-1-methyl-1H-pyrazol-4-yl)-N-(8-isopropyl-5-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)quinazolin-2-yl)thiazol-5-amine. MS m / z (ESI): 546.2 [M + H] + .

[0158] Example 14 Preparation of 2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-N-(8-isopropyl-5-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)quinazolin-2-yl)thiazol-5-amine [ka] See Reference Example 1 for the preparation of 2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-N-(8-isopropyl-5-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)quinazolin-2-yl)thiazol-5-amine. MS m / z(ESI):530.2[M+H] + .

[0159] Example 15 Preparation of N-(2-(1-cyclopropyl-1H-pyrazolyl-4-yl)-3-fluoropyridin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine [ka] See Reference Example 1 for the preparation of N-(2-(1-cyclopropyl-1H-pyrazolyl-4-yl)-3-fluoropyridin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine. MS m / z(ESI):549.2[M+H] + .

[0160] Example 16 Preparation of N-(3-fluoro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka] See Reference Example 1 for the preparation of N-(3-fluoro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine. MS m / z (ESI): 523.2 [M + H] + .

[0161] Example 17 Preparation of N-(2-(1,3-dimethyl-1H-pyrazolyl-4-yl)-3-fluoropyridin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine [ka] For the preparation of N-(2-(1,3-dimethyl-1H-pyrazolyl-4-yl)-3-fluoropyridin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine, see Reference Example 1. MS m / z (ESI): 537.2 [M + H] + .

[0162] Example 18 Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)-3-fluoropyridin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine [ka] For the preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)-3-fluoropyridin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine, see Reference Example 1 or Example 5. MS m / z(ESI):557.2[M+H] + .

[0163] Example 19 Preparation of N-(3-fluoro-2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine [ka] For the preparation of N-(3-fluoro-2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine, see Reference Example 1. MS m / z (ESI): 541.2 [M + H] + .

[0164] Example 20 Preparation of 1-isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-3-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-1H-pyrazole[4,3-c]pyridin-6-amine [ka] See Reference Example 1 for the preparation of 1-isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-3-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-1H-pyrazole[4,3-c]pyridin-6-amine. MS m / z (ESI): 496.2 [M + H] + .

[0165] Example 21 Preparation of N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-1H-pyrazole[4,3-c]pyridin-6-amine [ka] For the preparation of N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-1H-pyrazole[4,3-c]pyridin-6-amine, see Reference Example 1. MS m / z (ESI): 522.2 [M + H] + .

[0166] Example 22 Preparation of N-(2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-1H-pyrazole[4,3-c]pyridin-6-amine [ka] For the preparation of N-(2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-1H-pyrazole[4,3-c]pyridin-6-amine, see Reference Example 1. 1 H NMR (400 MHz, DMSO-d6) δ 10.00(s,1H),8.58(s,1H),8.33(d,J=6.0Hz,1H),8.18(s,1H),8.04(s,1H) ,7.04-6.99(m,1H),4.68-4.60(m,1H),4.37(d,J=7.4Hz,1H),4.18(d,J=6. 6Hz,1H),3.82(s,3H),3.80-3.75(m,1H),3.55-3.50(m,2H),2.98(s,3H),2 .93-2.86(m,1H),2.54(s,3H),1.52(d,J=6.1Hz,3H),1.43(d,J=5.6Hz,6H); MS m / z(ESI):510.2[M+H] + .

[0167] Example 23 Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-1H-pyrazole[4,3-c]pyridin-6-amine [ka] For the preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-1H-pyrazole[4,3-c]pyridin-6-amine, see Reference Example 1 or Example 5. MS m / z(ESI):530.2[M+H] + .

[0168] Example 24 Preparation of N-(2-(3-fluoro-1-methyl-1H-pyrazolyl-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)-1H-pyrazole[4,3-c]pyridin-6-amine [ka] For the preparation of N-(2-(3-fluoro-1-methyl-1H-pyrazolyl-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)-1H-pyrazole[4,3-c]pyridin-6-amine, see Reference Example 1. MS m / z(ESI):514.2[M+H] + .

[0169] Example 25 Preparation of 1-isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-3-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-1H-pyridine[3,2-c]pyridin-6-amine [ka] See Reference Example 1 for the preparation of 1-isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-3-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-1H-pyridine[3,2-c]pyridin-6-amine. MS m / z(ESI):495.2[M+H] + .

[0170] Example 26 Preparation of N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-1H-pyridine[3,2-c]pyridin-6-amine [ka] For the preparation of N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-1H-pyridine[3,2-c]pyridin-6-amine, see Reference Example 1. MS m / z(ESI):521.2[M+H] + .

[0171] Example 27 Preparation of N-(2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-1H-pyridine[3,2-c]pyridin-6-amine [ka] For the preparation of N-(2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-1H-pyridine[3,2-c]pyridin-6-amine, see Reference Example 1. MS m / z(ESI):509.2[M+H] + .

[0172] Example 28 Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-1H-pyridine[3,2-c]pyridin-6-amine [ka] For the preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-1H-pyridine[3,2-c]pyridin-6-amine, see Reference Example 1 or Example 5. MS m / z(ESI):529.2[M+H] + .

[0173] Example 29 Preparation of N-(2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-1H-pyridine[3,2-c]pyridin-6-amine [ka] For the preparation of N-(2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-1H-pyridine[3,2-c]pyridin-6-amine, see Reference Example 1. MS m / z(ESI):513.2[M+H] + .

[0174] Example 30 Preparation of N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3R)-2-methyl-3-(nitromethyl)azetin-1-yl)isoquinolin-3-amine [ka] See Reference Example 1 for the preparation of N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3R)-2-methyl-3-(nitromethyl)azetin-1-yl)isoquinolin-3-amine. MS m / z (ESI): 499.2 [M + H] + .

[0175] Example 31 Preparation of 5-isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-8-((2R,3R)-2-methyl-3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine [ka] See Reference Example 1 for the preparation of 5-isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-8-((2R,3R)-2-methyl-3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine. MS m / z(ESI):473.2[M+H] + .

[0176] Example 32 Preparation of N-(2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3R)-2-methyl-3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine [ka] See Reference Example 1 for the preparation of N-(2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3R)-2-methyl-3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine. MS m / z (ESI): 487.2 [M + H] + .

[0177] Example 33 Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3R)-2-methyl-3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine [ka] See Reference Example 1 for the preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3R)-2-methyl-3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine. MS m / z(ESI):507.2[M+H] + .

[0178] Example 34 Preparation of N-(2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3R)-2-methyl-3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine [ka] See Reference Example 1 for the preparation of N-(2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3R)-2-methyl-3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine. MS m / z(ESI):491.2[M+H] + .

[0179] Example 35 Preparation of N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine [ka] See Reference Example 1 for the preparation of N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine. MS m / z(ESI):485.2[M+H] + .

[0180] Example 36 Preparation of 5-isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-8-(3-(nitromethyl)azacyclodextrin-1-yl)isoquinolin-3-amine [ka] See Reference Example 1 for the preparation of 5-isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-8-(3-(nitromethyl)azacyclodextrin-1-yl)isoquinolin-3-amine. MS m / z(ESI):459.2[M+H] + .

[0181] Example 37 Preparation of N-(2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine [ka] See Reference Example 1 for the preparation of N-(2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine. MS m / z(ESI):473.2[M+H] + .

[0182] Example 38 Preparation of N-(2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine [ka] See Reference Example 1 for the preparation of N-(2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine. MS m / z (ESI): 477.2 [M + H] + .

[0183] Example 39 Preparation of ((2R,3S)-1-(3-((2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonyl fluoride [ka] See Reference Example 1 for the preparation of ((2R,3S)-1-(3-((2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonyl fluoride. MS m / z (ESI): 536.2 [M + H] + .

[0184] Example 40 Preparation of ((2R,3S)-1-(5-isopropyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)-2-methylnitrid-3-yl)methanesulfonyl fluoride [ka] See Reference Example 1 for the preparation of ((2R,3S)-1-(5-isopropyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)-2-methylnitrid-3-yl)methanesulfonyl fluoride. MS m / z(ESI):510.2[M+H] + .

[0185] Example 41 Preparation of ((2R,3S)-1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonyl fluoride [ka] See Reference Example 1 for the preparation of ((2R,3S)-1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonyl fluoride. MS m / z(ESI):524.2[M+H] + .

[0186] Example 42 Preparation of ((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonyl fluoride [ka] See Reference Example 1 for the preparation of ((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonyl fluoride. MS m / z(ESI):544.2[M+H] + .

[0187] Example 43 Preparation of ((2R,3S)-1-(3-((2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonyl fluoride [ka] See Reference Example 1 for the preparation of ((2R,3S)-1-(3-((2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonyl fluoride. MS m / z(ESI):528.2[M+H] + .

[0188] Example 44 Preparation of N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methanesulfonamide [ka] Step 1. Synthesis of N-(1-(3-chloro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methanesulfonamide [ka] 8-Bromo-3-chloro-5-isopropylisoquinoline (300 mg, 1.05 mmol) and N-(azetidin-3-yl)methanesulfonamide (158 mg, 1.05 mmol) were dissolved in dioxane (10 mL), 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 125 ° C. in a microwave oven for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and dichloromethane was added and separated from water. The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The target compound, N-(1-(3-chloro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methanesulfonamide (170 mg, 45.6%), was obtained. MS m / z(ESI):354.1[M+H] + . Step 2. Synthesis of N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methanesulfonamide [ka] N-(1-(3-chloro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methanesulfonamide (50 mg, 0.14 mmol) and 2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (30 mg, 0.14 mmol) were dissolved in dioxane (5 mL), and cesium carbonate (81 mg, 0.25 mmol) and Xantphos Pd G4 (26 mg, 27 μmol) were added. The mixture was subjected to a microwave reaction at 120° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and dichloromethane was added. The organic layer was separated from the water and dried over anhydrous sodium sulfate. The organic layer was filtered and the organic solvent was concentrated under reduced pressure. The residue was then separated by column chromatography to obtain the target compound, N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methanesulfonamide (11 mg, 14.9%). 1 H NMR(400MHz,DMSO-d6)δ 10.16(s,1H),9.08(s,1H),8.57(s,1H),8.42-8.39(m,1H),8.33(s,1H),7.85-7.82(m,1H),7.43(d,J=7.6Hz,1H),7.29-7.25(m,1H),6.45 (d,J=8.2Hz,1H),4.57-4.51(m,2H),4.40-4.33(m,1H),3.95-3.91(m,2H),3.90(s,3H),3.59-3.51(m,1H),2.98(s,3H),1.31-1.28(m,6H); MS m / z(ESI):527.1[M+H] + .

[0189] Example 45 Preparation of N-((2R,3S)-1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonimide [ka] For the preparation of N-((2R,3S)-1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonimide, see Reference Example 1 or Example 44. MS m / z(ESI):521.2[M+H] + .

[0190] Example 46 Preparation of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonimide [ka] For the preparation of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonimide, see Reference Example 1 or Example 44. MS m / z (ESI): 541.2 [M + H] + .

[0191] Example 47 Preparation of N-((2R,3S)-1-(3-((2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonimide [ka] For the preparation of N-((2R,3S)-1-(3-((2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonimide, see Reference Example 1 or Example 44. MS m / z(ESI):525.2[M+H] + .

[0192] Example 48 Preparation of 5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(1-methyl-5-nitro-1H-pyridin-3-yl)pyrimidin-4-yl)isoquinolin-3-amine [ka] See Reference Example 1 for the preparation of 5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-N-(2-(1-methyl-5-nitro-1H-pyridin-3-yl)pyrimidin-4-yl)isoquinolin-3-amine. MS m / z(ESI):550.2[M+H] + .

[0193] Example 49 Preparation of N-(2-(1,2-dimethyl-5-nitro-1H-pyridin-3-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka] See Reference Example 1 for the preparation of N-(2-(1,2-dimethyl-5-nitro-1H-pyridin-3-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine. MS m / z (ESI): 564.2 [M + H] + .

[0194] Example 50 Preparation of N-(2-(2-chloro-1-methyl-5-nitro-1H-pyridin-3-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka] For the preparation of N-(2-(2-chloro-1-methyl-5-nitro-1H-pyridin-3-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, see Reference Example 1. MS m / z (ESI): 584.2 [M + H] + .

[0195] Example 51 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-1,5-dihydro-2H-pyridin-2-one [ka] See Reference Example 1 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-1,5-dihydro-2H-pyridin-2-one. MS m / z(ESI):521.2[M+H] + .

[0196] Example 52 Preparation of 3-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1-methyl-1,5-dihydro-2H-pyridin-2-one [ka] See Reference Example 1 for the preparation of 3-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1-methyl-1,5-dihydro-2H-pyridin-2-one. MS m / z(ESI):521.2[M+H] + .

[0197] Example 53 Preparation of 5-isopropyl-N-(2-(1-methyl-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka] See Reference Example 1 for the preparation of 5-isopropyl-N-(2-(1-methyl-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine. MS m / z(ESI):507.2[M+H] + .

[0198] Example 54 Preparation of 5-isopropyl-N-(2-(2-methyl-2H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka] See Reference Example 1 for the preparation of 5-isopropyl-N-(2-(2-methyl-2H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine. MS m / z(ESI):507.2[M+H] + .

[0199] Example 55 Preparation of N-(6-(3-chloro-1-methyl-1H-pyrazol-4-yl)-5-fluoropyridin-2-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine [ka] For the preparation of N-(6-(3-chloro-1-methyl-1H-pyrazol-4-yl)-5-fluoropyridin-2-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine, see Reference Example 1 or Example 5. MS m / z(ESI):557.2[M+H] + .

[0200] Example 56 Preparation of N-(6-(3-chloro-1-methyl-1H-pyrazol-4-yl)-5-methoxypyridin-2-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine [ka] For the preparation of N-(6-(3-chloro-1-methyl-1H-pyrazol-4-yl)-5-methoxypyridin-2-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine, see Reference Example 1 or Example 5. MS m / z (ESI): 569.2 [M + H] + .

[0201] Example 57 Preparation of 2-(3-chloro-1-methyl-1H-pyrazol-4-yl)-6-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-yl)amino)nicotinonitrile [ka] For the production method of 2-(3-chloro-1-methyl-1H-pyrazol-4-yl)-6-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-yl)amino)nicotinonitrile, see Reference Example 1 or Example 5. MS m / z (ESI): 564.2 [M + H] + .

[0202] Example 58 Preparation of N-(5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)-8-methyl-6,8-dihydropyrazole[4',3':4,5]pyran[3,2-b]pyridin-2-amine [ka] For the preparation of N-(5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)-8-methyl-6,8-dihydropyrazole[4',3':4,5]pyran[3,2-b]pyridin-2-amine, see Reference Example 1. MS m / z(ESI):533.2[M+H] + .

[0203] Example 59 Preparation of N-((2R,3S)-1-(7-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-1-isopropyl-2,6-naphthyridin-4-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide [ka] Step 1: Synthesis of 5-bromo-N-(tert-butyl)-2-chloroisonicotinamide [ka] 5-Bromo-2-chloroisonicotinic acid (20 g, 84.60 mmol) and 2-methylpropan-2-amine (7.31 g, 100 mmol) were dissolved in DMF (150 mL), and HATU (38 g, 100 mmol) was added portionwise. The mixture was allowed to react at room temperature for 3 hours. Ethyl acetate was added, and the mixture was separated from water. The organic phase was washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain the target compound, 5-bromo-N-(tert-butyl)-2-chloroisonicotinamide (15.50 g, 62.8%). MS m / z (ESI): 291.0 [M + H] + . Step 2: Synthesis of (E)-N-(tert-butyl)-2-chloro-5-(2-ethoxyvinyl)isonicotinamide [ka] 5-Bromo-N-(tert-butyl)-2-chloroisonicotinamide (15.50 g, 53.16 mmol) was dissolved in dioxane (150 mL) and water (30 mL), and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11.59 g, 58.50 mmol), cesium carbonate (32.58 g, 100 mmol), and PdCl(dppf) (3.89 g, 5.32 mmol) were added. The mixture was heated to 80°C and reacted for 2 hours. The reaction mixture 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 (E)-N-(tert-butyl)-2-chloro-5-(2-ethoxyvinyl)isonicotinamide (9.50 g, 63.2%). MS m / z(ESI):283.1[M+H] + . Step 3 Synthesis of 7-chloro-2,6-naphthyridin-1-ol [ka] (E)-N-(tert-butyl)-2-chloro-5-(2-ethoxyvinyl)isonicotinamide (9.50 g, 33.59 mmol) was dissolved in TFA (50 mL), heated to 100° C., and reacted for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude target compound, 7-chloro-2,6-naphthyridin-1-ol (5.66 g, 93.3%). MS m / z (ESI): 181.0 [M + H] + . Step 4 Synthesis of 4-bromo-7-chloro-2,6-naphthyridin-1-ol [ka] 7-Chloro-2,6-naphthyridin-1-ol (5.66 g, 31.34 mmol) was dissolved in dichloromethane (75 mL), NBS (6.69 g, 37.61 mmol) was added, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was filtered under reduced pressure, and the filter cake was collected and dried to give the crude target compound, 4-bromo-7-chloro-2,6-naphthyridin-1-ol (5.80 g, 71.3%). MS m / z (ESI): 259.0 [M + H] + . Step 5 Synthesis of 4-bromo-7-chloro-2,6-naphthyridin-1-yl trifluoromethanesulfonic acid [ka] 4-Bromo-7-chloro-2,6-naphthyridin-1-ol (5.80 g, 22.35 mmol) was dissolved in dichloromethane (80 mL) and TEA (4.52 g, 44.70 mmol). The reaction mixture was cooled to -75 °C, and (TfO)2O (25.39 g, 90 mmol) was slowly added dropwise. The mixture was then allowed to react at -75 °C for 0.5 hours, then slowly warmed to room temperature and allowed to react for 0.5 hours. The reaction was quenched by adding water, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by column chromatography to obtain the target compound, 4-bromo-7-chloro-2,6-naphthyridin-1-yl trifluoromethanesulfonic acid (5.71 g, 65.3%). MS m / z (ESI): 391.0 [M + H] + . Step 6 Synthesis of 4-bromo-7-chloro-1-iodo-2,6-naphthyridine [ka] 4-Bromo-7-chloro-2,6-naphthyridin-1-yltrifluoromethanesulfonic acid (5.71 g, 14.58 mmol) and NaI (10.94 g, 73 mmol) were mixed in ACN (100 mL). The reaction mixture was cooled to 0°C, and a solution of trifluoromethanesulfonic acid (4.50 g, 30 mmol) in ACN (10 mL) was slowly added dropwise. The mixture was allowed to react at room temperature for 2 hours. The mixture was partitioned with EA and water. The organic phase was washed with saturated aqueous NaCl, separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude target compound, 4-bromo-7-chloro-1-iodo-2,6-naphthyridine (5.28 g, 98.0%). MS m / z(ESI):369.0[M+H] + . Step 7 Synthesis of 4-bromo-7-chloro-1-(prop-1-en-2-yl)-2,6-naphthyridine [ka] 4-Bromo-7-chloro-1-iodo-2,6-naphthyridine (5.28 g, 14.29 mmol) was dissolved in dioxane (50 mL) and HO (5 mL), and isopropenylboronic acid pinacol ester (2.35 g, 14 mmol), potassium carbonate (4.60 g, 33.40 mmol), and PdCl(dppf) (610 mg, 0.84 mmol) were added. The mixture was heated to 100 °C and reacted for 4 hours. The reaction mixture 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, 4-bromo-7-chloro-1-(prop-1-en-2-yl)-2,6-naphthyridine (2.05 g, 50.6%). MS m / z (ESI): 283.0 [M + H] + . Step 8 Synthesis of 4-bromo-7-chloro-1-isopropyl-2,6-naphthyridine [ka] 4-Bromo-7-chloro-1-(prop-1-en-2-yl)-2,6-naphthyridine (2.05 g, 7.23 mmol) was dissolved in ethyl acetate (80 mL), PtO (2.04 g, 9 mmol) was added, and the mixture was stirred at room temperature for 3 hours under a hydrogen gas atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and then separated by column chromatography to obtain the target compound, 4-bromo-7-chloro-1-isopropyl-2,6-naphthyridine (1.20 g, 58.1%). MS m / z (ESI): 285.0 [M + H] + . Step 9 Synthesis of N-((2R,3S)-1-(7-chloro-1-isopropyl-2,6-naphthyridin-4-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide [ka] 4-Bromo-7-chloro-1-isopropyl-2,6-naphthyridine (471 mg, 1.65 mmol) and N-methyl-N-((2R,3S)-2-methylazetidin-3-yl)methanesulfonamide trifluoroacetate (470 mg, 1.70 mmol) were mixed in dioxane (10 mL), and cesium carbonate (1.15 g, 3.54 mmol) and Xantphos Pd G4 (164 mg, 0.17 mmol) were added. The mixture was heated to 100° C. and stirred for 5 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was separated from water using dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent. The mixture was separated by column chromatography to obtain the target compound, N-((2R,3S)-1-(7-chloro-1-isopropyl-2,6-naphthyridin-4-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (230 mg, 36.4%). MS m / z(ESI):383.1[M+H] + . Step 10: Synthesis of N-((2R,3S)-1-(7-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-1-isopropyl-2,6-naphthyridin-4-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide [ka] N-((2R,3S)-1-(7-chloro-1-isopropyl-2,6-naphthyridin-4-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (100 mg, 0.26 mmol) and 2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (55 mg, 0.26 mmol) were dissolved in dioxane (5 mL), and cesium carbonate (274 mg, 0.84 mmol) and BrettPhos Pd G4 (24 mg, 26 μmol) were added. The mixture was heated to 100° C. and stirred for 12 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was partitioned between water and dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent. The residue was separated by column chromatography to obtain the target compound, N-((2R,3S)-1-(7-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-1-isopropyl-2,6-naphthyridin-4-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (56 mg, 38.7%). MS m / z (ESI): 556.2 [M + H] + .

[0204] Example 60 Preparation of N-(1-(7-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-1-isopropyl-2,6-naphthyridin-4-yl)azetidin-3-yl)-N-methylmethanesulfonamide [ka] See Example 59 for the preparation of N-(1-(7-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-1-isopropyl-2,6-naphthyridin-4-yl)azetidin-3-yl)-N-methylmethanesulfonamide. MS m / z (ESI): 522.2 [M + H] + .

[0205] Example 61 Preparation of N-((2R,3S)-1-(7-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-1-isopropyl-2,6-naphthyridin-4-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide [ka] See Example 59 for the preparation of N-((2R,3S)-1-(7-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-1-isopropyl-2,6-naphthyridin-4-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide. MS m / z (ESI): 536.2 [M + H] + .

[0206] Example 62 Preparation of 2-(3-fluoro-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] For the production method of 2-(3-fluoro-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, see Reference Example 1 or 2. MS m / z (ESI): 554.2 [M + H] + .

[0207] Example 63 Preparation of (S)-N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-9-methyl-5-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-8,9-dihydro-7H-cyclopentane[f]isoquinolin-2-amine [ka] For the preparation of (S)—N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-9-methyl-5-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-8,9-dihydro-7H-cyclopentane[f]isoquinolin-2-amine, see Reference Example 1 or Example 5. MS m / z(ESI):552.2[M+H] + .

[0208] Example 64 Preparation of (R)-N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-9-methyl-5-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-8,9-dihydro-7H-cyclopentane[f]isoquinolin-2-amine [ka] For the preparation of (R)—N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-9-methyl-5-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-8,9-dihydro-7H-cyclopentane[f]isoquinolin-2-amine, see Reference Example 1 or Example 5. MS m / z(ESI):552.2[M+H] + .

[0209] Example 65 Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5,5-dimethyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-4,5-dihydrocyclopentane[de]isoquinolin-3-amine [ka] For the preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5,5-dimethyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-4,5-dihydrocyclopentane[de]isoquinolin-3-amine, see Reference Example 1 or Example 5. MS m / z(ESI):552.2[M+H] + .

[0210] Example 66 Preparation of N-((2R,3S)-1-(5-isopropyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonimide [ka] For the preparation of N-((2R,3S)-1-(5-isopropyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonimide, see Reference Example 1 or Example 44. MS m / z(ESI):507.2[M+H] + .

[0211] Example 67 Preparation of N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide [ka] Step 1. Synthesis of N-(1-(3-chloro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide [ka] N-(1-(3-chloro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methanesulfonamide (300 mg, 0.85 mmol) was dissolved in DMF (6 mL), cesium carbonate (552 mg, 1.70 mmol) and iodomethane (144 mg, 1.02 mmol) were added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, dichloromethane was added, and the mixture was separated from water. The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The mixture was then separated by column chromatography to obtain the target compound, N-(1-(3-chloro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide (150 mg, 48.1%). MS m / z(ESI):368.1[M+H] + . Step 2: Synthesis of N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide [ka] N-(1-(3-chloro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide (60 mg, 0.16 mmol) and 2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (34 mg, 0.16 mmol) were dissolved in dioxane (5 mL), and cesium carbonate (104 mg, 0.32 mmol) and Xantphos Pd G4 (26 mg, 27 μmol) were added. The mixture was subjected to a microwave reaction at 120° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and dichloromethane was added. The mixture was separated from water. The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was then separated by column chromatography to obtain the target compound, N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide (18 mg, 20.4%). 1 H NMR(400MHz,DMSO-d6)δ 10.15(s,1H),9.12(s,1H),8.56(s,1H),8.41-8.39(m,1H),8.33(s,1H),7.43(d,J=7.6Hz,1H),7.32-7.27(m,1H),6.47(d,J=8.2Hz,1H) ,4.70-4.65(m,1H),4.43-4.38(m,2H),4.25-4.21(m,2H),3.90(s,3H),3.61-3.54(m,1H),2.96(s,3H),2.93(s,3H),1.31-1.28(m,6H); MS m / z (ESI): 541.2 [M + H] + .

[0212] Example 68 Preparation of N-((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)-N-methylmethanesulfonamide [ka] See Example 67 for the preparation of N-((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)-N-methylmethanesulfonamide. MS m / z(ESI):555.2[M+H] + .

[0213] Example 69 Preparation of N-(1-(3-((2-(3-chloro-1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide [ka] See Example 67 for the preparation of N-(1-(3-((2-(3-chloro-1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide. MS m / z(ESI):544.2[M+H] + .

[0214] Example 70 Preparation of N-((2R,3S)-1-(3-((2-(3-chloro-1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide [ka] See Example 67 for the preparation of N-((2R,3S)-1-(3-((2-(3-chloro-1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide. MS m / z(ESI):558.2[M+H] + .

[0215] Example 71 Preparation of N-(1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide [ka] See Example 67 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)-N-methylmethanesulfonamide. MS m / z(ESI):521.2[M+H] + .

[0216] Example 72 Preparation of N-((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-methylmethanesulfonamide [ka] See Example 67 for the preparation of N-((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-methylmethanesulfonamide. MS m / z(ESI):535.2[M+H] + .

[0217] Example 73 Preparation of N-(2-(3-chloro-1-(2-(methylamino)ethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka] For the preparation of N-(2-(3-chloro-1-(2-(methylamino)ethyl)-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 2. MS m / z (ESI): 583.2 [M + H] + .

[0218] Example 74 Preparation of N-(2-(3-chloro-1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka] For the preparation of N-(2-(3-chloro-1-(2-(dimethylamino)ethyl)-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 2. MS m / z (ESI): 597.2 [M + H] + .

[0219] Example 75 Preparation of N-(1-(3-((2-(1-(2-aminoethyl)-3-chloro-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide [ka] See Example 67 for the preparation of N-(1-(3-((2-(1-(2-aminoethyl)-3-chloro-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide. MS m / z (ESI): 570.2 [M + H] + .

[0220] Example 76 Preparation of N-(1-(3-((2-(3-chloro-1-(2-(methylamino)ethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide [ka] See Example 67 for the preparation of N-(1-(3-((2-(3-chloro-1-(2-(methylamino)ethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide. MS m / z (ESI): 584.2 [M + H] + .

[0221] Example 77 Preparation of N-(1-(3-((2-(3-chloro-1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide [ka] See Example 67 for the preparation of N-(1-(3-((2-(3-chloro-1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide. MS m / z (ESI): 598.2 [M + H] + .

[0222] Example 78 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] See Example 67 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. MS m / z (ESI): 585.2 [M + H] + .

[0223] Example 79 Preparation of N-(1-(3-((2-(3-chloro-1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide [ka] See Example 67 for the preparation of N-(1-(3-((2-(3-chloro-1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide. MS m / z (ESI): 583.2 [M + H] + .

[0224] Example 80 Preparation of N-(2-(3-chloro-1-(((S)-oxetan-2-yl)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] For the preparation of N-(2-(3-chloro-1-(((S)-oxetan-2-yl)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 Reference Example 1 or 2. MS m / z (ESI): 596.2 [M + H] + .

[0225] Example 81 Preparation of N-(2-(3-chloro-1-(((R)-oxetan-2-yl)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] For the preparation of N-(2-(3-chloro-1-(((R)-oxetan-2-yl)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 Reference Example 1 or 2. MS m / z (ESI): 596.2 [M + H] + .

[0226] Example 82 Preparation of (S)—N-(1-(3-((2-(3-chloro-1-(oxetan-2-ylmethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide [ka] See Example 67 for a method for preparing (S)—N-(1-(3-((2-(3-chloro-1-(oxetan-2-ylmethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide. MS m / z (ESI): 597.2 [M + H] + .

[0227] Example 83 Preparation of (R)—N-(1-(3-((2-(3-chloro-1-(oxetan-2-ylmethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide [ka] See Example 67 for the preparation of (R)—N-(1-(3-((2-(3-chloro-1-(oxetan-2-ylmethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide. MS m / z (ESI): 597.2 [M + H] + .

[0228] Example 84 Preparation of N-(1-(3-((2-(3-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide [ka] See Example 67 for the preparation of N-(1-(3-((2-(3-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide. MS m / z (ESI): 577.2 [M + H] + .

[0229] Example 85 Preparation of N-(2-(3-chloro-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] For the preparation of N-(2-(3-chloro-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 Reference Example 1 or 2. MS m / z (ESI): 576.2 [M + H] + .

[0230] Example 86 Preparation of N-(1-(3-((2-(3-chloro-1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide [ka] See Example 67 for the preparation of N-(1-(3-((2-(3-chloro-1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide. MS m / z (ESI): 585.2 [M + H] + .

[0231] Example 87 Preparation of N-(1-(3-((2-(3-chloro-1-(2-cyanoethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide [ka] See Example 67 for the preparation of N-(1-(3-((2-(3-chloro-1-(2-cyanoethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide. MS m / z(ESI):580.2[M+H] + .

[0232] Example 88 Preparation of N-(1-(3-((2-(3-chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide [ka] See Example 67 for the preparation of N-(1-(3-((2-(3-chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide. MS m / z (ESI): 611.2 [M + H] + .

[0233] Example 89 Preparation of N-(1-(3-((2-(5-fluoro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide [ka] See Example 67 for the preparation of N-(1-(3-((2-(5-fluoro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide. MS m / z(ESI):525.2[M+H] + .

[0234] Example 90 Preparation of N-(2-(5-fluoro-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] See Reference Example 1 for the preparation of N-(2-(5-fluoro-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. MS m / z(ESI):524.2[M+H] + .

[0235] Example 91 Preparation of N-(1-(3-((2-(5-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide [ka] See Example 67 for the preparation of N-(1-(3-((2-(5-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide. MS m / z (ESI): 541.2 [M + H] + .

[0236] Example 92 Preparation of N-(2-(5-chloro-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] See Reference Example 1 for the preparation of N-(2-(5-chloro-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. 1H NMR (400 MHz, DMSO-d6) δ 10.24(s,1H),9.10(s,1H),8.67(s,1H),8.42(d,J=5.8Hz,1H),8.18(s,1H), 7.45(d,J=8.0Hz,1H),7.24(d,J=5.6Hz,1H),6.58(d,J=8.1Hz,1H),4.72-4.6 4(m,1H),4.24-4.18(m,1H),3.90(s,3H),3.69-3.63(m,1H),3.60-3.50(m,3 H),3.00(s,3H),2.92-2.86(m,1H),1.43(d,J=6.0Hz,3H),1.35-1.30(m,6H); MS m / z(ESI):540.2[M+H] + .

[0237] Example 93 Preparation of N-(1-(3-((2-(5-fluoro-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide [ka] See Example 67 for the preparation of N-(1-(3-((2-(5-fluoro-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide. MS m / z (ESI): 539.2 [M + H] + .

[0238] Example 94 Preparation of N-(1-(3-((2-(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide [ka] See Example 67 for the preparation of N-(1-(3-((2-(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide. MS m / z(ESI):555.2[M+H] + .

[0239] Example 95 Preparation of N-(2-(5-chloro-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] See Reference Example 1 for the preparation of N-(2-(5-chloro-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. MS m / z (ESI): 554.2 [M + H] + .

[0240] Example 96 Preparation of (R)-2-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)tetrahydrothiophene 1,1-dioxide [ka] For the preparation of (R)-2-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)tetrahydrothiophene 1,1-dioxide, see Reference Example 1 or Example 5. MS m / z(ESI):552.2[M+H] + .

[0241] Example 97 Preparation of (S)-2-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)tetrahydrothiophene 1,1-dioxide [ka] For the preparation of (S)-2-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)tetrahydrothiophene 1,1-dioxide, see Reference Example 1 or Example 5. MS m / z(ESI):552.2[M+H] + .

[0242] Example 98 Preparation of (R)-2-(1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)tetrahydrothiophene 1,1-dioxide [ka] See Reference Example 1 for the preparation of (R)-2-(1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)tetrahydrothiophene 1,1-dioxide. MS m / z(ESI):532.2[M+H] + .

[0243] Example 99 Preparation of (S)-2-(1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)tetrahydrothiophene 1,1-dioxide [ka] See Reference Example 1 for the preparation of (S)-2-(1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)tetrahydrothiophene 1,1-dioxide. MS m / z(ESI):532.2[M+H] + .

[0244] Example 100 Preparation of N-(((1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methyl)(methyl)(carbonyl)-16-sulfanylidene)cyanoamide [ka] See Example 67 or Example 5 for the preparation of N-(((1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methyl)(methyl)(carbonyl)-16-sulfanylidene)cyanoamide. MS m / z(ESI):550.2[M+H] + .

[0245] Example 101 Preparation of N-(((1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methyl)(methyl)(carbonyl)-16-sulfanylidene)cyanoamide [ka] See Example 67 or Example 5 for the preparation of N-(((1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methyl)(methyl)(carbonyl)-16-sulfanylidene)cyanoamide. MS m / z(ESI):550.2[M+H] + .

[0246] Example 102 Preparation of ((1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)imino)dimethyl-16-sulfanone [ka] See Example 67 or Example 5 for the preparation of ((1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)imino)dimethyl-16-sulfanone. 1 H NMR(400MHz,DMSO-d6)δ 10.14(s,1H),9.09(s,1H),8.55(s,1H),8.40(d,J=5.8Hz,1H),8.33(s,1H),7.41(d,J=8.0Hz,1H),7.27(d,J=6.0Hz,1H),6.4 1(d,J=8.0Hz,1H),4.48-4.39(m,3H),3.90(s,3H),3.82-3.78(m,2H),3.58-3.55(m,1H),3.05(s,6H),1.30(d,J=6.8Hz,6H); MS m / z(ESI):525.2[M+H] + .

[0247] Example 103 Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((1s,3s)-3-((methylsulfonyl)methyl)cyclobutyl)isoquinolin-3-amine [ka] See Example 67 or Example 5 for the preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((1s,3s)-3-((methylsulfonyl)methyl)cyclobutyl)isoquinolin-3-amine. MS m / z(ESI):525.2[M+H] + .

[0248] Example 104 Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((1r,3r)-3-((methylsulfonyl)methyl)cyclobutyl)isoquinolin-3-amine [ka] See Example 67 or Example 5 for the preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((1r,3r)-3-((methylsulfonyl)methyl)cyclobutyl)isoquinolin-3-amine. MS m / z(ESI):525.2[M+H] + .

[0249] Example 105 Preparation of N-((1s,3s)-3-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)cyclobutyl)-N-methylmethanesulfonamide [ka] See Example 67 for the preparation of N-((1s,3s)-3-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)cyclobutyl)-N-methylmethanesulfonamide. MS m / z(ESI):540.2[M+H] + .

[0250] Example 106 Preparation of N-((1r,3r)-3-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)cyclobutyl)-N-methylmethanesulfonamide [ka] See Example 67 for a method for preparing N-((1r,3r)-3-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)cyclobutyl)-N-methylmethanesulfonamide. MS m / z(ESI):540.2[M+H] + .

[0251] Example 107 Preparation of 3-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-1,2,3-oxathiazolidine 2,2-dioxide [ka] For the preparation of 3-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-1,2,3-oxathiazolidine 2,2-dioxide, see Reference Example 1 or Example 5. MS m / z(ESI):555.2[M+H]+ .

[0252] Example 108 Preparation of 3-(1-(3-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)oxazolidin-2-one [ka] See Reference Example 1 or Example 5 for the preparation of 3-(1-(3-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)oxazolidin-2-one. MS m / z (ESI): 519.2 [M + H] + .

[0253] Example 109 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] See Example 5 for a method for preparing 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. 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] + .

[0254] Example 110 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)-2-methylpropan-2-ol [ka] See Reference Example 2 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)-2-methylpropan-2-ol. MS m / z (ESI): 598.2 [M + H] + .

[0255] Example 111 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)-2,2-dimethylpropanenitrile [ka] See Reference Example 2 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)-2,2-dimethylpropanenitrile. MS m / z(ESI):607.2[M+H] + .

[0256] Example 112 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)-2-methylpropanenitrile [ka] See Reference Example 2 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)-2-methylpropanenitrile. 1 H NMR(400MHz,DMSO-d6)δ 10.20(s,1H),9.11(s,1H),8.51-8.40(m,3H),7.43(d,J=7.8Hz,1H),7 .36(s,1H),6.58(d,J=8.0Hz,1H),4.68(t,J=7.6Hz,1H),4.46-4.40(m, 2H),4.21(t,J=6.4Hz,1H),3.65(t,J=7.0Hz,1H),3.59-3.50(m,4H),3. 00(s,3H),2.96-2.85(m,1H),1.43(d,J=6.0Hz,3H),1.33-1.26(m,9H); MS m / z (ESI): 593.2 [M + H] + .

[0257] Example 113 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)-1,1,1-trifluoropropan-2-ol [ka] 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)-1,1,1-trifluoropropan-2-ol, see Reference Example 2. 1 H NMR(400MHz,DMSO-d6)δ 10.20(s,1H),9.10(s,1H),8.51-8.41(m,3H),7.45(d,J=8.0Hz,1H),6.86-6.81(m,1H),6.58(d,J=8.0Hz,1H),5.34-5.30(m,1H) ,4.70-4.66(m,1H),4.30-4.19(m,2H),3.66-3.48(m,5H),3.00(s,3H),2.92-2.87(m,1H),2.03-1.95(m,1H),1.33-1.27(m,9H); MS m / z (ESI): 638.2 [M + H] + .

[0258] Example 114 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-one [ka] See Reference Example 2 for a method for preparing 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-one. MS m / z (ESI): 582.2 [M + H] + .

[0259] Example 115 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)propionitrile [ka] See Reference Example 2 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)propionitrile. 1 H NMR(400MHz,DMSO)δ 10.24(s,1H),9.10(s,1H),8.55(s,1H),8.48(s,1H),8.44(d,J=5.9Hz,1H),7.43(d,J =8.0Hz,1H),7.36(d,J=4.3Hz,1H),6.58(d,J=8.1Hz,1H),5.93(q,J=7.1Hz,1H),4.68( t,J=7.5Hz,1H),4.23-4.17(m,1H),3.65(t,J=7.1Hz,1H),3.60-3.50(m,3H),3.00(s,3 H),2.95-2.82(m,1H),1.86(d,J=7.1Hz,3H),1.43(d,J=6.0Hz,3H),1.30-1.26(m,6H); MS m / z (ESI): 579.2 [M + H] + .

[0260] Example 116A Preparation of N-(2-(3-chloro-1-(2-methoxypropyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka] For the preparation of N-(2-(3-chloro-1-(2-methoxypropyl)-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 2. 1 H NMR(400MHz,DMSO-d6)δ 10.19(s,1H),9.10(s,1H),8.53(s,1H),8.40(s,1H),8.30(s,1H),7.43(d,J=8.0Hz,1 H),7.30(d,J=5.1Hz,1H),6.58(d,J=8.1Hz,1H),4.68(t,J=7.5Hz,1H),4.35-4.06(m,3 H),3.88-3.68(m,1H),3.68-3.43(m,4H),3.20(s,3H),3.00(s,3H),2.90(dt,J=14.6, 7.2Hz,1H),1.43(d,J=6.0Hz,3H),1.30(dd,J=12.1,6.3Hz,6H),1.11(d,J=6.2Hz,3H); MS m / z (ESI): 598.2 [M + H] + .

[0261] Example 116 Preparation of N-(2-(3-chloro-1-((S)-2-methoxypropyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka] For the preparation of N-(2-(3-chloro-1-((S)-2-methoxypropyl)-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 2. MS m / z (ESI): 598.2 [M+H] + .

[0262] Example 117 Preparation of N-(2-(3-chloro-1-((R)-2-methoxypropyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka] For the preparation of N-(2-(3-chloro-1-((R)-2-methoxypropyl)-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 2. MS m / z (ESI): 598.2 [M+H] + .

[0263] Example 118 Preparation of (S)-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)-2-methylpropanenitrile [ka] See Reference Example 2 for the preparation of (S)-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)-2-methylpropanenitrile. 1 H NMR(400MHz,DMSO-d6)δ 10.20(s,1H),9.10(s,1H),8.47-8.41(m,3H),7.43(d,J=8.0Hz,1H),7.3 5(d,J=4.6Hz,1H),6.58(d,J=8.1Hz,1H),4.68(t,J=7.5Hz,1H),4.47-4. 38(m,2H),4.22-4.19(m,1H),3.65(t,J=7.1Hz,1H),3.60-3.50(m,4H),3 .00(s,3H),2.94-2.87(m,1H),1.43(d,J=6.1Hz,3H),1.30-1.27(m,9H); MS m / z (ESI): 593.2 [M + H] + .

[0264] Example 119 Preparation of (R)-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)-2-methylpropanenitrile [ka] See Reference Example 2 for the preparation of (R)-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)-2-methylpropanenitrile. 1H NMR(400MHz,DMSO-d6)δ 10.20(s,1H),9.10(s,1H),8.47-8.41(m,3H),7.43(d,J=8.0Hz,1H),7.3 5(d,J=4.6Hz,1H),6.58(d,J=8.1Hz,1H),4.68(t,J=7.5Hz,1H),4.47-4. 38(m,2H),4.22-4.19(m,1H),3.65(t,J=7.1Hz,1H),3.60-3.50(m,4H),3 .00(s,3H),2.94-2.87(m,1H),1.43(d,J=6.1Hz,3H),1.30-1.27(m,9H); MS m / z (ESI): 593.2 [M + H] + .

[0265] Example 120 Preparation of N-(2-(3-chloro-1-methyl-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] For the preparation of N-(2-(3-chloro-1-methyl-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, see Example 5. Alternatively, it may be prepared according to the following route: Step 1: Synthesis of 3-chloro-6-fluoro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline [ka] 8-Bromo-3-chloro-6-fluoro-5-isopropylisoquinoline (500 mg, 1.65 mmol) and (2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine (297 mg, 1.82 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. The mixture was heated to 100°C and stirred for 12 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and separated with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The resulting mixture was separated by column chromatography to obtain the target compound, 3-chloro-6-fluoro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline (418 mg, 65.8%). MS m / z(ESI):385.1[M+H] + . Step 2: Synthesis of N-(2-(3-chloro-1-methyl-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] 3-Chloro-6-fluoro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline (100 mg, 0.26 mmol) and 2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (54 mg, 0.26 mmol) were dissolved in dioxane (5 mL), and cesium carbonate (274 mg, 0.84 mmol) and BrettPhos Pd G4 (24 mg, 26 μmol) were added, and the mixture was heated to 100° C. and stirred for 12 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and separated with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The resulting mixture was separated by column chromatography to obtain the target compound, N-(2-(3-chloro-1-methyl-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 (61 mg, 42%). 1 H NMR(400MHz,DMSO-d6)δ 10.14(s,1H),8.96(s,1H),8.53(s,1H),8.35(d,J=5.8Hz,1H),8.24(s,1H),7.19(d,J=5.8Hz,1H),6.27(d,J=14.4Hz,1H),4.70-4. 62(m,1H),4.21-4.14(m,1H),3.83(s,3H),3.72-3.64(m,1H),3.57-3.41(m,3H),2.93(s,3H),2.87-2.77(m,1H),1.39-1.26(m,9H); MS m / z(ESI):558.2[M+H] + .

[0266] Example 121 Preparation of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide [ka] See Example 67 for the preparation of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide.

[0267] Or prepared according to the following route: Step 1 Synthesis of N-((2R,3S)-1-(3-chloro-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide [ka] 8-Bromo-3-chloro-6-fluoro-5-isopropylisoquinoline (500 mg, 1.65 mmol) and N-methyl-N-((2R,3S)-2-methylazetidin-3-yl)methanesulfonamide trifluoroacetate (470 mg, 1.70 mmol) were mixed in dioxane (10 mL), and cesium carbonate (1.15 g, 3.54 mmol) and Xantphos Pd G4 (164 mg, 0.17 mmol) were added. The mixture was heated to 100° C. and stirred for 5 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was separated from water using dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then separated by column chromatography to obtain the target compound, N-((2R,3S)-1-(3-chloro-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (330 mg, 50.0%). 1H NMR(400MHz,DMSO-d6)δ 9.08(s,1H),8.07(s,1H),6.68-6.65(m,1H),4.76-4.69(m,1H),4.59-4.55(m,1H),4.26-4.22(m,1H),3 .98-3.96(m,1H),3.67-3.59(m,1H),2.95(s,3H),2.83(s,3H),1.40(d,J=6.0Hz,3H),1.37-1.31(m,6H); MS m / z (ESI): 400.1 [M + H] + . Step 2: Synthesis of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide [ka] N-((2R,3S)-1-(3-chloro-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (100 mg, 0.25 mmol) and 2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (55 mg, 0.25 mmol) were dissolved in dioxane (5 mL), and cesium carbonate (274 mg, 0.84 mmol) and BrettPhos Pd G4 (24 mg, 26 μmol) were added. The mixture was heated to 100° C. and stirred for 12 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was separated with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then separated by column chromatography to obtain the target compound N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (73 mg, 50.9%). 1H NMR(400MHz,DMSO-d6)δ 10.21(s,1H),9.05(s,1H),8.60(s,1H),8.42(d,J=5.8Hz,1H),8.30(s,1 H),7.28(d,J=6.0Hz,1H),6.47-6.43(m,1H),4.71-4.69(m,1H),4.53-4.4 9(m,1H),4.23-4.18(m,1H),3.94-3.91(m,1H),3.89(s,3H),3.63-3.58(m ,1H),2.95(s,3H),2.84(s,3H),1.40(d,J=6.0Hz,6H),1.36-1.32(m,3H); MS m / z (ESI): 573.2 [M + H] + .

[0268] Example 122 Preparation of N-((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)-N-methylmethanesulfonamide [ka] See Example 67 or 121 for the preparation of N-((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)-N-methylmethanesulfonamide. 1H NMR(400MHz,DMSO-d6)δ 10.21(s,1H),9.12(s,1H),8.61(s,1H),8.41(d,J=5.8Hz,1H),8.34(s,1H),7.4 6(d,J=8.0Hz,1H),7.26(d,J=5.6Hz,1H),6.67(d,J=8.0Hz,1H),4.66-4.63(m,1 H),4.45-4.41(m,1H),4.21-4.18(m,1H),3.91(s,3H),3.82-3.79(m,1H),3.59- 3.55(m,1H),2.95(s,3H),2.83(s,3H),1.41(d,J=6.0Hz,3H),1.33-1.31(m,6H); MS m / z(ESI):555.2[M+H] + .

[0269] Example 123 Preparation of N-((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)methanesulfonamide [ka] See Example 44 for the preparation of N-((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)methanesulfonamide. 1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),9.03(s,1H),8.54(s,1H),8.34(d,J=5.8Hz,1 H),8.27(s,1H),7.70(d,J=8.0Hz,1H),7.38(d,J=8.0Hz,1H),7.18(d,J=5.8Hz,1H) ,6.57(d,J=8.0Hz,1H),4.73-4.71(m,1H),4.08-4.06(m,1H),3.89-3.87(m,1H),3. 84(s,3H),3.62-3.59(m,2H),2.89(s,3H),1.36(d,J=6.0Hz,3H),1.24-1.22(m,6H); MS m / z (ESI): 541.2 [M + H] + .

[0270] Example 124 Preparation of N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide [ka] See Example 67 or 120 for the preparation of N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide. 1 H NMR(400MHz,DMSO-d6)δ 10.18(s,1H),9.06(s,1H),8.56(s,1H),8.42(d,J=5.8Hz,1H),8.30(s,1H),7.31(d,J=5.8Hz,1H),6.28-6.25(m,1H),4.70 -4.68(m,1H),4.46-4.43(m,2H),4.32-4.29(m,2H),3.89(s,3H),3.59-3.56(m,1H),2.95-2.93(m,6H),1.38-1.36(m,6H); MS m / z (ESI): 559.2 [M + H]+ .

[0271] Example 125 Preparation of N-(2-(1,3-dimethyl-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] For the preparation of N-(2-(1,3-dimethyl-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, see Example 5 or 120. 1 H NMR(400MHz,DMSO-d6)δ 10.04(s,1H),8.96(s,1H),8.47(s,1H),8.31(d,J=5.8Hz,1H),8.07(s,1H),7.17-7.09(m,1H),6.31-6.23(m,1H),4.66(t,J=7.6Hz,1H),4. 18(t,J=6.2Hz,1H),3.77(s,3H),3.68(t,J=7.2Hz,1H),3.56-3.44(m,3H),2.93(s,3H),2.86-2.77(m,1H),2.44(s,3H),1.39-1.31(m,9H); MS m / z(ESI):538.2[M+H] + .

[0272] Example 126 Preparation of N-((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-methylmethanesulfonamide [ka] See Example 67 or 121 for the preparation of N-((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-methylmethanesulfonamide. 1 H NMR(400MHz,DMSO-d6)δ 10.11(s,1H),9.12(s,1H),8.58(s,1H),8.37(d,J=5.8Hz,1H),8.19(s,1H),7.46(d ,J=7.8Hz,1H),7.20(d,J=5.8Hz,1H),6.67(d,J=8.0Hz,1H),4.66-4.63(m,1H),4.4 4-4.42(m,1H),4.21-4.19(m,1H),3.85(s,3H),3.82-3.79(m,1H),3.58-3.56(m,1H) ),2.96(s,3H),2.83(s,3H),2.52(s,3H),1.41(d,J=6.0Hz,3H),1.34-1.31(m,6H); MS m / z(ESI):535.2[M+H] + .

[0273] Example 127 Preparation of N-((2R,3S)-1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide [ka] See Example 67 or 121 for the preparation of N-((2R,3S)-1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide. 1H NMR(400MHz,DMSO-d6)δ 10.12(s,1H),9.05(s,1H),8.55(s,1H),8.38(d,J=5.8Hz,1H),8.14(s, 1H),7.22(d,J=5.6Hz,1H),6.47(d,J=14.3Hz,1H),4.75-4.67(m,1H),4. 57-4.48(m,1H),4.27-4.19(m,1H),3.97-3.91(m,1H),3.84(s,3H),3.64 -3.52(m,1H),2.95(s,3H),2.84(s,3H),2.51(s,3H),1.46-1.37(m,9H); MS m / z (ESI): 553.2 [M + H] + .

[0274] Example 128 Preparation of N-((2R,3S)-1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide [ka] See Example 44 for the preparation of N-((2R,3S)-1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide. MS m / z(ESI):521.2[M+H] + .

[0275] Example 129 Preparation of N-(1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide [ka] See Example 67 or 120 for the preparation of N-(1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide. 1 H NMR(400MHz,DMSO-d6)δ 10.00(s,1H),9.00(s,1H),8.43(s,1H),8.32(d,J=5.8Hz,1H),8.07(s,1H),7.21-7.17(m,1H),6.23-6.15(m,1H),4.67-4.60(m,1H) ),4.39(t,J=8.2Hz,2H),4.29-4.22(m,2H),3.77(s,3H),3.55-3.47(m,1H),2.91-2.84(m,6H),2.44(s,3H),1.34(d,J=6.6Hz,6H); MS m / z (ESI): 539.2 [M + H] + .

[0276] Example 130 Preparation of N-(1-(6-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-isopropyl-2,7-naphthyridin-1-yl)azetidin-3-yl)-N-methylmethanesulfonamide [ka] See Example 67 for the preparation of N-(1-(6-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-isopropyl-2,7-naphthyridin-1-yl)azetidin-3-yl)-N-methylmethanesulfonamide. 1H NMR(400MHz,DMSO-d6)δ 10.37(s,1H),9.12(s,1H),8.48-8.46(m,2H),8.34(s,1H),8.00(s,1H),7.35(d,J=8.0Hz, 1H),4.74-4.49(m,5H),3.91(s,3H),3.45-3.40(m,1H),2.95(s,6H),1.31(d,J=7.6Hz,6H); MS m / z (ESI): 542.2 [M + H] + .

[0277] Example 131 Preparation of N-(1-(7-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-1-isopropyl-2,6-naphthyridin-4-yl)azetidin-3-yl)-N-methylmethanesulfonamide [ka] See Example 67 for the preparation of N-(1-(7-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-1-isopropyl-2,6-naphthyridin-4-yl)azetidin-3-yl)-N-methylmethanesulfonamide. 1 H NMR(400MHz,DMSO-d6)δ 10.38(s,1H),9.21(s,1H),8.73(s,1H),8.44(d,J=5.8Hz,1H),8.37(s,1H),7.65(s,1H),7.23(d,J=5.8Hz,1H),4.73(t, J=7.0Hz,1H),4.55-4.48(m,2H),4.39-4.33(m,2H),3.91(s,3H),3.84-3.77(m,1H),2.96(s,6H),1.31(d,J=6.8Hz,6H); MS m / z (ESI): 542.2 [M + H] + .

[0278] Example 132 Preparation of N-(2-(3-chloro-1-methyl-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] See Example 5 for the preparation of N-(2-(3-chloro-1-methyl-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. 1 H NMR(400MHz,DMSO-d6)δ 10.39(s,1H),9.09(s,1H),8.48-8.45(m,2H),8.34(s,1H),8.01(s,1H) ),7.32(d,J=8.0Hz,1H),4.88-4.86(m,1H),4.58-4.55(m,1H),4.02-3 .98(m,1H),3.91(s,3H),3.57-3.54(m,2H),3.44-3.36(m,1H),3.00(s ,3H),2.91-2.88(m,1H),1.50(d,J=7.6Hz,3H),1.31(d,J=7.6Hz,6H); MS m / z (ESI): 541.2 [M + H] + .

[0279] Example 133 Preparation of N-(2-(3-chloro-1-methyl-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] See Example 5 for the preparation of N-(2-(3-chloro-1-methyl-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. 1 H NMR(400MHz,DMSO-d6)δ 10.42(s,1H),9.17(s,1H),8.75(s,1H),8.44(d,J=5.8Hz,1H),8.37(s,1H),7.75(s,1H),7.224-7.15(m,1H),4.80-4.73(m,1H),4.36-4.3 0(m,1H),3.91(s,3H),3.85-3.76(m,2H),3.60-3.55(m,2H),3.01(s,3H),2.95-2.91(m,1H),1.49(d,J=6.2Hz,3H),1.31(d,J=6.6Hz,6H); MS m / z (ESI): 541.2 [M + H] + .

[0280] Example 134 Preparation of N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-(dimethylamino)-6-fluoroisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide [ka] See Example 67 or 120 for the preparation of N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-(dimethylamino)-6-fluoroisoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide. MS m / z(ESI):560.2[M+H] + .

[0281] Example 135 Preparation of (R)—N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-(1-methoxyethyl)isoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide [ka] See Example 67 or 120 for the preparation of (R)—N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-(1-methoxyethyl)isoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide. MS m / z (ESI): 575.2 [M + H] + .

[0282] Example 136 Preparation of (S)—N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-(1-methoxyethyl)isoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide [ka] See Example 67 or 120 for the preparation of (S)—N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-(1-methoxyethyl)isoquinolin-8-yl)azetidin-3-yl)-N-methylmethanesulfonamide. MS m / z (ESI): 575.2 [M + H] + .

[0283] Example 137 Preparation of N3-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-N5,N5-dimethyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline-3,5-diamine [ka] See Example 5 or 120 for the preparation of N3-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-N5,N5-dimethyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline-3,5-diamine. MS m / z (ESI): 559.2 [M + H] + .

[0284] Example 138 Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-5-((R)-1-methoxyethyl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka] For the preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-5-((R)-1-methoxyethyl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, see Example 5 or 120. MS m / z (ESI): 574.2 [M + H] + .

[0285] Example 139 Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-5-((S)-1-methoxyethyl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka] For the preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-5-((S)-1-methoxyethyl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, see Example 5 or 120. MS m / z (ESI): 574.2 [M + H] + .

[0286] Example 140 Preparation of N-(2-(3-chloro-1-(2-methyltetrahydro-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] For the preparation of N-(2-(3-chloro-1-(2-methyltetrahydro-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 Reference Example 2. 1H NMR(400MHz,DMSO-d6)δ 10.11(s,1H),9.03(s,1H),8.46-8.32(m,3H),7.35(d,J=8.0Hz,1H),7.24 (s,1H),6.50(d,J=8.1Hz,1H),4.62-4.59(m,1H),4.17-4.11(m,1H),3.80 -3.41(m,7H),2.93(s,3H),2.85-2.78(m,1H),2.27-1.90(m,4H),1.76-1. 68(m,1H),1.36(d,J=6.1Hz,3H),1.23-1.18(m,6H),1.09(d,J=6.4Hz,3H); MS m / z(ESI):624.2[M+H] + .

[0287] Example 141 Preparation of N-(2-(3-chloro-1-(2-oxaspiro[3.3]heptan-6-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] For the preparation of N-(2-(3-chloro-1-(2-oxaspiro[3.3]heptan-6-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 Reference Example 2. 1 H NMR(400MHz,DMSO-d6)δ 10.18(s,1H),9.09(s,1H),8.63-8.39(m,3H),7.43(d,J=8.0Hz,1H),7.31-7.23(m,1H),6.71-6.65(m,1H),4.88-4.5 1(m,5H),4.25-4.20(m,1H),3.61-3.50(m,2H),3.00(s,3H),2.90-2.60(m,4H),2.14-2.00(m,4H),1.44-1.21(m,9H); MS m / z (ESI): 622.2 [M + H] + .

[0288] Example 142 Preparation of N-(2-(3-chloro-1-((S)-tetrahydrofuran-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] For the preparation of N-(2-(3-chloro-1-((S)-tetrahydrofuran-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 Reference Example 2. 1 H NMR (400 MHz, DMSO-d6) δ 10.13(s,1H),9.10(s,1H),8.47-8.40(m,3H),7.43(d,J=8.0Hz,1H),7.33 -7.26(m,1H),6.58(d,J=8.0Hz,1H),5.35-5.30(m,1H),5.10-5.06(m,1H) ,4.65-4.60(m,1H),4.22-4.19(m,1H),4.01-3.95(m,3H),3.86-3.82(m,1 H),3.65-3.45(m,2H),2.99(s,3H),2.03-1.97(m,4H),1.31-1.27(m,9H); MS m / z (ESI): 596.2 [M + H] + .

[0289] Example 143 Preparation of N-(2-(3-chloro-1-((R)-tetrahydrofuran-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] For the preparation of N-(2-(3-chloro-1-((R)-tetrahydrofuran-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 Reference Example 2. 1 H NMR (400 MHz, DMSO-d6) δ 10.19(s,1H),9.10(s,1H),8.47-8.40(m,3H),7.43(d,J=7.2Hz,1H),7.30(br s,1H),6.56(d,J=7.6Hz,1H),5.09-5.06(m,1H),4.70-4.65(m,1H),4.23-4.1 8(m,1H),4.03-3.83(m,4H),3.86-3.80(m,1H),3.65-3.52(m,2H),2.99(s,3H) ),2.91-2.88(m,1H),2.35-2.30(m,1H),2.03-1.95(m,2H),1.37-1.16(m,9H); MS m / z (ESI): 596.2 [M + H] + .

[0290] Example 144 Preparation of N-(2-(3-chloro-1-(((R)-tetrahydrofuran-2-yl)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] For the preparation of N-(2-(3-chloro-1-(((R)-tetrahydrofuran-2-yl)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 Reference Example 2. 1H NMR(400MHz,DMSO-d6)δ 10.12(s,1H),9.03(s,1H),8.44(s,1H),8.34(d,J=5.8Hz,1H),8.25(s,1H),7.36(d,J=8. 0Hz,1H),7.24(s,1H),6.51(d,J=8.2Hz,1H),4.61(t,J=7.5Hz,1H),4.23-4.03(m,4H),3. 73-3.63(m,1H),3.63-3.39(m,5H),2.93(s,3H),2.82(q,J=7.3Hz,1H),1.98-1.86(m,1H) ,1.83-1.64(m,2H),1.62-1.49(m,1H),1.36(d,J=6.0Hz,3H),1.23(dd,J=9.2,6.8Hz,6H); MS m / z(ESI):610.2[M+H] + .

[0291] Example 145 Preparation of N-(2-(3-chloro-1-(((S)-tetrahydrofuran-2-yl)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] For the preparation of N-(2-(3-chloro-1-(((S)-tetrahydrofuran-2-yl)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 Reference Example 2. 1H NMR(400MHz,DMSO-d6)δ 10.19(s,1H),9.10(s,1H),8.51(s,1H),8.41(d,J=5.8Hz,1H),8.32(s,1H),7.43(d,J=8.0Hz ,1H),7.33-7.28(m,1H),6.58(d,J=8.1Hz,1H),4.68(t,J=7.5Hz,1H),4.31-4.10(m,4H),3.82 -3.70(m,1H),3.68-3.61(m,2H),3.61-3.50(m,3H),3.00(s,3H),2.90(q,J=7.3Hz,1H),2.05 -1.93(m,1H),1.88-1.74(m,2H),1.69-1.56(m,1H),1.43(d,J=6.0Hz,3H),1.35-1.21(m,6H); MS m / z(ESI):610.2[M+H] + .

[0292] Example 146 Preparation of N-(2-(3-chloro-1-(((R)-1-methylazetidin-2-yl)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] For the preparation of N-(2-(3-chloro-1-(((R)-1-methylazetidin-2-yl)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 Reference Example 2. 1H NMR(400MHz,DMSO-d6)δ 10.20(s,1H),9.10(s,1H),8.54(s,1H),8.41(d,J=6.0Hz,1H),8.33(s,1H),7.44(d,J=8.0 Hz,1H),7.32-7.26(m,1H),6.58(d,J=8.0Hz,1H),4.72-4.66(m,1H),4.23-4.15(m,3H),3.6 7-3.61(m,1H),3.59-3.50(m,4H),3.00(s,3H),2.93-2.87(m,1H),2.73-2.66(m,1H),2.03 (s,3H),2.01-1.97(m,2H),1.86-1.80(m,1H),1.43(d,J=6.4Hz,3H),1.31(d,J=6.8Hz,6H); MS m / z(ESI):609.2[M+H] + .

[0293] Example 147 Preparation of N-(2-(3-chloro-1-(((S)-1-methylazetidin-2-yl)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] For the preparation of N-(2-(3-chloro-1-(((S)-1-methylazetidin-2-yl)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 Reference Example 2. 1H NMR(400MHz,DMSO-d6)δ 10.13(s,1H),9.03(s,1H),8.47(s,1H),8.34(d,J=6.0Hz,1H),8.27(s,1H),7.37(d,J=8. 0Hz,1H),7.22(s,1H),6.51(d,J=8.0Hz,1H),4.64-4.59(m,1H),4.16-4.09(m,3H),3.61- 3.55(m,1H),3.52-3.44(m,4H),2.93(s,3H),2.86-2.80(m,1H),2.66-2.61(m,1H),1.96( s,3H),1.93-1.88(m,2H),1.79-1.73(m,1H),1.36(d,J=6.0Hz,3H),1.24(d,J=6.8Hz,6H); MS m / z(ESI):609.2[M+H] + .

[0294] Example 148 Preparation of N-(2-(3-chloro-1-(((R)-1-methylpyrrolidin-2-yl)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] For the preparation of N-(2-(3-chloro-1-(((R)-1-methylpyrrolidin-2-yl)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 Reference Example 2. 1H NMR(400MHz,DMSO-d6)δ 10.19(s,1H),9.10(s,1H),8.57-8.20(m,3H),7.43(d,J=7.2Hz,1H),7.31(brs,1H),6.56(d,J=7.2Hz,1H),4.70-4.65(m ,1H),4.23-4.02(m,3H),3.73-3.53(m,5H),2.99-2.80(m,5H),2.35-2.20(m,4H),2.03-1.95(m,2H),1.75-1.17(m,11H); MS m / z(ESI):623.3[M+H] + .

[0295] Example 149 Preparation of N-(2-(3-chloro-1-(((S)-1-methylpyrrolidin-2-yl)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] For the preparation of N-(2-(3-chloro-1-(((S)-1-methylpyrrolidin-2-yl)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 Reference Example 2. MS m / z(ESI):623.3[M+H] + .

[0296] Example 150 Preparation of N-(2-(3-chloro-1-(2-methyloctahydrocyclopenta[c]pyridin-5-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] For the preparation of N-(2-(3-chloro-1-(2-methyloctahydrocyclopenta[c]pyridin-5-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 Reference Example 2. MS m / z(ESI):649.3[M+H] + .

[0297] Example 151A 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)cyclobutane-1-carbonitrile [ka] See Reference Example 2 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)cyclobutane-1-carbonitrile. 1 H NMR (400 MHz, DMSO-d6) δ 10.13(s,1H),9.03(s,1H),8.46(s,1H),8.42(s,1H),8.35(d,J=5.8Hz,1H) ,7.36(d,J=8.0Hz,1H),7.22(s,1H),6.51(d,J=8.0Hz,1H),4.90-4.84(m,1H ),4.63-4.59(m,1H),4.16-4.12(m,1H),3.60-3.55(m,1H),3.49-3.43(m,4H ),2.93(s,3H),2.84-2.76(m,5H),1.36(d,J=6.0Hz,3H),1.25-1.20(m,6H); MS m / z(ESI):605.2[M+H] + .

[0298] Example 151 Preparation of (1r,3r)-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)cyclobutane-1-carbonitrile [ka] See Reference Example 2 for the preparation of (1r,3r)-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)cyclobutane-1-carbonitrile. MS m / z(ESI):605.2[M+H] + .

[0299] Example 152 Preparation of (1s,3s)-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)cyclobutane-1-carbonitrile [ka] See Reference Example 2 for the preparation of (1s,3s)-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)cyclobutane-1-carbonitrile. MS m / z(ESI):605.2[M+H] + .

[0300] Example 153 Preparation of N-(2-(3-chloro-1-(3-methoxycyclobutyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka] For the preparation of N-(2-(3-chloro-1-(3-methoxycyclobutyl)-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 2. 1 H NMR(400MHz,DMSO-d6)δ 10.20(s,1H),9.09(s,1H),8.57(s,1H),8.44-8.39(m,2H),7.43(d,J=7.8Hz,1H),7.27 (s,1H),6.58(d,J=8.0Hz,1H),5.01(t,J=7.0Hz,1H),4.68(t,J=7.2Hz,1H),4.24-4.15 (m,1H),3.64(t,J=7.2Hz,1H),3.59-3.51(m,2H),3.21(s,3H),3.00(s,3H),2.94-2.86 (m,1H),2.76-2.65(m,2H),2.05-1.95(m,1H),1.43(d,J=6.0Hz,3H),1.37-1.20(m,9H); MS m / z(ESI):610.2[M+H] + .

[0301] Example 154A 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)cyclobutan-1-ol [ka] See Reference Example 2 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)cyclobutan-1-ol. 1 H NMR(400MHz,DMSO-d6)δ 10.11(s,1H),9.03(s,1H),8.46(s,1H),8.34(d,J=5.8Hz,1H),8.32(s,1H),7.36(d,J=7.8Hz,1H ),7.21(s,1H),6.51(d,J=8.0Hz,1H),5.27(d,J=6.8Hz,1H),4.63-4.59(m,1H),4.39-4.32(m,1H) ),4.16-4.10(m,1H),3.96-3.88(m,1H),3.58(t,J=7.2Hz,1H),3.53-3.43(m,3H),2.93(s,3H),2 .85-2.80(m,1H),2.72-2.65(m,2H),2.36-2.28(m,2H),1.36(d,J=6.0Hz,3H),1.24-1.19(m,6H); MS m / z (ESI): 596.2 [M + H] + .

[0302] Example 154 Preparation of (1s,3s)-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)cyclobutan-1-ol [ka] See Reference Example 2 for the preparation of (1s,3s)-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)cyclobutan-1-ol. MS m / z (ESI): 596.2 [M + H] + .

[0303] Example 155 Preparation of (1r,3r)-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)cyclobutan-1-ol [ka] See Reference Example 2 for the preparation of (1r,3r)-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)cyclobutan-1-ol. MS m / z (ESI): 596.2 [M + H] + .

[0304] Example 156 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)cyclobutan-1-one [ka] See Reference Example 2 for a method for preparing 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)cyclobutan-1-one. 1H NMR(400MHz,DMSO-d6)δ 10.29(s,1H),9.11(s,1H),8.88(s,1H),8.46(d,J=5.9Hz,1H),8.19(d,J=14.2Hz,1H) ,7.43(d,J=8.0Hz,1H),6.75(d,J=14.1Hz,1H),6.58(d,J=8.1Hz,1H),4.68(t,J=7.5Hz ,1H),4.26-4.15(m,1H),3.65(t,J=7.2Hz,1H),3.60-3.49(m,3H),3.00(s,3H),2.94- 2,85(m,1H),2.33(s,3H),2.05-1.93(m,2H),1.43(d,J=6.1Hz,3H),1.33-1.13(m,6H); MS m / z (ESI): 594.2 [M + H] + .

[0305] Example 157 Preparation of N-(2-(3-chloro-1-(5-methyl-5-azaspiro[3.4]octan-2-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] For the preparation of N-(2-(3-chloro-1-(5-methyl-5-azaspiro[3.4]octan-2-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 Reference Example 2. 1H NMR(400MHz,DMSO-d6)δ 10.19(s,1H),9.09(s,1H),8.45-8.38(m,3H),7.43(d,J=8.0Hz,1H),7.27(s,1H),6.5 9(d,J=8.0Hz,1H),5.36-5.30(m,1H),4.73-4.67(m,1H),4.223-4.17(m,1H),3.67-3.6 1(m,1H),3.58-3.52(m,4H),3.00(s,3H),2.94-2.88(m,1H),2.57-2.52(m,2H),2.45- 2.40(m,2H),2.21(s,3H),2.04-1.94(m,2H),1.43(d,J=6.0Hz,6H),1.34-1.26(m,6H); MS m / z(ESI):649.3[M+H] + .

[0306] Example 158 Preparation of N-(2-(3-chloro-1-(1-methylpiperidin-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] For the preparation of N-(2-(3-chloro-1-(1-methylpiperidin-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 Reference Example 2. 1H NMR(400MHz,DMSO-d6)δ 10.19(s,1H),9.10(s,1H),8.55-8.40(m,3H),7.43(d,J=8.0Hz,1H),7.26-7.21(m,1H),6.58(d,J=8.0Hz,1H),5.35-5.30(m,1H),4.70 -4.65(m,1H),4.22-4.17(m,2H),3.66-3.50(m,4H),2.99(s,3H),2.92-2.87(m,4H),2.21(s,3H),2.03-1.95(m,4H),1.33-1.27(m,9H); MS m / z(ESI):623.3[M+H] + .

[0307] Example 159 Preparation of N-(2-(3-chloro-1-(3,3-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] For the preparation of N-(2-(3-chloro-1-(3,3-difluorocyclobutyl)-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 2. 1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),9.03(s,1H),8.43(d,J=4.0Hz,2H),8.35(d,J=5.9Hz, 1H),7.36(d,J=8.0Hz,1H),7.26(d,J=5.9Hz,1H),6.51(d,J=8.0Hz,1H),4.99-4.84(m,1H), 4.61(t,J=7.5Hz,1H),4.16-4.09(m,1H),3.58(t,J=7.2Hz,1H),3.53-3.42(m,3H),3.17-3. 10(m,4H),2.93(s,3H),2.82(q,J=7.2Hz,1H),1.36(d,J=6.1Hz,3H),1.21(t,J=4.0Hz,6H); MS m / z(ESI):616.2[M+H] + .

[0308] Example 160 Preparation of N-(2-(3-chloro-1-(3-(dimethylamino)cyclobutyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka] For the preparation of N-(2-(3-chloro-1-(3-(dimethylamino)cyclobutyl)-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 2. MS m / z(ESI):623.3[M+H] + .

[0309] Example 161 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)-1-methylcyclobutane-1-carbonitrile [ka] See Reference Example 2 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)-1-methylcyclobutane-1-carbonitrile. 1 H NMR(400MHz,DMSO-d6)δ 10.13(s,1H),9.03(s,1H),8.45(s,1H),8.41(s,1H),8.34(d,J=6.0Hz,1H),7.38(s,1H) ),7.24(s,1H),6.51(d,J=8.0Hz,1H),5.28-5.24(m,1H),5.11-5.06(m,1H),4.64-4.59 (m,1H),4.14(t,J=6.4Hz,1H),3.60-3.52(m,1H),3.53-3.46(m,4H),2.93(s,3H),2.86 -2.78(m,1H),2.66-2.58(m,2H),1.52(s,3H),1.36(d,J=6.0Hz,3H),1.26-1.19(m,6H); MS m / z(ESI):619.2[M+H] + .

[0310] Example 162 Preparation of N-(2-(3-chloro-1-(3-(methoxymethyl)cyclobutyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka] For the preparation of N-(2-(3-chloro-1-(3-(methoxymethyl)cyclobutyl)-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 2. 1 H NMR(400MHz,DMSO)δ 10.20(s,1H),9.10(s,1H),8.59(s,1H),8.44-8.37(m,2H),7.43(d,J=8.0Hz,1H),7.26(d,J=5.0Hz,1H) ,6.58(d,J=8.1Hz,1H),4.99(p,J=7.8Hz,1H),4.68(t,J=7.5Hz,1H),4.21(p,J=5.9Hz,1H),3.65(t,J=7 .1Hz,1H),3.55(qt,J=9.9,5.1Hz,3H),3.47(d,J=6.0Hz,2H),3.32(s,3H),3.00(s,3H),2.95-2.81(m,1 H),2.68-2.53(m,3H),2.30(dt,J=15.4,6.0Hz,2H),1.43(d,J=6.0Hz,3H),1.29(dd,J=6.7,4.1Hz,6H); MS m / z(ESI):624.2[M+H] + .

[0311] Example 163 Preparation of (1s,3s)-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)-1-methylcyclobutan-1-ol [ka] See Reference Example 2 for the preparation of (1s,3s)-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)-1-methylcyclobutan-1-ol. MS m / z(ESI):610.2[M+H] + .

[0312] Example 164 Preparation of (1r,3r)-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)-1-methylcyclobutan-1-ol [ka] See Reference Example 2 for the preparation of (1r,3r)-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)-1-methylcyclobutan-1-ol. MS m / z(ESI):610.2[M+H] + .

[0313] Example 165 Preparation of N-(2-(3-chloro-1-(oxetan-2-ylmethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka] For the preparation of N-(2-(3-chloro-1-(oxetan-2-ylmethyl)-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 2. 1 H NMR(400MHz,DMSO-d6)δ 10.20(s,1H),9.10(s,1H),8.51(s,1H),8.42(d,J=5.8Hz,1H),8.36(s,1H),7.44( d,J=8.0Hz,1H),7.32(s,1H),6.58(d,J=8.0Hz,1H),5.33(t,J=4.8Hz,1H),5.08-5 .04(m,1H),4.68(t,J=7.6Hz,1H),4.57-4.28(m,5H),4.25-4.17(m,1H),3.72-3.4 4(m,4H),3.00(s,3H),2.95-2.85(m,1H),1.43(d,J=6.0Hz,3H),1.36-1.28(m,6H); MS m / z (ESI): 596.2 [M + H] + .

[0314] Example 166 Preparation of ((1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methyl)(imino)(methyl)-16-sulfanone [ka] See Example 5 for the preparation of ((1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methyl)(imino)(methyl)-16-sulfanone. 1H NMR(400MHz,DMSO-d6)δ 10.05(s,1H),9.10(s,1H),8.53(s,1H),8.36(d,J=5.8Hz,1H),8.18(s,1H) ),7.43(d,J=8.0Hz,1H),7.21(d,J=5.9Hz,1H),6.41(d,J=8.0Hz,1H),4.4 2-4.35(m,2H),4.05-3.93(m,2H),3.85(s,3H),3.74(s,1H),3.58-3.46(m ,3H),3.31-3.27(m,1H),2.93(s,3H),2.51(s,3H),1.33(d,J=6.8Hz,6H); MS m / z(ESI):505.2[M+H] + .

[0315] Example 167 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] See Example 5 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. 1 H NMR(400MHz,DMSO-d6)δ10.07(s,1H),9.09(s,1H),8.54(s,1H),8.37(d,J=5.8 Hz,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),4.46-4.36(m,2H),4.13(d,J=7.2Hz,2H),4.06-3.97(m,2H),3.85(s ,3H),3.58-3.51(m,4H),3.42-3.39(m,1H),2.51(s,3H),1.33(d,J=6.8Hz,6H); MS m / z(ESI):530.2[M+H] + .

[0316] Example 168 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] See Example 5 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. 1 H 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),4.3 2(q,J=8.1Hz,2H),4.25-4.12(m,2H),3.87(t,J=8.4Hz,1H),3.84(s,3H),3.51(dt, J=13.7,6.7Hz,1H),1.90-1.96(m,1H),1.29(d,J=6.2Hz,3H),1.23(d,J=6.8Hz,6H); MS m / z(ESI):533.2[M+H] + .

[0317] Example 169 Preparation of N3-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline-3,6-diamine [ka] See Example 5 for the preparation of N3-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline-3,6-diamine. MS m / z(ESI):555.2[M+H] + .

[0318] Example 170 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] See Reference Example 2 for the 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. 1 H NMR (400 MHz, 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),7.22(s,1H),6.58(d,J=8.0Hz,1H),4. 68(t,J=7.6Hz,1H),4.24-4.17(m,1H),3.69-3.62(m,1H),3.60-3.51(m,3H ),3.00(s,3H),2.93-2.85(m,1H),1.43(d,J=6.0Hz,3H),1.34-1.28(m,6H); MS m / z(ESI):526.2[M+H] + .

[0319] Example 171 Preparation of (S)-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] See Example 5 for the preparation of (S)-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. 1 H NMR(400MHz,DMSO-d6)δ 10.17(s,1H),9.12(s,1H),8.57(s,1H),8.40(d,J=5.9Hz,1H),8.33(s,1H) ),7.43(d,J=8.0Hz,1H),7.27(d,J=5.3Hz,1H),6.47(d,J=8.0Hz,1H),4.85 -4.62(m,2H),4.38(q,J=8.1Hz,2H),4.31-4.17(m,2H),3.97-3.82(m,4H), 3.57(dt,J=13.6,6.7Hz,2H),1.35(d,J=6.2Hz,3H),1.29(d,J=6.8Hz,6H); MS m / z(ESI):533.2[M+H] + .

[0320] Example 172 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] 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, see Reference Example 2. 1 H NMR (400 MHz, DMSO-d6) δ 10.20(s,1H),9.10(s,1H),8.53(s,1H),8.42(d,J=6.0Hz,1H),8.32(s,1H) ,7.44(d,J=8.0Hz,1H),7.29(s,1H),6.58(d,J=8.0Hz,1H),5.65-5.58(m,1H ),4.71-4.66(m,1H),4.49-4.13(m,6H),3.70-3.62(m,1H),3.60-3.53(m,3H ),3.00(s,3H),2.92-2.86(m,1H),1.43(d,J=6.0Hz,3H),1.35-1.27(m,6H); MS m / z(ESI):602.2[M+H] + .

[0321] Example 173 Preparation of 5-isopropyl-N-(2-(3-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka] See Reference Example 2 for the preparation of 5-isopropyl-N-(2-(3-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ 12.84(s,1H),10.10(s,1H),9.09(s,1H),8.66(s,1H),8.37(d,J=5.8Hz,1H),8 .10(s,1H),7.44(d,J=8.0Hz,1H),7.16(s,1H),6.57(d,J=8.0Hz,1H),4.71-4. 66(m,1H),4.22-4.18(m,1H),3.68-3.63(m,1H),3.59-3.49(m,3H),2.99(s,3H) ),2.92-2.87(m,1H),2.62(s,3H),1.43(d,J=6.0Hz,3H),1.31(d,J=6.8Hz,6H); MS m / z(ESI):506.2[M+H] + .

[0322] Example 174 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)tetrahydrothiophene 1,1-dioxide [ka] See Example 5 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)tetrahydrothiophene 1,1-dioxide. 1H NMR(400MHz,DMSO-d6)δ 10.14(s,1H),9.02(s,1H),8.53(s,1H),8.34(d,J=5.9Hz,1H),8.27(s,1H),7.38(d, J=8.0Hz,1H),7.21(d,J=5.2Hz,1H),6.43(d,J=8.1Hz,1H),4.41(d,J=8.6Hz,2H),4. 16(d,J=8.7Hz,2H),3.84(s,3H),3.54-3.48(m,1H),3.18-3.01(m,2H),2.29-2.23(m ,2H),1.96-1.91(m,1H),1.86-1.81(m,1H),1.59-1.54(m,2H),1.24(d,J=6.8Hz,6H); MS m / z(ESI):552.2[M+H] + .

[0323] Example 175 Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)-6-methylpyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine [ka] See Example 5 for the preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)-6-methylpyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine. 1H NMR(400MHz,DMSO-d6)δ 10.06(s,1H),9.09(s,1H),8.57(s,1H),8.32(s,1H),7.42(d,J=8.0Hz,1 H),7.11(s,1H),6.56(d,J=8.0Hz,1H),4.68(t,J=7.6Hz,1H),4.24-4.17 (m,1H),3.90(s,3H),3.68-3.63(m,1H),3.60-3.51(m,3H),3.00(s,3H), 2.92-2.85(m,1H),2.37(s,3H),1.43(d,J=6.0Hz,3H),1.32-1.27(m,6H); MS m / z (ESI): 554.2 [M + H] + .

[0324] Example 176 Preparation of N-(2-(3-chloro-1-(2,2-dimethyltetrahydro-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] For the preparation of N-(2-(3-chloro-1-(2,2-dimethyltetrahydro-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 Reference Example 2. MS m / z (ESI): 638.2 [M + H] + .

[0325] Example 177 Preparation of N-(2-(3-chloro-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] For the preparation of N-(2-(3-chloro-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 Reference Example 2. 1 H NMR(400MHz,DMSO-d6)δ 10.36(s,1H),9.10(s,1H),8.81(s,1H),8.60(brs,1H),8.46(d,J=7.2Hz,1H),7.89(d,J=60Hz,1H),7.42(d,J=7.2Hz,1H),7.33(brs,1 H),6.58(d,J=7.2Hz,1H),4.70-4.66(m,1H),4.22-4.19(m,1H),3.67-3.52(m,4H),3.00(s,3H),2.92-2.87(m,1H),1.37-1.16(m,9H); MS m / z (ESI): 576.2 [M + H] + .

[0326] Example 178 Preparation of N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methanesulfonamide [ka] See Example 44 for the preparation of N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methanesulfonamide. 1H NMR(400MHz,DMSO-d6)δ 10.24(s,1H),9.08(s,1H),8.63(s,1H),8.48(d,J=5.2Hz,1H),8.36(s,1H),7.92(d,J=7.2Hz,1H),7.35(brs,1H),6.36(d,J=8.0 Hz,1H),4.69-4.65(m,2H),4.44-4.41(m,1H),4.08-4.04(m,2H),3.95(s,3H),3.58-3.52(m,1H),3.04(s,3H),1.44-1.33(m,6H); MS m / z(ESI):545.2[M+H] + .

[0327] Example 179 Preparation of N-(2-(3-chloro-1-((2S,4S)-1,2-dimethylpiperidin-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] For the preparation of N-(2-(3-chloro-1-((2S,4S)-1,2-dimethylpiperidin-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 Reference Example 2. 1H NMR(400MHz,DMSO-d6)δ 10.12(s,1H),9.03(s,1H),8.48(s,1H),8.34(d,J=5.8Hz,1H),8.30(s,1H),7.36(d,J =8.0Hz,1H),7.16(s,1H),6.51(d,J=8.0Hz,1H),5.30-5.22(m,1H),4.61(t,J=7.6Hz, 1H),4.23-4.09(m,2H),3.62-3.39(m,4H),2.93(s,3H),2.89-2.77(m,2H),2.13(s,3H) ),1.97-1.83(m,5H),1.36(d,J=6.0Hz,3H),1.27-1.20(m,6H),1.01(d,J=6.0Hz,3H); MS m / z(ESI):637.2[M+H] + .

[0328] Example 180 Preparation of N-(2-(3-chloro-1-((3S,6R)-1,6-dimethylpiperidin-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] For the preparation of N-(2-(3-chloro-1-((3S,6R)-1,6-dimethylpiperidin-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 Reference Example 2. 1H NMR(400MHz,DMSO-d6)δ 10.11(s,1H),9.03(s,1H),8.44(s,1H),8.38-8.31(m,1H),8.28(s,1H),7.36(d,J=8.0Hz,1H), 7.23(s,1H),6.51(d,J=8.0Hz,1H),5.26(t,J=4.8Hz,1H),4.61(t,J=7.6Hz,1H),4.18-4.09(m,2 H),3.96-3.87(m,1H),3.58(d,J=7.2Hz,1H),3.53-3.42(m,3H),2.93(s,3H),2.87-2.77(m,1H), 2.19(s,3H),1.99-1.87(m,5H),1.36(d,J=6.2Hz,3H),1.26-1.19(m,6H),0.83(d,J=6.4Hz,3H); MS m / z(ESI):637.2[M+H] + .

[0329] Example 181 Preparation of N-(2-(3-chloro-1-((3R,6S)-1,6-dimethylpiperidin-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] For the preparation of N-(2-(3-chloro-1-((3R,6S)-1,6-dimethylpiperidin-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 Reference Example 2. 1H NMR(400MHz,DMSO-d6)δ 10.20(s,1H),9.12(s,1H),8.54(s,1H),8.46-8.40(m,1H),8.37(s,1H),7.45(d,J=8.0Hz ,1H),7.24(s,1H),6.60(d,J=8.0Hz,1H),5.41-5.29(m,1H),4.70(t,J=7.6Hz,1H),4.28- 4.19(m,2H),4.06-3.96(m,1H),3.71-3.45(m,4H),3.02(s,3H),2.96-2.87(m,1H),2.28( s,3H),2.07-1.97(m,5H),1.45(d,J=6.2Hz,3H),1.41-1.23(m,6H),0.93(d,J=6.4Hz,3H); MS m / z(ESI):637.2[M+H] + .

[0330] Example 182 Preparation of N-(2-(3-chloro-1-(((S)-oxetan-2-yl)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] For the preparation of N-(2-(3-chloro-1-(((S)-oxetan-2-yl)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 Reference Example 2. 1H NMR(400MHz,DMSO-d6)δ 10.20(s,1H),9.10(s,1H),8.51(s,1H),8.41(d,J=6.0Hz,1H),8.36(s,1H),7.43(d,J=8.0Hz, 1H),7.31(d,J=5.8Hz,1H),6.58(d,J=8.0Hz,1H),5.11-5.00(m,1H),4.68(t,J=7.6Hz,1H),4. 56-4.27(m,4H),4.26-4.15(m,1H),3.65(t,J=7.2Hz,1H),3.60-3.49(m,3H),3.00(s,3H),2.9 6-2.83(m,1H),2.77-2.64(m,1H),2.49-2.38(m,1H),1.43(d,J=6.0Hz,3H),1.34-1.27(m,6H); MS m / z (ESI): 596.2 [M + H] + .

[0331] Example 183 Preparation of (R)-5-((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)methyl)pyrrolidin-2-one [ka] See Reference Example 2 for a method for preparing (R)-5-((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)methyl)pyrrolidin-2-one. 1H NMR(400MHz,DMSO-d6)δ 10.25(s,1H),9.10(s,1H),8.66(s,1H),8.51-8.33(m,1H),8.24(s,1H),7.81(s,1H),7.44 (t,J=7.8Hz,1H),7.26(s,1H),6.61(t,J=16.8Hz,1H),4.68(t,J=7.5Hz,1H),4.35-4.16(m ,3H),4.16-3.92(m,1H),3.66(t,J=7.1Hz,1H),3.61-3.47(m,3H),3.00(s,3H),2.96-2.79 (m,1H),2.18-2.05(m,3H),1.98-1.89(m,1H),1.43(d,J=6.1Hz,3H),1.32(t,J=6.3Hz,6H); MS m / z(ESI):623.2[M+H] + .

[0332] Example 184 Preparation of (S)-5-((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)methyl)pyrrolidin-2-one [ka] See Reference Example 2 for a method for preparing (S)-5-((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)methyl)pyrrolidin-2-one. 1H NMR(400MHz,DMSO-d6)δ 10.24(s,1H),9.10(s,1H),8.65(s,1H),8.43(d,J=5.9Hz,1H),8.27-8.14(m,1H),7.79(d,J=12.8Hz ,1H),7.44(d,J=8.0Hz,1H),7.25(s,1H),6.56(t,J=13.9Hz,1H),4.68(t,J=7.5Hz,1H),4.29-4.16( m,3H),4.10-3.80(m,1H),3.66(t,J=7.1Hz,1H),3.61-3.47(m,3H),3.00(s,3H),2.96-2.79(m,1H), 2.18-2.05(m,3H),1.94(dt,J=10.0,5.7Hz,1H),1.43(d,J=6.0Hz,3H),1.32(dd,J=6.7,2.9Hz,6H); MS m / z(ESI):623.2[M+H] + .

[0333] Example 185 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)butyronitrile [ka] See Reference Example 2 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)butyronitrile. 1H NMR(400MHz,DMSO-d6)δ 10.19(s,1H),9.10(s,1H),8.50(s,1H),8.49(s,1H),8.42(d,J=5.9Hz,1H),7.43(d,J=8.0 Hz,1H),7.33(s,1H),6.58(d,J=8.0Hz,1H),4.84-4.79(m,1H),4.68(t,J=7.5Hz,1H),4.20 (t,J=6.2Hz,1H),3.65(t,J=7.1Hz,1H),3.60-3.48(m,3H),3.18(d,J=6.7Hz,2H),3.00(s, 3H),2.92-2.86(m,1H),1.55(d,J=6.7Hz,3H),1.43(d,J=6.0Hz,3H),1.29(t,J=6.8Hz,6H); MS m / z (ESI): 593.2 [M + H] + .

[0334] Example 186 Preparation of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide [ka] See Example 44 for the preparation of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide. 1 H NMR (400 MHz, DMSO-d6) δ 10.16(s,1H),8.96(s,1H),8.54(s,1H),8.35(d,J=7.2Hz,1H),8.24(s,1H),7.71(d,J=7.6Hz,1H),7.20(brs,1H),6.36 (brs,1H),4.82-4.77(m,1H),4.16-4.10(m,1H),3.88-3.83(m,4H),3.62-3.54(m,2H),2.90(s,3H),1.37-1.16(m,9H); MS m / z (ESI): 559.2 [M + H] + .

[0335] Example 187 Preparation of N3-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-N5,N5-dimethyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline-3,5-diamine [ka] See Example 5 for the preparation of N3-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-N5,N5-dimethyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline-3,5-diamine. 1 H NMR(400MHz,DMSO-d6)δ 10.23(s,1H),9.07(s,1H),8.86(s,1H),8.42-8.34(m,2H),7.23(d,J=8.2Hz,1H),7.13(d,J=5.8Hz,1H),6.54(d,J=8.3Hz,1H),4.66 -4.59(m,1H),4.21-4.12(m,1H),3.93(s,3H),3.62-3.46(m,3H),3.00(s,3H),2.92-2.84(m,1H),2.75(s,6H),1.41(d,J=6.0Hz,3H); MS m / z (ESI): 541.2 [M + H] + .

[0336] Example 188 Preparation of N-(2-(3-chloro-1-((4-methyloxetan-2-yl)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] For the preparation of N-(2-(3-chloro-1-((4-methyloxetan-2-yl)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 Reference Example 2. MS m / z(ESI):610.2[M+H] + . Biological Test Evaluation

[0337] The present invention will be further explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0338] 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 example is to test the activity of compounds to inhibit the kinase activity of EGFR del19 / T790M / C797S and EGFR L858R / T790M / C797S mutations.

[0339] Experimental equipment: Centrifuge (5810R) was purchased from Eppendorf, pipettes were purchased from Eppendorf or Rainin, and the microplate reader was a full-function microplate reader with model number SynergyH1 purchased from BioTek, USA.

[0340] 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 mutations, phosphorylate the substrate, and characterize the kinase activity by measuring the amount of phosphorylated substrate produced during the reaction. The half-maximal inhibitory concentration (IC) of compounds for kinase activity inhibition against EGFR del19 / T790M / C797S or EGFR L858R / T790M / C797S mutations was calculated. 50 obtained.

[0341] The specific experimental procedures are as follows. Kinase reactions were performed in a white 384-well plate (Perkin Elmer #6008280). 1–5 μL of different concentrations of compounds diluted in 1% DMSO in ddH2O were added to each well. 1–5 μL of 1% DMSO in ddH2O was added to the positive control wells. 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) was added to each well. 1–5 μL of Dilution buffer was added to the negative control wells. 1–5 μL of 4 μM 4× substrate TK solution prepared in 10× Dilution buffer was added to all wells. Finally, Dilution buffer was added to all wells. The reaction was initiated by adding 1 to 5 μL of 24 μM 4xATP solution diluted with buffer. After 120 minutes at room temperature, 10 μL of detection solution (TK antibody 16 nM, XL665 0.5 μM) was added to each well and the reaction was continued for 20 minutes at room temperature in the dark. The chemiluminescence values ​​were then detected using a BioTek Synergy H1 microplate reader.

[0342] How to process experimental data: The percent inhibition data of the compound-treated wells was calculated through the positive control wells (DMSO control wells) and negative control wells (no kinase added) on the plate. The IC was calculated by fitting a four-parameter nonlinear logistic equation of the different concentrations and the corresponding percent inhibition data using GraphPad Prism. 50 values ​​were calculated.

[0343] Experimental results and conclusions: The examples of the present invention were shown to have good inhibitory effects on EGFR L858R / T790M / C797S and EGFR del19 / T790M / C797S drug-resistant mutant kinases.

[0344] Test Example 2: Cell proliferation inhibition experiment Experimental Objective: The objective of this experiment is to test the growth 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.

[0345] Experimental equipment: Centrifuge (Eppendorf 5810R) Microplate reader (BioTek Synergy H1) Pipette (Eppendorf or Rainin) Carbon dioxide incubator (Thermo 311) Cytometer (Life Countess II)

[0346] Experimental reagents and consumables: Ba / F3 EGFR Del19 / T790M / C797S cells purchased from Beijing Hongyuan Bochuang Biotechnology 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

[0347] Experimental 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°C and 5% CO2. After growing to a certain density, the cells were collected by centrifugation, counted, and adjusted to the appropriate cell density. The cells were seeded into a white 96-well plate at 90 μL per well and cultured overnight in an incubator at 37°C and 5% CO2. The prepared compound solutions at different concentrations were added at 10 μL per well, along with the corresponding solvent controls. After culturing in an incubator at 37°C and 5% CO2 for 72 hours, 50 μL of CellTiter-Glo solution was added to each well, shaken to mix evenly, and incubated in the dark for 10 minutes. The plates were then read using a BioTek Synergy H1 microplate reader.

[0348] How to process experimental data: The luminescence signal values ​​were used to calculate the inhibition rate, and nonlinear regression curve fitting was performed using Graphpad Prism software to determine the IC. 50 The values ​​obtained are as shown in the table below:

[0349] [Table 1]

[0350] [Table 2]

[0351] [Table 3-1] [Table 3-2]

[0352] Testing Conclusion: From the above scheme, it has become clear that the compounds of the present invention exhibit significant growth inhibitory activity in growth inhibitory activity tests on different EGFR C797S drug-resistant mutant cell lines.

[0353] Test Example 3: Pharmacokinetic evaluation test in rats 1. Research purpose: Using SD rats as test animals, the pharmacokinetic behavior of the compound of the present invention in the rat body (plasma) when orally administered at a dose of 5 mg / kg was examined.

[0354] 2. Experimental plan: 2.1 Experimental reagents: compounds of the present examples, self-prepared. JPEG2025509371000341.jpg181632.3 Formulation: Oral drug formulation: 20% solutol HS15 in 0.5% MC (methylcellulose) 20 g of solid Solutol HS15 and 0.5 g of solid MC powder were weighed and dissolved in 80 mL of purified water, vortexed to mix uniformly, and sonicated to obtain a clear solution of 20% solutol HS15 in 0.5% MC. The example compound is weighed and placed in a 20 mL glass bottle, and the solution is added thereto and subjected to ultrasonic treatment for 10 minutes to obtain a clear solution with a concentration of 0.5 mg / mL. 2.4 Administration: Three male SD rats were fasted overnight and then administered po, ​​with the po dose being 5 mg / kg and the administration volume being 10 mL / kg. 2.5 Sampling: Blood collection: 0.2 mL of blood was collected from the jugular vein of each rat before administration and 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The blood was placed in an EDTA-K2 anticoagulant tube and centrifuged at 6000 rpm at 4°C for 6 minutes to separate the plasma, which was then stored at -80°C and fed 4 hours after administration. 2.6 Sample Processing: 1) 40 μL of plasma sample was added to 160 μL of acetonitrile to precipitate, mixed, and then centrifuged at 3500 × g for 5 to 20 minutes. 2) The treated supernatant solution is taken and analyzed for the concentration of the test compound by LC / MS / MS, and the LC / MS / MS analysis instrument is AB Sciex API 4000 Qtrap. 2.7 Liquid phase analysis: ● Liquid phase conditions: Shimadzu LC-20AD pump Chromatography column: Agilent ZORBAX XDB-C18 (50 x 2.1 mm, 3.5 μm) Mobile phase: Solution A is 0.1% formic acid solution, and solution B is acetonitrile. ● Flow rate: 0.4mL / min ● Elution time: 0 to 4.0 minutes, elution solution is as follows:

[0355] [Table 4]

[0356] 3. Test results and analysis The main pharmacokinetic parameters were calculated using WinNonlin 6.1, and the rat drug experiment results are shown in Table 4 below:

[0357] [Table 5] 3.4 Experimental conclusions: The data in the table show that in pharmacokinetic evaluation experiments in rats, the compounds of the examples of the present invention showed high exposure after oral administration.

[0358] Test Example 4: In vivo pharmacodynamic study of compounds in a mouse primary B cell line Ba / F3EGFR Del19 / C797S nude mouse subcutaneously transplanted tumor model 1.1 Experimental Objective The in vivo potency of the compounds was evaluated in a mouse primary B cell line Ba / F3EGFR Del19 / C797S nude mouse subcutaneously transplanted tumor model.

[0359] 1.2 Laboratory equipment and reagents 1.2.1 Equipment 1. Refrigerator (BCD-268TN, Haier) 2. Biological safety cabinet (BSC-1300II A2, Shanghai Boken Industrial Co., Ltd. Medical Equipment Factory) 3. Clean bench (CJ-2F, Suzhou Feng Experimental Animal Equipment Co., Ltd.) 4. Electronic pipette helper (Easypet 3, Eppendorf) 5. Constant temperature water bath (HWS-12, Shanghai Yiheng Science) 6. CO2 incubator (Thermo-311, Thermo) 7. Centrifuge (Centrifuge 5720R, Eppendorf) 8. Fully automated cytometer (Countess II, Life Technologies) 9. Vernier (CD-6''AX, Mitoyo, Japan) 10. Cell culture flasks (T25 / T75 / T225, Corning) 11. Electronic balance (CPA2202S, Sartorius) 12. Electronic balance (BSA2202S-CW, Sartorius) 13. Ultrasonic cleaner (115F0032, Shanghai Science and Technology Center) 14. Pure water equipment (Pacific TII, Thermo) 15. Magnetic Stirrer (08-2G, Hasehisa) 1.2.2 Reagents 1. RPMI-1640 medium (22400-089, Gibco) 2. Fetal bovine serum (FBS) (10099-141C, Gibco) 3. Phosphate buffer solution (PBS) (10010-023, Gibco) 4. Kolliphor HS15 (42966-1KG, Sigma-Aldrich) 5. Methylcellulose M450 (69016482, National Pharmaceutical Reagent Co., Ltd.)

[0360] 1.3 Experimental procedures and data processing 1.3.1 Animals BALB / c nude mice, 6-8 weeks old, female, purchased from the Laboratory Animal Management Department of the Shanghai Institute of Life Planning. 1.3.2 Cell culture and cell suspension preparation a) One Ba / F3EGFR Del19 / C797S cell line was extracted from the cell bank and resuscitated in RPMI-1640 medium (RPMI-1640 + 10% FBS). The resuscitated cells were then cultured in a CO2 incubator (incubator temperature 37°C, CO2 concentration 5%). b, The cells were passaged every 3 days, and after passage, they were placed in a CO2 incubator and continued to be cultured. The process was repeated until the cell number met the pharmacodynamic requirements in vivo. c) Exponentially growing cells were collected and counted using an automated cytometer. Based on the counting results, cells were diluted to 2 × 10 in PBS. 7 The cells were resuspended at 1000 cells / mL and kept in an icebox. 1.3.3 Cell inoculation a) Before inoculation, nude mice were tagged with disposable universal ear tags for rats and mice. b. At the time of inoculation, mix the cell suspension evenly, aspirate 0.1-1 mL of cell suspension with a 1 mL syringe, remove air bubbles, and place the syringe on an ice pack. c) Fix the nude mouse with your left hand, disinfect the area on the right back of the nude mouse near the right shoulder (the inoculation site) with a 75% alcohol cotton ball, and start the inoculation after 30 seconds. d, Test nude mice were inoculated sequentially (each mouse was inoculated with 0.1 mL of cell suspension). 1.3.4 Tumor Measurement, Grouping, and Dosing of Tumor-Bearing Mice a) Based on the tumor growth status, tumor measurements were performed 9 to 12 days after inoculation, and the tumor size was calculated. Tumor volume calculation: Tumor volume (mm 3 ) = length (mm) x width (mm) x width (mm) / 2 b, Tumor-bearing mice were grouped using a random grouping method based on their body weight and tumor size; c) Based on the results of grouping, administration of the test drug was initiated (administration method: oral administration, administration volume: 10 mL / kg, administration frequency: once or twice daily, administration cycle: 14 days, vehicle: 10% Solutol HS15 / 0.5% MC). d) After the start of test drug administration, tumor masses were measured and weighed twice a week. e, After the experiment was completed, the animals were euthanized. f, Data was processed using software such as Excel. Calculation of the compound's tumor growth inhibition rate TGI (%): If tumors did not regress, TGI (%) = [1 - (mean tumor volume at the end of treatment in a treatment group - mean tumor volume at the start of treatment in the treatment group) / (mean tumor volume at the end of treatment in the solvent control group - mean tumor volume at the start of treatment in the solvent control group)] × 100%. If tumors regressed, TGI (%) = [1 - (mean tumor volume at the end of treatment in a treatment group - mean tumor volume at the start of treatment in the treatment group) / mean tumor volume at the start of treatment in the treatment group] × 100%.

[0361] 1.4 Experimental results and conclusions: The compounds of the preferred examples of the present invention showed excellent tumor-inhibiting effects in the model. When 50mpk QDs were orally administered, they showed excellent tumor-inhibiting effects, with tumor growth inhibition rates of TGI (%) > 80% and those of the preferred compounds of interest > 100%. When 75mpk QDs were orally administered, they showed excellent tumor-inhibiting effects, with tumor growth inhibition rates of TGI (%) > 100% and those of the preferred compounds of interest > 150%. When 120mpk QDs were orally administered, they showed excellent tumor-inhibiting effects, with tumor growth inhibition rates of TGI (%) > 150% and those of the preferred compounds of interest > 190%, and there was no significant weight loss.

Claims

1. Compounds shown in (II-G), their stereoisomers, or pharmaceutically acceptable salts thereof, 【Chemistry 1】 Here, M １ These are C, N, CH, Ring B is, 【Chemistry 2】 Selected from, R １ 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 selected from, 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 optionally be further substituted, or two of the R １ are linked to the atoms between them to form a cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, and the cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted, R ２ These 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 The amino group, alkyl group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are selected from and may be further optionally substituted. R ４ These 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 Selected from, where the amino group, alkyl group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may be further optionally substituted. Or, one of the R ２ and one R ４ These atoms bond to the atoms between them to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. R ａ The group is selected from hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, and the amino group, alkyl group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally 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. A compound, its stereoisomer, or its pharmaceutically acceptable salt, wherein p, m, and n5 are each independently 0, 1, 2, or 3.

2. Furthermore, as shown in general formula (VII-1), 【Transformation 3】 Here, M ５ These are N and CH, R ５ and R ６ These are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, and C １－６ alkyl group, C １－６ Deuterated alkyl groups, C １－６ Alkyl halogenated compounds, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Halide alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Selected from hydroxyalkyl groups, The compound according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt, characterized in that n6 is 0, 1, or 2.

3. R １ These are 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 Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl group, 3-12 member heterocyclyl group, C ６－１４ Aryl group, 5-14 membered heteroaryl group, -(CH ２ ) ｎ OR ａ ,-(CH ２ ) ｎ P(O) ｐ (R ａ ) ｎ５ ,-(CH ２ ) ｎ S(O)R ａａ N(R) ａａ ), - (CH ２ ) ｎ N = S(O)(R ａａ ) ２ ,-(CH ２ ) ｎ S(O) ｍ R ａ or - (CH ２ ) ｎ C(O)R ａ Selected from the above, 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 group, 3-12 member heterocyclyl group, C ６－１４ The aryl group and the 5-14 membered heteroaryl group can be optionally hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, or C １－６ alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Deuterated alkyl groups, C １－６ Alkyl halogenated compounds, C １－６ Alkoxy group, halogenated C １－６ an alkoxy group, C １－６ a hydroxyalkyl group, C ３－１２ a cycloalkyl group, a 3- to 12-membered heterocyclyl group, C ６－１２ an aryl group, a 5- to 12-membered heteroaryl group, -OR ａａ -S(O)R ａａ N(R ａａ ), -N=S(O)(R ａａ ) ２ , -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 them, or two of the R １ are linked to the atoms between them to form a C ３－１２ cycloalkyl group, a 3- to 12-membered heterocyclyl group, C ６－１４ aryl group and a 5- to 14-membered heteroaryl group, and the C ３－１２ cycloalkyl group, a 3- to 12-membered heterocyclyl group, C ６－１４ aryl group and a 5- to 14-membered heteroaryl group are optionally further substituted with one or more of 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 Preferably, R １ These are 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 Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl group, 3-12 member heterocyclyl group, C ６－１４ Aryl group, 5-14 member heteroaryl group, -OR ａ , -P(O) ｐ (R ａ ) ｎ５ , -S(O) ｍ R ａ or -C(O)R ａ Selected from the above, 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 group, 3-12 member heterocyclyl group, C ６－１４ The aryl group and the 5-14 membered heteroaryl group can be optionally hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, or C １－６ alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Deuterated alkyl groups, C １－６ Alkyl halogenated compounds, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl group, 3-12 member heterocyclyl group, 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 It may be further replaced by one or more of the following Rs, or two of the following Rs. １ It is linked to the atoms between them, C ３－１２ Cycloalkyl group, 3-12 member heterocyclyl group, C ６－１４ Forming an aryl group and a 5-14 membered heteroaryl group, the C ３－１２ Cycloalkyl group, 3-12 member heterocyclyl group, C ６－１４ The aryl group and the 5-14 membered heteroaryl group can be optionally hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, or C １－６ alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ They may be further substituted with one or more hydroxyalkyl groups. More preferably, R １ These are hydrogen, deuterium, oxo, thio, 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 ３－８ Cycloalkyl group, 3-10 membered heterocyclyl group, 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 ａ Selected from, 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, 3-10 membered heterocyclyl group, C ６－１０ The aryl group and the 5-12 membered heteroaryl group can be optionally hydrogen, deuterium, oxo, thio, 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 Deuterated alkyl groups, C １－３ Alkyl halogenated compounds, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, 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 It may be further replaced with one or more of the following: R ａａ The group is independently selected from hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, and the amino group, alkyl group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. The compound according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt, characterized in that n is independently 0, 1, 2, or 3.

4. R ２ These are 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 Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl group, 3-12 member heterocyclyl group, C ６－１４ Aryl group, 5-14 member heteroaryl group, -OR ａ , -P(O) ｐ (R ａ ) ｎ５ , -S(O) ｍ R ａ or -C(O)R ａ Selected from the above, 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 group, 3-12 member heterocyclyl group, C ６－１４ The aryl group and the 5-14 membered heteroaryl group can be optionally hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, or C １－６ alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Deuterated alkyl groups, C １－６ Alkyl halogenated compounds, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl group, 3-12 member heterocyclyl group, 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 It may be further replaced with one or more of the following: Preferably, R ２ These are hydrogen, deuterium, oxo, thio, 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 group, 3-10 membered heterocyclyl group, 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 Selected from the above, 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, 3-10 membered heterocyclyl group, C ６－１２ The aryl group and the 5-12 membered heteroaryl group can be optionally hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, C １－２ alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Alkyl halogenated compounds, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－１０ Cycloalkyl group, 3-10 membered heterocyclyl group, 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 It may be further replaced with one or more of the following: R ａａ Each general formula compound according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt, is characterized in that each of the above is independently selected from hydrogen, deuterium, 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, or heteroaryl group, and the amino group, alkyl group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted.

5. R ４ These are 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 Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl group, 3-12 member heterocyclyl group, C ６－１４ Aryl group, 5-14 member heteroaryl group, -OR ａ , -P(O) ｐ (R ａ ) ｎ５ , -S(O) ｍ R ａ or -C(O)R ａ Selected from the above, 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 group, 3-12 member heterocyclyl group, C ６－１４ The aryl group and the 5-14 membered heteroaryl group are optionally selected as R ４－１ It may be further replaced with one or more of the following: R ４－１ These are 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 Alkyl halogenated compounds, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl group, 3-12 member heterocyclyl group, 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 Selected from, and optionally, R ４－１ These are 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 Alkyl halogenated compounds, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl group, 3-12 member heterocyclyl group, C ６－１２ Substituted with one or more aryl groups or 5- to 12-membered heteroaryl groups, where amino groups, C １－６ alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Deuterated alkyl groups, C １－６ Alkyl halogenated compounds, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, C １－６ Hydroxyalkyl groups can optionally include hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, and C. １－６ alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Deuterated alkyl groups, C １－６ Alkyl halogenated compounds, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, C １－６ Substituted with one or more hydroxyalkyl groups, preferably R ４ These are 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 Alkoxy group, C １－３ Hydroxyalkyl group, C ３－１０ Cycloalkyl group, 3-10 membered heterocyclyl group, 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 Selected from the above, 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, 3-10 membered heterocyclyl group, C ６－１２ The aryl group and the 5-10 membered heteroaryl group are optionally selected as R ４－１ It may be further replaced with one or more of the following: R ４－１ These are 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 Alkyl halogenated compounds, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－１０ Cycloalkyl group, 3-10 membered heterocyclyl group, 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 Selected from, and optionally, R ４－１ These are 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 Alkyl halogenated compounds, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－１０ Cycloalkyl group, 3-10 membered heterocyclyl group, C ６－１２ Substituted with one or more aryl groups or 5- to 12-membered heteroaryl groups, where amino groups, C １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Alkyl halogenated compounds, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl groups can optionally include hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, and C. １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Alkyl halogenated compounds, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Substituted with one or more hydroxyalkyl groups, Or, one of the R ２ and one R ４ It is linked to the atoms between them, C ３－１２ Cycloalkyl group, 3-12 member heterocyclyl group, C ６－１４ Forming an aryl group or a 5-14 membered heteroaryl group, the C ３－１２ Cycloalkyl group, 3-12 member heterocyclyl group, C ６－１４ The aryl group and the 5-14 membered heteroaryl group can be optionally hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, or C １－６ alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Deuterated alkyl groups, C １－６ Alkyl halogenated compounds, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl group, 3-12 member heterocyclyl group, C ６－１２ The group may be further substituted with one or more aryl groups or 5- to 12-membered heteroaryl groups. R ａａ Each general formula compound according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt, is characterized in that each of the above is independently selected from hydrogen, deuterium, 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, or heteroaryl group, and the amino group, alkyl group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted.

6. R ａ These are 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 group, 3-12 member heterocyclyl group, C ６－１４ Selected from aryl groups and 5- to 14-membered heteroaryl groups, 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 group, 3-12 member heterocyclyl group, C ６－１４ The aryl group and the 5-14 membered heteroaryl group can optionally be hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, or C １－６ alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Deuterated alkyl groups, C １－６ Alkyl halogenated compounds, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl group, 3-12 member heterocyclyl group, C ６－１２ The group may be further substituted with one or more aryl groups or 5- to 12-membered heteroaryl groups. Preferably, R ａ These are 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 group, 3-10 membered heterocyclyl group, C ６－１２ Selected from aryl groups and 5- to 12-membered heteroaryl groups, 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, 3-10 membered heterocyclyl group, C ６－１２ The aryl group and the 5-12 membered heteroaryl group can optionally be hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, or C. １－３ alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Alkyl halogenated compounds, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－１０ Cycloalkyl group, 3-10 membered heterocyclyl group, C ６－１０ They may be further substituted with one or more aryl groups or 5- to 10-membered heteroaryl groups. R ａａ These are, independently, hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and 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 group, 3-12 member heterocyclyl group, C ６－１４ Selected from aryl groups and 5- to 14-membered heteroaryl groups, 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 group, 3-12 member heterocyclyl group, C ６－１４ The aryl group and the 5-14 membered heteroaryl group can optionally be hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, or C １－６ alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Deuterated alkyl groups, C １－６ Alkyl halogenated compounds, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ Cycloalkyl group, 3-12 member heterocyclyl group, C ６－１２ The group may be further substituted with one or more aryl groups or 5- to 12-membered heteroaryl groups. Preferably, R ａａ These are, independently, hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and 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, 3-10 membered heterocyclyl group, C ６－１２ Selected from aryl groups and 5- to 12-membered heteroaryl groups, 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, 3-10 membered heterocyclyl group, C ６－１２ The aryl group and the 5-12 membered heteroaryl group can optionally be hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, or C １－３ alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Alkyl halogenated compounds, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－１０ Cycloalkyl group, 3-10 membered heterocyclyl group, C ６－１０ Each general formula compound according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt, is characterized in that it may be further substituted with one or more of an aryl group or a 5- to 10-membered heteroaryl group.

7. The aforementioned compounds are further represented by the general formulas (VII-2), (VII-3), or (VII-4), 【Chemistry 4】 R １ These are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, and 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, 3-10 membered heterocyclyl group, -(CH ２ ) ｎ OR ａ ,-(CH ２ ) ｎ P(O) ｐ (R ａ ) ｎ５ ,-(CH ２ ) ｎ S(O)R ａａ N(R) ａａ ), - (CH ２ ) ｎ N = S(O)(R ａａ ) ２ ,-(CH ２ ) ｎ S(O) ｍ R ａ or - (CH ２ ) ｎ C(O)R ａ Selected from, 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 and 3-10 membered heterocyclyl groups can optionally be hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, or C. １－３ alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Alkyl halogenated compounds, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl groups, -OR ａａ , -S(O)R ａａ N(R) ａａ ), -N=S(O)(R ａａ ) ２ , -P(O) ｐ (R ａａ ) ｎ５ , -S(O) ｍ R ａａ or -C(O)R ａａ It may be further replaced with one or more of the following: R ２ These are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, and C １－３ Alkyl alkyl groups, halogenated C １－３ alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Alkoxy group, C １－３ Selected from hydroxyalkyl groups, R ４ These are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, and 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, 3-10 membered heterocyclyl group, -S(O) ｍ R ａ or -C(O)R ａ Selected from, 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 groups and 3- to 10-membered heterocyclyl groups are optionally selected as R ４－１ It may be further replaced with one or more of the following: R ４－１ These are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, and C １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Alkyl halogenated compounds, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１２ Selected from aryl groups or 5- to 12-membered heteroaryl groups, R ４－１ These are 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 Alkyl halogenated compounds, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１２ Substituted with one or more aryl groups or 5- to 12-membered heteroaryl groups, where amino groups, C １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Alkyl halogenated compounds, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl groups can optionally include hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, and C. １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Alkyl halogenated compounds, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Substituted with one or more hydroxyalkyl groups, preferably R ４－１ These are 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 Alkyl halogenated compounds, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Selected from hydroxyalkyl groups, optionally, R ４－１ These are 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 Alkyl halogenated compounds, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－１０ Substituted with one or more cycloalkyl groups or 3- to 10-membered heterocyclyl groups, where an 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 Alkyl halogenated compounds, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl groups can optionally include hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, and C. １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Alkyl halogenated compounds, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Substituted with one or more hydroxyalkyl groups, R ５ These are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, and C １－３ Alkyl alkyl groups, halogenated C １－３ Alkyl alkyl groups, deuterated C １－３ alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Alkoxy group, C １－３ Selected from hydroxyalkyl groups, the amino group, C １－３ Alkyl alkyl groups, halogenated C １－３ Alkyl and deuterated C １－３ Alkyl groups can be optionally deuterium, halogen, cyano group, hydroxyl group, nitro group, or C １－３ Alkyl alkyl groups, halogenated C １－３ Alkyl or deuterated C １－３ They may be further substituted with one or more alkyl groups, preferably R ５ hydrogen, hydrogen, deuterium, oxo, thio, 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 Halide alkoxy group, C １－６ Selected from hydroxyalkyl groups, R ６ These are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, and C １－３ alkyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl group, 3-6 membered heterocyclyl group, -S(O) ｍ R ａ or -C(O)R ａ Selected from the above, the amino group, C １－３ alkyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl groups and 3-6 membered heterocyclyl groups can optionally be deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C １－３ They may be further substituted with one or more alkyl groups, preferably R ６ These are hydrogen, deuterium, oxo, thio, 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 Halide alkoxy group, C １－６ Selected from hydroxyalkyl groups, R ａ These are independently hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C １－３ alkyl group, C １－３ Alkyl halogenated compounds, C １－３ Deuterated 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 Selected from cycloalkyl groups and 3- to 10-membered heterocyclyl groups, preferably R ａ These are 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 Selected from cycloalkyl groups and 3- to 10-membered heterocyclyl groups, R ａａ These are, independently, hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and 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 ３－６ Cycloalkyl group, 3-6 membered heterocyclyl group, C １－３ Halogenated alkyl group or C １－３ Selected from deuterated alkyl groups, preferably R ａａ These are, independently, hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C １－３ alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C １－３ Alkoxy group, C １－３ Selected from hydroxyalkyl groups, x is 0, 1, 2, 3, y is 0, 1, 2, 3, p is 0, 1, 2, or 3. n is 0, 1, 2, or 3. m is 0, 1, 2, or 3. n5 is 0, 1, 2 or 3, and The compound according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt, characterized in that n6 is 0, 1, or 2.

8. Furthermore, as shown in the general formulas (VII-2-1), (VII-3-1), or (VII-4-1), 【Transformation 5】 Here, M １１ These are independently CH or N, R １－１ These are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl group, ethyl group, and methyl halide group. R １－２ These are independently an amino group, a hydroxyl group, a cyano group, and C １－３ Alkoxy group, C １－３ alkyl group, C ３－６ Selected from cycloalkyl groups and 3- to 8-membered heterocyclyl groups, the amino group, C １－３ Alkoxy group, C １－３ alkyl group, C ３－６ Cycloalkyl groups and 3- to 8-membered heterocyclyl groups can optionally be hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, or C. １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Alkyl halogenated compounds, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl groups, -C(O)R ｅｅ , -OR ｅｅ , -P(O) ｐ (R ｅｅ ) ｎ５ , -S(O) ｍ R ｅｅ It may be further replaced with one or more of the following, preferably R １－２ is, -NHS(O) ２ CH ３ , -NCH ３ S(O) ２ CH ３ ien-CH ２ S(O) ２ CH ３ ien-CH ２ SOCH ３ ien-CH ２ NO ２ methyl group, hydrogen, 【Transformation 6】 Methoxy group, cyano group, -CH ２ OCH ３ ien-CH ２ CN, -CH (CN) ２ , hydroxyl group, -CH ２ COCH ３ , 【Transformation 7】 Selected from, R ２－１ These are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl group, ethyl group, methyl halide group, and ethyl halide group. R ２－２ These are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl group, ethyl group, methyl halide group, and ethyl halide group. R ２－３ These are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl group, ethyl group, methyl halide group, and ethyl halide group. R ２－４ These are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl group, ethyl group, methyl halide group, and ethyl halide group. R ５ These are, independently, an amino group, C １－３ Alkyl alkyl groups, halogenated C １－３ Alkyl or deuterated C １－３ Selected from alkyl groups, the amino group, C １－３ Alkyl alkyl groups, halogenated C １－３ Alkyl and deuterated C １－３ Alkyl groups can be optionally deuterium, halogen, cyano group, hydroxyl group, nitro group, or C １－３ Alkyl alkyl groups, halogenated C １－３ Alkyl or deuterated C １－３ They may be further substituted with one or more alkyl groups. R ４ These are, independently, halogen, amino group, hydroxyl group, cyano group, nitro group, and 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 group, 3-8 membered heterocyclyl group, -S(O) ｍ R ｄ or -C(O)R ｄ Selected from the above, 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 Cycloalkyl groups and 3- to 8-membered heterocyclyl groups are optionally one or more R groups. ４－１ It may be further replaced with R ４－１ These are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, and C １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Alkyl halogenated compounds, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１２ Selected from aryl groups or 5- to 12-membered heteroaryl groups, R ４－１ These are 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 Alkyl halogenated compounds, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１２ Substituted with one or more aryl groups or 5- to 12-membered heteroaryl groups, where amino groups, C １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Alkyl halogenated compounds, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl groups can optionally include hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, and C. １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Alkyl halogenated compounds, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Substituted with one or more hydroxyalkyl groups, preferably R ４ Fluorine, chlorine, cyano group, trifluoromethyl group, methyl group, ethyl group, nitro group, hydroxy group, methoxy group, -OCD ３ ,hydrogen, 【Transformation 8】 Cyclopropyl group, 【Chemistry 9】 difluoromethyl group, 【Chemistry 10】 Selected from, more preferably R ４ Fluorine, chlorine, cyano group, trifluoromethyl group, methyl group, ethyl group, nitro group, hydroxy group, methoxy group, -OCD ３ ,hydrogen, 【Chemistry 11】 Cyclopropyl group, 【Chemistry 12】 difluoromethyl group, 【Chemistry 13】 Selected from, R ６－１ These are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, and C １－３ alkyl group, C １－３ Alkyl halogenated compounds, C １－３ Deuterated alkyl groups, C １－３ Alkoxy group, C １－３ Selected from hydroxyalkyl groups, R ６－２ These are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, and C １－３ alkyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl group, 3-6 membered heterocyclyl group, -S(O) ｍ R ｅ or -C(O)R ｅ Selected from the above, the amino group, C １－３ alkyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl groups and 3-6 membered heterocyclyl groups can optionally be deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C １－３ They may be further substituted with one or more alkyl groups. R ｄ These are independently hydrogen, deuterium, amino group, hydroxyl group, cyano group, nitro group, and C １－３ alkyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl group, 3-6 membered heterocyclyl group, C １－３ Halogenated alkyl group or C １－３ Selected from deuterated alkyl groups, R ｅ is independently selected from hydrogen, deuterium, 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 group, 3- to 6-membered heterocyclyl group, C １－３ halogenated alkyl group or C １－３ deuterated alkyl group, and R ｅｅ is independently selected from hydrogen, deuterium, 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 group, 3- to 6-membered heterocyclyl group, C １－３ halogenated alkyl group or C １－３ deuterated alkyl group, and m is independently 0, 1, or 2. p is independently 0, 1, or 2, and The compound according to claim 7, its stereoisomer, or its pharmaceutically acceptable salt, characterized in that n5 is independently 0, 1, or 2.

9. Furthermore, as shown in the general formulas (VII-2-1-1), (VII-3-1-1), or (VII-4-1-1), 【Chemistry 14】 Here, M １２ Independently, combined, NR ９ or CR １０ R １１ Selected from, R ９ These are independently selected from hydrogen, deuterium, methyl group, ethyl group, monofluoromethyl group, difluoromethyl group, or trifluoromethyl group. R １０ These are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl group, ethyl group, monofluoromethyl group, difluoromethyl group, or trifluoromethyl group. R １１ These are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl group, ethyl group, monofluoromethyl group, difluoromethyl group, or trifluoromethyl group. R １－１ These are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl group, ethyl group, monofluoromethyl group, difluoromethyl group, or trifluoromethyl group. R ２－１ These are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl group, ethyl group, methyl halide group, and ethyl halide group. R ２－２ These are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl group, ethyl group, methyl halide group, and ethyl halide group. R ２－３ These are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl group, ethyl group, methyl halide group, and ethyl halide group. R ２－４ These are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl group, ethyl group, methyl halide group, and ethyl halide group. R ５ These are, independently, an amino group, C １－３ Alkyl alkyl groups, halogenated C １－３ Alkyl or deuterated C １－３ Selected from alkyl groups, the amino group, C １－３ Alkyl alkyl groups, halogenated C １－３ Alkyl or deuterated C １－３ Alkyl groups can be optionally deuterium, halogen, cyano group, hydroxyl group, nitro group, or C １－３ Alkyl alkyl groups, halogenated C １－３ Alkyl and deuterated C １－３ They may be further substituted with one or more alkyl groups. Preferably, R ５ These are independently an isopropyl group, -CH(Me)OMe, or -N(Me) ２ Selected from, R ４ These are, independently, halogen, amino group, hydroxyl group, cyano group, nitro group, and 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 group, 3-8 membered heterocyclyl group, -S(O) ｍ R ｄ or -C(O)R ｄ Selected from the above, 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 Cycloalkyl groups and 3- to 8-membered heterocyclyl groups are optionally one or more R groups. ４－１ It may be further replaced with R ４－１ is independently selected from 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 group, 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 is 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 group, 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, substituted with one or more of them, where the amino group, C １－３ alkyl group, C ２－４ alkenyl group, C ２－４ alkynyl group, C １－３ deuterated alkyl group, C １－３ halogenated alkyl group, C １－３ alkoxy group, halogenated C １－３ alkoxy group, C １－３ hydroxyalkyl group is optionally 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 group, C １－３ Alkyl halogenated compounds, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Substituted with one or more hydroxyalkyl groups, preferably R ４ Fluorine, chlorine, cyano group, trifluoromethyl group, methyl group, ethyl group, nitro group, hydroxy group, methoxy group, -OCD ３ ,hydrogen, 【Chemistry 15】 Cyclopropyl group, 【Chemistry 16】 difluoromethyl group, 【Chemistry 17】 Selected from, more preferably R ４ Fluorine, chlorine, cyano group, trifluoromethyl group, methyl group, ethyl group, nitro group, hydroxy group, methoxy group, -OCD ３ ,hydrogen, [Chemistry 18] Cyclopropyl group, 【Chemistry 19】 difluoromethyl group, 【Chemistry 20】 Selected from, R ６－１ These are independently hydrogen, deuterium, oxo, halogen, amino group, hydroxyl group, cyano group, nitro group, and C １－３ alkyl group, C １－３ Alkoxy group, C １－３ Selected from hydroxyalkyl groups, R ６－２ These are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, and C １－３ alkyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl group, 3-6 membered heterocyclyl group, -S(O) ｍ R ｅ or -C(O)R ｅ Selected from the above, the amino group, C １－３ alkyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl groups and 3- to 8-membered heterocyclyl groups can optionally be deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, or C １－３ They may be further substituted with one or more alkyl groups. R ｄ These are independently hydrogen, deuterium, amino group, hydroxyl group, cyano group, nitro group, and C １－３ alkyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl group, 3-6 membered heterocyclyl group, C １－３ Alkyl halogenated compounds, C １－３ Selected from deuterated alkyl groups, R ｅ These are independently hydrogen, deuterium, amino group, hydroxyl group, cyano group, nitro group, and C １－３ alkyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl group, 3-6 membered heterocyclyl group, C １－３ Alkyl halogenated compounds, C １－３ Selected from deuterated alkyl groups, and The compound according to claim 8, its stereoisomer, or its pharmaceutically acceptable salt, characterized in that m is independently 0, 1, or 2.

10. Furthermore, as shown in the general formulas (VII-2-1-2), (VII-3-1-2), or (VII-4-1-2), 【Chemistry 21】 Here, M １２ Independently, combined, NR ９ or CR １０ R １１ Selected from, R ９ These are independently selected from hydrogen, deuterium, methyl group, ethyl group, monofluoromethyl group, difluoromethyl group, or trifluoromethyl group. R １０ These are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl group, ethyl group, monofluoromethyl group, difluoromethyl group, or trifluoromethyl group. R １１ These are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl group, ethyl group, monofluoromethyl group, difluoromethyl group, or trifluoromethyl group. R １－１ These are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl group, ethyl group, monofluoromethyl group, difluoromethyl group, or trifluoromethyl group. R ２－１ These are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl group, ethyl group, methyl halide group, and ethyl halide group. R ２－２ These are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl group, ethyl group, methyl halide group, and ethyl halide group. R ２－３ These are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl group, ethyl group, methyl halide group, and ethyl halide group. R ２－４ These are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl group, ethyl group, methyl halide group, and ethyl halide group. R ５ These are, independently, an amino group, C １－３ Alkyl alkyl groups, halogenated C １－３ Alkyl or deuterated C １－３ Selected from alkyl groups, the amino group, C １－３ Alkyl alkyl groups, halogenated C １－３ Alkyl or deuterated C １－３ Alkyl groups can be optionally deuterium, halogen, cyano group, hydroxyl group, nitro group, or C １－３ Alkyl alkyl groups, halogenated C １－３ Alkyl and deuterated C １－３ They may be further substituted with one or more alkyl groups. Preferably, R ５ These are independently an isopropyl group, -CH(Me)OMe, or -N(Me) ２ Selected from, L ４ Independently, combined, C １－３ Alkylene group, C ２－４ Alkenylene group, C ２－４ Alkynylene group, -(CH ２ ) ｎ７ NH(CH ２ ) ｎ８ -, - (CH ２ ) ｎ９ O(CH ２ ) ｎ１０ - Selected from, the C １－３ Alkylene group, C ２－４ Alkenylene group, C ２－４ Alkynylene group, -(CH ２ ) ｎ７ NH(CH ２ ) ｎ８ -, - (CH ２ ) ｎ９ O(CH ２ ) ｎ１０ - is optionally a halogen, amino group, hydroxyl group, cyano group, nitro group, or C １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Alkyl halogenated compounds, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Substituted with one or more hydroxyalkyl groups, Ring F is independent of C ３－６ Selected from a cycloalkyl group or a 3- to 8-membered heterocyclyl group, preferably, the ring F is independently 【Chemistry 22】 Selected from, more preferably, ring F is independently, 【Chemistry 23】 Selected from, R １２ These are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, and C １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Alkyl halogenated compounds, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Selected from hydroxyalkyl groups, the C １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Alkyl halogenated compounds, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Hydroxyalkyl groups can optionally include halogens, amino groups, hydroxyl groups, cyano groups, nitro groups, and C. １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Alkyl halogenated compounds, C １－３ Alkoxy group, halogenated C １－３ Alkoxy group, C １－３ Substituted with one or more hydroxyalkyl groups, R ６－１ These are independently hydrogen, deuterium, oxo, halogen, amino group, hydroxyl group, cyano group, nitro group, and C １－３ alkyl group, C １－３ Alkoxy group, C １－３ Selected from hydroxyalkyl groups, R ６－２ These are independently hydrogen, deuterium, oxo, thio, halogen, amino group, hydroxyl group, cyano group, nitro group, and C １－３ alkyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl group, 3-6 membered heterocyclyl group, -S(O) ｍ R ｅ or -C(O)R ｅ Selected from the above, the amino group, C １－３ alkyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl groups and 3- to 8-membered heterocyclyl groups can optionally be deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, or C １－３ They may be further substituted with one or more alkyl groups. R ｄ These are independently hydrogen, deuterium, amino group, hydroxyl group, cyano group, nitro group, and C １－３ alkyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl group, 3-6 membered heterocyclyl group, C １－３ Alkyl halogenated compounds, C １－３ Selected from deuterated alkyl groups, R ｅ These are independently hydrogen, deuterium, amino group, hydroxyl group, cyano group, nitro group, and C １－３ alkyl group, C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl group, 3-6 membered heterocyclyl group, C １－３ Alkyl halogenated compounds, C １－３ Selected from deuterated alkyl groups, m is independently 0, 1, or 2. n7 is independently 0, 1, or 2. n8 is independently 0, 1, or 2. n9 is independently 0, 1, or 2. n10 is independently 0, 1 or 2, and The compound according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt, characterized in that u is independently 0, 1, or 2.

11. The specific compounds are, 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 The compound described in claim 1, its stereoisomer, or its pharmaceutically acceptable salt.

12. A method for producing a compound represented by the general formula (II-G) described in claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the step of reacting a compound represented by formula (XV) with a compound represented by formula (XVI) to obtain a compound represented by formula (II-G), 【Transformation 33】 The method is characterized in that, here, X is a halogen, preferably chlorine.

13. A pharmaceutical composition comprising a therapeutically effective amount of each compound of the general formula described in claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

14. Application of a compound according to any one of claims 1 to 11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, in the manufacture of an EGFR inhibitor drug.

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

16. An application of a compound according to any one of claims 1 to 11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, in the manufacture of a drug for treating cancer, wherein the cancer is preferably selected from ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, cholangiocarcinoma, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, multiple myeloma, melanoma, or mesothelioma, more preferably the cancer is non-small cell lung cancer, and even more preferably the cancer is EGFR Applications include L858R / T790M, Del19 / T790M, Del19 / C797S, L858R / C797S, Del19 / T790M / C797S, or L858R / T790M / C797S mutant non-small cell lung cancer.

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