Pyrimidine compounds as AXL inhibitors

Abstract

The present invention discloses a pyrimidine compound as an AXL inhibitor. The structure of the pyrimidine compound is shown in general formula I, and the definitions of each substituent are as described in the specification. The present invention also provides a preparation method thereof. The pyrimidine compound of the present invention has significant AXL inhibitory activity and can be used as an AXL inhibitor. #imgabs0#

Description

[0001] This application claims priority to Chinese invention patent application No. 202010471712.7 filed with the Intellectual Property Office of the People's Republic of China on May 29, 2020, and Chinese invention patent application No. 202110003579.7 filed with the Intellectual Property Office of the People's Republic of China on January 5, 2021. The entire contents of which are hereby incorporated herein by reference in their entirety. Technical Field

[0002] The present invention belongs to the field of medical technology, and particularly relates to pyrimidine compounds, wherein the compounds are AXL kinase inhibitors. The present invention also relates to using the compounds to treat diseases related to AXL activity. Background Art

[0003] Receptor tyrosine kinases (RTKs) are multidomain transmembrane proteins that act as sensors for extracellular ligands. Ligand receptor binding induces receptor dimerization and activation of its intracellular kinase domain, which in turn leads to the recruitment, phosphorylation, and activation of multiple downstream signaling cascades (Robinson, DR, et al., Oncogene, 19:5548-5557, 2000). To date, 58 RTKs have been identified in the human genome, which regulate a variety of cellular processes, including cell survival, growth, differentiation, proliferation, adhesion, and motility (Segaliny, AI, et al., J. Bone Oncol, 4:1-12, 2015).

[0004] AXL (also known as UFO, ARK, and Tyro7) belongs to the TAM family of receptor tyrosine kinases, which also includes Mer and Tyro3. Among them, AXL and Tyro3 have the most similar gene structure, while AXL and Mer have the most similar tyrosine kinase domain amino acid sequences. Like other receptor tyrosine kinases (RTKs), the structure of the TAM family contains an extracellular domain, a transmembrane domain, and a conserved intracellular kinase domain. The extracellular domain of AXL has a unique structure that juxtaposes immunoglobulin and type III fibronectin repeat units and is reminiscent of the structure of neutral cell adhesion molecules. TAM family members have a common ligand, growth arrest-specific protein 6 (Gas6), which can bind to all TAM receptor tyrosine kinases. After AXL binds to Gas6, it will lead to receptor dimerization and AXL autophosphorylation, thereby activating multiple downstream signal transduction pathways and participating in multiple processes of tumorigenesis (Linger, RM et al., Ther. Targets, 14 (10), 1073-1090, 2010; Rescigno, J et al., Oncogene, 6 (10), 1909-1913, 1991).

[0005] AXL is widely expressed in normal human tissues, such as monocytes, macrophages, platelets, endothelial cells, cerebellum, heart, skeletal muscle, liver and kidney, among which myocardium and skeletal muscle have the highest expression, bone marrow CD34+ cells and stromal cells also have high expression, and normal lymphoid tissues have very low expression (Wu YM, Robinson DR, Kung HJ, Cancer Res, 64 (20), 7311-7320, 2004; hung BI et al., DNA Cell Biol, 22 (8), 533-540, 2003). In studies on many cancer cells, it was found that AXL gene was overexpressed or ectopically expressed in hematopoietic cells, stromal cells and endothelial cells. In various leukemias and most solid tumors, the overexpression of AXL kinase is particularly prominent. By inhibiting AXL receptor tyrosine kinase, the survival signal of tumor cells can be reduced, the invasion ability of tumors can be blocked, and the sensitivity of targeted drug therapy and chemotherapy can be increased. Therefore, finding effective AXL inhibitors is an important direction for the current development of tumor targeted drugs. Summary of the invention

[0006] In one aspect, the present invention provides a pyrimidine compound represented by formula I or a pharmaceutically acceptable salt thereof,

[0007]

[0008] Wherein, X is CH or N;

[0009] R 1 is a 5-12 membered saturated heterocyclic ring or a 5-8 membered saturated carbocyclic ring, which is optionally replaced by one or more C 1-6 Alkyl, C 1-6 substituted with alkoxy, halogen, cyano, deuterium or hydroxyl, and R 1 Not for , and ;

[0010] R 2 is a halogen;

[0011] Ring A is selected from phenyl, 5-6 membered heteroaryl or 9-12 membered benzoheterocyclyl, wherein phenyl, 5-6 membered heteroaryl are optionally substituted by one or more R 3 Substituted, 9-12 membered benzoheterocyclic group is optionally or one or more R 3 replace;

[0012] R 3 Selected from: deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C3-10 Cycloalkyloxy, , , , , , , , , , , , , , or , where the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with hydroxy, halogen, cyano, C 1-3 Alkoxy or 4-7 membered heterocycloalkyl substitution;

[0013] In one embodiment, R 3 Selected from: deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, , , , , , , , , , , , , , or , where the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with hydroxy, halogen, cyano, C 1-3 Alkoxy or 4-7 membered heterocycloalkyl substitution;

[0014] R 4 , R 5 Independently selected from C 1-6 Alkyl, hydroxyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy or C 3-10 Cycloalkyl, wherein the C 1-6 The alkyl group is optionally substituted with deuterium, hydroxyl, halogen, cyano or C 1-3 Alkoxy substituted; or R 4 , R 5 It can form a 3-6-membered phosphorus-containing saturated monocyclic ring together with the adjacent P atom;

[0015] R 6 Selected from C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 4-7 membered heterocycloalkyl or 5-7 membered heteroaryl;

[0016] R 7 , R 8 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 4-7 membered heterocycloalkyl or 5-7 membered heteroaryl, wherein the C 1-6 The alkyl group is optionally substituted with hydroxy, halogen, cyano or C 1-3 Alkoxy substituted; or R 7 , R 8 Together with their adjacent N atoms, they form a 3-6-membered nitrogen-containing saturated monocyclic ring;

[0017] R 9 , R 10 Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-10 Cycloalkyl;

[0018] R 11 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-7 membered heterocycloalkyl or 5-7 membered heteroaryl;

[0019] R 12 Selected from C 3-10 Cycloalkyl, 4-7 membered heterocycloalkyl or 5-7 membered heteroaryl, which is optionally substituted by one or more hydroxyl, halogen, cyano, C 1-6 The alkyl group is substituted with 3-7 membered heterocycloalkyl.

[0020] In some embodiments, X is CH.

[0021] In some embodiments, X is N.

[0022] In some embodiments, R 1 is a 5-12 membered saturated heterocyclic ring or a 5-7 membered saturated carbocyclic ring, which is optionally replaced by one or more C 1-6 Alkyl, C 1-6 substituted with alkoxy, halogen, cyano, deuterium or hydroxyl, and R 1 Not for , and ;

[0023] In some embodiments, R 1 is a 5-8 membered saturated heterocyclic ring or a 5-8 membered saturated carbocyclic ring, which is optionally substituted by one or more C 1-6 Alkyl, C 1-6 substituted with alkoxy, halogen, cyano, deuterium or hydroxyl, and R 1 Not for , and .

[0024] In some embodiments, R 1 is a 5-8 membered saturated heterocyclic ring or a 5-8 membered saturated carbocyclic ring, which is optionally substituted by one or more methyl, methoxy, fluorine, chlorine, cyano, deuterium or hydroxyl groups, and R 1 Not for , and .

[0025] In some embodiments, R 1 is a 5-8 membered saturated heterocyclic ring or a 5-8 membered saturated carbocyclic ring, which is optionally substituted with one or more methyl, methoxy, chlorine, cyano, deuterium or hydroxyl groups, and R 1 Not for , and .

[0026] In some embodiments, R 1 is a 5-8 membered saturated heterocyclic ring or a 5-8 membered saturated carbocyclic ring, which is optionally substituted by one or more methoxy, fluorine, cyano or hydroxyl groups, and R 1 Not for , and .

[0027] In some embodiments, R 1 is a 5-8 membered saturated heterocyclic ring or a 5-8 membered saturated carbocyclic ring, which is optionally substituted by one or more fluorine, cyano or deuterium, and R 1 Not for , and .

[0028] In some embodiments, R 1 is a 5-8 membered saturated heterocyclic ring or a 5-8 membered saturated carbocyclic ring, which is optionally substituted by one or more fluorine or cyano groups, and R 1 Not for , and .

[0029] In some embodiments, R 1is a 5-8 membered saturated heterocyclic ring or a 5-8 membered saturated carbocyclic ring, which is optionally substituted with one or more deuteriums, and R 1 Not for , and .

[0030] In some embodiments, R 1 is a 5-8 membered saturated heterocyclic ring or a 5-8 membered saturated carbocyclic ring, which is optionally substituted with one or more methoxy groups, and R 1 Not for , and .

[0031] In some embodiments, R 1 is a 5-8 membered saturated heterocyclic ring or a 5-8 membered saturated carbocyclic ring, which is optionally substituted by one or more hydroxyl groups, and R 1 Not for , and .

[0032] In some embodiments, R 1 is a 5-8 membered saturated heterocyclic ring or a 5-8 membered saturated carbocyclic ring, which is optionally substituted by two fluorine rings, and R 1 Not for , and .

[0033] In some embodiments, R 1 is a 5-8 membered saturated heterocyclic ring or a 5-8 membered saturated carbocyclic ring, which is optionally substituted with one cyano group, and R 1 Not for , and .

[0034] In some embodiments, R 1 is a 5-8 membered saturated heterocyclic ring or a 5-8 membered saturated carbocyclic ring, which is optionally substituted with one methoxy group, and R 1 Not for , and .

[0035] In some embodiments, R 1 is a 5-8 membered saturated heterocyclic ring or a 5-8 membered saturated carbocyclic ring, which is optionally substituted with one hydroxyl group, and R 1 Not for , and .

[0036] In some embodiments, R 1is a 5-8 membered saturated heterocyclic ring or a 5-8 membered saturated carbocyclic ring, which is optionally substituted with one fluorine, and R 1 Not for , and .

[0037] In some embodiments, R 1 is an unsubstituted 5-8 membered saturated heterocyclic ring or an unsubstituted 5-8 membered saturated carbocyclic ring, and R 1 Not for .

[0038] In some embodiments, R 1 is an unsubstituted 5-8 membered saturated heterocyclic ring, and R 1 Not for .

[0039] In some embodiments, R 1 is a 5-7 membered saturated heterocyclic ring or a 5-7 membered saturated carbocyclic ring, which is optionally substituted by one or more C 1-6 Alkyl, C 1-6 substituted with alkoxy, halogen, cyano, deuterium or hydroxyl, and R 1 Not for , and .

[0040] In some embodiments, R 1 is a 5-7 membered saturated heterocyclic ring or a 5-7 membered saturated carbocyclic ring, which is optionally substituted by one or more methyl, methoxy, fluorine, chlorine, cyano, deuterium or hydroxyl groups, and R 1 Not for , and .

[0041] In some embodiments, R 1 is a 5-7 membered saturated heterocyclic ring or a 5-7 membered saturated carbocyclic ring, which is optionally substituted with one or more methyl, methoxy, chlorine, cyano, deuterium or hydroxyl groups, and R 1 Not for , and .

[0042] In some embodiments, R 1 is a 5-7 membered saturated heterocyclic ring or a 5-7 membered saturated carbocyclic ring, which is optionally substituted by one or more methoxy, fluorine, cyano or hydroxyl groups, and R 1 Not for , and .

[0043] In some embodiments, R 1is a 5-7 membered saturated heterocyclic ring or a 5-7 membered saturated carbocyclic ring, which is optionally substituted by one or more fluorine, cyano or deuterium, and R 1 Not for , and .

[0044] In some embodiments, R 1 is a 5-7 membered saturated heterocyclic ring or a 5-7 membered saturated carbocyclic ring, which is optionally substituted by one or more fluorine or cyano groups, and R 1 Not for , and .

[0045] In some embodiments, R 1 is a 5-7 membered saturated heterocyclic ring or a 5-7 membered saturated carbocyclic ring, which is optionally substituted with one or more deuteriums, and R 1 Not for , and .

[0046] In some embodiments, R 1 is a 5-7 membered saturated heterocyclic ring or a 5-7 membered saturated carbocyclic ring, which is optionally substituted by one or more methoxy groups, and R 1 Not for , and .

[0047] In some embodiments, R 1 is a 5-7 membered saturated heterocyclic ring or a 5-7 membered saturated carbocyclic ring, which is optionally substituted by one or more hydroxyl groups, and R 1 Not for , and .

[0048] In some embodiments, R 1 is a 5-7 membered saturated heterocyclic ring or a 5-7 membered saturated carbocyclic ring, which is optionally substituted by two fluorine rings, and R 1 Not for , and .

[0049] In some embodiments, R 1 is a 5-7 membered saturated heterocyclic ring or a 5-7 membered saturated carbocyclic ring, which is optionally substituted with one cyano group, and R 1 Not for , and .

[0050] In some embodiments, R 1is a 5-7 membered saturated heterocyclic ring or a 5-7 membered saturated carbocyclic ring, which is optionally substituted with a methoxy group, and R 1 Not for , and .

[0051] In some embodiments, R 1 is a 5-7 membered saturated heterocyclic ring or a 5-7 membered saturated carbocyclic ring, which is optionally substituted with one hydroxyl group, and R 1 Not for , and .

[0052] In some embodiments, R 1 is a 5-7 membered saturated heterocyclic ring or a 5-7 membered saturated carbocyclic ring, which is optionally substituted with one fluorine, and R 1 Not for , and .

[0053] In some embodiments, R 1 is an unsubstituted 5-7 membered saturated heterocyclic ring or an unsubstituted 5-7 membered saturated carbocyclic ring, and R 1 Not for .

[0054] In some embodiments, R 1 is an unsubstituted 5-7 membered saturated heterocyclic ring, and R 1 Not for .

[0055] In some typical embodiments, R 1 for , , , , , , , , , , , , , , , , , , , or .

[0056] In some typical embodiments, R 1 for , , , , , , , , , , , , , , or .

[0057] In some typical embodiments, R 1 for , , , , , , , , , , or .

[0058] In some typical embodiments, R 1 for , , , , , , , , or .

[0059] In some typical embodiments, R 1 for , , , , , , , , , , , or .

[0060] In some typical embodiments, R 1 for , , , , , , , , , , , , , or .

[0061] In some typical embodiments, R 1 for , , , , , , , , , , , , , , , , , , or .

[0062] In some typical embodiments, R 1 for , , , , , , , , , , or .

[0063] In some typical embodiments, R 1 for , , , , , , , , , or .

[0064] In some typical embodiments, R 1 for , , , , , , , or .

[0065] In some typical embodiments, R 1 for , , , , , , , or .

[0066] In some typical embodiments, R 1 for , , , , , or .

[0067] In some typical embodiments, R 1 for , , , , , , .

[0068] In some more typical embodiments, R 1 for , , , , or .

[0069] In some more typical embodiments, R 1 for , , or .

[0070] In some more typical embodiments, R 1 for .

[0071] In some embodiments, R 2 is F, Cl or Br.

[0072] In some typical embodiments, R 2 For Cl.

[0073] In some embodiments, ring A is phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzo five-membered heterocyclic group or benzo six-membered heterocyclic group, wherein the group is optionally replaced by one or more R 3 replace.

[0074] In some embodiments, ring A is phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, , , , , , , , or wherein the group is optionally replaced by one or more R 3 replace.

[0075] In some typical embodiments, ring A is phenyl, furanyl, thiazolyl, pyridinyl, , or wherein the group is optionally replaced by one or more R 3 replace.

[0076] In some typical embodiments, ring A is phenyl, pyridyl, or wherein the group is optionally replaced by one or more R 3 replace.

[0077] In some typical embodiments, ring A is phenyl or pyridyl, wherein the group is optionally substituted with one or more R 3 replace.

[0078] In some more typical embodiments, Ring A is phenyl, wherein said group is optionally substituted with one or more R 3 replace.

[0079] In some embodiments, R 3 Selected from: deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyloxy, , , , , , , , , , , , , , or , where the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with hydroxy, halogen, cyano, C 1-3 Alkoxy or 4-7 membered heterocycloalkyl substitution;

[0080] In some embodiments, R 3 Selected from: deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, , , , , , , , , or , where the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with hydroxy, halogen, cyano, C 1-3 The group may be substituted with an alkoxy group or a 4-7 membered heterocycloalkyl group.

[0081] R 3 Selected from: deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyloxy, , , , , , , , , or , where the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with hydroxy, halogen, cyano, C 1-3 The group may be substituted with an alkoxy group or a 4-7 membered heterocycloalkyl group.

[0082] In some typical embodiments, R 3 Selected from: deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, , , , , , , , , or , where the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with hydroxy, F, Cl, Br, cyano, C 1-3 The group may be substituted with an alkoxy group or a 4-7 membered heterocycloalkyl group.

[0083] In some more typical embodiments, R 3 Selected from deuterium, fluorine, chlorine, bromine, C 1-6 Alkyl, C 1-6 Alkoxy, , , , , , , , , or , where the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted by methoxy, hydroxy, fluoro, cyano or replace.

[0084] In some more typical embodiments, R 3 Selected from deuterium, fluorine, chlorine, bromine, C 1-6 Alkyl, C 1-6 Alkoxy, , , , , , , , , or , where the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with hydroxy, fluorine, cyano or replace.

[0085] In some more typical embodiments, R 3 Selected from fluorine, chlorine, C 1-6 Alkyl, C 1-6 Alkoxy, , , , , , , , , or , where the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted by methoxy, hydroxy, fluoro, cyano or replace.

[0086] In some more typical embodiments, R 3 Selected from fluorine, chlorine, C 1-6 Alkyl, C 1-6 Alkoxy, , , , , , , , , or , where the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with hydroxy, fluorine, cyano or replace.

[0087] In some more typical embodiments, R 3 Selected from: deuterium, fluorine, chlorine, bromine, methyl, trifluoromethyl, , , , , , , , , , , , , , , , , , , , , or .

[0088] In some more typical embodiments, R 3 Selected from: deuterium, fluorine, chlorine, bromine, methyl, trifluoromethyl, , , , , , , , , , , , , , , , or .

[0089] In some more typical embodiments, R 3 Selected from: fluorine, chlorine, methyl, trifluoromethyl, , , , , , , , , , , , , , or .

[0090] In some more typical embodiments, R 3 Selected from: deuterium, fluorine, chlorine, bromine, methyl, trifluoromethyl, , , , , , , , , , , , , or .

[0091] In some more typical embodiments, R 3 Selected from: fluorine, chlorine, methyl, trifluoromethyl, , , , , , , , , , , or .

[0092] In some more typical embodiments, R 3 Selected from: fluorine, chlorine, methyl, trifluoromethyl, , , , , , , , , , , , , or .

[0093] In some more typical embodiments, R 3 Selected from: fluorine, chlorine, methyl, trifluoromethyl, , , , , , , , , , , or .

[0094] In some more typical embodiments, R 3 Selected from: fluorine, chlorine, methyl, trifluoromethyl, , , , , , , , , or .

[0095] In some more typical embodiments, R 3 Fluorine, methyl, , or .

[0096] In some typical embodiments, R 3 For fluorine, chlorine, methyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyloxy, , or .

[0097] In some typical embodiments, R 3 Fluorine, chlorine, cyano, methyl, C 1-3 Alkoxy, C 3-6 Cycloalkyloxy, , or .

[0098] In some embodiments, R 4 , R 5 Independently selected from C 1-6 Alkyl or C 3-10 Cycloalkyl, wherein the C 1-6 The alkyl group is optionally substituted with deuterium, hydroxyl, halogen, cyano or C 1-3 Alkoxy substituted; or R 4 , R 5 Together with their adjacent P atoms, they form a 3-6 membered phosphorus-containing saturated monocyclic ring.

[0099] In some more typical embodiments, R 4 , R 5 Independently selected from C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with deuterium, hydroxyl, halogen, cyano or C 1-3 Alkoxy substitution.

[0100] In some typical embodiments, R 4 , R 5 Independently selected from C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with deuterium.

[0101] In some more typical embodiments, R 4 , R 5 independently selected from methyl, ethyl, n-propyl, isopropyl, CD 3 , CH 2 D. CHD 2 , CH 2 CD 3 , CD 2 CD 3 , CH 2 CH 2 CD 3 , CH (CD 3 ) 2 or CD (CD 3 ) 2 .

[0102] In some more typical embodiments, R 4 , R 5 Independently selected from methyl or CD 3 .

[0103] In some more typical embodiments, R 4 , R 5 All are methyl.

[0104] In some more typical embodiments, R 4 , R5 All CD 3 .

[0105] In some embodiments, R 6 C 1-6 Alkyl, C 3-10 Cycloalkyl or 4-7 membered heterocycloalkyl.

[0106] In some embodiments, R 6 C 1-6 Alkyl or C 3-10 Cycloalkyl.

[0107] In some typical embodiments, R 6 is methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0108] In some more typical embodiments, R 6 is methyl, isopropyl or cyclopropyl.

[0109] In some embodiments, R 7 , R 8 are independently selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl or 4-7 membered heterocycloalkyl, wherein the C 1-6 The alkyl group is optionally substituted with hydroxy, halogen, cyano or C 1-3 Alkoxy substituted; or R 7 , R 8 Together with their adjacent nitrogen atoms, they form a 3-6 membered nitrogen-containing saturated monocyclic ring.

[0110] In some typical embodiments, R 7 , R 8 independently selected from hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl or 5-membered heterocycloalkyl, wherein the C 1-6 The alkyl group is optionally substituted with a hydroxyl, F, cyano or C 1-3 Alkoxy substituted; or R 7 , R 8 Together with their neighboring N atoms, they form , or .

[0111] In some more typical embodiments, R 7 , R 8 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, CH 2 CH 2 OCH 3 CF 3 , or ; or R 7 , R 8 Together with their neighboring N atoms, they form , or .

[0112] In some more typical embodiments, R 7 is hydrogen or methyl, and R 8 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, CH 2 CH 2 OCH 3 CF 3 , or ; or R 7 , R 8 Together with their neighboring N atoms, they form .

[0113] In some more typical embodiments, R 7 is hydrogen, and R 8 Selected from hydrogen, methyl, cyclopropyl, CH 2 CH 2 OCH 3 or ; or R 7 , R 8 Together with their neighboring N atoms, they form .

[0114] In some typical embodiments, R 7 is hydrogen, and R 8 is selected from hydrogen, methyl, cyclopropyl or ; or R 7 , R 8 Together with their neighboring N atoms, they form .

[0115] In some embodiments, R 9 , R 10 Independently selected from C 1-6 Alkyl or C 3-10 Cycloalkyl.

[0116] In some more typical embodiments, R 9 , R 10 Independently selected from C 1-6 alkyl.

[0117] In some more typical embodiments, R 9 , R 10Independently selected from methyl, ethyl, n-propyl, isopropyl or tert-butyl.

[0118] In some typical embodiments, R 9 , R 10 All are methyl.

[0119] In some embodiments, R 11 It is a 4-7 membered heterocycloalkyl group.

[0120] In some more typical embodiments, R 11 It is a 5-membered heterocycloalkyl.

[0121] In some embodiments, R 12 C 3-10 Cycloalkyl or 5-7 membered heteroaryl, which is optionally substituted by one or more C 1-6 Alkyl substitution.

[0122] In some embodiments, R 12 is a 5-7 membered heteroaryl group, which is optionally substituted by one or more C 1-6 Alkyl substitution.

[0123] In some embodiments, R 12 is cyclopropyl or 5-membered heteroaryl, which is optionally substituted by one or more methyl groups.

[0124] In some embodiments, R 12 is a 5-membered heteroaryl group which is optionally substituted by one or more methyl groups.

[0125] In some more typical embodiments, R 12 is cyclopropyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or tetrazolyl, which is optionally substituted by one or more methyl groups.

[0126] In some more typical embodiments, R 12 is pyrazolyl, imidazolyl, thiazolyl, oxazolyl, 1,2,3-triazolyl or 1,2,4-triazolyl, which is optionally substituted by one or more methyl groups.

[0127] In some more typical embodiments, R 12 is cyclopropyl, imidazolyl, oxazolyl, 1,2,4-triazolyl or tetrazolyl, which is optionally substituted by one or more methyl groups.

[0128] In some more typical embodiments, R 12 is imidazolyl, oxazolyl or 1,2,4-triazolyl, which is optionally substituted by one or more methyl groups.

[0129] In some more typical embodiments, R12 Selected from , , , , or .

[0130] In some more typical embodiments, R 12 Selected from , , , or .

[0131] In some more typical embodiments, R 12 Selected from , or .

[0132] In some typical embodiments, R 12 Selected from , , or .

[0133] In some typical embodiments, R 12 Selected from or .

[0134] In some more typical embodiments, R 3 is selected from deuterium, fluorine, chlorine, bromine, methyl, trifluoromethyl, , , , , , , , , , , , ,

[0135] , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0136] In some more typical embodiments, R 3 is selected from deuterium, fluorine, chlorine, bromine, methyl, trifluoromethyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0137] In some more typical embodiments, R 3 Selected from fluorine, chlorine, methyl, trifluoromethyl, , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0138] In some more typical embodiments, R 3 Selected from fluorine, chlorine, methyl, trifluoromethyl, , , , , , , , , , , , , , , , , , , , , , , or .

[0139] In some more typical embodiments, R 3 Selected from fluorine, chlorine, methyl, trifluoromethyl, , , , , , , , , , , , , , , , , , , , or .

[0140] In some more typical embodiments, R 3 Selected from fluorine, chlorine, methyl, , , , , , , , , , , , , , , , , or .

[0141] In some more typical embodiments, R 3 Selected from fluorine, chlorine, methyl, , , , , , , , , , , , , , , or .

[0142] In some more typical embodiments, R 3 For fluorine, chlorine, methyl, , , , , , , , , , or .

[0143] In some more typical embodiments, R 3 Selected from fluorine, methyl, , , , or .

[0144] In some more typical embodiments, R 3 Selected from fluorine, methyl, , , or .

[0145] In some more typical embodiments, R 3 Selected from fluorine, methyl, or .

[0146] In some more typical embodiments, R 3 Selected from fluorine, or .

[0147] In some more typical embodiments, R 3 Selected from or .

[0148] In some embodiments, the aforementioned compound of formula I has a structure as shown in the following compound of formula I-1 or a pharmaceutically acceptable salt thereof:

[0149]

[0150] Among them, R 1 , R 2 , Ring A is as defined in the compound of formula I.

[0151] In some embodiments, Ring A is selected from phenyl, pyridyl, , , , or wherein the group is optionally replaced by one or two R 3 Replacement, R 3 The definition of is as defined in the compound of formula I.

[0152] In some embodiments, Ring A is selected from phenyl, pyridyl, or wherein the group is optionally replaced by one or two R 3 Replacement, R 3 The definition of is as defined in the compound of formula I.

[0153] In some embodiments, the compound of the aforementioned formula I has a structure as shown in the following formula I-2 compound or a pharmaceutically acceptable salt thereof:

[0154]

[0155] Among them, R 1 , R 2 , Ring A is as defined in the compound of formula I.

[0156] In some embodiments, R 1 Selected from , , or .

[0157] In some typical embodiments, R 1 Selected from or .

[0158] In some embodiments, the aforementioned compound of Formula I has a structure as shown in Formula II or a pharmaceutically acceptable salt thereof:

[0159]

[0160] II

[0161] Among them, X, R 1 , R 2 , R 3 The definition is consistent with that in the compound of formula I;

[0162] n is an integer from 0 to 4;

[0163] In some embodiments, R a For deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyloxy, , , , or , where the C 1-6 Alkyl or C 1-6 The alkoxy group may be optionally substituted with one or more deuterium, methoxy, hydroxyl, halogen or cyano groups, wherein R 4 , R 5 , R 7 , R 8 , R 12 The same as the definition in the compound of formula I.

[0164] In some embodiments, R a For deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, , , , or , where the C 1-6 Alkyl or C 1-6 The alkoxy group may be optionally substituted with one or more deuterium, halogen or cyano groups, wherein R 4 , R 5 , R 7 , R 8 , R12 The same as the definition in the compound of formula I.

[0165] In some embodiments, R a For deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, or , where the C 1-6 Alkyl or C 1-6 The alkoxy groups may be optionally substituted with one or more deuterium, halogen or cyano groups.

[0166] In some embodiments n is 0, 1 or 2.

[0167] Further in some embodiments n is 0 or 1.

[0168] In some more typical embodiments n is 1.

[0169] In some embodiments, R a Deuterium, chlorine, fluorine, bromine, cyano, hydroxyl, , , , , , , , or methyl or methoxy optionally substituted by one or more halogens, wherein R 4 , R 5 , R 7 , R 8 , R 12 The same as the definition in the compound of formula I.

[0170] In some embodiments, R a Deuterium, chlorine, fluorine, bromine, cyano, hydroxyl, , , or methyl or methoxy optionally substituted by one or more halogens, wherein R 4 , R 5 , R 7 , R 8 , R 12 The same as the definition in the compound of formula I.

[0171] In some embodiments, R a is deuterium, chlorine, fluorine, cyano, hydroxy, or methyl or methoxy optionally substituted by one or more halogens.

[0172] In some embodiments, R a Deuterium, chlorine, fluorine, bromine, cyano, hydroxyl, , , or methyl or methoxy optionally substituted by 1 or more fluorine groups, wherein R 4 , R 5 , R 7 , R 8 , R 12 The same as the definition in the compound of formula I.

[0173] In some embodiments, R a is deuterium, chlorine, fluorine, cyano, hydroxyl or methyl or methoxy optionally substituted by one or more fluorine groups.

[0174] In some typical embodiments, R a is deuterium, fluorine, chlorine, bromine, methyl, trifluoromethyl, , , , , , , , , , , , , , , , , , or .

[0175] In some more typical embodiments, R a is deuterium, chlorine, fluorine, bromine, cyano, hydroxyl, methyl, trifluoromethyl, methoxy, , , , , , or .

[0176] In some more typical embodiments, R a is chlorine, fluorine, cyano, hydroxyl, methyl, trifluoromethyl, methoxy, , , or .

[0177] In some more typical embodiments, R a is chlorine, fluorine, cyano, hydroxyl, methyl, methoxy, , , or .

[0178] In some more typical embodiments, R a For fluorine, chlorine, methyl, , , , , , , , , or .

[0179] In some more typical embodiments, R a is chlorine, fluorine, cyano, methyl, methoxy or .

[0180] In some more typical embodiments, R a is deuterium, chlorine, fluorine, cyano, hydroxy, methyl, trifluoromethyl, difluoromethyl or methoxy.

[0181] In some more typical embodiments, R a is chloro, fluoro, cyano, hydroxy, methyl, trifluoromethyl or methoxy.

[0182] In some more typical embodiments, R a is chlorine, fluorine, cyano, hydroxy, methoxy or methyl.

[0183] In some more typical embodiments, R a Chloro, fluoro, cyano, hydroxyl, methoxy, or methyl.

[0184] In some more typical embodiments, R a for or methyl.

[0185] In some more typical embodiments, R a It is methyl.

[0186] In some more typical embodiments, R a for .

[0187] In some embodiments, R 3 for , , , , , , or , where R 4 , R 5 , R6 , R 7 , R 8 , R 9 , R 10 , R 12 The definition of is as defined in the compound of formula I.

[0188] In some embodiments, R 3 for , , or , where R 4 , R 5 , R 6 , R 7 , R 8 , R 12 The definition of is as defined in the compound of formula I.

[0189] In some embodiments, R 3 for , or , where R 4 , R 5 , R 7 , R 8 , R 12 The definition of is as defined in the compound of formula I.

[0190] In some embodiments, R 3 for , ,or , which may optionally be substituted by one or more deuteriums.

[0191] In some embodiments, R 3 for or , which may optionally be substituted by one or more deuteriums.

[0192] In some embodiments, R 3 for .

[0193] In some embodiments, R 3 for .

[0194] In some embodiments, the compound of the aforementioned formula II has a structure as shown in the following formula II-1 compound or a pharmaceutically acceptable salt thereof:

[0195]

[0196] Among them, R 1 , R 2 , R3 , R a , n are as defined in the compound represented by formula II.

[0197] In some embodiments, the compound of the aforementioned formula II has a structure as shown in formula III or a pharmaceutically acceptable salt thereof:

[0198]

[0199] III

[0200] Among them, X, R 1 , R 2 , R 3 , R a The definition of is consistent with that of the compound of formula II.

[0201] In some embodiments, the compound of the aforementioned formula II has a structure as shown in the following formula III-1 or a pharmaceutically acceptable salt thereof:

[0202]

[0203] Where R 1 , R 2 , R 3 , R a The definition of is the same as that of the compound represented by formula II.

[0204] In some embodiments, the compound of the aforementioned formula I has a structure as shown in formula IV or a pharmaceutically acceptable salt thereof:

[0205]

[0206] IV

[0207] Among them, X, R 1 , R 2 The definition is consistent with that in the compound of formula I;

[0208] n is an integer from 0 to 4;

[0209] Ring B is selected from phenyl, 5-6 membered heteroaryl or optionally Substituted 9-12 membered benzoheterocyclyl;

[0210] R b For deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyloxy, , , , or , where the C1-6 Alkyl or C 1-6 The alkoxy group may be optionally substituted with one or more methoxy, hydroxy, deuterium, halogen or cyano groups, wherein R 4 , R 5 , R 7 , R 8 , R 12 The same as the definition in the compound of formula I.

[0211] In some embodiments, R b For deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, , , , or , where the C 1-6 Alkyl or C 1-6 The alkoxy group may be optionally substituted with one or more deuterium, halogen or cyano groups, wherein R 4 , R 5 , R 7 , R 8 , R 12 The same as the definition in the compound of formula I.

[0212] In some embodiments, X, R 1 , R 2 The definition is consistent with that in the compound of formula I;

[0213] n is an integer from 0 to 4;

[0214] Ring B is selected from phenyl, 5-6 membered heteroaryl or optionally Substituted 9-12 membered benzoheterocyclyl;

[0215] R b For deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, or , where the C 1-6 Alkyl or C 1-6 The alkoxy groups may be optionally substituted with one or more deuterium, halogen or cyano groups.

[0216] In some embodiments n is 0, 1, 2 or 3.

[0217] In some further embodiments n is 0, 1 or 2.

[0218] In still further embodiments n is 0 or 1.

[0219] In some more typical embodiments n is 1.

[0220] In some embodiments, R b Deuterium, chlorine, fluorine, bromine, cyano, hydroxyl, , , or methyl or methoxy optionally substituted by one or more halogens, wherein R 4 , R 5 , R 7 , R 8 , R 12 The same as the definition in the compound of formula I.

[0221] In some embodiments, R b Deuterium, chlorine, fluorine, bromine, cyano, hydroxyl, , , or methyl or methoxy optionally substituted by 1 or more fluorine groups, wherein R 4 , R 5 , R 7 , R 8 , R 12 The same as the definition in the compound of formula I.

[0222] In some more typical embodiments, R b is deuterium, chlorine, fluorine, bromine, cyano, hydroxyl, methyl, trifluoromethyl, , , , , , or .

[0223] In some more typical embodiments, R b is chlorine, fluorine, cyano, hydroxyl, methyl, trifluoromethyl, , , or .

[0224] In some more typical embodiments, R b Chloro, fluoro, cyano, hydroxyl, methyl, , , or .

[0225] In some more typical embodiments, R b is chlorine, fluorine, cyano, methyl, methoxy or .

[0226] In some embodiments, R bis deuterium, chlorine, fluorine, cyano or methyl or methoxy optionally substituted by one or more halogens.

[0227] In some typical embodiments, R b is deuterium, chlorine, fluorine, cyano or methyl or methoxy optionally substituted by one or more fluorine groups.

[0228] In some typical embodiments, R b is deuterium, fluorine, chlorine, bromine, methyl, trifluoromethyl, , , , , , , , , , , , , , , , , or .

[0229] In some more typical embodiments, R b For fluorine, chlorine, methyl, , , , , , , , , or .

[0230] In some more typical embodiments, R b is deuterium, chlorine, fluorine, cyano, methyl, trifluoromethyl, difluoromethyl or methoxy.

[0231] In some more typical embodiments, R b is chlorine, fluorine, cyano, methyl or methoxy.

[0232] In some more typical embodiments, R b For chlorine, fluorine, cyano, or methyl.

[0233] In some more typical embodiments, R b is chlorine, fluorine, cyano or methyl.

[0234] In some more typical embodiments, R b It is methyl.

[0235] In some more typical embodiments, R b for .

[0236] In some embodiments, Ring B is phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzo five-membered heterocyclic ring or benzo six-membered heterocyclic ring.

[0237] In some embodiments, Ring B is phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, , , , , , , , or .

[0238] In some typical embodiments, ring B is phenyl, furanyl, thiazolyl, pyridinyl, , or .

[0239] In some typical embodiments, ring B is phenyl, pyridyl, or .

[0240] In some typical embodiments, ring B is phenyl, pyridyl or .

[0241] In some more typical embodiments, Ring B is phenyl or pyridyl.

[0242] In some more typical embodiments, Ring B is phenyl.

[0243] In some embodiments, and Adjacent to each other in the B ring.

[0244] In some typical embodiments, R 1 for , , , , , , , , , , , , , , , , , , or .

[0245] In some embodiments, R 1 for , , , , , , , , , , or .

[0246] In some typical embodiments, R 1 for , , , , , , , or .

[0247] In some typical embodiments, R 1 for , , , , , , , or .

[0248] In some typical embodiments, R 1 for , , , , , or .

[0249] In some embodiments, R 1 Selected from , , , , , , , or .

[0250] In some typical embodiments, R 1 for , , , , , , .

[0251] In some more typical embodiments, R 1 for , , or .

[0252] In some more typical embodiments, R 1 for .

[0253] In some embodiments, the compound of the aforementioned formula IV has a structure as shown in formula IV-1 or a pharmaceutically acceptable salt thereof:

[0254]

[0255] IV-1

[0256] Among them, R 1 , R 2 , R b The definitions of n and ring B are consistent with those of formula IV.

[0257] In some embodiments, the compound of the aforementioned formula IV has a structure as shown in formula V or a pharmaceutically acceptable salt thereof:

[0258]

[0259] V

[0260] Among them, X, R 1 , R 2 , R b The definitions of n are consistent with those in the compound of formula IV.

[0261] In some embodiments, the compound of the aforementioned formula IV has a structure as shown in formula VI or a pharmaceutically acceptable salt thereof:

[0262]

[0263] VI

[0264] Among them, X, R 1 , R 2 , R b The definition of is consistent with that of the compound of formula IV.

[0265] In some typical embodiments, R 1 for , , , , , , , , , , , , , , , , , , or .

[0266] In some embodiments, R 1 for , , , , , , , , , , or .

[0267] In some typical embodiments, R 1 for , , , , , , , or .

[0268] In some typical embodiments, R 1 for , , , , , , , or .

[0269] In some typical embodiments, R 1 for , , , , , or .

[0270] In some typical embodiments, R 1 for , , , , , , .

[0271] In some more typical embodiments, R 1 for .

[0272] In some more typical embodiments, R b For fluorine, chlorine, methyl, , , , , , , , , or .

[0273] In some more typical embodiments, R b is deuterium, chlorine, fluorine, bromine, cyano, hydroxyl, methyl, trifluoromethyl, , , , , , or .

[0274] In some more typical embodiments, R b is chlorine, fluorine, cyano, hydroxyl, methyl, trifluoromethyl, , , or .

[0275] In some more typical embodiments, R b Chloro, fluoro, cyano, hydroxyl, methyl, , , or .

[0276] In some more typical embodiments, R b is chlorine, fluorine, cyano, methyl, methoxy, or .

[0277] In some more typical embodiments, R b is chlorine, fluorine, cyano, methyl, methoxy or .

[0278] In some more typical embodiments, R b It is methyl.

[0279] In some more typical embodiments, R b for .

[0280] In some specific embodiments, the present invention provides the following compounds, or pharmaceutically acceptable salts thereof,

[0281]

[0282] .

[0283] Further, in some specific embodiments, the compound The isomers of , were chirally separated by chiral liquid chromatography, the retention time of chiral HPLC was 1.96 min, and the specific chromatographic separation conditions were as follows:

[0284] Chromatographic column: Chiralpak IA, 2x25cm, particle size 5um;

[0285] Mobile phase A: hexane (10 mM ammonia-methanol), mobile phase B: ethanol;

[0286] Flow rate: 18ml / min;

[0287] Gradient: 50% B isocratic in 16 min;

[0288] Detection wavelength: 220 / 254nm dual wavelength detection;

[0289] Column temperature: 25℃.

[0290] Further, in some specific embodiments, the compound The isomers of , were chirally separated by chiral liquid chromatography, the chiral HPLC retention time was 3.58min, and the specific chromatographic separation conditions were as follows:

[0291] Chromatographic column: Chiralpak IA, 2x25cm, particle size 5um;

[0292] Mobile phase A: hexane (10 mM ammonia-methanol), mobile phase B: ethanol;

[0293] Flow rate: 18ml / min;

[0294] Gradient: 50% B isocratic in 16 min;

[0295] Detection wavelength: 220 / 254nm dual wavelength detection;

[0296] Column temperature: 25℃.

[0297] Further, in some specific embodiments, the compound The isomers of , were chirally separated by chiral liquid chromatography, the chiral HPLC retention time was 8.10min, and the specific chromatographic conditions were as follows:

[0298] Chromatographic column: CHIRALPAK IF, 2 x 25 cm, particle size 5 μm;

[0299] Mobile phase A: n-hexane (0.1% diethanolamine), mobile phase B: ethanol;

[0300] Flow rate: 20ml / min;

[0301] Gradient: 20% B isocratic in 21 min;

[0302] Detection wavelength: 220 / 254nm dual wavelength detection;

[0303] Column temperature: 25℃.

[0304] In some specific embodiments, the compound The isomers of , were chirally separated by chiral liquid chromatography, the chiral HPLC retention time was 1.67min, and the specific chromatographic conditions were as follows:

[0305] Chromatographic column: CHIRALPAK IG, 2cmx25cm, particle size 5 μm;

[0306] Mobile phase A: methyl tert-butyl ether (10 mM ammonia-methanol), mobile phase B: ethanol;

[0307] Flow rate: 20ml / min;

[0308] Gradient: 20% B isocratic in 10 min;

[0309] Detection wavelength: 220 / 254 nm dual wavelength detection;

[0310] Column temperature: 25℃.

[0311] In some specific embodiments, the compound The isomers of , were chirally separated by chiral liquid chromatography, the chiral HPLC retention time was 9.8min, and the specific chromatographic conditions were as follows:

[0312] Chromatographic column: CHIRALPAK IC, 2cmx25cm, particle size 5 μm;

[0313] Mobile phase A: n-hexane (10 mM ammonia-methanol), mobile phase B: ethanol;

[0314] Flow rate: 20ml / min;

[0315] Gradient: 50% B isocratic in 12 min;

[0316] Detection wavelength: 220 / 254 nm;

[0317] Column temperature: 25℃.

[0318] In some specific embodiments, the compound The isomers of , were chirally separated by chiral liquid chromatography, the retention time of chiral HPLC was 13.5min, and the specific chromatographic conditions were as follows:

[0319] Chromatographic column: CHIRALPAK IC, 2cmx25cm, particle size 5 μm;

[0320] Mobile phase A: methyl tert-butyl ether (10 mM ammonia-methanol), mobile phase B: methanol;

[0321] Flow rate: 20ml / min;

[0322] Gradient: 10% B isocratic in 27 min;

[0323] Detection wavelength: 220 / 254 nm;

[0324] Column temperature: 25℃.

[0325] In some specific embodiments, the compound The isomers of , were chirally separated by chiral liquid chromatography, the retention time of chiral HPLC was 10.8min, and the specific chromatographic conditions were as follows:

[0326] Chromatographic column: CHIRALPAK IF, 2cmx25cm, particle size 5 μm;

[0327] Mobile phase A: methyl tert-butyl ether (10 mM ammonia-methanol), mobile phase B: ethanol;

[0328] Flow rate: 15ml / min;

[0329] Gradient: 30% B isocratic in 24 min;

[0330] Detection wavelength: 220 / 254 nm;

[0331] Column temperature: 25℃.

[0332] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the chiral HPLC retention time was 6.5min, and the specific chromatographic conditions were as follows:

[0333] Chromatographic column: CHIRALPAK IG, 2cmx25cm, particle size 5 μm;

[0334] Mobile phase A: methyl tert-butyl ether (10 nM amine-methanol solution), mobile phase B: ethanol;

[0335] Flow rate: 20ml / min;

[0336] Gradient: 30% B isocratic in 11 min;

[0337] Detection wavelength: 220 / 254 nm;

[0338] Column temperature: 25℃.

[0339] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the retention time of chiral HPLC was 12.4min, and the specific chromatographic conditions were as follows:

[0340] Chromatographic column: CHIRALPAK IE, 2cmx25cm, particle size 5 μm;

[0341] Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol;

[0342] Flow rate: 18ml / min;

[0343] Gradient: 20% B isocratic in 17 min;

[0344] Detection wavelength: 220 / 254 nm;

[0345] Column temperature: 25℃.

[0346] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the retention time of chiral HPLC was 12.1min, and the specific chromatographic conditions were as follows:

[0347] Chromatographic column: CHIRALPAK IG, 2x25 cm, filler 5 μm;

[0348] Mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol;

[0349] Flow rate: 20ml / min;

[0350] Gradient: 50% B isocratic in 18 min;

[0351] Detection wavelength: 220 / 254 nm;

[0352] Column temperature: 25℃.

[0353] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the retention time of chiral HPLC was 16.0min, and the specific chromatographic conditions were as follows:

[0354] Chromatographic column: CHIRALPAK IF, 2cmx25cm, particle size 5 μm;

[0355] Mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol;

[0356] Flow rate: 20ml / min;

[0357] Gradient: 30% B isocratic in 23 min;

[0358] Detection wavelength: 220 / 254 nm;

[0359] Column temperature: 25℃.

[0360] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the chiral HPLC retention time was 18.4min, and the specific chromatographic conditions were as follows:

[0361] Chromatographic column: CHIRALPAK IG, 3cmx25cm, particle size 5 μm;

[0362] Mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol;

[0363] Flow rate: 20ml / min;

[0364] Gradient: 50% B isocratic in 21 min;

[0365] Detection wavelength: 220 / 254 nm;

[0366] Column temperature: 25℃.

[0367] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the retention time of chiral HPLC was 16.4min, and the specific chromatographic conditions were as follows:

[0368] Chromatographic column: CHIRALPAK IG, 2cmx25cm, particle size 5 μm;

[0369] Mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol;

[0370] Flow rate: 20ml / min;

[0371] Gradient: 30% B isocratic in 21 min;

[0372] Detection wavelength: 220 / 254 nm;

[0373] Column temperature: 25℃.

[0374] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the chiral HPLC retention time was 12.7min, and the specific chromatographic conditions were as follows:

[0375] Chromatographic column: CHIRALPAK IA, 2cmx25cm, particle size 5 μm;

[0376] Mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol;

[0377] Flow rate: 20ml / min;

[0378] Gradient: 50% B isocratic in 16 min;

[0379] Detection wavelength: 220 / 254 nm;

[0380] Column temperature: 25℃.

[0381] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the retention time of chiral HPLC was 13.7min, and the specific chromatographic conditions were as follows:

[0382] Chromatographic column: CHIRALPAK IF, 5cmx25cm, particle size 5 μm;

[0383] Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol;

[0384] Flow rate: 15ml / min;

[0385] Gradient: 25% B isocratic in 15 min;

[0386] Detection wavelength: 220 / 254 nm;

[0387] Column temperature: 25℃.

[0388] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the retention time of chiral HPLC was 13.7min, and the specific chromatographic conditions were as follows:

[0389] Chromatographic column: CHIRALPAK IA, 2cmx25cm, particle size 5 μm;

[0390] Mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol;

[0391] Flow rate: 20ml / min;

[0392] Gradient: 30% B isocratic in 20 min;

[0393] Detection wavelength: 220 / 254 nm;

[0394] Column temperature: 25℃.

[0395] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the chiral HPLC retention time was 17.9min, and the specific chromatographic conditions were as follows:

[0396] Chromatographic column: CHIRALPAK IA, 5cmx25cm, particle size 5 μm;

[0397] Mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol;

[0398] Flow rate: 20ml / min;

[0399] Gradient: 20% B isocratic in 29 min;

[0400] Detection wavelength: 220 / 254 nm;

[0401] Column temperature: 25℃.

[0402] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the retention time of chiral HPLC was 3.65min, and the specific chromatographic conditions were as follows:

[0403] Chromatographic column: CHIRALPAK IF, 2cmx25cm, particle size 5 μm;

[0404] Mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol;

[0405] Flow rate: 15ml / min;

[0406] Gradient: 30% B isocratic in 20 min;

[0407] Detection wavelength: 220 / 254 nm;

[0408] Column temperature: 25℃.

[0409] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the chiral HPLC retention time was 23.7min, and the specific chromatographic conditions were as follows:

[0410] Chromatographic column: CHIRALPAK IE, 3cmx25cm, particle size 5 μm;

[0411] Mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol;

[0412] Flow rate: 15ml / min;

[0413] Gradient: 50% B isocratic in 32 min;

[0414] Detection wavelength: 220 / 254 nm;

[0415] Column temperature: 25℃.

[0416] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the retention time of chiral HPLC was 1.85min, and the specific chromatographic conditions were as follows:

[0417] Chromatographic column: CHIRALPAK IA, 2cmx25cm, particle size 5 μm;

[0418] Mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol;

[0419] Flow rate: 15ml / min;

[0420] Gradient: 50% B isocratic in 14 min;

[0421] Detection wavelength: 254 nm;

[0422] Column temperature: 25℃.

[0423] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the retention time of chiral HPLC was 15.7min, and the specific chromatographic conditions were as follows:

[0424] Chromatographic column: CHIRALPAK IG, 3cmx25cm, particle size 5 μm;

[0425] Mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol;

[0426] Flow rate: 20ml / min;

[0427] Gradient: 20% B isocratic in 20 min;

[0428] Detection wavelength: 220 / 254nm;

[0429] Column temperature: 25℃.

[0430] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the retention time of chiral HPLC was 13.5min, and the specific chromatographic conditions were as follows:

[0431] Chromatographic column: CHIRALPAK IG, 2cmx25cm, particle size 5 μm;

[0432] Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol;

[0433] Flow rate: 20ml / min;

[0434] Gradient: 10% B isocratic in 21 min;

[0435] Detection wavelength: 220 / 254nm;

[0436] Column temperature: 25℃.

[0437] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the retention time of chiral HPLC was 11.4min, and the specific chromatographic conditions were as follows:

[0438] Chromatographic column: CHIRALPAK ID, 2cmx25cm, particle size 5 μm;

[0439] Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol;

[0440] Flow rate: 20ml / min;

[0441] Gradient: 10% B isocratic in 24 min;

[0442] Detection wavelength: 220 / 254nm;

[0443] Column temperature: 25℃.

[0444] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the chiral HPLC retention time was 11.7min, and the specific chromatographic conditions were as follows:

[0445] Chromatographic column: CHIRALPAK IF, 2cmx25cm, particle size 5 μm;

[0446] Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol;

[0447] Flow rate: 15ml / min;

[0448] Gradient: 30% B isocratic in 18 min;

[0449] Detection wavelength: 220 / 254nm;

[0450] Column temperature: 25℃.

[0451] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the chiral HPLC retention time was 11.7min, and the specific chromatographic conditions were as follows:

[0452] Chromatographic column: CHIRALPAK IF, 2cmx25cm, particle size 5 μm;

[0453] Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol;

[0454] Flow rate: 15ml / min;

[0455] Gradient: 30% B isocratic in 18 min;

[0456] Detection wavelength: 220 / 254nm;

[0457] Column temperature: 25℃.

[0458] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the retention time of chiral HPLC was 8.6min, and the specific chromatographic conditions were as follows:

[0459] Chromatographic column: CHIRALPAK ID, 2x25cm, particle size 5μm;

[0460] Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol;

[0461] Flow rate: 20ml / min;

[0462] Gradient: 25% B in 13 min, isocratic;

[0463] Detection wavelength 220 / 254 nm;

[0464] Column temperature: 25℃.

[0465] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the retention time of chiral HPLC was 10.8min, and the specific chromatographic conditions were as follows:

[0466] Chromatographic column: CHIRALPAK ID, 2x25cm, particle size 5μm;

[0467] Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol;

[0468] Flow rate: 20ml / min;

[0469] Gradient: 25% B in 13 min, isocratic;

[0470] Detection wavelength 220 / 254 nm;

[0471] Column temperature: 25℃.

[0472] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the retention time of chiral HPLC was 13.4min, and the specific chromatographic conditions were as follows:

[0473] Chromatographic column: CHIRALPAK IF, 5x25 cm, filler 5 μm;

[0474] Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1

[0475] 5ml / min;

[0476] Gradient: 20% B in 17.5 min, isocratic;

[0477] Detection wavelength: 220 / 254 nm, column temperature: 25°C.

[0478] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the retention time of chiral HPLC was 16.2min, and the specific chromatographic conditions were as follows:

[0479] Chromatographic column: CHIRALPAK IF, 5x25 cm, filler 5 μm;

[0480] Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1

[0481] 5ml / min;

[0482] Gradient: 20% B in 17.5 min, isocratic;

[0483] Detection wavelength: 220 / 254 nm;

[0484] Column temperature: 25℃.

[0485] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the retention time of chiral HPLC was 13.4min, and the specific chromatographic conditions were as follows:

[0486] Chromatographic column: CHIRALPAK IF, 5x25 cm, filler 5 μm;

[0487] Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol;

[0488] Flow rate: 15ml / min;

[0489] Gradient: 20% B in 17.5 min, isocratic;

[0490] Detection wavelength: 220 / 254 nm;

[0491] Column temperature: 25℃.

[0492] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the retention time of chiral HPLC was 16.2min, and the specific chromatographic conditions were as follows:

[0493] Chromatographic column: CHIRALPAK IF, 5x25 cm, filler 5um;

[0494] Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol;

[0495] Flow rate: 15ml / min;

[0496] Gradient: 20% B in 17.5 min, isocratic;

[0497] Detection wavelength: 220 / 254 nm;

[0498] Column temperature: 25℃.

[0499] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the retention time of chiral HPLC was 5.9min, and the specific chromatographic conditions were as follows:

[0500] Chromatographic column: CHIRALPAK IE, 2x25 cm, filler 5 μm;

[0501] Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol;

[0502] Flow rate: 19ml / min;

[0503] Gradient: 35% B in 11 min, isocratic;

[0504] Detection wavelength: 220 / 254 nm;

[0505] Column temperature: 25℃.

[0506] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the chiral HPLC retention time was 9.0min, and the specific chromatographic conditions were as follows:

[0507] Chromatographic column: CHIRALPAK IE, 2x25 cm, filler 5 μm;

[0508] Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol;

[0509] Flow rate: 19ml / min;

[0510] Gradient: 35% B in 11 min, isocratic;

[0511] Detection wavelength: 220 / 254 nm;

[0512] Column temperature: 25℃.

[0513] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the chiral HPLC retention time was 9.1min, and the specific chromatographic conditions were as follows:

[0514] Chromatographic column: CHIRALPAK IE, 2x25 cm, filler 5 μm;

[0515] Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol;

[0516] Flow rate: 19ml / min;

[0517] Gradient: 35% B in 12 min, isocratic;

[0518] Detection wavelength: 220 / 254 nm;

[0519] Column temperature: 25℃.

[0520] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the chiral HPLC retention time was 10.6min, and the specific chromatographic conditions were as follows:

[0521] Chromatographic column: CHIRALPAK IE, 2x25 cm, filler 5 μm;

[0522] Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol;

[0523] Flow rate: 19ml / min;

[0524] Gradient: 35% B in 12 min, isocratic;

[0525] Detection wavelength: 220 / 254 nm;

[0526] Column temperature: 25℃.

[0527] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the chiral HPLC retention time was 7.9min, and the specific chromatographic conditions were as follows:

[0528] Chromatographic column: CHIRALPAK IE, 2x25 cm, filler 5 μm;

[0529] Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol;

[0530] Flow rate: 20ml / min;

[0531] Gradient: 25% B in 12 min, isocratic;

[0532] Detection wavelength: 220 / 254 nm;

[0533] Column temperature: 25℃.

[0534] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the chiral HPLC retention time was 10.0min, and the specific chromatographic conditions were as follows:

[0535] Chromatographic column: CHIRALPAK IE, 2x25 cm, filler 5 μm;

[0536] Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol;

[0537] Flow rate: 20ml / min;

[0538] Gradient: 25% B in 12 min, isocratic;

[0539] Detection wavelength: 220 / 254 nm;

[0540] Column temperature: 25℃.

[0541] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the retention time of chiral HPLC was 13.2min, and the specific chromatographic conditions were as follows:

[0542] Chromatographic column: CHIRALPAK IE, 2x25 cm, filler 5 μm;

[0543] Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol;

[0544] Flow rate: 15ml / min;

[0545] Gradient: 30% B in 20 min, isocratic;

[0546] Detection wavelength: 220 / 254 nm;

[0547] Column temperature: 25℃.

[0548] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the chiral HPLC retention time was 17.9min, and the specific chromatographic conditions were as follows:

[0549] Chromatographic column: CHIRALPAK IE, 2x25 cm, filler 5 μm;

[0550] Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol;

[0551] Flow rate: 15ml / min;

[0552] Gradient: 30% B in 20 min, isocratic;

[0553] Detection wavelength: 220 / 254 nm;

[0554] Column temperature: 25℃.

[0555] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the retention time of chiral HPLC was 6.7min, and the specific chromatographic conditions were as follows:

[0556] Chromatographic column: CHIRALPAK IE, 2x25 cm, filler 5 μm;

[0557] Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol;

[0558] Flow rate: 20ml / min;

[0559] Gradient: 30% B in 20 min, isocratic;

[0560] Detection wavelength: 220 / 254 nm;

[0561] Column temperature: 25℃.

[0562] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the chiral HPLC retention time was 8.45min, and the specific chromatographic conditions were as follows:

[0563] Chromatographic column: CHIRALPAK IE, 2x25 cm, filler 5 μm;

[0564] Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol;

[0565] Flow rate: 20ml / min;

[0566] Gradient: 30% B in 20 min, isocratic;

[0567] Detection wavelength: 220 / 254 nm;

[0568] Column temperature: 25℃.

[0569] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the retention time of chiral HPLC was 13.2min, and the specific chromatographic conditions were as follows:

[0570] Chromatographic column: CHIRALPAK IF, 2x25 cm, filler 5 μm;

[0571] Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol;

[0572] Flow rate: 15ml / min;

[0573] Gradient: 30% B in 20 min, isocratic;

[0574] Detection wavelength: 220 / 254 nm;

[0575] Column temperature: 25℃.

[0576] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the chiral HPLC retention time was 17.9min, and the specific chromatographic conditions were as follows:

[0577] Chromatographic column: CHIRALPAK IF, 2x25 cm, filler 5 μm;

[0578] Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol;

[0579] Flow rate: 15ml / min;

[0580] Gradient: 30% B in 20 min, isocratic;

[0581] Detection wavelength: 220 / 254 nm;

[0582] Column temperature: 25℃.

[0583] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the retention time of chiral HPLC was 7.5min, and the specific chromatographic conditions were as follows:

[0584] Chromatography CHIRALPAK IG, 2x25 cm, packing 5 μm;

[0585] Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol;

[0586] Flow rate: 20ml / min;

[0587] Gradient: 25% B in 9 min, isocratic;

[0588] Detection wavelength: 220 / 254 nm;

[0589] Column temperature: 25℃.

[0590] In some specific embodiments, The isomers of , were chirally separated by chiral liquid chromatography, the chiral HPLC retention time was 11.2min, and the specific chromatographic conditions were as follows:

[0591] Chromatography CHIRALPAK IG, 2x25 cm, packing 5 μm;

[0592] Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol;

[0593] Flow rate: 20ml / min;

[0594] Gradient: 25% B in 9 min, isocratic;

[0595] Detection wavelength: 220 / 254 nm;

[0596] Column temperature: 25℃.

[0597] In some specific embodiments, Isomers were chirally separated by chiral liquid chromatography. The retention time of chiral HPLC was 6.7 min. The specific chromatographic conditions were as follows:

[0598] Chromatography CHIRALPAK IG, 2x25 cm, packing 5 μm;

[0599] Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol;

[0600] Flow rate: 19ml / min;

[0601] Gradient: 30% B in 9 min, isocratic;

[0602] Detection wavelength: 220 / 254 nm;

[0603] Column temperature: 25℃.

[0604] In some specific embodiments, Isomers were chirally separated by chiral liquid chromatography. The retention time of chiral HPLC was 7.8 min. The specific chromatographic conditions were as follows:

[0605] Chromatography CHIRALPAK IG, 2x25 cm, packing 5 μm;

[0606] Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol;

[0607] Flow rate: 19ml / min;

[0608] Gradient: 30% B in 9 min, isocratic;

[0609] Detection wavelength: 220 / 254 nm;

[0610] Column temperature: 25℃.

[0611] On the other hand, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, I-1, I-2, II, II-1, III, III-1, IV, IV-1, V, or VI or a pharmaceutically acceptable salt thereof.

[0612] In some embodiments, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, I-1, I-2, II, II-1, III, III-1, IV, IV-1, V, or VI or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0613] The pharmaceutical composition of the present invention can be administered by any suitable route or method, for example, by oral or parenteral (e.g., intravenous) administration. The therapeutically effective amount of the compound of formula I, I-1, I-2, II, II-1, III, III-1, IV, IV-1, V, or VI is from about 0.001 mg to 50 mg / Kg body weight / day, preferably from 0.01 mg to 50 mg / Kg body weight / day.

[0614] For oral administration, the pharmaceutical composition of the present invention is generally provided in the form of tablets, capsules or solutions. Tablets may contain the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The carrier includes, but is not limited to, a diluent, a disintegrant, a binder, a lubricant, a colorant or a preservative. Capsules include hard capsules and soft capsules.

[0615] For parenteral administration, the pharmaceutical composition of the present invention can be administered by intravenous injection, intramuscular injection or subcutaneous injection. It is usually provided in a sterile aqueous solution or suspension or lyophilized powder, and the appropriate pH and isotonicity are adjusted.

[0616] On the other hand, the present invention also provides the use of a compound of Formula I, I-1, I-2, II, II-1, III, III-1, IV, IV-1, V, or VI in the preparation of a medicament for preventing and / or treating a disease or disease state mediated by AXL protein kinase.

[0617] On the other hand, the present invention also provides a method for preventing and / or treating a disease or disease state mediated by AXL protein kinase, which comprises administering to an individual in need thereof a compound of formula I, I-1, I-2, II, II-1, III, III-1, IV, IV-1, V, or VI of the present invention or a pharmaceutical composition of the present invention.

[0618] On the other hand, the present invention also provides a compound of formula I, I-1, I-2, II, II-1, III, III-1, IV, IV-1, V, or VI of the present invention or a pharmaceutical composition of the present invention for preventing and / or treating a disease or condition mediated by AXL protein kinase.

[0619] Examples of diseases or disease states mediated by AXL protein kinase include, but are not limited to, autoimmune diseases.

[0620] In another aspect, the present invention provides a method for preparing a compound of formula I, I-1, I-2, II, II-1, III, III-1, IV, IV-1, V, or VI, including but not limited to the following synthetic schemes:

[0621] Synthesis Scheme 1:

[0622]

[0623] Where R 1 , R 2 The definitions of , X and ring A are the same as those of Formula I in the general formula.

[0624] The compound of formula H-1-1 is reacted with H-1-2 in a solvent (such as N,N-dimethylformamide or tetrahydrofuran) and a base (such as sodium hydride or lithium hexamethyldisilazide) to prepare the compound of formula H-1-3, and the compound of formula H-1-3 and formula H-1-4 are reacted in a solvent (such as n-butanol) and an acid (such as trifluoroacetic acid or p-toluenesulfonic acid) to prepare the compound of formula I.

[0625] In another aspect, the present invention provides a method for preparing a compound of formula I-1, II-1, III-1 or IV-1, including but not limited to the following synthesis scheme:

[0626] Synthesis Scheme 2:

[0627]

[0628] Where R 2 The definition of ring A is the same as that of formula I-1, R 1 The definition of is the same as that of Formula I.

[0629] The compound of formula H-2-1 is reacted with H-2-2 in a solvent (e.g. N,N-dimethylformamide or tetrahydrofuran) and a base (e.g. sodium hydride or lithium hexamethyldisilazide) to prepare a compound of formula H-2-3. The compound of formula H-2-3 and formula H-2-4 are reacted in a solvent (e.g. N,N-dimethylformamide) and an acid (e.g. hydrochloric acid) to prepare a compound of formula H-2-5. The compound of formula H-2-5 is reacted in a solvent (e.g. dichloromethane) and a reducing agent (e.g. sodium cyanoborohydride) with R 1H or its acid addition salt (e.g. hydrochloride, R 1 A specific example of a H acid addition salt is 2-azabicyclo[3.1.0]hexane hydrochloride) to obtain a compound of formula H-2-6; optionally, an optically pure target product is prepared by chiral resolution.

[0630] Further, the present invention provides the following compounds as intermediates for synthesizing compounds of formula I:

[0631] .

[0632] Further, the present invention provides the following compounds as intermediates for synthesizing compounds of formula I:

[0633] .

[0634] Related definitions

[0635] Unless otherwise specified, the following terms used in the specification and claims have the following meanings:

[0636] The "compounds" of the present invention may be asymmetric, for example, having one or more chiral centers. Unless otherwise indicated, the "compounds" of the present invention refer to any one stereoisomer or a mixture of two or more stereoisomers. Stereoisomers include, but are not limited to, enantiomers and diastereomers. The compounds of the present invention containing asymmetric carbon atoms can be isolated in an optically pure form or in the form of a mixture of two or more stereoisomers. The optically pure form can be resolved from a mixture of two or more stereoisomers, or synthesized by using chiral starting materials or chiral reagents.

[0637] The compounds of the present invention also include tautomeric forms. Tautomeric forms are derived from the exchange of a single bond with an adjacent double bond accompanied by the migration of a proton. For example: Under certain conditions, it can be transformed into .

[0638] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both occurring and not occurring of said event or circumstance.

[0639] The numerical ranges herein refer to the individual integers in the given range. For example, "C 1-6 ” means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0640] The term "membered" refers to the number of backbone atoms that make up the ring. For example, "5-7 membered" means that the number of backbone atoms that make up the ring is 5, 6, or 7. Thus, for example, pyridine is a six-membered ring, while thiophene is a five-membered ring.

[0641] The term "substituted" means that any one or more hydrogen atoms on a specific atom or group are replaced by a substituent, as long as the valence state of the specific atom or group is normal and the substituted compound is stable. , means that two hydrogen atoms are replaced. Unless otherwise specified, the type and number of substituents can be any on the basis of what is chemically feasible.

[0642] When any variable (such as R 3 ) occurs more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is replaced by one or more R 3 is replaced by, then in each case R 3 Also, combinations of substituents and / or variations thereof are permissible only if such combinations result in stable compounds.

[0643] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain or branched saturated hydrocarbon groups, having the indicated number of carbon atoms. 1-6 "Alkyl" includes C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl groups, examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl, 3-hexyl, etc. It may be divalent, such as methylene, ethylene.

[0644] The term "alkoxy" refers to a group having an alkyl-O-structure, wherein the alkyl group is a linear or branched saturated monovalent hydrocarbon group, such as "C1-C3 alkoxy" including methoxy, ethoxy, n-propoxy, isopropoxy.

[0645] The term "C 2-6 "Alkenyl" is used to refer to a straight or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, which can be located at any position of the group. Examples include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, etc.

[0646] The term "C 2-6 "Alkynyl" is used to refer to a straight or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, which can be located at any position of the group. Examples include, but are not limited to, ethynyl, propynyl, butynyl, etc.

[0647] The term "heterocycloalkyl" refers to a saturated monocyclic ring system having ring carbon atoms and 1 to 2 ring heteroatoms, wherein the heteroatoms are independently selected from nitrogen, sulfur or oxygen atoms. In heterocycloalkyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom as long as the atom valence permits. Examples include, but are not limited to, , .

[0648] The term "saturated carbocycle" refers to a saturated cycloalkane.

[0649] The term "5-12 membered saturated heterocyclic ring" refers to a 5-12 membered saturated non-aromatic system having ring carbon atoms and 1, 2 or 3 ring heteroatoms or heteroatoms, wherein the heteroatoms or heteroatoms are independently selected from nitrogen, sulfur, oxygen, sulfoxide, sulfone, , or In heterocyclic groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as long as the valence permits. The heterocyclic ring may be a monocyclic or polycyclic ring system, such as a bicyclic ring, in which two or more rings are present in fused, bridged or spiro form, and in which at least one ring contains 1, 2 or 3 ring heteroatoms or heteroatom groups. Examples include, but are not limited to , , , , , , , , , , .

[0650] The term "5- to 8-membered saturated heterocycle" refers to a 5- to 8-membered saturated non-aromatic system having ring carbon atoms and 1, 2 or 3 ring heteroatoms or heteroatom groups, and the other definitions are consistent with the 5- to 12-membered saturated heterocycle.

[0651] The term "5-7 membered saturated heterocycle" refers to a 5-7 membered saturated non-aromatic system having ring carbon atoms and 1, 2 or 3 ring heteroatoms or heteroatom groups, and the other definitions are consistent with the 5-12 membered saturated heterocycle.

[0652] The term "5-7 membered heteroaryl" refers to a monovalent aromatic group containing at least one 5-, 6- or 7-membered ring independently selected from nitrogen, oxygen and sulfur heteroatoms. Examples include, but are not limited to, pyridyl, pyrimidinyl, thienyl, imidazolyl.

[0653] The term "5-6 membered heteroaryl" refers to a monovalent aromatic group containing at least one 5-, 6-membered ring independently selected from nitrogen, oxygen and sulfur heteroatoms. Examples include, but are not limited to, pyridyl, pyrimidinyl, thienyl, imidazolyl.

[0654] The term "9-12 membered benzoheterocyclyl" refers to a bicyclic ring system having 9-12 ring atoms, wherein one ring is a benzene ring and the other is a saturated, partially unsaturated or unsaturated 5-6 membered heterocyclic ring containing 1-2 heteroatoms selected from nitrogen, oxygen and sulfur, and the two share a pair of adjacent ring atoms. Examples include, but are not limited to , , , , .

[0655] The term "cycloalkyl" refers to a monocyclic saturated hydrocarbon system, without heteroatoms and without double bonds. Examples of the term "3-10 membered cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0656] the term" " " refers to the chemical bond connection. When " ", and the connection position is uncertain, it means that the connection site is limited to " "Any atom on the single ring where it is located, as long as the atomic valence allows. For example, It means that the connection site is only located at any carbon atom on the benzene ring in the bicyclic ring and must meet the requirements of atomic valence bonds.

[0657] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0658] Substituent R 3 , R a , R b The substituents and / or their variants are allowed only if such combinations will produce stable compounds. It will be appreciated by those skilled in the art that for a group containing one or more R 3 Any group of substituents will not introduce any substitution or substitution pattern that is sterically impossible and / or synthetically impossible.

[0659] The term "deuterium substitution" refers to the substitution of one or more CH bonds in a compound or group with CD bonds, and deuterium substitution can be mono-substitution, di-substitution, poly-substitution or full-substitution. The "deuterium substitution" method adopts conventional methods in the art, for example, commercial deuterated raw materials can be used, or deuterium can be introduced into the compound according to methods disclosed in the prior art.

[0660] The term "effective amount" or "therapeutically effective amount" refers to a non-toxic but sufficient amount of a drug or pharmaceutical agent to achieve the desired effect.

[0661] The term "pharmaceutically acceptable carrier" refers to those carriers that have no significant irritation to the body and do not damage the biological activity and performance of the active compound. It includes but is not limited to any diluent, disintegrant, binder, glidant, wetting agent approved by the State Food and Drug Administration for human or animal use.

[0662] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness of the free acids and bases of a particular compound without biological adverse effects, such as acid (including organic acids and inorganic acids) addition salts or base (including organic bases and inorganic bases) addition salts.

[0663] Unless otherwise specified, the abbreviations of the present invention have the following meanings:

[0664] M: mol / L

[0665] mM:mmol / L

[0666] nM: nmol / L

[0667] 1 H NMR: nuclear magnetic resonance

[0668] MS(ESI+): Mass Spectrometry

[0669] DMSO- d 6 Deuterated dimethyl sulfoxide

[0670] CDCl 3: Deuterated chloroform

[0671] DTT: dithiothreitol

[0672] SEB: Supplemented Enzymatic Buffer

[0673] IMDM (Iscove's Modified Dulbecco's Medium): Iscove's Modified Dulbecco's Medium.

[0674] Room temperature: 25℃. DETAILED DESCRIPTION

[0675] The preparation method of compound of the present invention is described in more detail below, but these specific preparation methods do not constitute any restriction to the scope of the present invention.In addition, reaction conditions such as reactant, solvent, alkali, the amount of compound used, reaction temperature, reaction time etc. are not limited to the following examples.

[0676] The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known in the art. Such a combination can be easily performed by those skilled in the art.

[0677] Part I Preparation

[0678] Preparation Example 17-Amino-2-methylisoindolin-1-one

[0679]

[0680] a) Preparation of 2-methyl-7-nitroisoindol-1-one

[0681] Dissolve 7-nitroisoindole-1-one (450 mg) in N,N-dimethylformamide (15 mL), add potassium carbonate (690 mg) and iodomethane (430 mg), stir overnight at room temperature, pour the reaction solution into water, extract with ethyl acetate, and purify by column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound (300 mg). MS (ESI+): 193.02 (M+H).

[0682] b) Preparation of 7-amino-2-methylisoindolin-1-one

[0683] Dissolve 2-methyl-7-nitroisoindol-1-one (300 mg) in methanol (30 mL), add palladium carbon (30 mg) and hydrazine hydrate (438 mg), stir at room temperature for 6 hours, filter the reaction solution with diatomaceous earth, concentrate to dryness, and purify by column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound (245 mg). MS (ESI+): 162.98 (M+H).

[0684] Preparation Example 2 N-(2-aminophenyl)methanesulfonamide

[0685]

[0686] Add o-phenylenediamine (500 mg), triethylamine (1403 mg), and 10 mL of anhydrous dichloromethane to the reaction flask. After all the solution is dissolved, add a dichloromethane solution of methanesulfonyl chloride (1095 mg) dropwise at 0°C. After the addition is complete, gradually warm the temperature to room temperature and react for 12 hours. After the reaction is complete, quench the reaction solution with 1 ml of methanol, adjust the pH of the system to 8 with 1 M hydrochloric acid, and then concentrate to dryness to obtain a crude product. The crude product is purified by column chromatography (dichloromethane / methanol = 20:1) to obtain 505 mg of the title compound.

[0687] MS(ESI+): 187.1(M+H).

[0688] Preparation Example 3 3-(Tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine

[0689]

[0690] a) Synthesis of 7-nitro-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

[0691] Dissolve 7-nitro-2,3,4,5-tetrahydro-1H-benzo[D]azepine (1920 mg), tetrahydropyran-4-one (1100 mg), and acetic acid (1110 mg) in 30 ml of methanol and stir for 1 hour. Add sodium triacetoxyborohydride (3180 mg) in batches and react overnight. After the reaction, filter and concentrate the filtrate to dryness. Purify by column chromatography (dichloromethane / methanol = 20:1) to obtain 1380 mg of the title compound. MS (ESI+): 277.2 (M+H).

[0692] b) Synthesis of 3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine

[0693] Dissolve 7-nitro-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1380 mg) in 50 ml of methanol, add 10% palladium carbon (150 mg) under nitrogen protection, and drop 80% hydrazine hydrate (2 ml). The reaction releases gas, and the reaction is filtered after 3 hours. The mother liquor is concentrated to dryness under reduced pressure to obtain 1200 mg of the title compound. MS (ESI+): 247.2 (M+H).

[0694] Preparation Example 4 2-Amino-5-cyano-N-methylbenzamide

[0695]

[0696] Dissolve 2-amino-5-cyano-N-methylbenzoic acid (500 mg), methylamine solution (6.2 mmol, 3.1 ml), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.36 g) and N,N-diisopropylethylamine (1.2 g) in N,N-dimethylformamide (15 mL). Stir at room temperature for 4 h. Add 80 mL of ethyl acetate to dilute the reaction solution and wash it with 50 ml of saturated sodium chloride aqueous solution × 3. Take the organic layer and concentrate it to dryness to obtain the title compound (550 mg). MS (ESI+): 176.1 (M+H).

[0697] Preparation Example 5 2-Amino-N-methyl-5-(trifluoromethyl)benzamide

[0698]

[0699] At 0℃, add 2-amino-5-(trifluoromethyl)benzoic acid (100 mg) and methylamine (31 mg), N,N-dimethylformamide (5 ml), N,N-diisopropylethylamine (194 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (285 mg), and move to room temperature to react for 2.0h. After the reaction is completed, add 20 ml of water, separate the liquids, extract the organic layer with ethyl acetate, combine the organic layers, dry over anhydrous sodium sulfate, remove the solvent by vacuum rotary evaporation, and purify by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 76 mg of the title compound. MS(ESI+): 219.1(M+H).

[0700] Preparation Example 6 2-Amino-5-chloro-N-methylbenzamide

[0701]

[0702] 2-amino-5-chloro-benzoic acid (250 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (665 mg) and N,N-diisopropylethylamine (377 mg) were added to the reaction bottle in sequence, dissolved in 10 mL of anhydrous N,N-dimethylformamide, activated at room temperature for 10 min, and then slowly added a tetrahydrofuran solution of methylamine (1.75 mmol, 0.9 mL) and reacted at room temperature for 1 h. After the reaction was completed, 100 mL of ethyl acetate was added to the reaction solution, washed three times with a saturated sodium chloride solution, the organic phases were combined, and concentrated to dryness under reduced pressure to obtain 495 mg of the crude title compound. MS (ESI+): 185.1 (M+H).

[0703] Preparation Example 7 N-(2-aminophenyl)cyclopropanesulfonamide

[0704]

[0705] Add o-phenylenediamine (500 mg), triethylamine (1403 mg) to the reaction flask, dissolve in 10 mL of anhydrous dichloromethane, and then drop cyclopropanesulfonyl chloride (715 mg) at 0°C. After the addition is complete, gradually warm the temperature to room temperature and react for 12 hours. After the reaction is complete, quench the reaction solution with 1 ml of methanol, adjust the pH of the system to 8 with 1 M hydrochloric acid, and then concentrate to dryness to obtain a crude product. The crude product was purified by column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound (1.094 g). MS (ESI+): 213.1 (M+H).

[0706] Preparation Example 8 4-Amino-2-methoxy-N-methylnicotinamide

[0707]

[0708] Dissolve 4-amino-2-methoxynicotinamide (1680 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4180 mg) and N,N-diisopropylethylamine (2580 mg) in N,N-dimethylformamide (15 mL), add 2M methylamine solution (5 mL) and stir at room temperature for 1 hour. After the reaction is completed, pour the reaction solution into 30 mL of water, extract with ethyl acetate 15 ml × 3, take the organic layer, concentrate to dryness, and obtain the title compound (900 mg) by column chromatography. MS (ESI+): 182.1 (M+H).

[0709] Preparation Example 9 4-Amino-6-methoxy-N-methylnicotinamide

[0710]

[0711] Dissolve 4-amino-6-methoxynicotinamide (1680 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4180 mg) and N,N-diisopropylethylamine (2580 mg) in N,N-dimethylformamide (15 mL), add 2M methylamine solution (5 mL, 10 mmol) and stir at room temperature for 1 hour. After the reaction is completed, pour the reaction solution into 30 mL of water, extract with 15 ml × 3 of ethyl acetate, take the organic layer, concentrate to dryness, and obtain a yellow oil (560 mg) by column chromatography. MS (ESI+): 182.1 (M+H).

[0712] Preparation Example 10 6-Amino-N-methylquinoxaline-5-carboxamide

[0713]

[0714] a) Preparation of N,N-di(tert-butyloxycarbonyl)-5-bromoquinoxaline-6-amine (2)

[0715] 6-Amino-5-bromoquinoxaline (1.0 g), 4-dimethylaminopyridine (0.05 g), di-tert-butyl carbonate (2.24 g) were dissolved in tetrahydrofuran (25 mL) at 40 o After stirring at C for 4 h, the reaction solution was poured into 50 mL of water for dilution, and then extracted with 50 mL of ethyl acetate × 3 times. The organic layer was concentrated to dryness and purified by column chromatography (dichloromethane / methanol = 40:1) to obtain the title compound (1.5 g). MS (ESI+): 424.1 (M+H).

[0716] b) Preparation of tert-butyl 6-((tert-butoxycarbonyl)amino)quinoxaline-5-carboxylate

[0717] Dissolve N,N-di(tert-butyloxycarbonyl)-5-bromoquinoxalin-6-amine (500 mg) in tetrahydrofuran (20 mL) and lower the temperature to -78 o C, n-butyl lithium (0.74 mL) was added under nitrogen protection, and the reaction was completed after 30 min. The reaction solution was quenched by adding 5 mL of saturated ammonium chloride solution, and the tetrahydrofuran layer was concentrated to dryness to obtain the title compound (320 mg). MS (ESI+): 346.2 (M+H).

[0718] c) Preparation of 6-aminoquinoxaline-5-carboxylic acid

[0719] Dissolve tert-butyl 6-((tert-butyloxycarbonyl)amino)aminoquinoxaline-5-carboxylate (100 mg) in dichloromethane (5 mL), add trifluoroacetic acid (164 mg), and react at room temperature for 8 h. After the reaction, purify by column chromatography (dichloromethane / methanol = 40:1) to obtain the title compound (40 mg). MS (ESI+): 290.1 ​​(M+H).

[0720] d) Preparation of 6-amino-N-methylquinoxaline-5-carboxamide

[0721] Dissolve 6-aminoquinoxaline-5-carboxylic acid (40 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (161 mg) and N,N-diisopropylethylamine (54 mg) in N,N-dimethylformamide (5 mL), add 2M methylamine solution (0.21 mL, 0.42 mmol) and stir at room temperature for 1 hour. After the reaction is completed, pour the reaction solution into 30 mL of water, extract with 15 ml of ethyl acetate × 3, take the organic layer, concentrate to dryness, and purify by column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound (28 mg). MS (ESI+): 203.1 (M+H).

[0722] Preparation Example 11 (2-amino-5-fluorophenyl) dimethylphosphine oxide

[0723]

[0724] The compound 4-fluoro-2-iodoaniline (2.0 g), dimethylphosphine oxide (0.79 g), potassium phosphate (2.14 g), tris(dibenzylideneacetone)dipalladium (0.153 g) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.097 g) were dissolved in DMF (15 mL) and heated to 100°C under nitrogen protection. oAfter 16 h of reaction, the reaction solution was cooled and filtered. The filtrate was dried by spin drying and 1M hydrochloric acid solution (30 mL) was added to adjust the pH to 1-2. The insoluble matter was removed by suction filtration. The filtrate was washed with dichloromethane (30 mL×2). The aqueous phase was taken and saturated sodium bicarbonate solution was added to adjust the pH to 8-9. Then, it was extracted with dichloromethane (50 mL×3). The dichloromethane was dried by spin drying to obtain the crude product. The title product (1.1 g) was obtained by slurrying with 30 mL of a mixed solvent of ethyl acetate and petroleum ether (5:1). MS (ESI+): 188.08 (M+H).

[0725] Preparation Example 12 (2-amino-5-chlorophenyl) dimethylphosphine oxide

[0726]

[0727] 4-Chloro-2-iodoaniline (1 g), dimethylphosphine oxide (368 mg), potassium phosphate (996 mg), tris(dibenzylideneacetone)dipalladium (366 mg), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (232 mg), N,N-dimethylformamide / water (3:1, 10 ml) were added to the reaction bottle in sequence, and nitrogen was replaced 5 times. The oil bath was reacted at 100°C for 3 hours. After the reaction was completed, the solvent was removed by vacuum rotary evaporation, and the title product was purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain 685 mg of the title product. MS (ESI+): 204.1 (M+H).

[0728] Preparation Example 13 (2-amino-5-methylphenyl)dimethylphosphine oxide

[0729]

[0730] 2-iodo-4-methylaniline (1 g), dimethylphosphine oxide (505 mg), palladium acetate (97 mg), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (249 mg), potassium phosphate (1.35 g), 15 mL N,N-dimethylformamide and 3 mL water were added to the reaction bottle in sequence, and the temperature was raised to 110°C for 3 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, and the insoluble inorganic salts and catalysts were filtered out. The filtrate was concentrated under reduced pressure and diluted with 30 mL of water. The pH was adjusted to 2 with 1M hydrochloric acid, and the insoluble matter was filtered out. The filtrate was washed with dichloromethane and the aqueous layer was separated. The aqueous layer was adjusted to pH 9 with 1M sodium hydroxide solution and extracted with dichloromethane. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain 1.6 g of the title product. MS (ESI+): 184.07 (M+H).

[0731] Preparation Example 14 (2-amino-5-cyanophenyl) dimethylphosphine oxide

[0732]

[0733] The compound 4-cyano-2-iodoaniline (0.98 g), dimethylphosphine oxide (0.376 g), potassium phosphate (1.02 g), tris(dibenzylideneacetone)dipalladium (0.073 g) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.046 g) were dissolved in N,N-dimethylformamide (10 mL) and heated to 100°C under nitrogen protection. o After 16 h of reaction, the reaction solution was cooled, filtered, and the filtrate was concentrated to dryness. 1M hydrochloric acid solution (30 mL) was added to adjust the pH to 1-2. The insoluble matter was removed by suction. The filtrate was washed with dichloromethane (30 mL × 2). The aqueous phase was taken and saturated sodium bicarbonate solution was added to adjust the pH to 8-9. Then, it was extracted with dichloromethane (50 mL × 3) and concentrated to dryness to obtain the title compound (0.7 g). MS (ESI+): 195.08 (M+H).

[0734] Preparation Example 15 (2-amino-5-methoxyphenyl) dimethylphosphine oxide

[0735]

[0736] The compound 4-methoxy-2-iodoaniline (1.0 g), dimethylphosphine oxide (0.376 g), potassium phosphate (1.02 g), tris(dibenzylideneacetone)dipalladium (0.073 g) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.046 g) were dissolved in N,N-dimethylformamide (10 mL) and heated to 100°C under nitrogen protection. o After 16 h of reaction, the reaction solution was cooled, filtered, and the filtrate was concentrated to dryness. 1M hydrochloric acid solution (30 mL) was added to adjust the pH to 1-2. The insoluble matter was removed by suction. The filtrate was washed with dichloromethane (30 mL×2). The aqueous phase was taken and saturated sodium bicarbonate solution was added to adjust the pH to 8-9. Then, it was extracted with dichloromethane (50 mL×3) and concentrated to dryness to obtain the title compound (0.7 g). MS (ESI+): 200.8 (M+H).

[0737] Preparation Example 16 (2-aminophenyl)bis(methyl- d 3 )Phosphine oxide

[0738]

[0739] Bis(methyl- d 3 ) Preparation of phosphine oxide

[0740] Add magnesium chips (3.6g) to a three-necked reaction flask, replace the atmosphere with nitrogen three times, then add 30ml of anhydrous ether, and stir at -10℃. Dilute deuterated iodomethane (20g) with 30ml of ether and slowly drip into the reaction flask. After dripping, reflux for 3h. After reflux, cool to 0℃, slowly drip 20ml of ether diethyl phosphite (6.35g), and after dripping, add saturated potassium carbonate cold water solution (19.2g, 20ml) to quench. Filter out the generated solids, wash the filter cake with ethanol twice, and concentrate the filtrate at -0.8Mpa and 50℃. Filter again to remove the solids, and the filtrate is the title product (12g).

[0741] b) (2-aminophenyl)bis(methyl- d 3 ) Preparation of phosphine oxide

[0742] In a 100 ml three-necked flask, add 2-iodoaniline (2.19 g), di(methyl- d 3 ) phosphine oxide (1.68g), potassium phosphate (3.17g), palladium acetate (916mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (578mg), N,N-dimethylformamide 15ml, water 3ml, nitrogen replacement 3 times, reaction at 110℃ for 3h. After the reaction is completed, vacuum drying, silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain 1.3g of the title product. MS (ESI+): 176.1 (M+H).

[0743] Preparation Example 17 (2-amino-5-fluorophenyl)bis(methyl- d 3 )Phosphine oxide

[0744]

[0745] In a 100 ml three-necked flask, add 4-fluoro-2-iodoaniline (1.18 g), bis(methyl- d 3 ) phosphine oxide (1.68g), potassium phosphate (2.12g), palladium acetate (92mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (58mg), N,N-dimethylformamide 15ml, water 3ml, nitrogen replacement 3 times, reaction at 110℃ for 3h. After the reaction is completed, the solid is filtered out, the filtrate is concentrated to dryness under reduced pressure, and the residue is added with 15ml of 2M hydrochloric acid to precipitate a yellow solid, which is filtered out to remove the insoluble matter. After the aqueous phase is washed twice with 15ml of dichloromethane, a saturated potassium carbonate solution is added to the aqueous phase to adjust the pH to 10, and then extracted twice with 15ml of dichloromethane, and the organic phase is concentrated to dryness to obtain the title compound (1g). MS(ESI+): 193.1(M+H).

[0746] Preparation Example 18 (4-amino-1,3-phenylene)bis(dimethylphosphine oxide)

[0747]

[0748] In a 100ml three-necked flask, add 2,4-diiodoaniline (2g), dimethylphosphine oxide (1.6g), potassium phosphate (2.12g), palladium acetate (92mg), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (58mg), and 15ml of N,N-dimethylformamide. After nitrogen replacement three times, react at 110℃ for 5h. After the reaction is completed, filter to remove the solid, and the filtrate is concentrated to dryness under reduced pressure. Add 3ml of 2M hydrochloric acid to the residue to precipitate a yellow solid, and remove the insoluble matter by suction filtration. After the aqueous phase is washed twice with 15ml of dichloromethane, add saturated potassium carbonate solution to the aqueous phase to adjust the pH to 7. The aqueous phase is concentrated to dryness and purified by column chromatography (dichloromethane / methanol = 20:1 v / v) to obtain the title compound (1.4g). MS(ESI+): 246.1(M+H).

[0749] Preparation Example 19 (2-amino-5-difluoromethoxyphenyl) dimethylphosphine oxide

[0750]

[0751] The compound 4-difluoromethoxy-2-iodoaniline (1.0 g), dimethylphosphine oxide (0.366 g), potassium phosphate (1.00 g), tris(dibenzylideneacetone)dipalladium (0.073 g) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.046 g) were dissolved in N,N-dimethylformamide (10 mL), heated to 100oC under nitrogen protection for 16 h, and then the reaction solution was cooled, filtered, and the filtrate was concentrated to dryness. 1M hydrochloric acid solution (30 mL) was added to adjust the pH to 1-2, and the insoluble matter was removed by suction. The filtrate was washed with dichloromethane (30 mL×2), and the aqueous phase was taken. Saturated sodium bicarbonate solution was added to adjust the pH to 8-9, and then extracted with dichloromethane (50 mL×3), and concentrated to dryness to obtain the title compound (0.7 g). MS(ESI+): 235.2(M+H).

[0752] Preparation Example 20 (2-Amino-5-(1H-tetrazol-1-yl)phenyl)dimethylphosphine oxide

[0753]

[0754] 1) 2-iodo-4-(1H-tetrazolyl-1-yl)aniline

[0755] Dissolve the compound 4-(1H-tetrazolyl-1-yl)aniline (0.97 g) in glacial acetic acid (30 ml), stir and cool at 0°C, and addN- Iodosuccinimide (1.57 g) was reacted for 15 min. Water (100 ml) and ethyl acetate (150 ml) were then added to the reaction solution. Potassium carbonate solid was added to adjust the pH to 9. After separation, the organic phase was washed with water (100 ml). The organic phase was concentrated to dryness to obtain 1.8 g of the title product.

[0756] 2) (2-amino-5-(1H-tetrazolyl-1-yl)phenyl)dimethylphosphine oxide

[0757] The compound 2-iodo-4-(1H-tetrazolyl-1-yl)aniline (1.68 g), dimethylphosphine oxide (0.685 g), potassium phosphate (2.48 g), tris(dibenzylideneacetone)dipalladium (0.267 g) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.338 g) were dissolved in N,N- Dimethylformamide (30 mL), heated to 100 ° C under nitrogen protection for 8 h. The reaction solution was cooled, filtered, and the filtrate was concentrated to dryness. 2M hydrochloric acid solution (30 mL) was added to adjust the pH to 2-3, and the insoluble matter was removed by suction. Potassium carbonate was added to the filtrate to adjust the pH to 9, and then extracted with ethyl acetate (100 mL×3). The organic phase was concentrated to dryness to obtain the title compound (0.3 g). MS (ESI+): 238.2 (M+H).

[0758] Preparation Example 21 3-(Tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine

[0759]

[0760] 1) 7-Nitro-3-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

[0761] Add dichloromethane (40 ml) to a 100 ml reaction bottle, add 7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azacyclic ring (1.9 g), 3-ketotetrahydrofuran (0.86 g), acetic acid (1.1 g) in sequence under room temperature stirring, and stir for 1 hour. Then add sodium triacetoxyborohydride (4.2 g) in batches and stir at room temperature overnight. After the reaction is completed, add sodium hydroxide solution (100 ml, 1 M) to quench. Then separate the liquids, concentrate the dichloromethane phase to dryness under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane: methanol = 20: 1 v / v) to obtain 2.5 g of the title product.

[0762] 2) 3-(Tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine

[0763] Methanol (40 ml) was added to a 100 ml reaction bottle, and the atmosphere was replaced with nitrogen three times. Hydrazine hydrate (10 ml, 80% w / w) and palladium carbon (0.25 g, 10% w / w) were added in sequence under stirring at room temperature, and stirred for 1 hour. Then the mixture was filtered, and the mother liquor was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1 v / v) to obtain 1.5 g of the title product. MS (ESI+): 233.2 (M+H).

[0764] Preparation Example 22 (2-amino-5-trifluoromethoxyphenyl) dimethylphosphine oxide

[0765]

[0766] The compound 4-trifluoromethoxy-2-iodoaniline (1.0 g), dimethylphosphine oxide (0.366 g), potassium phosphate (1.00 g), tris(dibenzylideneacetone)dipalladium (0.073 g) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.046 g) were dissolved in N,N-dimethylformamide (10 mL), heated to 100oC under nitrogen protection for 16 h, and then the reaction solution was cooled, filtered, and the filtrate was concentrated to dryness. 1M hydrochloric acid solution (30 mL) was added to adjust the pH to 1-2, and the insoluble matter was removed by suction. The filtrate was washed with dichloromethane (30 mL×2), and the aqueous phase was taken. A saturated sodium bicarbonate solution was added to adjust the pH to 8-9, and then extracted with dichloromethane (50 mL×3), and concentrated to dryness to obtain the title compound (0.7 g). MS(ESI+): 254.1(M+H).

[0767] Preparation Example 23 (2-amino-5-cyclopropylphenyl)dimethylphosphine oxide

[0768]

[0769] 1) 2-iodo-4-cyclopropylaniline

[0770] Dissolve the compound 4-cyclopropylaniline (1.0 g) in glacial acetic acid (30 ml), stir and cool at 0°C, and add N- Iodosuccinimide (1.57 g) was reacted for 15 min. Water (100 ml) and ethyl acetate (150 ml) were then added to the reaction solution. Potassium carbonate solid was added to adjust the pH to 9. After separation, the organic phase was washed with water (100 ml). The organic phase was concentrated to dryness to obtain 1.2 g of the title product.

[0771] 2) (2-amino-5-cyclopropylphenyl) dimethylphosphine oxide

[0772] The compound 2-iodo-4-cyclopropylaniline (1.2 g), dimethylphosphine oxide (0.685 g), potassium phosphate (2.48 g), tris(dibenzylideneacetone)dipalladium (0.267 g) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.338 g) were dissolved in N,N- Dimethylformamide (30 mL), heated to 100 ° C under nitrogen protection for 8 h. The reaction solution was cooled, filtered, and the filtrate was concentrated to dryness. 2M hydrochloric acid solution (30 mL) was added to adjust the pH to 2-3, and the insoluble matter was removed by suction. Potassium carbonate was added to the filtrate to adjust the pH to 9, and then extracted with ethyl acetate (100 mL×3). The organic phase was concentrated to dryness to obtain the title compound (0.3 g). MS (ESI+): 210.1 (M+H).

[0773] Preparation Example 24 (2-amino-5-isopropoxyphenyl)dimethylphosphine oxide

[0774]

[0775] 1) 2-iodo-4-isopropoxyaniline

[0776] Dissolve the compound 4-isopropoxyaniline (1.0 g) in glacial acetic acid (30 ml), stir and cool at 0°C, and add N- Iodosuccinimide (1.57 g) was reacted for 15 min. Water (100 ml) and ethyl acetate (150 ml) were then added to the reaction solution. Potassium carbonate solid was added to adjust the pH to 9. After separation, the organic phase was washed with water (100 ml). The organic phase was concentrated to dryness to obtain 1.2 g of the title product.

[0777] 2) (2-amino-5-isopropoxyphenyl) dimethylphosphine oxide

[0778] The compound 2-iodo-4-isopropoxyaniline (1.2 g), dimethylphosphine oxide (0.685 g), potassium phosphate (2.48 g), tris(dibenzylideneacetone)dipalladium (0.267 g) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.338 g) were dissolved in N,N- Dimethylformamide (30 mL), heated to 100 ° C under nitrogen protection for 8 h. The reaction solution was cooled, filtered, and the filtrate was concentrated to dryness. 2M hydrochloric acid solution (30 mL) was added to adjust the pH to 2-3, and the insoluble matter was removed by suction. Potassium carbonate was added to the filtrate to adjust the pH to 9, and then extracted with ethyl acetate (100 mL×3). The organic phase was concentrated to dryness to obtain the title compound (0.3 g). MS (ESI+): 226.1 (M+H).

[0779] Preparation Example 25 (2-amino-4-methoxy-5-fluorophenyl)dimethylphosphine oxide

[0780]

[0781] The compound 2-bromo-4-fluoro-5-methoxyaniline (2 g), dimethylphosphine oxide (0.85 g), potassium phosphate (2.48 g), palladium acetate (0.10 g) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.266 g) were dissolved in N,N- In dimethylformamide (40 mL), heat to 120°C under nitrogen protection and react for 48 h. The reaction solution was concentrated to dryness, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 40:1 v / v) to obtain the title compound (0.5 g). MS (ESI+): 218.1 (M+H).

[0782] Preparation Example 26 (2-amino-5-fluoro-6-chlorophenyl)dimethylphosphine oxide

[0783]

[0784] The compound 2-iodo-3-chloro-4-fluoroaniline (1.5 g), dimethylphosphine oxide (0.24 g), potassium phosphate (0.65 g), palladium acetate (0.06 g) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.09 g) were dissolved in N,N- In dimethylformamide (30 mL), heat to 120°C under nitrogen protection for 2 h. The reaction solution was concentrated to dryness, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1 v / v) to obtain the title compound (0.35 g). MS (ESI+): 222.1 (M+H).

[0785] Preparation Example 27 (2-amino-5-fluoro-6-chlorophenyl) dimethylphosphine oxide

[0786]

[0787] a) N-(4-fluoro-3-methoxyphenyl)-2,2-dimethylpropionamide

[0788] 4-Fluoro-3-methoxyaniline (5 g) and triethylamine (3.94 g) were added to dichloromethane (100 mL) under nitrogen atmosphere at room temperature, and then 2,2-dimethylpropanoyl chloride (4.27 g) was added dropwise under stirring, and the resulting mixture was stirred for 1 h. Water (100 mL) was added at room temperature to quench the reaction, and the mixture was extracted with dichloromethane (3 x100 mL). The combined organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether: ethyl acetate = (1:1 v / v) to obtain the title product (7.7 g). MS (ESI+): 226.1 (M+H).

[0789] b) N-(4-fluoro-2-iodo-3-methoxyphenyl)-2,2-dimethylpropanamide

[0790] N-(4-fluoro-3-methoxyphenyl)-2,2-dimethylpropanamide (1 g) was added to tetrahydrofuran (20 mL), and n-butyllithium (0.71 g) was added dropwise at 0°C under a nitrogen atmosphere, and the resulting mixture was stirred at 0°C under a nitrogen atmosphere for 2 hours. Iodine (1.41 g, dissolved in 10 mL tetrahydrofuran) was added dropwise to the above mixture at -78°C for 30 min. The resulting mixture was stirred at -78°C for another 2 hours. The reaction was quenched by adding a saturated aqueous ammonium chloride solution (10 mL) at 0°C. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether:ethyl acetate = (1:1 v / v) to give the title product (1.3 g). MS(ESI+):218.1(M+H).

[0791] c) N-[2-(Dimethylphosphoryl)-4-fluoro-3-methoxyphenyl]-2,2-dimethylpropanamide

[0792] Compound N-(4-fluoro-2-iodo-3-methoxyphenyl)-2,2-dimethylpropanamide (0.55 g), dimethylphosphine oxide (0.15 g), potassium phosphate (1.0 g), palladium acetate (0.04 g) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.18 g) were dissolved in N,N- Dimethylformamide (10 mL), heated to 120°C under nitrogen protection for 2 h. The reaction solution was concentrated to dryness, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1 v / v) to obtain the title compound (0.31 g). MS (ESI+): 302.1 (M+H).

[0793] d) (2-amino-5-fluoro-6-methoxyphenyl) dimethylphosphine oxide

[0794] N-[2-(Dimethylphosphoryl)-4-fluoro-3-methoxyphenyl]-2,2-dimethylpropanamide (290 mg) was added to hydrochloric acid (6M, 6 mL) and stirred overnight at 100°C under nitrogen atmosphere. The mixture was neutralized to pH=8 with saturated aqueous sodium carbonate solution. The aqueous layer was extracted with dichloromethane (3x5 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the title product (170 mg). MS(ESI+): 218.1 (M+H).

[0795] Example 1 (S)-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide

[0796]

[0797] Preparation of 2-((2,5-dichloropyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide

[0798] Add 10 ml of anhydrous N,N-dimethylformamide, 2-amino-N,N-dimethylbenzenesulfonamide (200 mg), 2,4,5-trichloropyrimidine (183 mg) to the reaction bottle in sequence, add sodium hydride (120 mg, 60%) at 0°C, and react at 0°C for 3 hours. After the reaction is completed, add 20 ml of water to quench, extract the reaction solution with 20 ml of ethyl acetate, concentrate the organic phase to dryness, and purify the crude product by column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain the title compound (223 mg).

[0799] b) Preparation of (S)-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide

[0800] Add n-butanol (10 ml), 2-((2,5-dichloropyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide (223 mg), trifluoroacetic acid 0.25 ml, (S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-amine (115 mg) to the reaction bottle in sequence, and react at 110°C for 5 hours. After the reaction is completed, concentrate to dryness, add 20 ml of ethyl acetate to the residue, and then wash it with 1M sodium hydroxide aqueous solution (10 ml) for 3 times. The organic phase is concentrated to dryness and purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain the title compound (180 mg).

[0801] 1H NMR (400 MHz, CDCl 3 ) δ 9.43 (s, 1H), 8.54 (dd, J = 8.4, 1.1 Hz,1H), 8.12 (s, 1H), 7.87 (dd, J = 8.0, 1.6 Hz, 1H), 7.56 (m, J = 8.7, 7.4, 1.6Hz, 1H), 7.31 (d, J = 6.5 Hz, 2H), 7.24 (d, J = 8.2 Hz, 1H), 7.13 (s, 1H), 7.04 (d, J = 8.8 Hz, 1H), 3.36 – 3.15 (m, 5H), 2.87 (m, 1H), 2.75 (m, 9H),2.38 (m, 2H), 2.09 – 1.92 (m, 4H), 1.57 (m, 2H). MS(ESI+): 541.2(M+H).

[0802] Example 2 (S)-3-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide

[0803]

[0804] The preparation method is described in Example 1, except that 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by 3-amino-N,N-dimethylbenzenesulfonamide.

[0805] 1 H NMR (400 MHz, CDCl 3 ) δ8.59 (s, 1H),8.10 (s, 1H), 8.02 (ddd, J =5.5, 3.5, 2.3 Hz, 1H), 7.93 – 7.88 (m, 1H), 7.56 – 7.49 (m, 2H), 7.31 (s,1H), 7.24 (dd, J = 8.0, 2.3 Hz, 1H), 7.19 (s, 1H), 7.02 (d, J = 8.0 Hz, 1H), 3.36 – 3.11 (m, 5H), 2.85 (m, 1H), 2.73 (m, 9H), 2.35 (m, 2H), 2.08 – 1.92(m, 4H), 1.55(m, 2H). MS(ESI+): 541.2(M+H).

[0806] Example 3 (S)-4-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide

[0807]

[0808] The preparation method is described in Example 1, except that 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by 4-amino-N,N-dimethylbenzenesulfonamide.

[0809] 1 H NMR (400 MHz, CDCl 3 ) δ8.11 (s, 1H), 7.87 – 7.79 (m, 2H), 7.73 (d, J= 8.6 Hz, 2H), 7.47 (d, J = 2.2 Hz, 1H), 7.41 (d, J = 12.3 Hz, 2H), 7.13 (dd,J = 8.1, 2.3 Hz, 1H), 7.04 (d, J = 8.1 Hz, 1H), 3.48 – 3.14 (m, 5H), 2.85 (m,1H), 2.71 (m, 9H), 2.44 (m, 2H), 2.04 (m, 4H), 1.56 (m, 2H). MS(ESI+): 541.2(M+H).

[0810] Example 4 (S)-5-chloro-N 2 -(7-(Pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-N 4 -(2-(Pyrrolidin-1-ylsulfonyl)phenyl)pyrimidine-2,4-diamine

[0811]

[0812] The preparation method is described in Example 1, except that 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by 1-(2-aminophenylsulfone)pyrrolidine.

[0813] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.43 (s, 1H), 9.32 (s, 1H), 8.52 (s, 1H), 8.27 (s, 1H), 7.88 (dd, J= 8.0, 1.5 Hz, 1H), 7.75 – 7.61 (m, 1H), 7.36 (dd, J =12.0, 4.7 Hz, 2H), 7.28 (d, J = 7.9 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 3.14 (t, J =6.7 Hz, 5H), 2.89 (s, 6H), 2.73 – 2.59 (m, 2H), 2.05 (s, 2H), 1.79 (s, 4H),1.73 – 1.57 (m, 4H), 1.45 (s, 2H). MS(ESI+): 567.2(M+H).

[0814] Example 5 (S)-5-chloro-N 2 -(7-(Pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-N 4 -(3-(Pyrrolidin-1-ylsulfonyl)phenyl)pyrimidine-2,4-diamine

[0815]

[0816] The preparation method is described in Example 1, except that 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by 3-(1-pyrrolylsulfonyl)aniline.

[0817] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.27 (s, 1H), 9.19 (s, 1H), 8.24 (t, J = 8.3Hz, 1H), 8.19 (s, 1H), 7.89 (d, J = 1.7 Hz, 1H), 7.55 (ddd, J = 11.0, 7.8, 4.7Hz, 2H), 7.38 (d, J = 1.8 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 8.2 Hz,1H), 3.17 (t, J= 6.7 Hz, 5H), 3.04 – 2.76 (m, 6H), 2.65 – 2.54 (m, 2H), 2.06(s, 2H), 1.80 (s, 4H), 1.69 – 1.58 (m, 4H), 1.42 (s, 2H). MS(ESI+): 567.2(M+H).

[0818] Example 6 (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)phenyl)(pyrrolidin-1-yl)methanone

[0819]

[0820] The preparation method is described in Example 1, except that the 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by (2-aminophenyl)(pyrrolidin-1-yl)methanone.

[0821] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.67 (s, 1H), 9.27 (s, 1H), 8.32 (d, J = 8.2Hz, 1H), 8.17 (s, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.45 (dd, J = 8.2, 4.7 Hz, 2H),7.30 (d, J = 8.0 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 3.50– 3.41 (m, 5H), 2.84 (s, 6H), 2.59 (d, J = 10.1 Hz, 2H), 2.03 (s, 2H), 1.81 (m,8H), 1.45 (s, 2H). MS(ESI+): 531.3 (M+H).

[0822] Example 7 (S)-3-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-N,N-dimethylfuran-2-carboxamide

[0823]

[0824] The preparation method is described in Example 1, except that 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced with 3-amino-N,N-dimethylfuran-2-carboxamide.

[0825] 1 H NMR (400 MHz, CDCl 3 ) δ10.67 (s, 1H), δ 8.04 (s, 1H), 7.55 (d, J =2.0 Hz, 1H), 7.49 – 7.32 (m, 3H), 7.23 (dd, J = 8.0, 2.3 Hz, 1H), 7.07 (d, J= 8.1 Hz, 1H), 3.46 – 3.11 (m, 10H), 2.95 – 2.68 (m, 5H), 2.40 (m, 2H), 2.03(m, 4H), 1.60 (m, 2H). MS(ESI+): 495.2(M+H).

[0826] Example 8 (S)-5-chloro-4-(2-isopropoxy)anilino-2-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)pyrimidine

[0827]

[0828] The preparation method is described in Example 1, except that 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by 2-(1-methylethoxy)aniline.

[0829] 1 H NMR (400 MHz, CDCl 3) δ 8.47 (d, J = 8.1 Hz, 1H), 8.05 (d, J = 3.6Hz, 2H), 7.42 (s, 1H), 7.30 (s, 1H), 7.16 (s, 1H), 7.04 (dd, J = 17.9, 8.1Hz, 2H), 6.93 (dd, J = 15.4, 7.8 Hz, 2H), 4.70 – 4.54 (m, 1H), 3.54 – 3.00(m, 5H), 2.96 – 2.68 (m, 4H), 2.38 (m, 2H), 2.03 (m, 4H), 1.55 (m, 2H), 1.41(m, 6H). MS(ESI+): 492.2(M+H).

[0830] Example 9 (S)-4-(Benzo[d][1,3]dioxol-4-yl)-5-chloro- 2 -(7-(Pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)pyrimidine-2,4-diamine

[0831]

[0832] The preparation method is described in Example 1, except that 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by 4-amino-1,3-benzodioxole.

[0833] 1 H NMR (400 MHz, CDCl 3 ) δ 8.04 (s, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.29 (s, 1H), 7.25 – 7.19 (m, 1H), 7.00 (d, J = 7.8 Hz, 2H), 6.83 (t, J = 8.1 Hz, 1H), 6.71 (d, J = 7.7 Hz, 1H), 5.99 – 5.93 (m, 2H), 3.56 – 3.05 (m, 5H), 2.85 (m, 1H), 2.71 (m, 3H), 2.37 (m, 2H), 2.03 (m, 4H),1.60 – 1.47 (m, 2H). MS(ESI+): 478.2(M+H).

[0834] Example 10 (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0835]

[0836] a) (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0837] Add 10 ml of anhydrous N,N-dimethylformamide, (2-aminophenyl) dimethylphosphine oxide (169 mg), and 2,4,5-trichloropyrimidine (183 mg) to the reaction bottle in sequence, and add sodium hydride (120 mg, 60%) at 0°C, and react at 0°C for 3 hours. After the reaction is completed, add 20 ml of water to quench, extract the reaction solution with 20 ml of ethyl acetate, concentrate the organic phase to dryness, and purify the crude product by column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain the title compound (200 mg).

[0838] b) (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0839] Add 10 ml of n-butanol, (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (158 mg), p-toluenesulfonic acid monohydrate (190 mg), (S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-amine (115 mg) to the reaction bottle in sequence, and react at 110°C for 5 hours. After the reaction is completed, concentrate to dryness, add 20 ml of ethyl acetate to the residue, and then wash it with 1M sodium hydroxide aqueous solution (10 ml) three times. The organic phase is concentrated to dryness and purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain the title compound (115 mg).

[0840] 1 H NMR (400 MHz, CDCl 3) δ 10.88 (s, 1H), 8.62 – 8.54 (m, 1H), 8.08 (s,1H), 7.51 – 7.43 (m, 1H), 7.37 (d, J = 2.3 Hz, 1H), 7.31 (m, 2H), 7.22 (s,1H), 7.15 (m, 1H), 7.04 (d, J = 8.1 Hz, 1H), 3.45 – 3.19 (m, 5H), 2.91 – 2.68 (m, 4H), 2.37 (m, 2H), 2.02 (m, 4H), 1.84 (m, 6H), 1.56 (m, 2H). MS(ESI+):510.2(M+H).

[0841] Example 11 (S)-2-(3-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)phenyl)acetonitrile

[0842]

[0843] The preparation method is described in Example 1, except that 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by 3-aminobenzeneacetonitrile.

[0844] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.17 (s, 1H), 8.91 (s, 1H), 8.28 (s, 1H), 8.16 (d, J = 17.6 Hz, 1H), 7.68 (t, J = 10.8 Hz, 1H), 7.60 (s, 1H), 7.37 (t,J = 7.9 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 6.98 –6.88 (m, 1H), 4.03 (m, 2H), 2.84 (s, 1H), 2.66 (s, 4H), 2.39 (m, 4H), 1.91(s, 2H), 1.72(s, 4H), 1.46 (s, 2H). MS(ESI+): 473.2(M+H).

[0845] Example 12 (S)-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide

[0846]

[0847] The preparation method is described in Example 1, except that the 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by 2-amino-N-methylbenzamide.

[0848] 1 H NMR (400 MHz, Chloroform- d ) δ 11.02 (s, 1H), 8.74 – 8.48 (m, 1H), 8.08 (s, 1H), 7.51 (dd, J = 8.0, 1.5 Hz, 1H), 7.43 (ddd, J = 8.7, 7.3, 1.5Hz, 1H), 7.36 (d, J = 2.3 Hz, 1H), 7.26 – 7.22 (m, 1H), 7.14 – 6.93 (m, 3H), 6.55 (m, 1H), 3.11 (m, 4H), 3.02 (m, 3H), 2.85 (m, 2H), 2.77 – 2.66 (m, 3H),2.30 (m, 2H), 1.95 (m, 4H), 1.51 (m, 2H). MS(ESI+): 491.2(M+H).

[0849] Example 13 (S)-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)benzamide

[0850]

[0851] The preparation method is described in Example 1, except that 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by 2-amino-benzamide.

[0852] 1 H NMR (400 MHz, CDCl 3) δ 11.18 (s, 1H), 8.67 (dd, J = 8.4, 1.1 Hz,1H), 8.08 (s, 1H), 7.60 (dd, J = 7.9, 1.6 Hz, 1H), 7.47 (ddd, J = 8.7, 7.3,1.6 Hz, 1H), 7.39 (d, J = 2.3 Hz, 1H), 7.28 (d, J = 2.4 Hz, 1H), 7.18 – 7.08 (m, 2H), 7.04 (d, J = 8.1 Hz, 1H), 3.48 – 3.12 (m, 5H), 2.93 – 2.65 (m, 5H),2.38-2.02 (m, 7H), 1.56 (m, 2H). MS(ESI+): 477.2(M+H).

[0853] Example 14 (S)-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-N-methylbenzenesulfonamide

[0854]

[0855] The preparation method is described in Example 1, except that the 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by 2-amino-N-methylbenzenesulfonamide.

[0856] 1 H NMR (400 MHz, CDCl 3 ) δ 8.06 (s, 1H), 7.53 (d, J = 2.3 Hz, 1H), 7.49 (dd, J = 8.2, 1.6 Hz, 1H), 7.24 – 7.11 (m, 3H), 7.03 (s, 1H), 6.59 (dd, J =8.2, 1.1 Hz, 1H), 6.47 (ddd, J = 8.2, 7.1, 1.1 Hz, 1H), 5.02 (s, 1H), 3.57(s, 3H), 3.35 – 3.04 (m, 5H), 2.95 (m, 2H), 2.77 (m, 2H), 2.37 (m, 2H), 2.01– 1.93 (m, 4H), 1.62 (m, 2H). MS(ESI+): 527.2(M+H).

[0857] Example 15 (S)-2-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)phenyl)propan-2-ol

[0858]

[0859] The preparation method is described in Example 1, except that the 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced with 2-(2-aminophenyl)propan-2-ol.

[0860] 1 H NMR (400 MHz, CDCl 3 ) δ 9.96 (s, 1H), 8.25 (dd, J = 8.1, 1.4 Hz,1H), 8.02 (s, 1H), 7.31 (m, 4H), 7.08 (m, 2H), 7.00 (d, J = 7.8 Hz, 1H), 3.41– 3.08 (m, 5H), 2.96 – 2.63 (m, 5H), 2.34 (m, 2H), 1.99 (m, 4H), 1.70 (s,6H), 1.58 – 1.44 (m, 2H). MS(ESI+): 492.2(M+H).

[0861] Example 16 (S)-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-5-fluorobenzamide

[0862]

[0863] 2-((2,5-dichloropyrimidin-4-yl)amino)-5-fluoro-benzamide

[0864] Add 2,4,5-trichloropyrimidine (1.33 mmol), 2-amino-5-fluoro-benzamide (1.1 mmol) and tetrahydrofuran (10 mL) to a 100 mL three-necked flask, stir and cool to -20°C, dropwise add lithium hexamethyldisilazide tetrahydrofuran solution (1.65 mmol, 1 mol / L), and naturally warm to room temperature for 8 h. After the reaction is completed, add saturated ammonium chloride solution to quench, add 30 mL ethyl acetate and 30 mL water to extract. Dry the organic phase with anhydrous sodium sulfate and concentrate to dryness under reduced pressure to obtain the title compound (470 mg). MS (ESI+): 300.9 (M+H).

[0865] b) (S)-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-5-fluorobenzamide

[0866] 2-((2,5-dichloropyrimidin-4-yl)amino)-5-fluoro-benzamide (0.9 mmol), (S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-amine (1.08 mmol), tris(dibenzylideneacetone)dipalladium (0.09 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl (0.27 mmol), cesium carbonate (1.8 mmol), 2-methyltetrahydrofuran (10 mL) and water (5 mL) were added to a 50 mL three-necked flask. Nitrogen protection. The reaction was then carried out at 76°C for 24 h. The aqueous phase was extracted with 30 mL of ethyl acetate, and the organic layer was concentrated to dryness under reduced pressure. 28 mg of the title compound was obtained by silica gel column chromatography.

[0867] 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.59 (s, 1H), 9.35 (s, 1H), 8.76 (s, 1H),8.35 (s, 1H), 8.25 (s, 1H), 7.88 (s, 1H), 7.69 (dd, J = 9.7, 3.0 Hz, 1H),7.43 (d, J = 1.9 Hz, 1H), 7.38-7.28 (m, 2H), 7.04 (d, J = 8.2 Hz, 1H), 2.96 –2.71 (m, 7H), 2.68 – 2.55 (m, 2H), 2.08 (br, 2H), 1.78 (br, 4H), 1.47 (br,2H).MS(ESI+): 495.2(M+H).

[0868] Example 17 (S)-5-chloro-N 4 -(2-(5-methyloxazol-2-yl)phenyl)-N 2 -(7-(Pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)pyrimidine-2,4-diamine

[0869]

[0870] The preparation method is described in Example 1, except that 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by 2-(5-methyl-2-oxazolyl)aniline.

[0871] 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.50 (s, 1H), 9.37 (s, 1H), 8.95 (d, J =7.3 Hz, 1H), 8.26 (s, 1H), 7.99 (dd, J = 7.9, 1.3 Hz, 1H), 7.48 – 7.39 (m,2H), 7.35 (d, J = 8.0 Hz, 1H), 7.25 – 7.15 (m, 2H), 7.02 (d, J = 8.1 Hz, 1H), 2.96-2.80 (m, 2H), 2.69-2.54 (m, 7H), 2.43 (s, 3H), 1.92 (br, 2H), 1.71 (br,4H), 1.52 (br, 2H). MS(ESI+): 515.2(M+H).

[0872] Example 18 (S)-N 4 -(2-(1H-imidazol-2-yl)phenyl)-5-chloro-N 2 -(7-(Pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)pyrimidine-2,4-diamine

[0873]

[0874] a) Preparation of N-(2-(1H-imidazol-2-yl)phenyl)-2,5-dichloropyrimidin-4-amine

[0875] 2-(1H-imidazole-2-yl)aniline (200 mg), 2,4,5-trichloropyrimidine (200 mg), and N,N-diisopropylethylamine (390 mg) were added to the reaction bottle in sequence, and the mixture was reacted in an oil bath at 80°C for 5.0 h. After the reaction was completed, water (50 ml) was added, and the aqueous layer was extracted with ethyl acetate (5 ml*3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain the title compound (152 mg).

[0876] b) Preparation of 2,5-dichloro-N-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-imidazol-2-yl)phenyl)pyrimidin-4-amine

[0877] Add N-(2-(1H-imidazole-2-yl)phenyl)-2,5-dichloropyrimidine-4-amine (150 mg), dihydropyran (84 mg), p-toluenesulfonic acid (19 mg), and ethyl acetate (10 ml) to the reaction flask in sequence. React at 50°C for 3.5 hours. After the reaction is completed, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate to dryness under reduced pressure. The crude product is purified by column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound (120 mg).

[0878] c) 5-Chloro-N 2 -((S)-7-(Pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-N 4 Preparation of -(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-imidazol-2-yl)phenyl)pyrimidine-2,4-diamine

[0879] To the reaction bottle were added (2,5-dichloro-N-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-imidazol-2-yl)phenyl)pyrimidin-4-amine) (120 mg), 5((S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-amine) (185 mg), tris(dibenzylideneacetone)dipalladium(0) (48 mg), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl (20 mg), cesium carbonate (460 mg), and N,N-dimethylformamide (9 ml) in sequence. The atmosphere was replaced with nitrogen five times. The reaction was carried out in a microwave oven at 130°C for 1 h. After the reaction was completed, the solid was removed by filtration, the filter cake was washed with dichloromethane, the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound (95 mg).

[0880] d) (S)-N 4 -(2-(1H-imidazol-2-yl)phenyl)-5-chloro-N 2 Preparation of -(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)pyrimidine-2,4-diamine

[0881] Add 5-chloro-N 2 -((S)-7-(Pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-N 4-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-imidazol-2-yl)phenyl)pyrimidine-2,4-diamine (95 mg), camphorsulfonic acid (187 mg), dichloromethane / methanol (5 ml:5 ml) were stirred at room temperature overnight. After the reaction was completed, water was added for extraction, and the organic phase was dried over anhydrous sodium sulfate and dried under reduced pressure. The obtained solid was purified by silica gel column chromatography to obtain the title compound (15 mg).

[0882] 1 H NMR (400 MHz, CDCl 3 ) δ 12.17 (s, 1H), 8.75 – 8.58 (m, 2H), 8.07 (s,1H), 7.58 (dd, J = 7.9, 1.3 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.32 – 7.28 (m,1H), 7.25 – 7.14 (m, 3H), 7.11 (d, J = 7.7 Hz, 1H), 7.01 – 6.94 (m, 2H), 3.06(s, 4H), 2.71 (m, 5H), 2.23 (m, 4H), 1.56 – 1.48 (m, 2H), 1.45 (s, 2H). MS(ESI+): 500.2(M+H).

[0883] Example 19 (S)-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-5-fluoro-N-methylbenzamide

[0884]

[0885] a) Preparation of 2-((2,5-dichloropyrimidin-4-yl)amino)-5-fluoro-N-methyl-benzamide

[0886] Add 2,4,5-trichloropyrimidine (1.2 mmol), 2-amino-5-fluoro-N-methyl-benzamide (1.0 mmol) and tetrahydrofuran (10 mL) to a 100 mL three-necked flask, add lithium hexamethyldisilazide (2.5 mmol) dropwise at -20°C, warm to room temperature and stir for 8 h. When the raw materials react completely, stop the reaction. Add saturated ammonium chloride solution to quench. Add 30 mL of ethyl acetate and 30 mL of water to the reaction solution, stir and extract. Extract the water layer again with 30 mL of ethyl acetate. Combine the organic phases, wash with water, saturated brine, and dry with anhydrous sodium sulfate. Filter, and concentrate the filtrate to dryness under reduced pressure to obtain the title compound (250 mg).

[0887] b) Preparation of (S)-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-5-fluoro-N-methylbenzamide

[0888] 2-((2,5-dichloropyrimidin-4-yl)amino)-5-fluoro-N-methyl-benzamide (0.38 mmol), (S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-amine (0.38 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.04 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl (0.12 mmol), cesium carbonate (0.76 mmol), 2-methyltetrahydrofuran (10 mL) and water (5 mL) were added to a 50 mL three-necked flask. Nitrogen protection was applied. The reaction was then carried out at 76 degrees for 24 h. The aqueous phase was extracted with 30 mL of ethyl acetate, the organic layer was concentrated to dryness, and the title compound (53 mg) was obtained by silica gel column chromatography.

[0889] 1 H NMR (400 MHz, DMSO- d6) δ 11.31 (s, 1H), 9.31 (s, 1H), 8.82 (d, J =4.6 Hz, 1H), 8.75-8.66 (m, 1H), 8.20 (s, 1H), 7.62 (dd, J = 9.6, 3.0 Hz, 1H),7.41 (d, J = 2.0 Hz, 1H), 7.36 – 7.26 (m, 2H), 7.01 (d, J = 8.2 Hz, 1H), 2.96-2.76 (m, 5H), 2.70-2.53 (m, 7H), 1.93 (m, 2H), 1.72 (br, 4H), 1.51 (m,2H). MS(ESI+): 509.1(M+H).

[0890] Example 20 (S)-4-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-N-methylnicotinamide

[0891]

[0892] Prepared by referring to the preparation method of Example 1, except that 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced with 4-amino-N-methylnicotinamide. MS (ESI+): 492.2 (M+H).

[0893] Example 21 (S)-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-N-methylnicotinamide

[0894]

[0895] a) Preparation of ethyl 2-((2,5-dichloropyrimidin-4-yl)amino)nicotinate

[0896] Sodium hydride (130.83 mg) was added to a solution of 2-aminonicotinic acid ethyl ester (543.59 mg) in N,N-dimethylformamide (15 mL) at 0°C. The reaction mixture was stirred for 20 minutes. 2,3,5-trichloropyrimidine (500 mg) was added at 0°C. The reaction mixture was stirred at 0°C for 3 hours. The reaction solution was poured into water (100 mL), and then ethyl acetate (100 mL) was added for extraction. The organic phase was washed with saturated sodium chloride solution (100 mL*3), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The crude product was purified by chromatography on a silica gel column (petroleum ether: ethyl acetate = 1:1) to obtain the title compound (0.2 g).

[0897] b) Preparation of (S)-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)nicotinate

[0898] At 20°C, add (S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-amine (220.68 mg) and p-toluenesulfonic acid (219.97 mg) to a dimethyl sulfoxide solution (10 mL) containing ethyl 2-((2,5-dichloropyrimidin-4-yl)amino)nicotinate (200 mg). The reaction mixture was stirred in a microwave at 150°C for 1 hour. The reaction solution was poured into water (100 mL) and extracted with dichloromethane (100 mL). The organic phase was washed with saturated sodium chloride solution (100 mL*3), dried over anhydrous sodium sulfate, and spun dry. The product was purified by chromatography on a silica gel plate (dichloromethane: methanol = 10:1) to obtain the title compound (0.2 g).

[0899] c) Preparation of (S)-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)nicotinic acid

[0900] Dissolve (S)-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)nicotinate (200 mg) in methanol (10 mL) at 20°C, and add sodium hydroxide (78.89 mg) and water (1 mL). Stir the reaction mixture at 80°C for 3 hours. Concentrate the reaction mixture to dryness to obtain the title compound (0.15 g).

[0901] d) Preparation of (S)-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-N-methylnicotinamide

[0902] To N,N-dimethylformamide (5 mL) in which (S)-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)nicotinic acid (150 mg) was dissolved, 2M methylamine tetrahydrofuran solution (0.18 mL) and diisopropylethylamine (121.43 mg) were added at 20°C. The reaction mixture was stirred for 2 minutes. 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (142.89 mg) was added and the reaction mixture was stirred at 20°C for 3 hours. The reaction solution was poured into water (100 mL) and extracted with dichloromethane (100 mL). The organic phase was washed with saturated sodium chloride solution (100 mL*3), dried over anhydrous sodium sulfate, and concentrated to dryness. The product was purified by chromatography on silica gel (dichloromethane:methanol=10:1) to obtain the title compound (20 mg).

[0903] 1 H NMR (400 MHz, DMSO- d 6 ) δ11.37 (s, 1H),9.35 (s, 1H), 9.02 (s, 1H),8.59 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 7.89 (s, 1H), 7.44 (s, 1H), 7.24(s, 1H), 6.96-7.05 (m, 1H), 3.17 (d, J = 4.8 Hz, 1H), 2.70-2.98 (m, 9H), 1.97-2.16 (m, 2H), 1.77 (m, 4H), 1.41 – 1.56 (m, 2H), 1.24 (d, J = 6.0 Hz,2H). MS(ESI+): 492.2(M+H).

[0904] Example 22 (S)-5-chloro-N 4 -(2-(isopropylsulfonyl)phenyl)-N 2 -(7-(Pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)pyrimidine-2,4-diamine

[0905]

[0906] The preparation method is described in Example 1, except that the 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by 2-(isopropylsulfonyl)aniline.

[0907] 1H NMR (400 MHz, CDCl 3 ) δ 9.59 (s, 1H), 8.62 – 8.54 (m, 1H), 8.14 (s,1H), 7.92 (d, J = 6.9 Hz, 1H), 7.60 (t, J = 7.4 Hz, 1H), 7.28 (d, J = 9.1 Hz,3H), 7.10 – 6.92 (m, 2H), 3.24 (dd, J = 13.4, 6.6 Hz, 1H), 3.07 (m, 4H), 2.96– 2.88 (m, 1H), 2.89 – 2.67 (m, 4H), 1.97 (m, 4H), 1.56 (m, 4H), 1.30 (t, J =11.9 Hz, 6H). MS(ESI+): 540.2(M+H).

[0908] Example 23 (S)-5-chloro-N 4 -(2-(methylsulfonyl)phenyl)-N 2 -(7-(Pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)pyrimidine-2,4-diamine

[0909]

[0910] The preparation method is described in Example 1, except that the 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by 2-(methylsulfonyl)aniline.

[0911] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.37 (m, 2H), 8.49 (d, J = 7.4 Hz, 1H), 8.24 (m, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.48 – 7.35(m, 2H), 7.30 (d, J = 7.9 Hz, 1H), 7.00 (d, J = 8.1 Hz, 1H), 3.27 (s, 3H), 3.10 (m, 4H), 2.62 (m, 3H), 2.50 (m, 2H), 2.17 (m, 2H), 1.85 (m, 4H), 1.41(d, J = 8.1 Hz, 2H). MS(ESI+): 512.2(M+H).

[0912] Example 24 (S)-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-N-cyclopropylbenzenesulfonamide

[0913]

[0914] The preparation method is described in Example 1, except that 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by 2-amino-N-cyclopropylbenzenesulfonamide.

[0915] 1 H NMR (400 MHz, DMSO- d6 ) δ 9.43 (s, 1H), 9.28 (s, 1H), 8.49 (d, J =8.3 Hz, 1H), 8.27 (s, 2H), 7.87 (td, J = 8.3, 1.6 Hz, 1H), 7.65 (ddd, J =8.6, 7.3, 1.7 Hz, 1H), 7.47 (d, J = 2.3 Hz, 1H), 7.40 – 7.26 (m, 2H), 7.01(d, J = 8.1 Hz, 1H), 3.10 (s, 4H), 2.81 (dd, J = 14.4, 7.6 Hz, 1H), 2.63 (s,3H), 2.14 (tt, J = 6.8, 3.5 Hz, 3H), 1.86 (d, J = 6.4 Hz, 4H), 1.42 (s, 2H), 0.54 – 0.26 (m, 5H). MS(ESI+): 553.2(M+H).

[0916] Example 25 (S)-N 4 -(2-(1H-1,2,4-triazol-5-yl)phenyl)-5-chloro-N 2 -(7-(Pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)pyrimidine-2,4-diamine

[0917]

[0918] The preparation method is described in Example 1, except that the 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by 2-(1H-1,2,4-thiazol-5-yl)aniline.

[0919] 1H NMR (400 MHz, DMSO- d 6 ) δ 11.48 (s, 1H), 9.34 (s, 1H), 8.82 (d, J =8.5 Hz, 1H), 8.69 (s, 1H), 8.22 (d, J = 3.2 Hz, 2H), 8.15 (dd, J = 7.9, 1.6Hz, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.45 – 7.30 (m, 2H), 7.21 (t, J = 7.5 Hz,1H), 7.03 (d, J = 8.1 Hz, 1H), 2.84 (s, 7H), 2.61 (t, J = 12.6 Hz, 2H), 2.05(s, 2H), 1.77(s, 4H), 1.49 (s, 2H). MS(ESI+): 501.2(M+H).

[0920] Example 26 (S)-5-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-N-methylthiazole-4-carboxamide

[0921]

[0922] a) Preparation of ethyl 5-((2,5-dichloropyrimidin-4-yl)amino)thiazole-4-carboxylate

[0923] Add 5-aminothiazole-4-carboxylic acid ethyl ester (1.27 mmol), 2,4,5-trichloropyrimidine (1.90 mmol) and tetrahydrofuran (10 mL) to a 100 mL single-mouth bottle. Stir and cool (external temperature -20 degrees). Then add sodium hydride (3.8 mmol) to the reaction solution in portions. Gradually warm to room temperature and stir for 8 hours. When the raw materials react completely, stop the reaction. Add saturated ammonium chloride solution to quench. Add 30 mL of ethyl acetate and 30 mL of water to the reaction solution, stir and extract. Extract the water layer again with 30 mL of ethyl acetate. Combine the organic phases, wash with water, saturated brine, and dry with anhydrous sodium sulfate. Filter and concentrate the filtrate to dryness to obtain the title compound (236 mg).

[0924] b) Preparation of (S)-5-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]amino)pyrimidin-4-yl)amino)thiazole-4-carboxylic acid ethyl ester

[0925] Ethyl 5-((2,5-dichloropyrimidin-4-yl)amino)thiazole-4-carboxylate (0.31 mmol), (S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-amine (0.34 mmol), n-butanol (4 mL) and trifluoroacetic acid (0.1 mL) were added to a 10 mL microwave tube and reacted at 120 degrees for 2 h under nitrogen protection. The mixture was concentrated to dryness to obtain the title compound (196 mg).

[0926] MS(ESI+): 513.1(M+H).

[0927] c) Preparation of (S)-5-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)thiazole-4-carboxylic acid

[0928] Add (S)-5-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]amino)pyrimidin-4-yl)amino)thiazole-4-carboxylic acid ethyl ester (0.38 mmol), methanol (5 mL) and tetrahydrofuran (5 mL) into a 50 mL three-necked flask and stir. Then add lithium hydroxide solution dropwise and stir overnight. After the reaction is completed, remove the solvent to dryness. Add 3 mL of water to the concentrated residue, adjust the pH to about 2 with 2N hydrogen chloride, and lyophilize to obtain the title compound, which is directly used in the next step.

[0929] d) Preparation of (S)-5-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-N-methylthiazole-4-carboxamide

[0930] (S)-5-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)thiazole-4-carboxylic acid (0.16 mmol), tetrahydrofuran solution of methylamine (0.24 mmol), triethylamine (0.32 mmol) and N,N-dimethylformamide (5 mL) were added to a 50 mL single-necked bottle and stirred at room temperature. Then, Carter condensation agent (0.32 mmol) was added and reacted for 1 hour. When the reaction was completed, 30 mL of water and 30 mL of ethyl acetate were added, stirred, extracted, and the organic layer was concentrated to dryness and purified by column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound (37 mg).

[0931] 1H NMR (400 MHz, DMSO- d 6 ) δ 12.10 (s, 1H), 9.44 (s, 1H), 8.71 (s, 1H), 8.57 (d, J = 4.8 Hz, 1H), 8.32 (s, 1H), 7.47 (s, 1H), 7.33 (d, J = 7.3 Hz,1H), 7.12 (d, J = 8.1 Hz, 1H), 3.06-2.97 (m, 2H), 2.89 – 2.60 (m, 10H), 2.24(br, 2H), 1.87 (s, 4H), 1.50 (br, 2H). MS(ESI+): 498.1(M+H).

[0932] Example 27 (S)-3-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-N-methylisonicotinamide

[0933]

[0934] The preparation method is described in Example 1, except that 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by 3-aminoisonicotinate.

[0935] 1 H NMR (400 MHz, DMSO- d 6 ) δ9.98 (s, 1H), 9.47 (s, 1H), 8.46 (d, J =5.0 Hz, 1H), 8.25– 8.38 (m, 2H), 7.85 (d, J = 4.8 Hz, 1H), 7.40 (s, 1H), 7.25- 7.32 (m, 1H), 6.98 (d, J = 8.1 Hz, 1H), 3.91 (s, 3H), 2.81 - 2.93 (m, 2H), 2.89 - 2.60 (m, 7H), 1.81 -1.96 (m, 2H), 1.65 - 1.77 (m, 4H), 1.44 - 1.59 (m,2H). MS(ESI+): 493.2(M+H).

[0936] Example 28 (S)-7-((5-chloro-2-(((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]amino))pyrimidin-4-yl)amino)-2-methylisoindol-1-one

[0937]

[0938] a) Preparation of 7-((2,5-dichloropyrimidin-4-yl)amino)-2-methylisoindol-1-one

[0939] 7-Amino-2-methylisoindolin-1-one (50 mg) and 2,4,5-trichloropyrimidine (113 mg) were dissolved in tetrahydrofuran (5 mL) and the temperature was lowered to -20 o C and then sodium hydride (37.2 mg) was added. The reaction was completed after 3 hours. The reaction solution was poured into ice water to quench, then extracted with ethyl acetate. The ethyl acetate phase was concentrated to dryness and purified by column chromatography (dichloromethane / methanol = 40:1) to obtain the title compound (65 mg). MS (ESI+): 308.96 (M+H).

[0940] b) Preparation of (S)-7-((5-chloro-2-(((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]amino))pyrimidin-4-yl)amino)-2-methylisoindol-1-one

[0941] 7-((2,5-dichloropyrimidin-4-yl)amino)-2-methylisoindol-1-one (55 mg) and (S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-amine (41 mg) were dissolved in n-butanol (5 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was heated to 120°C under nitrogen protection. o C for 8 h. After the reaction, 2 mL of saturated sodium bicarbonate solution was added to the reaction solution, and the organic phase was concentrated to dryness and purified by column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound (75 mg).

[0942] 1 H NMR (400 MHz, DMSO- d 6) δ 10.67 (s, 1H), 9.41 (s, 1H), 8.73 (d, J =8.3 Hz, 1H), 8.25 (s, 1H), 7.53 – 7.41 (m, 2H), 7.34 (d, J = 8.2 Hz, 1H),7.21 (d, J = 7.5 Hz, 1H), 7.05 (d, J = 8.1 Hz, 1H), 4.49 (s, 2H), 3.09 (s,3H), 2.97 – 2.81 (m, 2H), 2.69 – 2.56 (m, 7H), 1.97 (s, 2H), 1.80 – 1.66 (m,4H), 1.53 (s, 2H). MS(ESI+): 503.3(M+H).

[0943] Example 29 (S)-7-((5-chloro-2-(((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]amino))pyrimidin-4-yl)amino)isoindol-1-one

[0944]

[0945] The preparation method is described in Example 1, except that 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by 7-amino-isoindolin-1-one.

[0946] 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.72 (s, 1H), 9.44 (s, 1H), 8.81 (s, 1H), 8.74 (d, J = 8.3 Hz, 1H), 8.24 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 7.0 Hz, 1H), 7.36 (d, J = 7.7 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 4.41 (s, 2H), 2.93 – 2.75 (m, 7H), 2.73 – 2.60 (m, 2H), 2.07 (s, 2H), 1.77(d, J = 6.0 Hz, 4H), 1.50 (s, 2H). MS(ESI+): 489.1(M+H).

[0947] Example 30 (S)-N-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide

[0948]

[0949] The preparation method is described in Example 1, except that the 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by N-(2-aminophenyl)methanesulfonamide.

[0950] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.25 (s, 1H), 8.63 (s, 1H), 8.24 (s, 1H), 8.16 (s, 1H), 7.96 (d, J = 6.9 Hz, 1H), 7.46 – 7.34 (m, 3H), 7.31 –7.12 (m,2H), 6.91 (d, J = 8.1 Hz, 1H), 3.01 – 2.72 (m, 8H), 2.59 (d, J = 11.3 Hz, 4H), 2.08 (s, 2H), 1.80 (s, 4H), 1.41 (s, 2H). MS(ESI+): 527.2(M+H).

[0951] Example 31 2-((5-chloro-2-((3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide

[0952]

[0953] Prepared by referring to the preparation method of Example 1, the 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by 2-amino-N-methylbenzamide;

[0954] The target product is obtained by replacing the (S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-amine in step b) with 3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine.

[0955] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.58 (s, 1H), 9.35 (s, 1H), 8.74 (dd, J =12.7, 7.1 Hz, 2H), 8.16 (d, J = 7.2 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.52 –7.41 (m, 2H), 7.35 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.01 (d, J= 8.1 Hz, 1H), 3.89 (d, J = 8.1 Hz, 4H), 2.91 – 2.59 (m, 12H), 1.63 (d, J =11.6 Hz, 2H), 1.52 (dt, J = 11.8, 8.0 Hz, 2H). MS(ESI+): 507.2(M+H).

[0956] Example 32 2-((5-chloro-2-((3-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide

[0957]

[0958] Prepared according to the preparation method of Example 1, the 2-amino-N, N-dimethylbenzenesulfonamide in step a) was replaced with 2-amino-N-methylbenzamide;

[0959] The target product is obtained by replacing (S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-amine in step b) with 3-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine.

[0960] 1 H NMR (400 MHz, DMSO- d 6) δ 11.60 (s, 1H), 9.39 (s, 1H), 8.75 (dd, J =11.5, 6.7 Hz, 2H), 8.24 – 8.19 (m, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.48 (d, J= 9.1 Hz, 2H), 7.40 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.04 (d, J= 8.0 Hz, 1H), 3.18 (s, 1H), 2.96 – 2.75 (m, 11H), 1.88 (s, 2H), 1.62 (d, J =26.3 Hz, 2H), 1.51 (s, 4H). MS(ESI+): 491.2(M+H).

[0961] Example 33 (S)-3-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-N-methylpicolinamide

[0962]

[0963] Prepared by referring to the preparation method of Example 1, except that 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced with 3-amino-N-methyl-2-pyridinecarboxamide. MS (ESI+): 492.2 (M+H).

[0964] Example 34 (S)-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]amino)pyrimidin-4-yl)amino)-5-cyano-N-methylbenzamide

[0965]

[0966] The preparation method is described in Example 1, except that the 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by 2-amino-5-cyano-N-methylbenzamide.

[0967] 1 H NMR (400 MHz, DMSO- d 6) δ 11.98 (s, 1H), 9.47 (s, 1H), 8.97 (d, 2H), 8.28 (d, J = 9.4 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 7.83 (dd, J = 8.8, 2.0Hz, 1H), 7.42 (d, J = 2.2 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.1Hz, 1H), 2.90 (m, 1H), 2.83 (m, 4H), 2.63 (d, J = 6.2 Hz, 3H), 2.56 (m, 4H),1.93 (s, 2H), 1.71 (m, 4H), 1.52 (s, 2H). MS(ESI+): 516.1(M+H).

[0968] Example 35 (S)-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-N-methyl-5-(trifluoromethyl)benzamide

[0969]

[0970] The preparation method is described in Example 1, except that the 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by 2-amino-N-methyl-5-(trifluoromethyl)benzamide.

[0971] 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.92 (s, 1H), 9.48 (s, 1H), 9.01 (m, 2H), 8.30 (s, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 8.9 Hz, 1H), 7.52 (d, J= 1.5 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 3.10 (s,3H), 2.84 (d, J = 4.4 Hz, 3H), 2.78 – 2.57 (m, 4H), 2.33 (s, 2H), 2.18 (s,2H), 1.85 (s, 4H), 1.46 (s, 2H). MS(ESI+): 559.2(M+H).

[0972] Example 36 (S)-5-chloro-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide

[0973]

[0974] The preparation method is described in Example 1, except that the 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by 2-amino-5-chloro-N-methylbenzamide.

[0975] 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.51 (s, 1H), 9.39 (s, 1H), 8.89 (d, J =4.5 Hz, 1H), 8.74 (d, J = 8.7 Hz, 1H), 8.22 (d, J = 10.7 Hz, 1H), 7.84 (d, J= 2.5 Hz, 1H), 7.56 – 7.43 (m, 2H), 7.32 (d, J = 7.9 Hz, 1H), 7.05 (d, J =8.2 Hz, 1H), 2.98 (m, 5H), 2.81 (d, J = 4.5 Hz, 5H), 2.70 – 2.57 (m, 2H),2.12 (s, 2H), 1.81 (s, 4H), 1.47 (s, 2H). MS(ESI+): 525.1(M+H).

[0976] Example 37 (S)-2-((5-chloro-2-(((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino))pyrimidin-4-yl)amino)-5-methoxy-N-methylbenzamide

[0977]

[0978] The preparation method is described in Example 1, except that the 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by 2-amino-5-methoxy-N-methylbenzamide.

[0979] 1 H NMR (400 MHz, DMSO- d 6) δ 11.13 (s, 1H), 9.26 (s, 1H), 8.75 (d, J =4.5 Hz, 1H), 8.54 (d, J = 8.7 Hz, 1H), 8.15 (s, 1H), 7.45 (d, J = 1.8 Hz,1H), 7.33-7.27(m, 2H), 7.04 (dd, J = 9.1, 2.9 Hz, 1H), 7.00 (d, J = 8.2 Hz,1H), 3.83 (s, 3H), 2.89 – 2.71 (m, 10H), 2.62-2.52 (m, 2H), 2.00 (br, 2H), 1.75 (br, 4H), 1.49 (br, 2H). MS(ESI+): 521.2(M+H).

[0980] Example 38 (S)-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-N-(2-methoxyethyl)benzamide

[0981]

[0982] Prepared by referring to the preparation method of Example 1, except that 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced with 2-amino-N-(2-methoxyethyl)benzamide. MS (ESI+): 535.1 (M+H).

[0983] Example 39 2-((5-chloro-2-((S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-N-(tetrahydrofuran-3-yl)benzamide

[0984]

[0985] Prepared by referring to the preparation method of Example 1, except that 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced with 2-amino-N-(tetrahydro-3-furanyl)benzamide. MS (ESI+): 547.2 (M+H).

[0986] Example 40 (S)-5-chloro-N 4 -(2-(morpholinomethyl)phenyl)-N 2 -(7-(Pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)pyrimidine-2,4-diamine

[0987]

[0988] The preparation method is described in Example 1, except that the 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by 2-(morpholine-4-methyl)aniline.

[0989] 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.06 (s, 1H), 9.28 (s, 1H), 8.33 – 8.10 (m, 2H), 7.49 (s, 1H), 7.38 – 7.21 (m, 3H), 7.08 (t, J = 7.3 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H), 3.61 (d, J = 9.2 Hz, 6H), 3.10 – 2.75 (m, 6H), 2.67 (s, 1H), 2.59 (t, J = 11.9 Hz, 2H), 2.40 (s, 4H), 2.09 (s, 2H), 1.79 (s, 4H), 1.44 (s,2H). MS(ESI+): 533.2(M+H).

[0990] Example 41 (S)-N-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)phenyl)cyclopropanesulfonamide

[0991]

[0992] The preparation method is described in Example 1, except that the 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by N-(2-aminophenyl)cyclopropanesulfonamide.

[0993] 1 H NMR (400 MHz, DMSO- d 6) δ 9.27 (s, 1H), 8.56 (s, 1H), 8.18 (d, J =13.3 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.48 – 7.36 (m, 2H), 7.31 (t, J = 7.1Hz, 1H), 7.24 (t, J = 6.9 Hz, 2H), 6.92 (d, 1H), 3.02 (s, 6H), 2.78 (m, 1H), 2.57 (m, 3H), 2.09 (m, 2H), 1.82 (m, 4H), 1.40 (m,2H), 0.84 (m, Hz, 4H). MS(ESI+): 553.2(M+H).

[0994] Example 42 (S)-4-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

[0995]

[0996] The product is prepared by referring to the preparation method of Example 1, except that the 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by 4-amino-6-methoxy-N-methylnicotinamide. The product is the demethylation byproduct of Preparation Example 44.

[0997] 1 H NMR (400 MHz, DMSO- d 6 ) δ 14.30 (s, 1H), 11.98 (s, 1H), 10.69 (d,1H), 9.53 (s, 1H), 8.36 (s, 1H),8.14 (d, 1H), 7.44 (m, 2H), 7.29 (d, 1H),7.04 (d, 1H),2.92-2.83(m, 5H), 2.68-2.33 (m, 7H), 1.86 (m, 2H), 1.69(m, 4H),1.54 (m, 2H). MS(ESI+): 508.2(M+H).

[0998] Example 43 (S)-4-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-6-methoxy-N-methylnicotinamide

[0999]

[1000] The preparation method is described in Example 1, except that 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced with 4-amino-6-methoxy-N-methylnicotinamide.

[1001] 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.63 (s, 1H), 8.36 (s, 1H), 8.30 (d, 2H), 7.36 (m, 2H), 7.13 (d, 1H), 6.98 (d, 1H) , 6.26 (s, 1H) ,4.00 (s, 3H),3.07(s,3H), 2.90 (m, 4H), 2.74 (m, 2H), 2.50 (s, 2H), 1.87 (m, 3H), 1.69(m, 4H),1.54 (m, 2H). MS(ESI+): 522.3(M+H).

[1002] Example 44 (S)-4-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-2-methoxy-N-methylnicotinamide

[1003]

[1004] Prepare according to the preparation method of Example 1, except that 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced with 4-amino-2-methoxy-N-methylnicotinamide.

[1005] 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.21 (s, 1H), 9.48 (s, 1H), 8.65 (d, 1H), 8.53 (m, 1H), 8.32 (s, 1H), 8.12 (d, 1H), 7.44 (m, 1H), 7.33 (d, 1H), 7.04 (d, 1H) , 3.96 (s, 3H), 3.98-2.83(m, 6H), 2.40-2.61 (m, 5H), 1.85 (m, 3H), 1.69(m,4H), 1.54 (m, 2H). MS(ESI+): 522.3(M+H).

[1006] Example 45 (S)-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-5-hydroxy-N-methylbenzamide

[1007]

[1008] The preparation method is described in Example 1, except that the 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by 2-amino-5-hydroxy-N-methylbenzamide.

[1009] 1 HNMR (400 MHz, DMSO d 6 )δ10.85(s,1H),9.57(s,1H),9.22(s,1H),8.63(d,J=4.6Hz,1H),8.38(d,J=8.8Hz,1H),8.12(s,1H),7.45(s,1H),7.32(d,J=7.3Hz,1H),7.1 0(d,J=2.7Hz,1H),6.02-6.91(m,2H),3.00–2.70(m,7H),2.65-2.56(m ,2H),2.14–1.94(m,2H),1.78(s,4H),1.58-1.43(m,2H),1.23(s,3H). MS(ESI+): 507.3(M+H).

[1010] Example 46 2-((5-chloro-2-((3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)amino)pyrimidin-4-yl)amino)-5-fluoro-N-methylbenzamide

[1011]

[1012] Prepared by referring to the preparation method of Example 1, the 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by 2-amino-5-fluoro-N-methylbenzamide;

[1013] The target product is obtained by replacing the (S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-amine in step b) with 3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine.

[1014] 1 HNMR (400MHz, DMSO-d 6 )δ11.31(s,1H),9.32(s,1H),8.82(s,1H),8.65(s,1H),8.19(s,1H),7.63(d,1H),.39(d,1H),7.30(d,2H),7.00(d ,1H),3.87(m,2H),3.87(m,2H),2.81-2.78(m,5H),2.70(m,3H),2.65(m,4H),1.63-1.56(m,2H),1.54-1.45(m,2H). MS(ESI+): 525.2(M+H).

[1015] Example 47 (S)-(6-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[1016]

[1017] a) Preparation of 5-iodoquinoxaline-6-amine

[1018] Dissolve quinoxaline-6-amine (2900 mg) in a mixture of 50 ml of dichloromethane and 80 ml of saturated sodium bicarbonate, add iodine chloride (3900 mg) dropwise at 0°C, react for 1 hour, separate the layers, evaporate the organic phase under reduced pressure, and purify the crude product by silica gel column chromatography to obtain the title compound (3 g).

[1019] b) Preparation of (6-aminoquinoxaline-5-yl)dimethylphosphine oxide

[1020] In a 100ml three-necked flask, add 5-iodoquinoxaline-6-amine (2710mg), dimethylphosphine oxide (780mg), potassium phosphate (3180mg), palladium acetate (112mg), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (518mg), 30ml of N,N-dimethylformamide, and 6ml of water, replace the atmosphere with nitrogen three times, and react at 120°C for 24h. After the reaction is complete, add 200ml of dichloromethane and 100ml of water, separate the liquids, filter the obtained organic phase, concentrate to dryness under reduced pressure, and purify by reverse phase column chromatography (acetonitrile / water) to obtain the title compound (1.3g).

[1021] c) Preparation of 6-((2,5-dichloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[1022] Dissolve (6-aminoquinoxaline-5-yl)dimethylphosphine oxide (183 mg) and 2,4,5-trichloropyrimidine (221 mg) in THF (5 mL), lower the temperature to -20°C, add sodium hydride (80 mg, 60%), and move to room temperature after 30 minutes to continue the reaction for 5 hours. Add 5 mL of saturated ammonium chloride solution to quench the reaction solution, extract with 10 ml of ethyl acetate, concentrate the organic phase to dryness, and use silica gel column chromatography to obtain the title compound (120 mg).

[1023] d) Preparation of (S)-(6-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[1024] 6-((2,5-Dichloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (25 mg) and (S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-amine (16.5 mg) were dissolved in n-butanol (3 mL), trifluoroacetic acid (0.3 mL) was added, and the mixture was stirred at 120 °C. o C for 4 h. The reaction solution was neutralized by adding 2 M sodium hydroxide solution (2 mL), separated, the aqueous phase was extracted with ethyl acetate, and the organic phases were combined, concentrated to dryness, and purified by column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound (35 mg).

[1025] 1 H NMR (400 MHz, CDCl3) δ 12.78 (d, J = 3.0 Hz, 1H), 9.17 (dd, J = 9.6,4.1 Hz, 1H), 8.83–8.65 (m, 2H), 8.17 (d, J = 2.6 Hz, 1H), 8.09 (d, J = 9.5 Hz,1H), 7.36 – 7.28 (m, 2H), 7.07 (d, J = 8.2 Hz, 2H), 3.09 (m, 4H), 2.89 (m, 1H), 2.82 – 2.60 (m, 4H), 2.33 (m, 2H), 2.20 – 2.03 (m, 6H), 1.96 (m, 4H), 1.55(m, 2H). MS(ESI+): 562.2(M+H).

[1026] Example 48 (S)-6-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-N-methylquinoxaline-5-carboxamide

[1027]

[1028] a) Preparation of 6-((2,5-dichloropyrimidin-4-yl)amino)-N-methylquinoxaline-5-carboxamide

[1029] 6-Amino-N-methylquinoxaline-5-carboxamide (25 mg) and 2,4,5-trichloropyrimidine (68 mg) were dissolved in tetrahydrofuran (5 mL) and the temperature was lowered to -20 o C, then sodium hydride (15 mg) was added, and after 30 minutes, the mixture was moved to room temperature and the reaction was continued for 5 hours. The reaction solution was quenched by adding 5 mL of saturated ammonium chloride solution, and the tetrahydrofuran layer was taken. The aqueous phase was extracted with ethyl acetate and the organic phases were combined and concentrated to dryness. The title compound (27 mg) was obtained by column chromatography purification (dichloromethane / methanol = 20:1). MS: 1 / 2 [M+H] + : 175.1.

[1030] b) Preparation of (S)-6-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-N-methylquinoxaline-5-carboxamide

[1031] 6-((2,5-Dichloropyrimidin-4-yl)amino)-N-methylquinoxaline-5-carboxamide (25 mg) and (S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-amine (16.5 mg) were dissolved in n-butanol (3 mL), trifluoroacetic acid (0.3 mL) was added, and the mixture was stirred at 120 °C. o C for 4 h. The reaction solution was neutralized by adding 2 M sodium hydroxide solution (2 mL), separated, the aqueous phase was extracted with ethyl acetate, and the organic phases were combined, concentrated to dryness, and purified by column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound (1.5 mg). MS (ESI+): 543.3 (M+H).

[1032] Example 49 7-((5-chloro-2-((3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)amino)pyrimidin-4-yl)amino)-2-methylisoindol-1-one

[1033]

[1034] Prepared by referring to the preparation method of Example 1, the 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced by 7-amino-2-methylisoindolin-1-one;

[1035] The target product is obtained by replacing the (S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-amine in step b) with 3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine.

[1036] 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.67 (s, 1H), 9.45 (s, 1H), 8.25 (s, 1H), 7.48 (d, J = 8.3 Hz, 2H), 7.36 (dd, J = 8.1, 2.2 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H),7.14 – 7.07 (m, 1H), 7.06 (s, 1H), 4.49 (s, 2H), 3.90 (dd, J = 11.0, 4.1 Hz,2H), 3.28 (td, J = 11.7, 2.0 Hz, 3H), 3.09 (s, 3H), 2.89 – 2.74 (m, 8H), 1.75 –1.60 (m, 2H), 1.54 (qd, J = 11.9, 4.4 Hz, 2H). MS(ESI+): 519.2(M+H).

[1037] Example 50 (2-((5-chloro-2-((S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)phenyl)(imino)(methyl)-λ 6 -Sulfamethoxazole

[1038]

[1039] a) Preparation of 2-aminobenzyl sulfide

[1040] At 0°C, titanium trichloride (5 ml) was added dropwise to a solution of 2-nitroanisole (169 mg) in tetrahydrofuran (5 ml). After the addition was complete, the mixture was moved to room temperature for 4.0 h. After the reaction was completed, sodium hydroxide (2 M) was added to adjust the pH to 9. The organic layer was extracted with ethyl acetate, combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the title compound (125 mg). MS (ESI+): 140.1 (M+H).

[1041] b) Preparation of 2,5-dichloro-N-(2-(methylthio)phenyl)pyrimidin-4-amine

[1042] At 0℃, sodium hydride (72 mg) was added to a solution of 2-aminoanisyl thioether (120 mg) in N,N-dimethylformamide (3 ml), stirred for 10 min, and then 2,4,5-trichloropyrimidine (329 mg) was added, and then the mixture was moved to room temperature for 3.0 h. After the reaction was completed, 1 ml of ammonium chloride was used for quenching, the liquid was separated, and the organic layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The title compound (65 mg) was obtained after purification by column chromatography (petroleum ether / ethyl acetate = 50 / 1). MS (ESI+): 286.2 (M+H).

[1043] c) Preparation of tert-butyl (2,5-dichloropyrimidin-4-yl) (2-(methylthio)phenyl)carbamate

[1044] To a solution of 2,5-dichloro-N-(2-(methylthio)phenyl)pyrimidin-4-amine (65 mg) in dichloromethane (3 ml), di-tert-butyl dicarbonate (99 mg) and 4-dimethylaminopyridine (14 mg) were added and reacted at room temperature for 2 h. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 20:1) to obtain the title compound (72 mg). MS (ESI+): 386.1 (M+H).

[1045] d) Preparation of tert-butyl (2,5-dichloropyrimidin-4-yl) (2-(S-methylsulfonylimino)phenyl)carbamate

[1046] Add ammonium acetate (57 mg) and iodobenzene diacetate (122 mg) to a solution of tert-butyl (2,5-dichloropyrimidin-4-yl) (2-(methylthio)phenyl) carbamate (72 mg) in ethanol (3 ml) and react at room temperature for 2 h. After the reaction is complete, remove the solvent by rotary evaporation under reduced pressure, and purify the crude product by column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain the title compound (55 mg). MS (ESI+): 417.1 (M+H).

[1047] e) Preparation of tert-butyl (2,5-dichloropyrimidin-4-yl) (2-(S-methyl-N-(2,2,2-trifluoroacetyl)sulfonyl imide)phenyl) carbamate

[1048] Trifluoroacetic acid (55 mg), 4-dimethylaminopyridine (2 mg), and triethylamine (33 mg) were added to a solution of tert-butyl (2,5-dichloropyrimidin-4-yl) (2-(S-methylsulfonylimino)phenyl) carbamate (55 mg) in dichloromethane (3 ml). The mixture was reacted at room temperature for 3.0 h. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain the title compound (42 mg). MS (ESI+): 513.1 (M+H).

[1049] f) N-((2-((5-chloro-2-((S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)phenyl)(methyl)(oxy)-λ 6 Preparation of -sulfonyl)-2,2,2-trifluoroacetamide

[1050] To a solution of tert-butyl (2,5-dichloropyrimidin-4-yl) (2-(S-methyl-N-(2,2,2-trifluoroacetyl)sulfonylimide)phenyl)carbamate (42 mg) in n-butanol (3 ml) was added (S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-amine (28 mg) and trifluoroacetic acid (0.1 ml). The mixture was reacted at 120°C for 2.0 h. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure to obtain the title compound (25 mg). MS (ESI+): 607.1 (M+H).

[1051] g) (2-((5-chloro-2-((S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)phenyl)(imino)(methyl)-λ 6 - Preparation of sulfadiazine

[1052] N-((2-((5-chloro-2-((S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)phenyl)(methyl)(oxy)-λ 6 -sulfonyl)-2,2,2-trifluoroacetamide (25 mg), ethanol (3 ml), potassium carbonate (41 mg), react at room temperature for 3 hours. After the reaction is completed, the solvent is removed by rotary evaporation under reduced pressure, and the title compound (6 mg) is obtained by silica gel column chromatography.

[1053] 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.82 (s, 1H), 9.39 (s, 1H), 8.66 (d, J =8.3 Hz, 1H), 8.26 (s, 1H), 7.93 (dd, J = 7.9, 1.6 Hz, 1H), 7.71 – 7.58 (m, 1H), 7.46 – 7.26 (m, 3H), 7.00 (d, J = 8.2 Hz, 1H), 5.15 (s, 1H), 3.12 (s, 4H), 2.85(s, 3H), 2.67 (m, 3H), 2.33 (m, 2H), 2.04 – 1.88 (m, 2H), 1.72 (m, 4H), 1.58– 1.43 (m, 2H). MS(ESI+): 511.3(M+H).

[1054] Example 51 (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]amino)pyrimidin-4-yl)amino)-5-fluorophenyl)dimethylphosphine oxide

[1055]

[1056] The preparation method is described in Example 1, except that the 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced with (2-amino-5-fluorophenyl) dimethylphosphine oxide.

[1057] 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.84 (s, 1H), 9.28 (s, 1H), 8.50 (s, 1H), 8.17 (s, 1H), 7.53 (ddd, J = 13.9, 8.8, 3.1 Hz, 1H), 7.41 – 7.29 (m, 2H), 7.26(dd, J = 8.2, 2.2 Hz, 1H), 6.97 (d, J= 8.2 Hz, 1H), 2.84 (m, 2H), 2.56 (s, 7H), 1.87 (s, 2H), 1.81 (s, 3H), 1.78 (s, 3H), 1.70 (s, 4H), 1.50 (s, 2H). MS(ESI+): 528.2(M+H).

[1058] Example 52 (S)-(5-chloro-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]amino)pyrimidin-4-yl)amino)-5-chlorophenyl)dimethylphosphine oxide

[1059]

[1060] The preparation method is described in Example 1, except that the 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced with (2-amino-5-chlorophenyl) dimethylphosphine oxide.

[1061] 1 H NMR (400 MHz, DMSO -d 6 ) δ 11.12 (s, 1H), 9.33 (s, 1H), 8.57 (s, 1H), 8.19 (s, 1H), 7.69 (dd, J = 13.7, 2.4 Hz, 1H), 7.49 (dd, J = 9.0, 2.4 Hz, 1H),7.42 (d, J = 2.1 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H), 3.17(s, 2H), 2.95 – 2.75 (m, 2H), 2.64-2.53 (m, 5H), 1.91 (s, 2H), 1.84 (s, 3H),1.80 (s, 3H), 1.71 (s, 4H), 1.52 (s, 2H). MS(ESI+): 544.2(M+H).

[1062] Example 53 (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]amino)pyrimidin-4-yl)amino)-5-methylphenyl)dimethylphosphine oxide

[1063]

[1064] The preparation method is described in Example 1, except that the 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced with (2-amino-5-methylphenyl) dimethylphosphine oxide.

[1065] 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.92 (s, 1H), 9.25 (s, 1H), 8.39 (s, 1H), 8.14 (s, 1H), 7.55 – 7.37 (m, 2H), 7.29 (ddd, J = 14.0, 8.1, 2.1 Hz, 2H), 6.96(d, J = 8.2 Hz, 1H), 2.96 – 2.76 (m, 2H), 2.70 – 2.54 (m, 4H), 2.44 (s, 3H), 2.34 (s, 3H), 1.89 (d, J = 11.2 Hz, 2H), 1.78 (s, 3H), 1.74 (s, 3H), 1.70 (s,4H), 1.51 (s, 2H). MS(ESI+): 524.2(M+H).

[1066] Example 54 (S)-4-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-3-(dimethylphosphoryl)benzonitrile

[1067]

[1068] The preparation method is described in Example 1, except that the 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced with (2-amino-5-cyanophenyl) dimethylphosphine oxide.

[1069] 1 H NMR (400 MHz, DMSO- d6) δ 11.72 (s, 1H), 9.43 (s, 1H), 8.85 (s,1H), 8.26 (s, 1H), 8.17 – 8.09 (m, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.40 (s,1H), 7.27 (d, J = 8.2 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 2.88 (s, 2H), 2.66(m, 1H), 2.51 (s, 4H), 2.32 (p, J = 1.8 Hz, 2H), 2.00 (s, 2H), 1.86 (s, 3H),1.84 (s, 3H),1.68 (s, 4H), 1.52 (s, 2H).MS(ESI+): 535.3(M+H).

[1070] Example 55 (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]amino)pyrimidin-4-yl)amino)-5-methoxyphenyl)dimethylphosphine oxide

[1071]

[1072] The preparation method is described in Example 1, except that the 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced with (2-amino-5-methoxyphenyl) dimethylphosphine oxide.

[1073] 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.53 (s, 1H), 9.21 (s, 1H), 8.27 (d, J =6.9 Hz, 1H), 8.12 (s, 1H), 7.38 (d, J = 2.3 Hz, 1H), 7.23 (dd, J = 8.1, 2.2 Hz,1H), 7.16 (dd, J = 14.4, 3.0 Hz, 1H), 7.09 (dd, J = 9.1, 2.9 Hz, 1H), 6.93 (d, J =8.1 Hz, 1H), 3.82 (s, 3H), 2.83 (m, 2H), 2.55 (d, J= 6.1 Hz, 4H), 2.47-2.4 (m, 3 H), 1.87 (m, 2H), 1.77 (s, 3H), 1.74 (s, 3H), 1.68 (d, J = 6.2 Hz, 4H), 1.50(s, 2H). MS(ESI+): 540.2(M+H).

[1074] Example 56 (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)phenyl)bis(methyl- d 3 )Phosphine oxide

[1075]

[1076] Prepared according to the preparation method of Example 1, the 2-amino-N,N-dimethylbenzenesulfonamide in step a) was replaced by (2-aminophenyl)bis(methyl- d 3 )Phosphine oxide can be used.

[1077] 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.11 (s, 1H), 9.28 (s, 1H), 8.57 (d, J =6.1 Hz, 1H), 8.17 (s, 1H), 7.60 (ddd, J = 13.9, 7.7, 1.6 Hz, 1H), 7.49 (t, J =7.9 Hz, 1H), 7.39 (d, J = 2.3 Hz, 1H), 7.31 (dd, J = 8.1, 2.3 Hz, 1H), 7.19 (td, J = 7.6, 2.0 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H), 4.20 – 3.94 (m, 1H), 3.17 (d, J=4.8 Hz, 2H), 2.87 (s, 2H), 2.53 (s, 4H), 1.85 (s, 2H), 1.73 – 1.64 (m, 4H),1.51 (s, 2H). MS(ESI+):516.3(M+H).

[1078] Example 57 (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)bis(methyl- d 3 )Phosphine oxide

[1079]

[1080] Prepared according to the preparation method of Example 1, the 2-amino-N,N-dimethylbenzenesulfonamide in step a) was replaced by (2-amino-5-fluorophenyl)bis(methyl- d 3 )Phosphine oxide can be used.

[1081] 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.80 (s, 1H), 9.27 (s, 1H), 8.49 (s, 1H), 8.16 (s, 1H), 7.52 (ddd, J = 14.0, 8.7, 3.1 Hz, 1H), 7.39 – 7.30 (m, 2H), 7.26(dd, J = 8.1, 2.2 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 2.93 – 2.66 (m, 2H), 2.62 –2.53 (m, 7H), 1.88 (d, J = 2.2 Hz, 2H), 1.68 (q, J = 3.9 Hz, 4H), 1.44 (s, 2H).MS(ESI+): 534.2(M+H).

[1082] Example 58 Preparation of Compounds 58-1 to 58-4

[1083]

[1084] a) (2-((2,5-dichloropyrimidin-4-yl)amino)-5-fluorophenyl)dimethylphosphine oxide

[1085] The compound (2-amino-5-fluorophenyl) dimethylphosphine oxide (1.1 g) and 2,4,5-trichloropyrimidine (1.18 g) were dissolved in N,N-dimethylformamide (15 mL), and N,N-diisopropylethylamine (1.52 g) was added, and the mixture was heated to 70°C for 5 h. The reaction solution was diluted with 50 mL of water, and then the diluent was extracted with ethyl acetate (80 mL×3). The ethyl acetate layer was washed with saturated sodium chloride solution 3 times (50 mL×3), and the organic layer was dried over anhydrous sodium sulfate and concentrated to dryness to obtain a crude product. The title compound (1.08 g) was obtained by slurrying with ethanol (20 mL). MS (ESI+): 334.06 (M+H).

[1086] b) Preparation of 2-((5-chloro-4-((2-(dimethylphosphoryl)-4-fluorophenyl)amino)pyrimidin-2-yl)amino)-5,6,8,9-tetrahydro-7H-benzo[7]annulene-7-one

[1087] N,N-dimethylformamide (5 ml), 2-amino-5,6,8,9-tetrahydrobenzo[7]annulene-7-one (200.00 mg), 2,5-dichloro-N-[2-(dimethylphosphoryl)-4-fluorophenyl]pyrimidin-4-amine (343.20 mg) were added to the reaction flask, and a 4M hydrochloric acid solution in 1,4-dioxane (80.00 mg) was added under nitrogen protection and stirring. The reaction mixture was irradiated with microwave radiation at 130 °C for 10 minutes, concentrated under reduced pressure, and diluted with N,N-dimethylformamide (5 ml). The precipitated solid was collected by filtration and washed with petroleum ether / ethyl acetate (5:1) (2x5 mL) to obtain a filtrate of the title product. The filtrate was concentrated to 5 ml under reduced pressure and purified by preparative liquid chromatography (column: XBridge Prep OBD C18 column, 30×150 mm, filler particle size 5 μm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: 25% B to 65% B in 10 min; UV detection wavelength 220 nm; product retention time: 7.53 min) to obtain the pure title product (100 mg). MS (ESI+): 473.05 (M+H).

[1088] c) Preparation of compounds 58-1, 58-2, 58-3, and 58-4

[1089] A stirred mixture of 2-azabicyclo[3.1.0]hexane hydrochloride (75.87 mg) and magnesium sulfate (101.81 mg) was added to dichloromethane (5 mL), and triethylamine (85.59 mg) was added at room temperature under a nitrogen atmosphere. The mixture was stirred for 10 minutes, and 2-[(5-chloro-4-[[2-(dimethylphosphoryl)-4-fluorophenyl]amino]pyrimidin-2-yl)amino]-5,6,8,9-tetrahydrobenzo[7]annulene-7-one (100.00 mg) was added to the mixture, and stirred at 35°C for 1 hour. Sodium cyanoborohydride (39.87 mg) was added to the mixture, and stirred at 35°C for 3 hours. The resulting mixture was filtered, and the filter cake was washed with dichloromethane (3 x 10 mL). The mother liquor was concentrated under reduced pressure, and the residue was purified by reverse phase high performance liquid chromatography (column: XBridge-Prep-OBD C18 column, 30×150 mm, filler particle size 5 μm; mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 25% B to 65% B, 10 min; detection wavelength: 220 nm; isomer mixture retention time: 8.62 min) to obtain the title product (a mixture of 4 isomers).

[1090] Chiral separation was performed by chiral liquid chromatography (Chiralpak IA, 2x25 cm, filler particle size 5 μm; mobile phase A: n-hexane (10 mM ammonia-methanol), mobile phase B: ethanol; flow rate: 18 ml / min; gradient: 50% B isocratic in 16 min; detection wavelength: 220 / 254 nm; column temperature: 25 °C)

[1091] Isomer 58-1 (12.2 mg). Chiral HPLC retention time: 1.96 min.

[1092] 1 H NMR (400 MHz, DMSO -d 6 ): δ 10.84 (s, 1H), 9.27 (s, 1H), 8.50 (d, J =8.4 Hz, 1H), 8.17 (s, 1H), 7.53 (ddd, J = 13.9, 8.7, 3.0 Hz, 1H), 7.38 (d, J =2.3 Hz, 1H), 7.39 – 7.30 (m, 1H), 7.26 (d, J = 8.0 Hz, 1H), 6.97 (d, J= 8.1 Hz,1H), 2.95 – 2.82 (m, 3H), 2.71 – 2.65 (m, 1H), 2.48 – 2.41 (m, 2H), 2.26 (t, J = 6.6 Hz, 1H), 1.99 – 1.84 (m, 3H), 1.82 (s, 3H), 1.80 (s, 1H), 1.78 (s, 3H), 1.77 – 1.71 (m, 1H), 1.69 – 1.62 (m, 1H), 1.47 (s, 1H), 1.35 (s, 1H), 0.62(q, J = 4.2, 3.6 Hz, 1H), 0.09 (q, J = 5.6 Hz, 1H). MS(ESI+): 540.15(M+H).

[1093] Isomer 58-2 (10.6 mg), chiral HPLC retention time is 3.58 min.

[1094] 1 H NMR (400 MHz, DMSO -d 6 ): δ 10.83 (s, 1H), 9.27 (s, 1H), 8.50 (s, 1H), 8.17 (s, 1H), 7.53 (ddd, J = 14.0, 8.8, 3.0 Hz, 1H), 7.39 – 7.30 (m, 2H),7.27 (d, J = 7.9 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 2.91 (t, J = 8.3 Hz, 2H), 2.85– 2.78 (m, 1H), 2.68 (s, 1H), 2.46 (s, 2H), 2.26 (t, J = 6.6 Hz, 1H), 1.86 (s, 3H), 1.80 (d, J = 13.7 Hz, 8H), 1.70 – 1.63 (m, 1H), 1.46 (s, 1H), 1.34 (s,1H), 0.61 (d, J = 6.8 Hz, 1H), 0.09 (q, J= 5.6 Hz, 1H). MS(ESI+): 540.15(M+H).

[1095] Isomer 58-3 (12.7 mg), chiral HPLC retention time: 1.39 min.

[1096] 1 H NMR (400 MHz, DMSO -d 6 ): δ 10.82 (s, 1H), 9.27 (s, 1H), 8.49 (s, 1H), 8.17 (s, 1H), 7.53 (ddd, J = 13.9, 8.8, 3.0 Hz, 1H), 7.39 – 7.30 (m, 2H), 7.30 – 7.23 (m, 1H), 6.98 (d, J = 8.1 Hz, 1H), 2.96 – 2.87 (m, 2H), 2.78 (s,1H), 2.68 (s, 1H), 2.46 (s, 2H), 2.26 (t, J = 6.6 Hz, 1H), 1.99 – 1.85 (m, 3H), 1.80 (d, J = 13.7 Hz, 8H), 1.65 (s, 1H), 1.48 (s, 1H), 1.35 (s, 1H), 0.62 (s,1H), 0.09 (d, J = 8.0 Hz, 1H). MS(ESI+): 540.15(M+H).

[1097] Isomer 58-4 (12.2 mg), chiral HPLC retention time: 1.58 min.

[1098] 1 H NMR (400 MHz, DMSO -d 6 ): δ 10.84 (s, 1H), 9.27 (s, 1H), 8.50 (s, 1H), 8.17 (s, 1H), 7.53 (ddd, J = 14.0, 8.8, 3.1 Hz, 1H), 7.41 – 7.30 (m, 2H),7.26 (d, J = 7.8 Hz, 1H), 6.97 (d, J= 8.1 Hz, 1H), 2.94 - 2.82 (m, 3H), 2.69 (s,1H), 2.46 (s, 3H), 2.05 - 1.84 (m, 3H), 1.80 (d, J = 13.7 Hz, 8H), 1.66 (s,1H), 1.47 (s, 1H), 1.36 (s, 1H), 0.63 (s, 1H), 0.10 (s, 1H). MS(ESI+): 540.15(M+H).

[1099] Example 59 Preparation of Compounds 59-1 and 59-2

[1100]

[1101] Prepared with reference to the preparation method of Example 58, 2-azabicyclo[3.1.0]hexane hydrochloride in step b) was replaced with 3-azabicyclo[3.1.0]hexane hydrochloride. The crude product was purified by reverse phase high performance liquid chromatography (column: XBridge-Prep-OBD C18 column, 30×150 mm, filler particle size 5 μm; mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 25B~65 B, 10min; detection wavelength: 220 nm; isomer mixture retention time: 8.62 minutes) to obtain a mixture of isomers.

[1102] The isomeric mixture was chiral separated by chiral liquid chromatography (column: CHIRALPAK IF, 2 x 25 cm, filler particle size 5 μm; mobile phase A: n-hexane (0.1% diethanolamine), mobile phase B: ethanol; flow rate: 20 ml / min; gradient: 20% B isocratic in 21 minutes; detection wavelength: 220 / 254 nm; column temperature: 25°C), and the following was obtained after separation:

[1103] Isomer 59-1 (16.8 mg). Chiral HPLC retention time: 8.10 min.

[1104] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ10.83 (s, 1H), 9.26 (s, 1H), 8.49 (s,1H), 8.17 (s, 1H), 7.53 (ddd, J = 13.9, 8.7, 3.0 Hz, 1H), 7.33 (dq,J = 8.7, 3.0Hz, 2H), 7.26 (dd, J = 8.2, 2.2 Hz, 1H), 6.96 (d, J = 8.1 Hz, 1H), 2.95 – 2.80(m, 4H), 2.39 (s, 3H), 2.31 – 2.21 (m, 1H), 1.81 (s, 3H), 1.78 (s, 3H), 1.77– 1.61 (m, 2H), 1.51 (s, 2H), 1.38 (s, 2H), 1.24 (s, 1H), 0.60 (q, J = 3.7 Hz,1H), 0.31 (s, 1H). MS(ESI+): 540.15(M+H)

[1105] Isomer 59-2 (15.3 mg), chiral HPLC retention time is 10.29 min.

[1106] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 10.83 (s, 1H), 9.26 (s, 1H), 8.49 (s, 1H), 8.17 (s, 1H), 7.53 (ddd, J = 13.9, 8.7, 3.0 Hz, 1H), 7.33 (dq, J = 8.8,3.1 Hz, 2H), 7.26 (dd, J = 8.2, 2.3 Hz, 1H), 6.96 (d, J = 8.1 Hz, 1H), 2.89 (m,4H), 2.43 (m, 3H), 2.26 (t, J = 6.7 Hz, 1H), 1.81 (s, 3H), 1.78 (s, 4H), 1.76 –1.72 (m, 1H), 1.69 – 1.61 (m, 1H), 1.51 (s, 2H), 1.38 (s, 2H), 0.59 (q, J = 3.7Hz, 1H), 0.31 (s, 1H). MS(ESI+): 540.15(M+H)

[1107] Example 60 Preparation of Compounds 60-1 and 60-2

[1108]

[1109] The product was prepared by referring to the preparation method of Example 58, except that the 2-azabicyclo[3.1.0]hexane hydrochloride in step b) was replaced with 2-azabicyclo[2.1.1]hexane hydrochloride. The crude product was purified by reverse phase high performance liquid chromatography (column: XBridge-Prep-OBD C18 column, 30×150 mm, filler particle size 5 μm; mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 25% B to 65% B, 10 min; detection wavelength: 220 nm; isomer mixture retention time: 8.62 minutes) to obtain an isomer mixture.

[1110] Chiral separation of isomer mixture was performed by chiral liquid chromatography (column: CHIRALPAK IG, 2 cm x 25 cm, filler particle size 5 μm; mobile phase A: methyl tert-butyl ether (10 mM ammonia-methanol), mobile phase B: ethanol; flow rate: 20 ml / min,

[1111] Gradient: 20% B in 10 min; detection wavelength 220 / 254 nm; column temperature: 25°C), after separation:

[1112] Isomer 60-1 (28.7 mg), chiral HPLC retention time: 1.67 min.

[1113] 1 H NMR (400 MHz, DMSO -d 6 , ppm) : δ 10.84 (s, 1H), 9.27 (s, 1H), 8.50 (s, 1H), 8.17 (s, 1H), 7.53 (ddd, J = 14.0, 8.8, 3.1 Hz, 1H), 7.39 – 7.30 (m,2H), 7.27 (dd, J = 8.2, 2.3 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 3.65 (d, J = 6.5 Hz,1H), 2.85 (d, J = 37.1 Hz, 2H), 2.73 – 2.62 (m, 3H), 2.57 (d, J = 14.5 Hz, 3H),1.92 (d, J= 12.8 Hz, 2H), 1.82 (s, 3H), 1.78 (s, 3H), 1.61 (s, 2H), 1.48 –1.20 (m, 4H). MS(ESI+): 540.15(M+H)

[1114] Isomer 60-2 (27.7 mg), chiral HPLC retention time: 2.31 min.

[1115] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 10.84 (s, 1H), 9.27 (s, 1H), 8.51 (s, 1H), 8.17 (s, 1H), 7.53 (ddd, J = 13.9, 8.8, 3.0 Hz, 1H), 7.41 – 7.30 (m,2H), 7.27 (dd, J = 8.1, 2.2 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H), 3.65 (d, J = 6.5 Hz,1H), 2.86 (m, 2H), 2.74 – 2.62 (m, 3H), 2.57 (d, J = 14.5 Hz, 3H), 1.92 (d, J =14.3 Hz, 2H), 1.82 (s, 3H), 1.78 (s, 3H), 1.61 (d, J = 4.3 Hz, 2H), 1.48 – 1.21(m, 4H). MS(ESI+): 540.15(M+H)

[1116] Example 61 (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]amino)pyrimidin-4-yl)amino)-5-hydroxyphenyl)dimethylphosphine oxide

[1117]

[1118] (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]amino)pyrimidin-4-yl)amino)-5-methoxyphenyl)dimethylphosphine oxide (140 mg) and dichloromethane (10 mL) were added to a 25 mL single-necked bottle and stirred. The temperature was then lowered to -20°C. Boron tribromide (150 mg) was added dropwise to the reaction solution. After the addition, the temperature was gradually raised to room temperature and stirred overnight. The temperature was then lowered to -20°C, sodium bicarbonate was added dropwise to obtain a saturated solution, and extracted with dichloromethane (10 mL). The organic layers were combined, concentrated to dryness, and purified by silica gel column chromatography (dichloromethane: methanol = 20: 1 v / v) to obtain 16 mg of the title product.

[1119] 1 H NMR (400 MHz, DMSO- d 6 , ppm ): δ10.19 (s, 1H), 9.69 (s, 1H), 9.17 (s,1H), 8.07 (d, J = 16.1 Hz, 2H), 7.37 (d, J = 2.3 Hz, 1H), 7.28 – 7.16 (m,1H), 7.03 (dd, J = 14.3, 2.9 Hz, 1H), 6.95 (dd, J = 8.9, 2.8 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 2.82 (m, 2H), 2.55 (m, 4H), 2.44 (d, J = 12.7 Hz, 3H),1.84 (s, 2H), 1.70 (s, 3H), 1.69 (s, 4H), 1.67 (s, 3H), 1.50 (s, 2H). MS(ESI+): 526.2(M+H).

[1120] Example 62 Preparation of Compounds 62-1 and 62-2

[1121]

[1122] The product was prepared by referring to the preparation method of Example 58, except that the 2-azabicyclo[3.1.0]hexane hydrochloride in step c) was replaced with 5-azaspiro[2.4]heptane hydrochloride. The crude product was purified by reverse phase high performance liquid chromatography (column: Xselect CSHOBD column, 30×150 mm, filler particle size 5 μm; mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 25% B to 55% B, 8 min; detection wavelength: 254 / 220 nm) to obtain 60 mg of an isomer mixture.

[1123] The isomer mixture was chirally separated by chiral liquid chromatography (column: CHIRALPAK IC, 2cmx25cm, filler particle size 5 μm; mobile phase A: n-hexane (10 mM ammonia-methanol), mobile phase B: ethanol; flow rate: 20 ml / min, gradient: 50% B isocratic in 12 min; detection wavelength 220 / 254 nm; column temperature: 25°C). After separation, the following was obtained:

[1124] Isomer 62-1 (27.2 mg). HPLC retention time: 7.9 min.

[1125] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ10.84 (s, 1H), 9.27 (s, 1H), 8.50 (s,1H), 8.17 (s, 1H), 7.53 (m, 1H), 7.39 – 7.29 (m, 2H), 7.27 (d, J = 8.1 Hz, 1H),6.97 (d, J = 8.2 Hz, 1H), 2.88 (m, 2H), 2.73 (m, 2H), 2.48 (m, 2H), 2.43 (m,2H), 1.90 – 1.68 (m, 11H), 1.50 (s, 2H), 0.51 (m, 4H). MS(ESI+): 554.2(M+H)

[1126] Isomer 62-2 (28.2 mg). HPLC retention time: 9.8 min.

[1127] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 10.84 (s, 1H), 9.27 (s, 1H), 8.50 (s, 1H), 8.17 (s, 1H), 7.53 (ddd, J = 13.9, 8.7, 3.1 Hz, 1H), 7.39 – 7.30 (m,2H), 7.27 (dd, J = 7.9, 2.0 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H), 2.87 (s, 2H), 2.73(t, J = 6.8 Hz, 2H), 2.59 (s, 2H), 2.51 – 2.41 (m,2H), 1.92 – 1.68 (m, 11H), 1.50 (s, 2H), 0.56 – 0.45 (m, 4H). MS(ESI+): 554.2(M+H)

[1128] Example 63 Preparation of Compounds 63-1, 63-2, 63-3, and 63-4

[1129]

[1130] Prepared by referring to the preparation method of Example 58, except that 2-azabicyclo[3.1.0]hexane hydrochloride in step c) was replaced with 2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride. The crude product was purified by preparative high performance liquid chromatography under the following conditions (column: Xselect CSH-OBD column 30x150mm filler particle size 5μm; mobile phase A: water (10mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: 20%B~53%B in 8 minutes; wavelength: 210 nm; retention time: 7.02min) to obtain a white mixture of 4 isomers.

[1131] The four isomer mixtures were purified by chiral HPLC column (IC column: CHIRALPAK ID, 2x25 cm (filler 5 μm); mobile phase A: methyl tert-butyl ether (10 mM ammonia-methanol), mobile phase B: methanol; flow rate: 20 ml / min; gradient: 10% B in 27 minutes, isocratic; detection wavelength: 220 / 254 nm; column temperature: 25 °C)

[1132] Isomer 63-1 (20 mg) was obtained with a HPLC retention time of 13.5 min.

[1133] 1 H NMR (400 MHz, DMSO-d 6 , ppm ): δ 10.83 (s, 1H), 9.26 (s, 1H), 8.50 (s, 1H), 8.17 (s, 1H), 7.53 (t, J = 11.4 Hz, 1H), 7.35 (s, 2H), 7.30 – 7.23 (m,1H), 6.96 (d, J = 8.2 Hz, 1H), 4.33 (s, 1H), 3.89 (d, J = 7.5 Hz, 1H), 3.69 (s,1H), 3.55 (s, 1H), 3.44 (s, 2H), 2.99 (d, J = 9.3 Hz, 1H), 2.87 (s, 2H), 2.68(s, 1H), 2.33 (m, 1H), 1.80 (m, 8H), 1.72 (d, J = 9.4 Hz, 1H), 1.61 (m, 1H), 1.40 (m, 2H). MS(ESI+): 556.2(M+H);

[1134] Isomer 63-2 (14.7 mg), HPLC retention time 16.8 min.

[1135] 1 H NMR (400 MHz, DMSO- d 6 , ppm ): δ 10.83 (s, 1H), 9.26 (s, 1H), 8.50 (s,1H), 8.17 (s, 1H), 7.53 (m, 1H), 7.35 (m, 2H), 7.29 – 7.24 (m, 1H), 6.96 (d, J = 8.2 Hz, 1H), 4.33 (s, 1H), 3.89 (d, J = 7.5 Hz, 1H), 3.69 (s, 1H), 3.55 (s,2H), 2.99 (m, 1H), 2.87 (m, 2H), 2.68 (m, 2H), 2.33 (m, 1H), 1.80 (m,8H), 1.72(m, 1H), 1.61 (m, 1H), 1.40 (m, 2H). MS(ESI+): 556.2(M+H);

[1136] and a mixture of isomer 63-3 and isomer 63-4 (42 mg)

[1137] The mixture of isomer 63-3 and isomer 63-4 was purified again by chiral liquid chromatography (column: Chiralpak IC, 2x25cm, filler particle size 5μm; mobile phase A: methyl tert-butyl ether (10 mM ammonia-methanol), mobile phase B: isopropanol; flow rate: 20ml / min; gradient: 30%B in 21 min, isocratic; detection wavelength: 220 / 254nm; column temperature: 25℃) to obtain:

[1138] Isomer 63-3 (14.7 mg), HPLC retention time 9.2 min.

[1139] 1 H NMR: (400 MHz, DMSO- d 6 , ppm ): δ 10.84 (s, 1H), 9.26 (s, 1H), 8.50 (s, 1H), 8.17 (s, 1H), 7.57 – 7.47 (m, 1H), 7.39 – 7.24 (m, 3H), 6.97 (m, 1H), 4.33 (m, 1H), 3.90 (m, 1H), 3.69 (m, 1H), 3.53 (m, 1H), 3.00 (m, 1H), 2.86 (s, 3H), 2.70 (m, 2H), 2.33 (m, 1H), 1.80 (m, 8H), 1.72 (m, 1H), 1.61 (m,1H), 1.40 (m, 2H).MS(ESI+): 556.2(M+H);

[1140] Isomer 63-4 (15 mg), HPLC retention time 18.9 min.

[1141] 1 H NMR: (400 MHz, DMSO- d 6 , ppm ): δ 10.84 (s, 1H), 9.26 (s, 1H), 8.50 (s, 1H), 8.17 (s, 1H), 7.53 (m, 1H), 7.39 – 7.22 (m, 3H), 6.97 (d, J = 8.2 Hz,1H), 4.33 (d, J= 2.1 Hz, 1H), 3.89 (m, 1H), 3.71 – 3.67 (m, 1H), 3.53 (m, 1H), 3.00 (m, 1H), 2.87 (m, 2H), 2.70 (m, 1H), 2.55 (m, 2H), 2.33 (m, 1H), 1.80(m, 8H), 1.72 (m, 1H), 1.61 (m, 1H), 1.39 (m, 2H). MS(ESI+): 556.2(M+H).

[1142] Example 64 (2-((5-chloro-2-(((S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)phenyl)(methyl)(methylimino)-λ 6 - Preparation of sulfadiazine

[1143]

[1144] a) 2-Methylthionitrobenzene

[1145] 1-Fluoro-2-nitrobenzene (1.4 g), isopropanol (15 ml), sodium methyl mercaptan (2.1 g) were added to the reaction flask in sequence and reacted at room temperature for 3 h. After the reaction was completed, the reaction solution was cooled to 0°C, filtered, and the filter cake was washed with water (10 ml*2) and dried to obtain 1.62 g of the title product.

[1146] b) Imino(methyl)(2-nitrophenyl)-λ 6 - Preparation of sulfadiazine

[1147] Compound 2-methylthionitrobenzene (400 mg), ethanol (15 ml), iodophenyl diacetic acid (1.5 g), and ammonium acetate (0.74 g) were added to the reaction bottle in sequence and reacted at room temperature for 2 h. After the reaction was completed, the solvent was removed by concentration under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1 v / v) to obtain 374 mg of the title product.

[1148] c) Methyl(methylimino)(2-nitrophenyl)-λ 6 Preparation of sulfadiazine

[1149] Add imino(methyl)(2-nitrophenyl)-λ 6-sulfamethoxazole (370 mg), N,N-dimethylformamide (2 ml), sodium hydride (89 mg, 60% w / w), iodomethane (315 mg) were added dropwise and reacted at room temperature for 1 hour. After the reaction was completed, the solvent was removed by concentration under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1 v / v) to obtain 289 mg of the title product.

[1150] d)(2-aminophenyl)(methyl)(methoxyimino)-λ 6 Preparation of sulfadiazine

[1151] Under ice-cooling conditions, methyl(methylimino)(2-nitrophenyl)-λ 6 Titanium trichloride (6 ml) was added dropwise to a solution of sulfadiazine (235 mg) in tetrahydrofuran (5 ml). After the addition was complete, the temperature was gradually raised to room temperature for 2 h. After the reaction was complete, 2M sodium hydroxide was added dropwise to neutralize the reaction solution to a weak alkaline state. The reaction solution was filtered, and the filter cake was washed with ethyl acetate (10 ml*3). The organic layers were combined, dried, and concentrated to obtain 182 mg of the title product.

[1152] e)(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)(methyl)(methylimino)-λ 6 Preparation of sulfadiazine

[1153] At 0°C, 2,4,5-trichloropyrimidine (217 mg), (2-aminophenyl)(methyl)(methylimino)-λ 6 Sulfadiazine (182 mg), N,N-dimethylformamide (5 ml), sodium hydride (48 mg, 60% w / w). Gradually warm to room temperature and react for 2 hours. After the reaction is completed, quench with saturated ammonium chloride solution, separate the layers, extract the aqueous phase with ethyl acetate, combine the organic layers, dry over anhydrous sodium sulfate, concentrate, and purify by silica gel column chromatography (dichloromethane / methanol = 20 / 1 v / v) to obtain 170 mg of the title product.

[1154] f)(2-((5-chloro-2-(((S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)amino)pyrimidin-4-yl)amino)phenyl)(methyl)(methylimino)-λ 6 - Preparation of sulfadiazine

[1155] Add (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)(methyl)(methylimino)-λ 6Sulfadiazine (170 mg), N,N-dimethylformamide (5 ml), (S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-amine (118 mg), p-toluenesulfonic acid monohydrate (194 mg), 400W microwave at 120°C for 1 h. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the title product (46 mg) was obtained after purification by silica gel column chromatography (dichloromethane: methanol = 20: 1 v / v).

[1156] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 10.83 (s, 1H), 9.39 (s, 1H), 8.75 (d, J = 6.8 Hz, 1H), 8.26 (s, 1H), 7.89 (dd, J = 7.9, 1.5 Hz, 1H), 7.64 (t, J= 7.9 Hz, 1H), 7.40 (s, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.00 (d, J = 8.1 Hz,1H), 3.18 (s, 3H), 2.88 (s, 2H), 2.71 (s, 3H), 2.67 – 2.52 (m, 7H), 1.92 (s,2H), 1.71 (s, 4H), 1.51 (s, 2H). MS(ESI+): 525.2(M+H).

[1157] Example 65 (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]amino)pyrimidin-4-yl)amino)-3-fluoro-5-methylphenyl)dimethylphosphine oxide

[1158]

[1159] The preparation method can be referred to Example 47, except that the quinoxaline-6-amine in step a) is replaced by 2-fluoro-4-methylaniline.

[1160] 1 H NMR (400 MHz, DMSO- d 6 , ppm ): δ8.96 (s, 1H), 7.52 (d, J = 12.2 Hz, 1H), 7.42 (d, J = 10.7 Hz, 1H), 7.22 (s, 1H), 6.98 (d, J = 8.1 Hz, 1H), 6.74(dd, J = 13.7, 8.0 Hz, 2H), 6.29 (d, J = 28.4 Hz, 1H), 2.85 – 2.67 (m, 2H), 2.42 (d, J = 12.2 Hz, 7H), 1.89 (s, 2H), 1.80 (s, 2H), 1.68 (d, J = 6.1 Hz,4H), 1.62 (s, 3H), 1.59 (s, 3H), 1.45 (s, 2H). MS(ESI+): 542.2(M+H).

[1161] Example 66 2-((5-chloro-2-((3-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)dimethylphosphine oxide

[1162]

[1163] Prepared according to the preparation method of Example 1, the 2-amino- N,N - dimethylbenzenesulfonamide was replaced by (2-amino-5-fluorophenyl) dimethylphosphine oxide;

[1164] The target product is obtained by replacing (S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-amine in step b) with 3-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine.

[1165] 1 H NMR (400 MHz, DMSO- d 6 , ppm ): δ 10.87 (s, 1H), 9.31 (s, 1H), 8.50 (s, 1H), 8.17 (s, 1H), 7.56 – 7.49 (m, 1H), 7.37 – 7.28 (m, 3H), 6.98 (d, J= 7.9Hz, 1H), 3.86 – 3.71 (m, 3H), 3.67-3.47 (m, 3H), 3.22 (br, 1H), 2.85-2.68 (m,5H), 2.64 – 2.57 (m, 2H), 1.01-1.94 (m, 1H), 1.81 (s, 3H), 1.78 (s, 3H). MS(ESI+): 530.1(M+H).

[1166] Example 67 Preparation of Compounds 67-1 and 67-2

[1167]

[1168] Prepared by referring to the preparation method of Example 58, except that 2-azabicyclo[3.1.0]hexane hydrochloride in step c) was replaced with 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride. The crude product was purified by preparative high performance liquid chromatography under the following conditions (column: Xselect CSH-OBD column 30x150mm filler particle size 5μm; mobile phase A: water (10mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: 40%B~70%B in 8 minutes; wavelength: 254 / 220nm) to obtain 200mg of a mixture of two isomers.

[1169] The two isomer mixtures were purified by chiral HPLC: IC: column: CHIRALPAK IC, 2x25 cm (filler 5 μm); mobile phase A: n-hexane (10 mM ammonia-methanol), mobile phase B: ethanol; flow rate: 20 ml / min; gradient: 30% B in 12 minutes, isocratic; detection wavelength: 220 / 254 nm; column temperature: 25 °C)

[1170] Isomer 67-1 (91 mg, 36.98%) was obtained, with a HPLC retention time of 11.2 min:

[1171] 1 HNMR (400 MHz, DMSO- d 6 , ppm ): δ 10.84 (s, 1H), 9.27 (s, 1H), 8.50 (s,1H), 8.17 (s, 1H), 7.53 (m, 1H), 7.38 – 7.29 (m, 2H), 7.27 (d, J = 8.2 Hz, 1H),6.97 (d, J= 8.1 Hz, 1H), 3.31 (s, 3H), 3.03 (m, 2H), 2.84 (m, 4H), 2.32 (m,2H), 1.80 (m, 6H), 1.74 (m, 2H), 1.55 (m, 2H). MS(ESI+): 576.2(M+H).

[1172] Isomer 67-2 (93.4 mg, 37.96%) was obtained, with a HPLC retention time of 8.6 min:

[1173] 1 HNMR (400 MHz, DMSO- d 6 , ppm ): δ 10.84 (s, 1H), 9.27 (s, 1H), 8.50 (s, 1H), 8.17 (s, 1H), 7.53 (ddd, J = 13.9, 8.8, 3.1 Hz, 1H), 7.38 – 7.29 (m, 2H),7.27 (d, J = 7.9 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 3.31 (s, 3H), 3.03 (m, 2H), 2.84 (m, 4H), 2.32 (m, 2H), 1.80 (m, 6H), 1.74 (m, 2H), 1.55 (m, 2H). MS(ESI+): 576.2(M+H).

[1174] Example 68 Preparation of Compounds 68-1 and 68-2

[1175]

[1176] Prepared by referring to the preparation method of Example 58, (2-amino-5-fluorophenyl) dimethylphosphine oxide in step a) was replaced by (2-amino-5-methylphenyl) dimethylphosphine oxide, and 2-azabicyclo[3.1.0]hexane hydrochloride in step c) was replaced by 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride. The crude product was purified by preparative high performance liquid chromatography under the following conditions (column: Xselect CSH-OBD column 30x150mm filler particle size 5μm; mobile phase A: water (10mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: 45%B~75%B in 8 minutes; wavelength: 210nm; isomer mixture retention time: 6.57min) to obtain a mixture of two isomers.

[1177] The two isomer mixtures were purified by chiral HPLC column (column: CHIRALPAK IE, 2x25 cm (filler 5 μm); mobile phase A: n-hexane (10 mM ammonia-methanol), mobile phase B: ethanol; flow rate: 15 ml / min; gradient: 50% B in 25 minutes, isocratic; detection wavelength: 220 / 254 nm; column temperature: 25 °C)

[1178] Isomer 68-1 (85 mg) was obtained, with a HPLC retention time of 19.4 min:

[1179] 1 H NMR: (400 MHz, DMSO- d 6 , ppm ): δ 10.86 (s, 1H),9.24 (s, 1H),8.38 (s,1H),8.15 (s, 1H),7.43 (d, J = 15.2 Hz, 2H), 7.29 (m, 2H), 6.96 (m, 1H), 3.41(s, 3H), 3.05 (s, 2H), 2.86 (m, 4H), 2.34 (m, 5H), 1.76 (m, 8H), 1.54 (m 2H).MS(ESI+): 572.2(M+H).

[1180] Isomer 68-2 (85 mg) was obtained, with a HPLC retention time of 14.9 min:

[1181] 1 H NMR: (400 MHz, DMSO- d 6 , ppm ): δ 10.83 (s, 1H), 9.22 (s, 1H), 8.37 (s, 1H), 8.14 (d, J = 0.7 Hz, 1H), 7.47 – 7.36 (m, 2H), 7.28 (m, 2H), 6.96 (m,1H), 3.50 (s, 3H), 3.03 (m, 2H), 2.85 (m, 4H), 2.34 (m, 5H), 1.76 (m, 8H),1.55 (m, 2H). MS(ESI+): 572.2(M+H).

[1182] Example 69 Preparation of Compounds 69-1 and 69-2

[1183]

[1184] The product was prepared by referring to the preparation method of Example 58, except that the (2-amino-5-fluorophenyl)dimethylphosphine oxide in step a) was replaced by (2-amino-5-methylphenyl)dimethylphosphine oxide, and the 2-azabicyclo[3.1.0]hexane hydrochloride in step c) was replaced by 5-azaspiro[2.4]heptane hydrochloride. The crude product was purified by reverse phase high performance liquid chromatography (column: Xselect CSHOBD column, 30×150 mm, filler particle size 5 μm; mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 45%B to 75%B, 8 min; detection wavelength: 210 nm; retention time: 6.57 min) to obtain 60 mg of an isomer mixture.

[1185] Chiral separation of isomer mixture was performed by chiral liquid chromatography (column: CHIRALPAK IF, 2 cm x 25 cm, filler particle size 5 μm; mobile phase A: methyl tert-butyl ether (10 mM ammonia-methanol), mobile phase B: ethanol; flow rate: 15 ml / min,

[1186] Gradient: 30% B in 24 min; detection wavelength 220 / 254 nm; column temperature: 25℃; column temperature: 25℃), after separation:

[1187] Isomer 69-1 (76 mg). HPLC retention time: 10.8 min.

[1188] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 10.93 (s, 1H), 9.26 (s, 1H), 8.40 (s, 1H), 8.15 (s, 1H), 7.49 – 7.38 (m, 2H), 7.34 -7.23 (m, 2H), 6.97 (d, J = 8.1 Hz, 1H), 3.31 (s, 5H), 2.84 (m, 4H), 2.34 (s, 3H), 2.01-1.88 (m, 1H), 1.77 (m, 9H), 1.47 (m, 2H), 0.53 (m, 4H).

[1189] MS(ESI+): 550.2(M+H).

[1190] Isomer 69-2 (90 mg). HPLC retention time: 19.6 min.

[1191] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 10.93 (s, 1H), 9.26 (s, 1H), 8.40 (s, 1H), 8.15 (s, 1H), 7.49-7.38 (m, 2H), 7.34-7.23 (m, 2H), 6.97 (d, J = 8.1Hz, 1H), 3.31 (m, 5H), 2.84 (m, 4H), 2.34 (s, 3H), 2.01-1.88 (m, 1H), 1.77 (m,9H), 1.47 (m, 2H), 0.53 (m, 4H).

[1192] MS(ESI+): 550.2(M+H).

[1193] Example 70 Compound 70-1 70-2

[1194]

[1195] Prepared by referring to the preparation method of Example 58, replacing (2-amino-5-fluorophenyl) dimethylphosphine oxide in step a) with (2-amino-5-methylphenyl) dimethylphosphine oxide, and replacing 2-azabicyclo[3.1.0]hexane hydrochloride in step c) with 2-azabicyclo[2.1.1]hexane hydrochloride. The crude product was purified by preparative high performance liquid chromatography under the following conditions (column: Xselect CSH-OBD column 30x150mm filler particle size 5μm; mobile phase A: water (10mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: 10%B~40%B in 10 minutes; wavelength: 254 / 220nm;) to obtain 160mg of a mixture of two isomers.

[1196] The two isomer mixtures were purified by chiral HPLC column (column: CHIRALPAK IG, 2x25 cm, filler 5 μm); mobile phase A: methyl tert-butyl ether (10 nM amine-methanol solution), mobile phase B: ethanol; flow rate: 20 ml / min; gradient: 30% B in 11 minutes, isocratic; detection wavelength: 220 / 254 nm; column temperature: 25 ° C) to obtain:

[1197] Isomer 70-1 (mg), HPLC retention time 6.5min.

[1198] 1 H-NMR (400MHz, DMSO -d 6 , ppm ): δ 10.92 (s, 1H), 9.25 (s, 1H), 8.40 (s,1H), 8.15 (s, 1H), 7.50 – 7.36 (m, 2H), 7.30 (ddd, J = 10.8, 8.2, 2.1 Hz, 2H),6.98 (d, J = 8.1 Hz, 1H), 3.70 (s, 1H), 2.86 (d, J = 35.4 Hz, 2H), 2.72 (dt, J =6.5, 3.0 Hz, 3H), 2.64 – 2.53 (m, 3H), 2.34 (s, 3H), 1.92 (d, J = 18.7 Hz, 2H),1.77 (d, J = 13.5 Hz, 6H), 1.64 (s, 2H), 1.54 – 1.19 (m, 4H). MS(ESI+): 536.2(M+H).

[1199] Isomer 70-2 (mg), HPLC retention time 9.2min:

[1200] 1 HNMR (400 MHz, DMSO- d 6 , ppm ): δ 10.92 (s, 1H), 9.25 (s, 1H), 8.40 (s, 1H), 8.15 (s, 1H), 7.44 (dd, J = 12.6, 2.2 Hz, 2H), 7.30 (ddd, J = 11.0, 8.1, 2.2Hz, 2H), 6.98 (d, J = 8.1 Hz, 1H), 3.70 (s, 1H), 2.89 (s, 2H), 2.77 – 2.65 (m,3H), 2.65 – 2.54 (m, 3H), 2.34 (s, 3H), 1.92 (d, J = 18.1 Hz, 2H), 1.77 (d, J=13.5 Hz, 6H), 1.64 (s, 2H), 1.54 – 1.21 (m, 4H). MS(ESI+): 536.2(M+H).

[1201] Example 71 Preparation of Compounds 71-1 and 71-2

[1202]

[1203] Prepared by referring to the preparation method of Example 58, replacing (2-amino-5-fluorophenyl) dimethylphosphine oxide in step a) with (2-amino-5-methylphenyl) dimethylphosphine oxide, and replacing 2-azabicyclo[3.1.0]hexane hydrochloride in step c) with 3-azabicyclo[3.1.0]hexane hydrochloride. The crude product was purified by preparative high performance liquid chromatography under the following conditions (column: Xselect CSH-OBD column 30x150mm filler particle size 5μm; mobile phase A: water (10mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: 35%B~85%B in 8 minutes; wavelength: 254 / 220nm;) to obtain 140mg of a mixture of two isomers.

[1204] The two isomer mixtures were purified by chiral HPLC column (column: CHIRALPAK IE, 2x25 cm, filler 5 μm); mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol; flow rate: 18 ml / min; gradient: 20% B in 17 minutes, isocratic; detection wavelength: 220 / 254 nm column temperature: 25°C) to obtain:

[1205] Isomer 71-1 (45.8 mg), HPLC retention time 12.4 min:

[1206] 1 HNMR (400 MHz, DMSO- d 6 , ppm ): δ 10.90 (s, 1H), 9.24 (s, 1H), 8.37 (d, J = 5.8 Hz, 1H), 8.15 (s, 1H), 7.47 – 7.37 (m, 2H), 7.28 (m, 2H), 6.95 (d, J =8.2 Hz, 1H), 3.32 (s, 2H), 2.95 (d, J= 8.3 Hz, 2H), 2.87 (s, 2H), 2.42 – 2.36(m, 3H), 2.34 (s, 3H), 1.76 (m, 8H), 1.52 (s, 2H), 1.38 (s, 2H), 0.60 (m,1H), 0.32 (m, 1H). MS(ESI+): 536.2(M+H).

[1207] Isomer 71-2 (46.2 mg), HPLC retention time 14.5 min:

[1208] 1 HNMR (400 MHz, DMSO- d 6 , ppm ): δ 10.90 (s, 1H), 9.24 (s, 1H), 8.38 (s,1H), 8.15 (s, 1H), 7.47 – 7.37 (m, 2H), 7.34 – 7.22 (m, 2H), 6.95 (d, J = 8.1Hz, 1H), 3.33 (s, 2H), 2.95 (d, J = 8.3 Hz, 2H), 2.90 – 2.82 (m, 2H), 2.40 (s,3H), 2.34 (s, 3H), 1.76 (m, 8H), 1.52 (m, 2H), 1.41 – 1.35 (m, 2H), 0.60 (m,1H), 0.32 (m, 1H). MS(ESI+): 536.2(M+H).

[1209] Example 72 Compounds 72-1, 72-2, 72-3, 72-4

[1210]

[1211] Prepared by referring to the preparation method of Example 58, except that 2-azabicyclo[3.1.0]hexane hydrochloride in step c) was replaced with 2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride, and the crude product was purified by reverse phase high performance liquid chromatography (column: XBridge-Prep-OBD C18 column, 30×150 mm, filler particle size 5 μm; mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 25% B to 50% B, 8 min; detection wavelength: 254 / 220 nm) to obtain 275 mg of an isomer mixture.

[1212] The isomer mixture was chirally separated by chiral liquid chromatography (column: CHIRALPAK IG, 2cmx25cm, filler particle size 5 μm; mobile phase A: methyl tert-butyl ether (10 mM ammonia-methanol), mobile phase B: ethanol; flow rate: 20 ml / min, gradient: 15% B in 45 min, isocratic; detection wavelength 220 / 254 nm; column temperature: 25°C), and the following was obtained after separation:

[1213] Isomer 72-1 (36.4 mg), HPLC retention time: 1.67 min.

[1214] 1 H NMR (400 MHz, DMSO -d 6 , ppm) : (400 MHz, DMSO- d 6 , ppm ): δ 10.90 (s,1H), 9.24 (s, 1H), 8.40 (dd, J = 8.6, 4.4 Hz, 1H), 8.15 (s, 1H), 7.47 – 7.38(m, 2H), 7.29 (ddd, J = 12.4, 8.3, 2.2 Hz, 2H), 6.96 (d, J = 8.1 Hz, 1H), 4.33(t, J = 1.9 Hz, 1H), 3.90 (d, J = 7.5 Hz, 1H), 3.70 (s, 1H), 3.59 – 3.50 (m, 1H), 2.99 (dd, J = 9.6, 1.8 Hz, 1H), 2.86 (s, 2H), 2.71 (s, 1H), 2.53 (s, 1H), 2.48(s, 1H), 2.34 (s, 4H), 1.83 – 1.71 (m, 9H), 1.65 – 1.58 (m, 1H), 1.54 – 1.27(m, 2H). MS(ESI+): 552(M+H).

[1215] Isomer 72-2 (56.8 mg), HPLC retention time: 6.119 min.

[1216] 1 H NMR (400 MHz, DMSO -d6 , ppm ): (400 MHz, DMSO- d 6 , ppm ): δ 10.90 (s,1H), 9.25 (s, 1H), 8.39 (dd, J = 9.0, 4.5 Hz, 1H), 8.15 (s, 1H), 7.43 (dd, J =14.2, 2.2 Hz, 2H), 7.29 (ddd, J = 13.1, 8.3, 2.2 Hz, 2H), 6.96 (d, J = 8.1 Hz,1H), 4.33 (t, J = 1.9 Hz, 1H), 3.90 (d, J = 7.5 Hz, 1H), 3.70 (s, 1H), 3.53 (dd, J = 7.6, 1.7 Hz, 1H), 3.01 (dd, J = 9.6, 1.8 Hz, 1H), 2.86 (s, 2H), 2.72 (d, J =8.8 Hz, 1H), 2.57 (d, J = 11.9 Hz, 1H), 2.47 (d, J = 15.3 Hz, 1H), 2.33 (s, 4H), 1.76 (d, J = 13.5 Hz, 9H), 1.65 – 1.58 (m, 1H), 1.39 (s, 2H). MS(ESI+): 552(M+H).

[1217] Isomer 72-3 (60.3 mg), HPLC retention time: 7.224 min.

[1218] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 10.92 – 10.87 (m, 1H), 9.24 (s, 1H), 8.40 (d, J = 7.6 Hz, 1H), 8.15 (s, 1H), 7.47 – 7.38 (m, 2H), 7.29 (ddd, J= 11.7,8.3, 2.1 Hz, 2H), 6.96 (d, J = 8.1 Hz, 1H), 4.33 (s, 1H), 3.90 (d, J = 7.5 Hz,1H), 3.70 (s, 1H), 3.54 (d, J = 7.4 Hz, 1H), 2.99 (dd, J = 9.5, 1.6 Hz, 1H), 2.90– 2.83 (m, 2H), 2.72 (d, J = 8.5 Hz, 1H), 2.55 (d, J = 8.1 Hz, 1H), 2.48 (s, 1H), 2.34 (s, 4H), 1.76 (d, J = 13.5 Hz, 9H), 1.62 (d, J = 9.3 Hz, 1H), 1.39 (s, 2H).MS(ESI+): 552(M+H)

[1219] Isomer 72-4 (32.2 mg), HPLC retention time: 9.412 min.

[1220] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): (400 MHz, DMSO- d 6 , ppm ): δ 10.89 (s,1H), 9.24 (s, 1H), 8.39 (dd, J = 8.3, 4.3 Hz, 1H), 8.15 (s, 1H), 7.43 (dd, J =14.4, 2.1 Hz, 2H), 7.29 (ddd, J = 14.3, 8.3, 2.2 Hz, 2H), 6.96 (d, J = 8.1 Hz,1H), 4.34 (t, J = 2.0 Hz, 1H), 3.90 (d, J = 7.5 Hz, 1H), 3.71 (s, 1H), 3.54 (dd, J = 7.6, 1.7 Hz, 1H), 3.01 (dd,J = 9.6, 1.8 Hz, 1H), 2.86 (s, 2H), 2.73 (d, J =8.6 Hz, 1H), 2.61 – 2.54 (m, 1H), 2.47 (s, 1H), 2.36 (d, J = 9.2 Hz, 4H), 1.76(d, J = 13.5 Hz, 9H), 1.66 – 1.59 (m, 1H), 1.39 (s, 2H). MS(ESI+): 552(M+H).

[1221] Example 73 (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]amino)pyrimidin-4-yl)amino)-5-methylpyridin-3-yl)dimethylphosphine oxide

[1222]

[1223] Prepare by referring to the preparation method of Example 47, except that quinoxaline-6-amine in step a) is replaced by 2-amino-5-methylpyridine.

[1224] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 9.32 (s, 1H), 8.47 (s, 1H), 7.95 (d, J = 13.2 Hz, 1H), 7.66 (s, 1H), 7.37 (d, J = 2.3 Hz, 1H), 7.11 (d, J = 7.8 Hz,1H), 6.96 (d, J = 8.3 Hz, 1H), 2.75 (m, 7H), 2.36 (s, 3H), 2.29 (m, 2H), 1.97(m, 2H), 1.91 (s, 3H), 1.79 (s, 3H), 1.75 (m, 4H), 1.46 (s, 2H). MS(ESI+):525.4(M+H).

[1225] Example 74 (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-5-(trifluoromethyl)phenyl)dimethylphosphine oxide

[1226]

[1227] The preparation method is described in Example 47, except that the quinoxaline-6-amine in step a) is replaced by 4-trifluoromethylaniline.

[1228] 1 H NMR (400 MHz, DMSO- d6, ppm ): δ 9.74 (s, 1H), 9.31 (s, 1H), 8.18(s, 1H), 7.70 (dd, J = 11.5, 4.3 Hz, 1H), 7.59 (dd, J = 7.5, 3.0 Hz, 1H), 7.10 (t, J = 8.5 Hz, 2H), 7.06 (d, J = 7.6 Hz, 1H), 6.81 (d, J = 7.9 Hz, 1H), 2.83 (s, 7H), 2.62 (s, 2H), 2.04 (s, 2H), 1.88 (d, J = 13.8 Hz, 6H), 1.77(s, 4H), 1.49 (dd, J = 14.1, 3.7 Hz, 2H). MS(ESI+): 578.2(M+H).

[1229] Example 75 (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]amino)pyrimidin-4-yl)amino)-5-(difluoromethoxy)phenyl)dimethylphosphine oxide

[1230]

[1231] The preparation method is described in Example 10, except that the (2-aminophenyl)dimethylphosphine oxide in step a) is replaced by (2-amino-5-difluoromethoxyphenyl)dimethylphosphine oxide.

[1232] 1 H NMR (400 MHz, DMSO -d 6 , ppm ) δ 10.96 (s, 1H), 9.30 (s, 1H), 8.55 (s,1H), 8.28 (s, 0.5H), 8.18 (s, 1H), 7.52 – 7.45 (m, 1H), 7.44 (d, J = 2.9 Hz,0.25H), 7.39 (d, J = 2.3 Hz, 1H), 7.34 – 7.23 (m, 2H), 7.09 (s, 0.25H), 6.98 (d, J = 8.1 Hz, 1H), 2.87-2.80 (m, 2H), 2.65 (s, 7H), 1.91 (s, 2H), 1.82 (s,3H), 1.79 (s, 3H), 1.72 (q, J = 3.2 Hz, 4H), 1.51 (s, 2H). MS(ESI+): 576.2(M+H).

[1233] Example 76 (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]amino)pyrimidin-4-yl)amino)-5-(trifluoromethoxy)phenyl)dimethylphosphine oxide

[1234]

[1235] The preparation method is described in Example 10, except that the (2-aminophenyl)dimethylphosphine oxide in step a) is replaced by (2-amino-5-trifluoromethoxyphenyl)dimethylphosphine oxide.

[1236] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 11.18 (s, 1H), 9.35 (s, 1H), 8.66 (s, 1H), 8.22 (d, J = 8.9 Hz, 1H), 7.66 (d, J = 14.0 Hz, 1H), 7.52 – 7.37 (m,2H), 7.30 (d, J = 7.3 Hz, 1H), 7.00 (d, J = 8.1 Hz, 1H), 2.77 (d, J = 75.5 Hz, 7H),2.57 (d, J= 11.6 Hz, 2H), 2.06 (s, 2H), 1.91 – 1.69 (m, 10H), 1.49 (s, 2H). MS(ESI+): 594.2(M+H).

[1237] Example 77 (S)-4-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-3-(dimethylphosphoryl)-N-methylbenzamide

[1238]

[1239] Referring to the preparation method of step b) to step d) of Example 47, the 5-iodoquinoxaline-6-amine in step b) is replaced with 4-amino-3-iodo-N-methylbenzamide.

[1240] 1H NMR (400 MHz, DMSO -d 6 , ppm ): δ9.38 (s, 1H), 8.72 (s, 1H), 8.51 (q,J = 4.5 Hz, 1H), 8.29 (s, 1H), 8.09 – 7.88 (m, 2H), 7.47 (d, J = 2.3 Hz, 1H),7.29 (d, J = 8.2 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 2.82 (d, J = 4.5 Hz, 5H), 2.76 (s, 5H), 2.58 (t, J = 12.8 Hz, 2H), 2.01 (s, 2H), 1.87 (s, 3H), 1.83 (s,3H), 1.76 (d, J = 5.9 Hz, 4H), 1.49 (s, 2H). MS(ESI+): 567.2(M+H).

[1241] Example 78 (S)-4-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-3-(dimethylphosphoryl)benzamide

[1242]

[1243] (S)-4-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-3-(dimethylphosphoryl)benzonitrile (120 mg), 2 N sodium hydroxide (2 ml) and ethanol (10 mL) were added to a 30 mL microwave tube. Under nitrogen protection, microwave reaction was carried out at 150 ° C for 4 hours to stop the reaction. The reaction solution was concentrated to dryness, and the residue was purified by silica gel column chromatography to obtain 40 mg of the title product.

[1244] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 11.35 (s, 1H), 9.35 (s, 1H), 8.59(s, 1H), 8.21 (s, 1H), 8.09-7.92 (m, 2H), 7.45 (s, 1H), 7.25 (s, 1H), 7.01(d, J = 8.0 Hz, 1H), 3.39 (s, 2H), 2.91 – 2.55 (m, 9H), 2.08 (br, 2H), 1.87 –1.71 (m, 10H), 1.52 (br, 2H). MS(ESI+): 553.2(M+H).

[1245] Example 79 (S)-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-5-(dimethylphosphoryl)-N-methylbenzamide

[1246]

[1247] Referring to the preparation method of step b) to step d) of Example 47, the 5-iodoquinoxaline-6-amine in step b) is replaced with 2-amino-5-bromo-N-methylbenzamide.

[1248] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ9.41 (s, 1H), 8.95 (q, J = 4.6 Hz, 1H), 8.84 (d, J = 8.6 Hz, 1H), 8.26 (d, J = 2.2 Hz, 2H), 8.07 (d, J = 11.5Hz, 1H), 7.79 (t, J = 9.8 Hz, 1H), 7.49 (d, J = 2.3 Hz, 1H), 7.26 (s, 1H), 7.03 (d, J = 8.1 Hz, 1H), 2.84 (d, J = 4.4 Hz, 5H), 2.71 (s, 5H), 2.57 (s,2H), 1.98 (s, 2H), 1.81 – 1.70 (m, 7H), 1.68 (d, J = 1.9 Hz, 3H), 1.53 (s,2H). MS(ESI+): 567.2(M+H).

[1249] Example 80 (S)-(5-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-2-methylpyridin-4-yl)dimethylphosphine oxide

[1250]

[1251] Referring to the preparation method of step b) to step d) of Example 47, the 5-iodoquinoxaline-6-amine in step b) is replaced with 4-iodo-6-methylpyridin-3-amine.

[1252] 1 H NMR (400 MHz, CDCl 3 , ppm ): δ 8.86 (dd, J = 8.8, 5.5 Hz, 1H), 8.44 (s,1H), 8.06 (s, 1H), 7.44 (s, 1H), 7.34 (dd, J = 8.1, 2.3 Hz, 1H), 7.29 (s,1H), 7.13 (dd, J = 8.7, 2.0 Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 3.40 (m, 2H), 3.28 (m, 3H), 2.87 (m, 1H), 2.78 (m, 3H), 2.52 (s, 3H), 2.41 (m, 2H), 2.04(m, 4H), 1.87 (m, 6H), 1.65 – 1.51 (m, 2H). MS(ESI+): 525.1(M+H).

[1253] Example 81 (S)-(3-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]amino)pyrimidin-4-yl)amino)-6-methylpyridin-2-yl)dimethylphosphine oxide

[1254]

[1255] Referring to the preparation method of step b) to step d) of Example 47, the 5-iodoquinoxaline-6-amine in step b) is replaced with 4-iodo-6-methylpyridin-3-amine.

[1256] 1 H NMR (400 MHz, DMSO -d 6 , ppm ) δ 9.37 (s, 1H), 8.97 (s, 1H), 8.29 (s,1H), 8.20 (s, 1H), 7.42 (d, J = 2.3 Hz, 1H), 7.32 (td, J = 5.4, 2.6 Hz, 2H),7.04 (d, J = 8.1 Hz, 1H), 2.93 (m, 4H), 2.74 (m, 1H), 2.63 (m, 2H), 2.51 (m,5H), 2.12 (m, 2H), 1.78 (m, 10H), 1.49 (m, 2H). MS(ESI+): 525.1(M+H).

[1257] Example 82 (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]amino)pyrimidin-4-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)dimethylphosphine oxide

[1258]

[1259] Prepare according to the method of Example 47, except that quinoxaline-6-amine in step a) is replaced by 5-trifluoromethylpyridinediamine.

[1260] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 9.47 (s, 1H), 8.85 (s, 1H), 8.39 (dd, J = 13.3, 2.5 Hz, 1H), 8.33 (s, 1H), 8.25 (s, 1H), 7.60 – 7.49 (m, 2H), 6.97 (d, J = 8.1 Hz, 1H), 2.84 (m, 2H), 2.70 (m, 5H), 1.89 (m, 8H), 1.73 (m,4H), 1.49 (m, 2H). MS(ESI+): 579.2(M+H).

[1261] Example 83 Compound 83-1, 83-2

[1262]

[1263] Prepare by referring to the preparation method of Example 58, except that the (2-amino-5-fluorophenyl)dimethylphosphine oxide in step a) is replaced by (2-amino-5-difluoromethoxyphenyl)dimethylphosphine oxide, and the 2-azabicyclo[3.1.0]hexane hydrochloride in step c) is replaced by 2-azabicyclo[2.1.1]hexane hydrochloride.

[1264] The crude product was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column 30x150mm, filler particle size 5μm; mobile phase A: water (10mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60ml / min; gradient: 15%B~47%B in 8 minutes; wavelength: 254 / 220nm; column temperature: 25°C) to obtain 87mg of a mixture of two isomers.

[1265] The two isomer mixtures were purified by chiral HPLC column (column: CHIRALPAK IC, 2x25 cm, filler 5 μm); mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol; flow rate: 20 ml / min; gradient: 20% B in 12 minutes, isocratic; detection wavelength: 220 / 254 nm; column temperature: 25 °C)

[1266] Isomer 83-1 (23.8 mg), HPLC retention time 6.4 min:

[1267] 1 H NMR (400MHz, DMSO -d 6 , ppm ):δ 10.96 (s, 1H), 9.28 (s, 1H), 8.56 (s,1H), 8.18 (s, 1H), 7.50 – 7.42 (m, 1.25H), 7.40 (d, J = 2.3 Hz, 1H), 7.34 –7.23 (m, 2.5H), 7.08 (s, 0.25H), 6.98 (d, J = 8.1 Hz, 1H), 3.68 (s, 1H), 2.90(s, 2H), 2.76 – 2.63 (m, 2H), 2.58 (s, 2H), 1.92 (s, 2H), 1.81 (d, J = 13.7 Hz, 6H), 1.63 (s, 2H), 1.35 (d, J = 4.0 Hz, 4H), 1.24 (s, 2H). MS(ESI+): 588.2(M+H).

[1268] Isomer 83-2 (23.8 mg), HPLC retention time 10.4 min:

[1269] 1 H NMR (400MHz, DMSO -d 6 , ppm ): δ10.96 (s, 1H), 9.28 (s, 1H), 8.56 (s,1H), 8.18 (s, 1H), 7.50 – 7.43 (m, 1H), 7.40 (d, J = 2.3 Hz, 0.25H), 7.32 –7.25 (m, 2.5H), 7.08 (s, 0.25H), 6.98 (d,J = 8.2 Hz, 1H), 3.71 (s, 1H), 2.89(s, 2H), 2.75 – 2.69 (m, 2H), 2.58 (d, J = 11.5 Hz, 2H), 2.05 – 1.86 (m, 2H), 1.81 (d, J = 13.7 Hz, 6H), 1.64 (s, 2H), 1.35 (d, J = 4.6 Hz, 4H), 1.24 (s, 2H).MS(ESI+): 588.2(M+H).

[1270] Example 84 Compounds 84-1, 84-2

[1271]

[1272] The preparation method of Example 58 was referred to, except that (2-amino-5-fluorophenyl)dimethylphosphine oxide in step a) was replaced with (2-amino-5-difluoromethoxyphenyl)dimethylphosphine oxide, and 2-azabicyclo[3.1.0]hexane hydrochloride in step c) was replaced with 3-oxa-6-azabicyclo[3.1.1]heptane hydrochloride. The crude product was purified by preparative high performance liquid chromatography under the following conditions (column: XBridge Prep OBD C18 column 30x150mm, filler particle size 5μm; mobile phase A: water (10mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: 17%B~45%B in 12 minutes; isomer mixture retention time: 11.57 min; wavelength: 254 / 220nm; column temperature: 25°C) to obtain a mixture of two isomers.

[1273] The two isomer mixtures were purified by chiral HPLC column (column: CHIRALPAK IG, 2x25 cm, filler 5 μm); mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 20 ml / min; gradient: 50% B in 18 minutes, isocratic; detection wavelength: 220 / 254 nm; column temperature: 25 °C) to obtain:

[1274] Isomer 84-1 (24 mg), HPLC retention time 12.1 min:

[1275] 1 H NMR (400 MHz, DMSO -d 6 , ppm) :δ 10.94 (s, 1H), 9.29 (s, 1H), 8.54 (s,1H), 8.18 (s, 1H), 7.54 – 7.06 (m,5H), 6.97 (d, J = 8.1 Hz, 1H), 4.13 (dd, J =10.6, 2.8 Hz, 2H), 3.58 (d, J = 10.9 Hz, 2H), 3.52 (d, J = 6.0 Hz, 2H), 3.11 (s,1H), 2.80 (t, J = 11.1 Hz,1H), 2.65 (s, 3H), 2.40 – 2.29 (m, 1H), 1.80 (d, J =13.6 Hz, 8H), 1.68 (d, J = 7.8 Hz, 1H), 1.09 (s, 2H) . MS(ESI+): 604.2(M+H).

[1276] Isomer 84-2 (23 mg), HPLC retention time 15.5 min:

[1277] 1 H NMR (400 MHz, DMSO -d 6 , ppm) : δ 10.94 (s, 1H), 9.29 (s, 1H), 8.54(s, 1H), 8.18 (s, 1H), 7.54 – 7.06 (m,5H), 6.97 (d, J = 8.1 Hz, 1H), 4.13 (dd, J = 10.6, 2.8 Hz, 2H), 3.58 (d, J = 10.9 Hz, 2H), 3.52 (d, J = 6.0 Hz, 2H), 3.11(s, 1H), 2.80 (t, J = 11.1 Hz,1H), 2.65 (s, 3H), 2.40 – 2.29 (m, 1H), 1.80 (d, J = 13.6 Hz, 8H), 1.68 (d, J= 7.8 Hz, 1H), 1.09 (s, 2H) . MS(ESI+): 604.2(M+H).

[1278] Example 85 Compounds 85-1, 85-2

[1279]

[1280] The product was prepared by referring to the preparation method of Example 58, except that the (2-amino-5-fluorophenyl)dimethylphosphine oxide in step a) was replaced by (2-amino-5-difluoromethoxyphenyl)dimethylphosphine oxide, and the 2-azabicyclo[3.1.0]hexane hydrochloride in step c) was replaced by 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride. The crude product was purified by reverse phase high performance liquid chromatography (column: XBridge-Prep-OBD C18 column, 30×150 mm, filler particle size 5 μm; mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile (0.1% formic acid); flow rate: 60 mL / min; gradient: 20%B to 60%B, 8 min; detection wavelength: 220 nm; isomer mixture retention time: 6.12 minutes; column temperature: 25°C) to obtain 75 mg of isomer mixture.

[1281] The isomer mixture was chirally separated by chiral liquid chromatography (column: CHIRALPAK IF, 2cmx25cm, filler particle size 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 20ml / min, gradient: 30% B in 23min, isocratic; detection wavelength 220 / 254 nm; column temperature: 25℃), and the following was obtained after separation:

[1282] Isomer 85-1 (22.3 mg), HPLC retention time: 16.0 min.

[1283] 1 H NMR (400 MHz, DMSO -d 6 , ppm) : δ 10.95 (s, 1H), 9.27 (s, 1H), 8.55(s, 1H), 8.18 (d, J = 1.1 Hz, 1H), 7.51 – 7.42 (m, 1.3H), 7.39 (s, 1H), 7.34– 6.98 (m, 2.5H), 7.07 (s, 0.3H), 6.96(d, J = 8.0 Hz, 1H), 3.63 – 3.53 (m,2H), 3.45 (d, J = 10.2 Hz, 2H), 3.06 (s, 2H), 2.51 – 2.39 (m, 3H) 1.81 (m,7H), 1.79 – 1.64 (m, 5H), 1.63 – 1.25 (m, 3H), 1.24 (s, 1H). MS(ESI+): 618.2(M+H).

[1284] Isomer 85-2 (22.0 mg), HPLC retention time: 20.2 min.

[1285] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 10.95 (s, 1H), 9.27 (s, 1H), 8.55(s, 1H), 8.18 (s, 1H), 7.52 – 7.42 (m, 1H), 7.39 (d, J = 2.2 Hz, 1H), 7.33 –7.06 (m, 3H), 7.08 (s, 0.4H), 6.97 (d, J = 8.1 Hz, 1H), 3.57 (s, 2H), 3.45 (d, J = 10.2 Hz, 2H), 3.05 (s, 2H), 2.51 (s, 3H), 1.82 (m, 7H), 1.79-1.67(m,5H), 1.67 – 1.39 (m, 3H), 1.24 (s, 1H). MS(ESI+): 618.2(M+H).

[1286] Example 86 Compound 86-1, 86-2

[1287]

[1288] Prepared by referring to the preparation method of Example 58, replacing (2-amino-5-fluorophenyl)dimethylphosphine oxide in step a) with (2-amino-5-cyanophenyl)dimethylphosphine oxide, and replacing 2-azabicyclo[3.1.0]hexane hydrochloride in step c) with 2-azabicyclo[2.1.1]hexane hydrochloride. The crude product was purified by reverse phase HPLC (column: XBridge-Prep-OBD C18 column, 30×150 mm, filler particle size 5 μm; mobile phase A: water (0.05% hydrochloric acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5%B to 50%B, 8 min; detection wavelength: 210 nm; isomer mixture retention time: 6.02 minutes) to obtain 70 mg of isomer mixture.

[1289] The isomer mixture was chirally separated by chiral liquid chromatography (column: CHIRALPAK IG, 3cmx25cm, filler particle size 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 20ml / min, gradient: 50% B in 21min, isocratic; detection wavelength 220 / 254 nm; column temperature: 25℃), and the following was obtained after separation:

[1290] Isomer 86-1 (24.8 mg), HPLC retention time: 14.6 min.

[1291] 1 H NMR (400 MHz, DMSO -d 6 , ppm) : δ 11.74 (s, 1H), 9.44 (s, 1H), 8.87 (s, 1H), 8.27 (s, 1H), 8.13 (d, J = 13.8 Hz, 1H), 7.84 (d, J = 8.9 Hz, 1H), 7.42(s, 1H), 7.30 (d, J = 7.7 Hz, 1H), 7.04 (d, J = 8.1 Hz, 1H), 3.73 (s, 1H), 3.02-2.76 (m, 3H), 2.73 (s, 2H), 2.58 (d, J = 11.4 Hz, 2H), 2.00 (d, J = 14.2 Hz, 2H), 1.87 (m, 7H), 1.62 (m, 2H), 1.36 (s, 3H), 1.24 (s, 1H). MS(ESI+): 547.2(M+H).

[1292] Isomer 86-2 (24.9 mg), HPLC retention time: 18.4 min.

[1293] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 11.74 (s, 1H), 9.45 (s, 1H), 8.88 (s, 1H), 8.27 (s, 1H), 8.14 (dd, J = 13.9, 2.0 Hz, 1H), 7.85 (d, J = 9.0 Hz, 1H),7.43 (d, J = 2.3 Hz, 1H), 7.38 – 7.21 (m, 1H), 7.06 (d, J = 8.1 Hz, 1H), 3.81 (s,1H), 2.81 (d, J = 48.5 Hz, 5H), 2.62 (s, 2H), 2.06 (d, J = 18.6 Hz, 2H), 1.87 (d, J = 13.8 Hz, 7H), 1.66 (d, J = 51.2 Hz, 2H), 1.54 – 1.27 (m, 4H). MS(ESI+):547.2(M+H).

[1294] Example 87 Compounds 87-1, 87-2

[1295]

[1296] The product was prepared by referring to the preparation method of Example 58, except that the (2-amino-5-fluorophenyl)dimethylphosphine oxide in step a) was replaced by (2-amino-5-cyanophenyl)dimethylphosphine oxide, and the 2-azabicyclo[3.1.0]hexane hydrochloride in step c) was replaced by 3-oxa-6-azabicyclo[3.1.1]heptane hydrochloride. The crude product was purified by reverse phase high performance liquid chromatography (column: XBridge-Prep-OBD C18 column, 30×150 mm, filler particle size 5 μm; mobile phase A: water (0.05% hydrochloric acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5% B to 30% B, 8 min; detection wavelength: 210 nm; isomer mixture retention time: 7.05 min; column temperature: 25°C) to obtain an isomer mixture.

[1297] The isomer mixture was chirally separated by chiral liquid chromatography (column: CHIRALPAK IG, 2cmx25cm, filler particle size 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 20ml / min, gradient: 30% B in 21min, isocratic; detection wavelength 220 / 254 nm; column temperature: 25℃), and the following was obtained after separation:

[1298] Isomer 87-1 (23 mg), HPLC retention time: 16.4 min.

[1299] 1 H NMR (400 MHz, DMSO -d 6 , ppm) : δ 11.71 (s, 1H), 9.44 (s, 1H), 8.84 (s, 1H), 8.27 (s, 1H), 8.13 (dd, J = 13.9, 2.0 Hz, 1H), 7.88 – 7.76 (m, 1H),7.42 (d, J = 2.3 Hz, 1H), 7.33 – 7.23 (m, 1H), 7.04 (d, J = 8.2 Hz, 1H), 4.15 (d, J = 10.6 Hz, 2H), 3.59 (d, J = 10.8 Hz, 4H), 3.14 (s, 1H), 2.88 – 2.75 (m, 1H), 2.67 (d, J = 13.8 Hz, 3H), 2.36 (s, 1H), 1.87 (d, J = 13.7 Hz, 8H), 1.69 (d, J =7.7 Hz, 1H), 1.11 (s, 2H). MS(ESI+): 563.2(M+H).

[1300] Isomer 87-2 (23.5 mg), HPLC retention time: 18.9 min.

[1301] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 11.71 (s, 1H), 9.44 (s, 1H), 8.85 (s, 1H), 8.27 (s, 1H), 8.13 (dd, J = 13.9, 2.0 Hz, 1H), 7.84 (dd, J = 9.1, 2.0 Hz,1H), 7.42 (d, J = 2.3 Hz, 1H), 7.35 – 7.25 (m, 1H), 7.04 (d, J = 8.1 Hz, 1H),4.15 (d, J = 10.6 Hz, 2H), 3.60 (d, J = 11.6 Hz, 4H), 3.15 (s, 1H), 2.88 – 2.77(m, 1H), 2.69 (s, 3H), 2.37 (s, 1H), 1.87 (d, J = 13.7 Hz, 8H), 1.70 (s, 1H), 1.11 (s, 2H). MS(ESI+): 563.2(M+H).

[1302] Example 88 Compound 88-1, 88-2

[1303]

[1304] Prepared by referring to the preparation method of Example 58, replacing (2-amino-5-fluorophenyl)dimethylphosphine oxide in step a) with (2-amino-5-cyanophenyl)dimethylphosphine oxide, and replacing 2-azabicyclo[3.1.0]hexane hydrochloride in step c) with 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride. The crude product was purified by reverse phase high performance liquid chromatography (column: XBridge-Prep-OBD C18 column, 30×150 mm, filler particle size 5 μm; mobile phase A: water (10 mmol / L ammonium bicarbonate aqueous solution), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 20%B to 60%B, 6 min; detection wavelength: 220 nm; column temperature: 25°C) to obtain 65 mg of an isomer mixture.

[1305] The isomer mixture was chirally separated by chiral liquid chromatography (column: CHIRALPAK IA, 2cmx25cm, filler particle size 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 20ml / min, gradient: 50% B in 16min, isocratic; detection wavelength 220 / 254 nm; column temperature: 25℃), and the following was obtained after separation:

[1306] Isomer 88-1 (22.6 mg), HPLC retention time: 9.55 min.

[1307] 1 H NMR (400 MHz, DMSO -d 6 , ppm) : δ 11.71 (s, 1H), 9.44 (s, 1H), 8.84 (s, 1H), 8.27 (s, 1H), 8.13 (dd, J = 13.9, 2.0 Hz, 1H), 7.88 – 7.76 (m, 1H),7.42 (d, J = 2.3 Hz, 1H), 7.33 – 7.23 (m, 1H), 7.04 (d, J = 8.2 Hz, 1H), 4.15 (d, J = 10.6 Hz, 2H), 3.59 (d, J = 10.8 Hz, 4H), 3.14 (s, 1H), 2.88 – 2.75 (m, 1H), 2.67 (d, J = 13.8 Hz, 3H), 2.36 (s, 1H), 1.87 (m, 8H), 1.69 (d, J = 7.7 Hz, 1H),1.11 (s, 2H). MS(ESI+): 577.2(M+H).

[1308] Isomer 88-2 (23.5 mg), HPLC retention time: 12.7 min.

[1309] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 11.71 (s, 1H), 9.44 (s, 1H), 8.85 (s, 1H), 8.27 (s, 1H), 8.13 (dd, J= 13.9, 2.0 Hz, 1H), 7.84 (dd, J = 9.1, 2.0Hz, 1H), 7.42 (d, J = 2.3 Hz, 1H), 7.35 – 7.25 (m, 1H), 7.04 (d, J = 8.1 Hz, 1H),4.15 (d, J = 10.6 Hz, 2H), 3.60 (d, J = 11.6 Hz, 4H), 3.15 (s, 1H), 2.88 – 2.77(m, 1H), 2.69 (s, 3H), 2.37 (s, 1H), 1.87 (m, 8H), 1.70 (s, 1H), 1.11 (s,2H). MS(ESI+): 577.2(M+H).

[1310] Example 89 Compounds 89-1, 89-2

[1311]

[1312] The product was prepared by referring to the preparation method of Example 58, except that the (2-amino-5-fluorophenyl)dimethylphosphine oxide in step a) was replaced by (2-amino-5-methylphenyl)dimethylphosphine oxide, and the 2-azabicyclo[3.1.0]hexane hydrochloride in step c) was replaced by 3-oxa-6-azabicyclo[3.1.1]heptane hydrochloride. The crude product was purified by reverse phase high performance liquid chromatography (column: XBridge-Prep-OBD C18 column, 30×150 mm, filler particle size 5 um; mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 15% B to 50% B, 8 min; detection wavelength: 220 nm; isomer mixture retention time: 8.1 min; column temperature: 25°C) to obtain 92 mg of isomer mixture.

[1313] Chiral separation of isomer mixture was performed by chiral liquid chromatography (column: CHIRALPAK IF, 5 cm x 25 cm, filler particle size 5 μm; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol; flow rate: 15 ml / min,

[1314] Gradient: 25% B in 15 min; detection wavelength 220 / 254 nm; column temperature: 25°C), after separation:

[1315] Isomer 89-1 (21.7 mg). HPLC retention time: 13.7 min.

[1316] 1 H NMR ( 400 MHz, DMSO -d 6 , ppm ): δ 10.93 (s, 1H), 9.25 (s, 1H), 8.40 (s, 1H), 8.15 (s, 1H), 7.48 – 7.31 (m, 2H), 7.30 – 7.28 (m, 2H), 6.98 (d, J =8.2 Hz, 1H), 4.15 (d, J = 10.8 Hz, 2H), 3.56 (d, J = 22.1 Hz, 3H), 3.13 (s,2H), 2.78 (d, J = 8.0 Hz, 1H), 2.66 (s, 3H), 2.33 (s, 4H), 1.77 (d, J = 13.5Hz, 9H), 1.09 (s, 2H). MS(ESI+): 552.2 (M+H).

[1317] Isomer 89-2 (21.1 mg), HPLC retention time: 19.5 min.

[1318] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 10.92 (s, 1H), 9.25 (s, 1H), 8.40 (s, 1H), 8.15 (s, 1H), 7.43 (dd, J = 14.1, 2.1 Hz, 2H), 7.30 (t, J = 7.5 Hz,2H), 6.98 (d, J = 8.1 Hz, 1H), 4.15 (d, J = 10.7 Hz, 2H), 3.59 (s, 3H), 3.21- 3.07(s, 2H), 2.78 (d, J = 8.9 Hz, 1H), 2.66 (s, 3H), 2.33 (s, 4H), 1.76(dd, J = 13.7, 1.1 Hz, 9H), 1.09 (s, 2H). MS(ESI+): 552.2 (M+H).

[1319] Example 90 Compounds 90-1, 90-2

[1320]

[1321] The product was prepared by referring to the preparation method of Example 58, except that the (2-amino-5-fluorophenyl)dimethylphosphine oxide in step a) was replaced by (2-amino-5-methylphenyl)dimethylphosphine oxide, and the 2-azabicyclo[3.1.0]hexane hydrochloride in step c) was replaced by 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride. The crude product was purified by reverse phase high performance liquid chromatography (column: XBridge-Prep-OBD C18 column, 30×150 mm, filler particle size 5 um; mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 25% B to 60% B, 8 min; detection wavelength: 220 nm; isomer mixture retention time: 5.15 minutes) to obtain 63 mg of isomer mixture.

[1322] Chiral separation of isomer mixture was performed by chiral liquid chromatography (column: CHIRALPAK IA, 2 cm x 25 cm, filler particle size 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 20 ml / min,

[1323] Gradient: 30% B in 20 min; detection wavelength 220 / 254 nm; column temperature: 25°C), after separation:

[1324] Isomer 90-1 (29.5 mg). HPLC retention time: 13.7 min.

[1325] 1H NMR ( 400 MHz, DMSO -d 6 , ppm ): δ 10.92 (s, 1H), 9.23 (s, 1H), 8.40 (s, 1H), 8.15 (s, 1H), 7.50 – 7.34 (m, 2H), 7.29 (dd, J = 16.0, 8.4 Hz, 2H), 6.96 (d, J = 8.1 Hz, 1H), 3.58 (d, J = 7.4 Hz, 2H), 3.47 (s, 2H), 3.30 (s,4H), 3.04 (s, 2H), 2.34 (s, 4H), 1.77 (d, J = 13.5 Hz, 12H), 1.58 (s, 2H). MS(ESI+): 566.2 (M+H).

[1326] Isomer 90-2 (20.2 mg), HPLC retention time: 16.6 min.

[1327] 1H NMR (400 MHz, DMSO -d 6 , ppm ) δ 10.92 (s, 1H), 9.23 (s, 1H), 8.40 (s, 1H), 8.15 (s, 1H), 7.47 – 7.35 (m, 2H), 7.29 (dd, J = 15.5, 8.3 Hz, 2H), 6.96 (d, J = 8.1 Hz, 1H), 3.58 (d, J = 9.9 Hz, 2H), 3.47 (s, 2H), 3.31(s,4H), 3.04 (s, 2H), 2.34 (s, 4H), 1.77 (d, J = 13.5 Hz, 12H), 1.59 (s, 2H). MS(ESI+): 566.2 (M+H).

[1328] Example 91 Compounds 91-1, 91-2

[1329]

[1330] The product was prepared by referring to the preparation method of Example 58, except that the 2-azabicyclo[3.1.0]hexane hydrochloride in step c) was replaced with 3-oxo-6-azabicyclo[3.1.1]heptane hydrochloride. The crude product was purified by reverse phase high performance liquid chromatography (column: Xselect CSH OBD C18 column, 30×150 mm, filler particle size 5 um; mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 15% B to 52% B, 8 min; detection wavelength: 220 nm) to obtain 70 mg of an isomer mixture.

[1331] The isomer mixture was chirally separated by chiral liquid chromatography (column: CHIRALPAK IA, 5cmx25cm, filler particle size 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 20ml / min, gradient: 20% B in 29min, isocratic; detection wavelength 220 / 254 nm; column temperature: 25℃), and the following was obtained after separation:

[1332] Isomer 91-1 (25.5 mg). HPLC retention time: 17.9 min.

[1333] 1H NMR ( 400 MHz, DMSO -d 6 , ppm ) δ 10.87 (s, 1H), 9.28 (s, 1H), 8.52(s, 1H), 8.17 (s, 1H), 7.53 (ddd, J = 13.9, 8.8, 3.0 Hz, 1H), 7.33 (dt, J =18.0, 6.2 Hz, 3H), 6.98 (d, J = 8.1 Hz, 1H), 4.15 (d, J = 10.8 Hz, 2H), 3.56(m, 3H), 3.13 (s, 2H), 2.78 (d, J = 9.6 Hz, 1H), 2.67 (s, 3H), 2.37 (s, 1H),1.80 (m, 9H), 1.08 (s, 2H). MS(ESI+): 556.2 (M+H).

[1334] Isomer 91-2 (30.3 mg), HPLC retention time: 24.2 min.

[1335] 1 H NMR (400 MHz, DMSO -d 6 , ppm ) δ 10.87 (s, 1H), 9.28 (s, 1H), 8.52 (s,1H), 8.17 (s, 1H), 7.53 (ddd, J = 13.9, 8.8, 3.0 Hz, 1H), 7.33 (dt, J = 18.0,6.2 Hz, 3H), 6.98 (d, J = 8.1 Hz, 1H), 4.15 (d, J = 10.8 Hz, 2H), 3.56 (m,3H), 3.13 (s, 2H), 2.78 (d, J = 9.6 Hz, 1H), 2.67 (s, 3H), 2.37 (s, 1H), 1.80(m, 9H), 1.08(s, 2H). MS(ESI+): 556.2 (M+H).

[1336] Example 92 Compounds 92-1, 92-2

[1337]

[1338] The product was prepared by referring to the preparation method of Example 58, except that the 2-azabicyclo[3.1.0]hexane hydrochloride in step c) was replaced with 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride. The crude product was purified by reverse phase high performance liquid chromatography (column: Xselect CSH OBD C18 column, 30×150 mm, filler particle size 5 um; mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 15% B to 50% B, 8 min; detection wavelength: 220 nm) to obtain 130 mg of an isomer mixture.

[1339] The isomer mixture was chirally separated by chiral liquid chromatography (column: CHIRALPAK IF, 2cmx25cm, filler particle size 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 15 ml / min, gradient: 30% B isocratic in 20 min; detection wavelength 220 / 254 nm; column temperature: 25°C). After separation, the following was obtained:

[1340] Isomer 92-1 (28.9 mg), HPLC retention time: 3.65 min.

[1341] 1 H NMR (400 MHz, DMSO-d6, ppm ) δ 10.86 (s, 1H), 9.26 (s, 1H), 8.51(s, 1H), 8.17 (s, 1H), 7.53 (ddd, J = 14.0, 8.8, 3.1 Hz, 1H), 7.39 – 7.21 (m,3H), 6.97 (d, J = 8.1 Hz, 1H), 3.57 (d, J = 10.1 Hz, 2H), 3.45 (d, J = 10.0Hz, 2H), 3.30 (s, 4H), 3.04 (s, 2H), 2.41 (d, J = 20.5 Hz, 1H), 1.90 – 1.56(m, 14H). MS(ESI+): 570.2 (M+H).

[1342] Isomer 92-2 (28.9 mg), HPLC retention time: 4.85 min.

[1343] 1 H NMR (400 MHz, DMSO-d6 , ppm ) δ 10.86 (s, 1H), 9.26 (s, 1H), 8.51(s, 1H), 8.17 (s, 1H), 7.53 (ddd, J = 14.0, 8.8, 3.1 Hz, 1H), 7.39 – 7.31 (m,2H), 7.27 (d, J=8Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H), 3.57 (d, J = 10.1 Hz,2H), 3.45 (d, J = 10.0 Hz, 2H), 3.30 (s, 4H), 3.04 (s, 2H), 2.41 (d, J = 20.5Hz, 1H), 1.90 – 1.56 (m, 14H). MS(ESI+): 570.2 (M+H).

[1344] Example 93 Compounds 93-1, 93-2

[1345]

[1346] The product was prepared by referring to the preparation method of Example 58, except that the (2-amino-5-fluorophenyl)dimethylphosphine oxide in step a) was replaced by (2-amino-5-chlorophenyl)dimethylphosphine oxide, and the 2-azabicyclo[3.1.0]hexane hydrochloride in step c) was replaced by 3-oxa-6-azabicyclo[3.1.1]heptane hydrochloride. The crude product was purified by reverse phase high performance liquid chromatography (column: Xselect CSH OBD C18 column, 30×150 mm, filler particle size 5 um; mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 20% B to 55% B, 8 min; detection wavelength: 220 nm); to obtain 60 mg of an isomer mixture.

[1347] The isomer mixture was chiral separated by chiral liquid chromatography (column: CHIRALPAK IE, 3 cm x 25 cm, filler particle size 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 15 ml / min,

[1348] Gradient: 50% B in 32 min; detection wavelength 220 / 254 nm; column temperature: 25°C), after separation:

[1349] Isomer 93-1 (23.7 mg), HPLC retention time: 23.7 min.

[1350] 1 HNMR (400MHz, DMSO-d 6 , ppm ): δ 11.11 (s, 1H), 9.31 (s, 1H), 8.57 (s, 1H), 8.19 (s, 1H), 7.69 (dd, J = 13.6, 2.6 Hz, 1H), 7.49 (dd, J = 9.0, 2.6 Hz,1H), 7.41 (d, J = 2.3 Hz, 1H), 7.30 – 7.23 (m, 1H), 6.99 (d, J = 8.1 Hz, 1H),4.14 (d, J = 10.6 Hz, 2H), 3.63 – 3.51 (m, 4H), 3.13 (s, 1H), 2.80 (t, J = 11.3Hz, 1H), 2.66 (s, 3H), 2.36 (d, J = 6.9 Hz, 1H), 1.82 (d, J = 13.7Hz, 8H), 1.68(d, J = 7.8 Hz, 1H), 1.23-1.01(m,2H). MS(ESI+): 572.2 (M+H).

[1351] Isomer 93-2 (22.3 mg), HPLC retention time: 27.9 min.

[1352] 1 HNMR (400MHz, DMSO -d 6 , ppm ): δ 11.11 (s, 1H), 9.31 (s, 1H), 8.57 (s, 1H), 8.19 (s, 1H), 7.69 (dd, J = 13.6, 2.6 Hz, 1H), 7.49 (dd, J = 9.0, 2.6 Hz,1H), 7.41 (d, J = 2.3 Hz, 1H), 7.30 – 7.23 (m, 1H), 6.99 (d, J = 8.1 Hz, 1H),4.14 (d, J= 10.6 Hz, 2H), 3.63 – 3.51 (m, 4H), 3.13 (s, 1H), 2.80 (t, J = 11.3Hz, 1H), 2.66 (s, 3H), 2.36 (d, J = 6.9 Hz, 1H), 1.82 (d, J = 13.7Hz, 8H), 1.68(d, J = 7.8 Hz, 1H),1.23-1.01(m,2H). MS(ESI+): 572.2 (M+H).

[1353] Example 94 Compounds 94-1, 94-2

[1354]

[1355] The product was prepared by referring to the preparation method of Example 58, except that the (2-amino-5-fluorophenyl)dimethylphosphine oxide in step a) was replaced by (2-amino-5-chlorophenyl)dimethylphosphine oxide, and the 2-azabicyclo[3.1.0]hexane hydrochloride in step c) was replaced by 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride. The crude product was purified by reverse phase high performance liquid chromatography (column: Xselect CSH OBD column, 30×150 mm, filler particle size 5 um; mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 25% B to 65% B, 8 min; detection wavelength: 254 nm; column temperature: 25°C) to obtain 65 mg of an isomer mixture.

[1356] The isomer mixture was chirally separated by chiral liquid chromatography (column: CHIRALPAK IA, 2cmx25cm, filler particle size 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 15 ml / min, gradient: 50% B isocratic in 14 min; detection wavelength 254 nm; column temperature: 25°C). The following was obtained after separation:

[1357] Isomer 94-1 (25.1 mg), HPLC retention time: 1.85 min.

[1358] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 11.10 (s, 1H), 9.30 (s, 1H), 8.56(s, 1H), 8.19 (s, 1H), 7.69 (dd, J = 13.6, 2.5 Hz, 1H), 7.49 (dd, J = 9.1,2.5 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.27 – 7.20 (m, 1H), 6.98 (d, J = 8.1Hz, 1H), 3.58 (d, J = 10.1 Hz, 2H), 3.45 (d, J = 10.2 Hz, 2H), 3.28 (s, 4H), 3.04 (s, 2H), 2.39 (s, 1H), 1.82 (m, 12H), 1.77 (s, 2H). MS(ESI+): 586 (M+H).

[1359] Isomer 94-2 (23.4 mg), HPLC retention time: 2.73 min.

[1360] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 11.10 (s, 1H), 9.30 (s, 1H), 8.56(s, 1H), 8.19 (s, 1H), 7.69 (dd, J = 13.6, 2.5 Hz, 1H), 7.49 (dd, J = 9.1,2.5 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.27 – 7.20 (m, 1H), 6.98 (d, J = 8.1Hz, 1H), 3.58 (d, J = 10.1 Hz, 2H), 3.45 (d, J = 10.2 Hz, 2H), 3.28 (s, 4H), 3.04 (s, 2H), 2.39 (s, 1H), 1.82 (m, 12H), 1.77 (s, 2H). MS(ESI+): 586 (M+H).

[1361] Example 95 Compounds 95-1, 95-2

[1362]

[1363] The product was prepared by referring to the preparation method of Example 58, except that the 2-azabicyclo[3.1.0]hexane hydrochloride in step b) was replaced with 3-azabicyclo[3.1.0]hexane-6-carbonitrile. The crude product was purified by reverse phase high performance liquid chromatography (column: XBridge-Prep-OBD C18 column, 30×150 mm, filler particle size 5 um; mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 30% B to 68% B, 8 min; detection wavelength: 220 nm; isomer mixture retention time: 7.85 min) to obtain an isomer mixture.

[1364] Chiral separation of isomer mixture was performed by chiral liquid chromatography (column: CHIRALPAK IF, 5 cm x 25 cm, filler particle size 5 μm; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol; flow rate: 15 ml / min,

[1365] Gradient: 20% B in 17.5 min; detection wavelength 220 / 254 nm; column temperature: 25°C), after separation:

[1366] Isomer 95-1 (21.7 mg). HPLC retention time: 13.4 min.

[1367] 1 H NMR ( 400 MHz, DMSO -d 6 , ppm ): δ 10.82 (s, 1H), 9.25 (s, 1H), 8.49(s, 1H), 8.16 (s, 1H), 7.53 (ddd, J = 13.9, 8.8, 3.1 Hz, 1H), 7.38 – 7.30 (m,2H), 7.26 (dd, 2.15 (t,J = 2.7 Hz, 2H), 1.87 (t, J = 3.2 Hz, 1H), 1.79 (d, J = 13.7 Hz, 6H), 1.73(s, 2H), 1.45 (d, J = 16.5 Hz, 2H). MS(ESI+): 565.2 (M+H).

[1368] Isomer 95-2 (21.1 mg), HPLC retention time: 16.2 min.

[1369] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 10.82 (s, 1H), 9.25 (s, 1H), 8.49(s, 1H), 8.16 (s, 1H), 7.53 (ddd, J = 14.0, 8.7, 3.0 Hz, 1H), 7.37 – 7.29 (m,2H), 7.26 (dd, J = 8.1, 2.2 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 3.07 – 2.97(m, 2H), 2.94 – 2.69 (m, 2H), 2.54 (s, 1H), 2.43 (d, J = 9.0 Hz, 4H), 2.15(t, J = 2.6 Hz, 2H), 1.87 (t, J = 3.2 Hz, 1H), 1.79 (d, J = 13.6 Hz, 6H), 1.73 (s, 2H), 1.45 (d, J = 16.2 Hz, 2H). MS(ESI+): 565.2 (M+H).

[1370] Example 96 Compounds 96-1, 96-2

[1371]

[1372] The product was prepared by referring to the preparation method of Example 58, except that the (2-amino-5-fluorophenyl)dimethylphosphine oxide in step a) was replaced by (2-amino-5-chlorophenyl)dimethylphosphine oxide, and the 2-azabicyclo[3.1.0]hexane hydrochloride in step c) was replaced by 3-azabicyclo[3.1.0]hexane-6-carbonitrile. The crude product was purified by reverse phase high performance liquid chromatography (column: XselectCSH OBD C18 column, 30×150 mm, filler particle size 5 um; mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 45%B to 85%B, 8 min; detection wavelength: 254 nm) to obtain 58 mg of an isomer mixture.

[1373] Chiral separation of isomer mixture was performed by chiral liquid chromatography (column: CHIRALPAK IA, 2 cm x 25 cm, filler particle size 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 20 ml / min,

[1374] Gradient: 30% B in 37 min; detection wavelength 220 / 254 nm; column temperature: 25°C), after separation:

[1375] Isomer 96-1 (17.4 mg). HPLC retention time: 23 min.

[1376] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 11.10 (s, 1H), 9.30 (s, 1H), 8.55(s, 1H), 8.19 (s, 1H), 7.69 (dd, J = 13.6, 2.5 Hz, 1H), 7.48 (dd, J = 9.0,2.6 Hz, 1H), 7.39 (d, J = 2.3 Hz, 1H), 7.27 – 7.20 (m, 1H), 6.97 (d, J = 8.2Hz, 1H), 3.03 (d, J = 9.2 Hz, 2H), 2.83 (s, 2H), 2.54 (s, 1H), 2.43 (d, J = 9.0Hz, 4H), 2.15 (d, J = 2.7 Hz, 2H), 1.82 (m, 9H), 1.49 (s, 2H). MS(ESI+):581.2 (M+H).

[1377] Isomer 96-2 (23.1 mg), HPLC retention time: 30.8 min.

[1378] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 11.10 (s, 1H), 9.30 (s, 1H), 8.55(s, 1H), 8.19 (s, 1H), 7.69 (dd, J = 13.6, 2.5 Hz, 1H), 7.48 (dd, J = 9.0,2.6 Hz, 1H), 7.39 (d, J = 2.3 Hz, 1H), 7.27–7.20 (m, 1H), 6.97 (d, J = 8.2Hz, 1H), 3.03 (d, J = 9.2 Hz, 2H), 2.83 (s, 2H), 2.54 (s, 1H), 2.43 (d, J = 9.0Hz, 4H), 2.15 (d, J = 2.7 Hz, 2H), 1.87 (s, 1H), 1.82 (d, J = 13.7 Hz, 6H), 1.77-1.64(m,2H) 1.49 (s, 2H). MS(ESI+): 581.2 (M+H).

[1379] Example 97 Compounds 97-1, 97-2

[1380]

[1381] The product was prepared by referring to the preparation method of Example 58, except that the (2-amino-5-fluorophenyl)dimethylphosphine oxide in step a) was replaced by (2-amino-5-cyanophenyl)dimethylphosphine oxide, and the 2-azabicyclo[3.1.0]hexane hydrochloride in step c) was replaced by 3-azabicyclo[3.1.0]hexane-6-carbonitrile. The crude product was purified by reverse phase high performance liquid chromatography (column: YMC-Actus Triart C18 column, 30×150 mm, filler particle size 5 um; mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 45%B to 75%B, 10 min; detection wavelength: 220 nm; isomer mixture retention time: 8.72 minutes) to obtain 48 mg of isomer mixture.

[1382] The isomer mixture was chiral separated by chiral liquid chromatography (column: CHIRALPAK IF, 3 cm x 25 cm, filler particle size 5 μm; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol; flow rate: 20 ml / min,

[1383] Gradient: 10% B in 26 min; detection wavelength 220 / 254 nm; column temperature: 25°C), after separation:

[1384] Isomer 97-1 (20 mg)., HPLC retention time: 16.2 min.

[1385] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 11.72 (s, 1H), 9.42 (s, 1H), 8.85(s, 1H), 8.27 (s, 1H), 8.13 (dd, J = 13.8, 2.0 Hz, 1H), 7.90 – 7.77 (m, 1H),7.38 (d, J = 2.3 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 3.03 (dd, J = 9.3, 2.9 Hz, 2H), 2.86 (s, 2H), 2.69 - 2.66 (m, 1H), 2.44 (d, J= 9.2 Hz, 4H), 2.15 (d, J = 2.8 Hz, 2H), 1.87 (d, J = 13.7 Hz, 7H), 1.75 (s,2H), 1.49 (s, 2H). MS(ESI+): 572.2 (M+H).

[1386] Isomer 97-2 (20.2 mg), HPLC retention time: 23 min.

[1387] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 11.72 (s, 1H), 9.42 (s, 1H), 8.85(s, 1H), 8.27 (s, 1H), 8.13 (dd, J = 14.0, 2.0 Hz, 1H), 7.83 (d, J = 9.0 Hz,1H), 7.38 (d, J = 2.2 Hz, 1H), 7.32 – 7.25 (m, 1H), 7.02 (d, J = 8.1 Hz, 1H), 3.03 (d, J = 9.1 Hz, 2H), 2.84 (s, 2H), 2.69 – 2.66(m,1H), 2.44 (d, J = 9.0Hz, 4H), 2.15 (d, J = 2.7 Hz, 2H), 1.87 (d, J = 13.8 Hz, 7H), 1.75 (s, 2H), 1.49 (s, 2H). MS(ESI+): 572.2 (M+H).

[1388] Example 98 Compounds 98-1, 98-2

[1389]

[1390] The product was prepared by referring to the preparation method of Example 58, except that the (2-amino-5-fluorophenyl)dimethylphosphine oxide in step a) was replaced by (2-amino-5-methylphenyl)dimethylphosphine oxide, and the 2-azabicyclo[3.1.0]hexane hydrochloride in step c) was replaced by 3-azabicyclo[3.1.0]hexane-6-carbonitrile. The crude product was purified by reverse phase high performance liquid chromatography (column: YMC-Actus Triart C18 column, 30×150 mm, filler particle size 5 um; mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 50% B to 66% B, 10 min; detection wavelength: 220 nm; isomer mixture retention time: 8.72 minutes) to obtain 63 mg of isomer mixture.

[1391] The isomer mixture was chiral separated by chiral liquid chromatography (column: CHIRALPAK IF, 3 cm x 25 cm, filler particle size 5 μm; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol; flow rate: 15 ml / min,

[1392] Gradient: 20% B in 27 min; detection wavelength 220 / 254 nm; column temperature: 25°C), after separation:

[1393] Isomer 98-1 (20.5 mg). HPLC retention time: 19.1 min.

[1394] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 10.92 (s, 1H), 9.23 (s, 1H), 8.39 (s, 1H), 8.15 (s, 1H), 7.47 – 7.37 (m, 2H), 7.34 – 7.24 (m, 2H), 6.95 (d, J =8.1 Hz, 1H), 3.03 (d, J = 9.2 Hz, 2H), 2.83 (s, 2H), 2.69 – 2.66(m,1H), 2.44(d, J = 9.2 Hz, 4H), 2.34 (s, 3H), 2.16 (s, 2H), 1.88 (s, 1H), 1.77 (d, J =13.5 Hz, 8H), 1.49 (s, 2H). MS(ESI+): 561.2 (M+H).

[1395] Isomer 98-2 (20.4 mg), HPLC retention time was 25.1 min.

[1396] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 10.92 (s, 1H), 9.24 (s, 1H), 8.39(s, 1H), 8.15 (d, J = 2.2 Hz, 1H), 7.47 – 7.37 (m, 2H), 7.34 – 7.24 (m, 2H), 6.95 (d, J = 8.3 Hz, 1H), 3.02 (d, J = 9.3 Hz, 2H), 2.93 – 2.74 (m, 3H), 2.34 (s, 4H), 2.21 (s, 3H), 2.16 (s, 2H), 1.88 (s, 1H), 1.84 – 1.66 (m, 8H), 1.49(s, 2H). MS(ESI+): 561.2 (M+H).

[1397] Example 99 Compounds 99-1, 99-2

[1398]

[1399] The product was prepared by referring to the preparation method of Example 58, except that the (2-amino-5-fluorophenyl)dimethylphosphine oxide in step a) was replaced by (2-amino-5-difluoromethoxyphenyl)dimethylphosphine oxide, and the 2-azabicyclo[3.1.0]hexane hydrochloride in step c) was replaced by 3-azabicyclo[3.1.0]hexane-6-carbonitrile. The crude product was purified by reverse phase high performance liquid chromatography (column: XBridge-Prep-OBD C18 column, 30×150 mm, filler particle size 5 um; mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 35% B to 64% B, 10 min; detection wavelength: 220 nm; isomer mixture retention time: 9.6 minutes) to obtain an isomer mixture.

[1400] The isomer mixture was chiral separated by chiral liquid chromatography (column: CHIRALPAK IE, 2 cm x 25 cm, filler particle size 5 μm; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol; flow rate: 20 ml / min,

[1401] Gradient: 10% B in 24 min; detection wavelength 220 / 254 nm; column temperature: 25°C), after separation:

[1402] Isomer 99-1 (22.5 mg). HPLC retention time: 14.3 min.

[1403] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 10.96 (s, 1H), 9.27 (s, 1H), 8.55(s, 1H), 8.18 (s, 1H), 7.49 – 7.42 (m, 1H), 7.37 (d, J = 2.3 Hz, 1H), 7.29(d, J = 8.6 Hz, 2H), 7.26 – 7.20 (m, 1H), 6.96 (d, J = 8.1 Hz, 1H), 3.03 (d,J = 9.2 Hz, 2H), 2.84 (s, 2H), 2.55 (s, 1H), 2.42 (d, J = 9.2 Hz, 4H), 2.16(t, J = 2.6 Hz, 2H), 1.87 (s, 1H), 1.81 (d, J = 13.6 Hz, 6H), 1.71 (s, 2H), 1.50 (s, 2H). MS(ESI+): 613.2 (M+H).

[1404] Isomer 99-2 (22.4 mg), HPLC retention time: 21.25 min.

[1405] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 10.96 (s, 1H), 9.27 (s, 1H), 8.55(s, 1H), 8.18 (s, 1H), 7.49 – 7.42 (m, 1 H), 7.37 (d, J = 2.3 Hz, 1H), 7.32 –7.21 (m, 3H), 6.96 (d, J = 8.1 Hz, 1H), 3.03 (d, J = 9.2 Hz, 2H), 2.84 (s,2H), 2.55 (s, 1H), 2.42 (d, J = 9.2 Hz, 4H), 2.15 (d, J = 2.6 Hz, 2H), 1.87(s, 1H), 1.81 (d, J = 13.7 Hz, 6H), 1.71 (s, 2H), 1.51 (s, 2H). MS(ESI+):613.2 (M+H).

[1406] Example 100 Compounds 100-1, 100-2

[1407]

[1408] The product was prepared by referring to the preparation method of Example 58, except that the (2-amino-5-fluorophenyl)dimethylphosphine oxide in step a) was replaced by (2-amino-5-trifluoromethoxyphenyl)dimethylphosphine oxide, and the 2-azabicyclo[3.1.0]hexane hydrochloride in step c) was replaced by 3-oxa-6-azabicyclo[3.1.1]heptane hydrochloride. The crude product was purified by reverse phase high performance liquid chromatography (column: YMC-Actus Triart C18 column, 30×150 mm, filler particle size 5 um; mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 30%B to 60%B, 8 min; detection wavelength: 220 nm) to obtain 70 mg of an isomer mixture.

[1409] The isomer mixture was chirally separated by chiral liquid chromatography (column: CHIRALPAK IG, 2cmx25cm, filler particle size 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 20ml / min, gradient: 30% B isocratic in 25min; detection wavelength 220 / 254 nm; column temperature: 25℃), and the following was obtained after separation:

[1410] Isomer 100-1 (18.4 mg). HPLC retention time: 17.1 min.

[1411] 1 H NMR (400 MHz, DMSO -d 6 , ppm): δ 11.15 (s, 1H), 9.32 (s, 1H), 8.65 (s,1H), 8.21 (s, 1H), 7.66 (dd, J = 13.8, 2.9 Hz, 1H), 7.46(d, J =12.0 Hz,1H), 7.40(d, J =4.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 4.13 (dd, J =10.5, 5.5 Hz, 2H), 3.67 – 3.46 (m, 4H), 3.12 (s, 1H), 2.91 – 2.77 (m, 1H), 2.67 (d, J = 11.1 Hz, 3H), 2.35 (d, J= 7.1 Hz, 1H), 1.85 – 1.78 (m, 8H), 1.65(d, J =8 Hz, 1H),1.10 (s, 2H). MS(ESI+): 622.2 (M+H).

[1412] Isomer 100-2 (18.2 mg), HPLC retention time: 22.4 min.

[1413] 1 H NMR (400 MHz, DMSO -d 6 , ppm): δ 11.15 (s, 1H), 9.32 (s, 1H), 8.65 (s,1H), 8.21 (s, 1H), 7.66 (dd, J = 13.8, 2.9 Hz, 1H), 7.46(d, J =12.0 Hz,1H), 7.40(d, J =4.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 4.13 (dd, J =10.5, 5.5 Hz, 2H), 3.67 – 3.46 (m, 4H), 3.12 (s, 1H), 2.91 – 2.77 (m, 1H), 2.67 (d, J = 11.1 Hz, 3H), 2.35 (d, J = 7.1 Hz, 1H), 1.85 – 1.78 (m, 8H), 1.65(d, J =8 Hz, 1H),1.10 (s, 2H). MS(ESI+): 622.2 (M+H).

[1414] Example 101 Compounds 101-1, 101-2

[1415]

[1416] The product was prepared by referring to the preparation method of Example 58, except that the (2-amino-5-fluorophenyl)dimethylphosphine oxide in step a) was replaced by (2-amino-5-trifluoromethoxyphenyl)dimethylphosphine oxide, and the 2-azabicyclo[3.1.0]hexane hydrochloride in step c) was replaced by 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride. The crude product was purified by reverse phase high performance liquid chromatography (column: YMC-Actus Triart C18 column, 30×150 mm, filler particle size 5 um; mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 40%B to 70%B, 8 min; detection wavelength: 220 nm) to obtain 63 mg of an isomer mixture.

[1417] The isomer mixture was chirally separated by chiral liquid chromatography (column: CHIRALPAK IG, 2cmx25cm, filler particle size 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 20ml / min, gradient: 30% B isocratic in 23min; detection wavelength 220 / 254 nm; column temperature: 25℃), and the following was obtained after separation:

[1418] Isomer 101-1 (23.8 mg). HPLC retention time: 15.3 min.

[1419] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 11.16 (s, 1H), 9.30 (s, 1H), 8.65 (s, 1H), 8.21 (s, 1H), 7.66 (dd, J = 13.9, 2.8 Hz, 1H), 7.44 (d, J=12.0 Hz,1H), 7.37 (s, 1H), 7.24 (d, J = 7.9 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H), 3.58(d, J = 10.1 Hz, 2H), 3.45 (d, J = 10.2 Hz, 2H), 3.30 (s, 2H), 3.07 (s, 2H),2.47-2.30 (m, 2H), 1.85 (s, 7H), 1.82 (s. 4H), 1.76-1.65 (m, 4H). MS(ESI+):636.2 (M+H).

[1420] Isomer 101-2 (18.6 mg), HPLC retention time: 19.7 min.

[1421] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 11.16 (s, 1H), 9.30 (s, 1H), 8.65 (s, 1H), 8.21 (s, 1H), 7.66 (dd, J = 13.9, 2.8 Hz, 1H), 7.44 (d, J=12.0 Hz,1H), 7.37 (s, 1H), 7.24 (d, J = 7.9 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H), 3.58(d, J = 10.1 Hz, 2H), 3.45 (d, J = 10.2 Hz, 2H), 3.30 (s, 2H), 3.07 (s, 2H),2.47-2.30 (m, 2H), 1.85 (s, 7H), 1.82 (s. 4H), 1.76-1.65 (m, 4H). MS(ESI+):636.2 (M+H).

[1422] Example 102 Compounds 102-1, 102-2

[1423]

[1424] The product was prepared by referring to the preparation method of Example 58, except that the (2-amino-5-fluorophenyl)dimethylphosphine oxide in step a) was replaced by (2-amino-5-trifluoromethoxyphenyl)dimethylphosphine oxide, and the 2-azabicyclo[3.1.0]hexane hydrochloride in step c) was replaced by 3-azabicyclo[2.1.1]hexane hydrochloride. The crude product was purified by reverse phase high performance liquid chromatography (column: YMC-Actus Triart C18 column, 30×150 mm, filler particle size 5 um; mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 20%B to 60%B, 8 min; detection wavelength: 254 nm) to obtain 75 mg of an isomer mixture.

[1425] The isomer mixture was chirally separated by chiral liquid chromatography (column: CHIRALPAK IG, 3cmx25cm, filler particle size 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 20ml / min, gradient: 20% B isocratic in 20min; detection wavelength 220 / 254 nm; column temperature: 25℃), and the following was obtained after separation:

[1426] Isomer 102-1 (18.6 mg). HPLC retention time: 15.7 min.

[1427] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 11.16 (s, 1H), 9.31 (s, 1H), 8.66 (s, 1H), 8.21 (s, 1H), 7.66 (dd, J = 13.9, 2.8 Hz, 1H), 7.45 (d, J = 9.3 Hz, 1H),7.40 (d, J = 2.2 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 3.73– 3.57 (m, 1H), 2.90 (s, 2H), 2.68 (d, J = 18.6 Hz, 3H), 2.55 (s, 3H), 1.83 (d, J = 13.7 Hz, 8H), 1.61 (s, 2H), 1.34 (s, 4H). MS(ESI+): 606.05(M+H).

[1428] Isomer 102-2 (18.7 mg), HPLC retention time: 18.3 min.

[1429] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 11.16 (s, 1H), 9.31 (s, 1H), 8.66 (s, 1H), 8.21 (s, 1H), 7.66 (dd, J = 13.9, 2.9 Hz, 1H), 7.45 (d,J = 9.5 Hz, 1H),7.40 (d, J = 2.2 Hz, 1H), 7.29 – 7.23 (m, 1H), 6.98 (d, J = 8.1 Hz, 1H), 3.65 (s,1H), 2.90 (s, 2H), 2.68 (d, J = 19.3 Hz, 3H), 2.55 (s, 3H), 1.83 (d, J = 13.7 Hz,8H), 1.63 (d, J = 15.2 Hz, 2H), 1.34 (s, 4H). MS(ESI+): 606.10(M+H).

[1430] Example 103 Compounds 103-1, 103-2

[1431]

[1432] Prepare according to the preparation method of Example 58, except that the (2-amino-5-fluorophenyl) dimethylphosphine oxide in step a) is replaced by (2-amino-5-trifluoromethoxyphenyl) dimethylphosphine oxide, and the 2-azabicyclo[3.1.0]hexane hydrochloride in step c) is replaced by (1 R , 4 R )-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride was obtained, and the crude product was purified by reverse phase high performance liquid chromatography (column: Xselect CSH OBD column, 30×150 mm, filler particle size 5um; mobile phase A: 10mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 30%B~65%B, 8 min; detection wavelength: 220 nm; isomer mixture retention time: 6.65 minutes) to obtain 70 mg of isomer mixture.

[1433] Chiral separation of isomer mixture was performed by chiral liquid chromatography (column: CHIRALPAK IG, 2 cm x 25 cm, filler particle size 5 μm; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol; flow rate: 20 ml / min,

[1434] Gradient: 10% B in 21 min; detection wavelength 220 / 254 nm; column temperature: 25°C), after separation:

[1435] Isomer 103-1 (21.2 mg). HPLC retention time: 13.5 min.

[1436] 1 H-NMR (400MHz, DMSO -d 6 , ppm ): δ 11.14 (s, 1H), 9.30 (s, 1H), 8.65 (d, J = 9.3 Hz, 1H), 8.20 (s, 1H), 7.65 (dd, J = 13.8, 2.9 Hz, 1H), 7.44 (dd, J = 8.4,2.6 Hz, 1H), 7.38 (d, J = 2.3 Hz, 1H), 7.26 (dd, J = 8.0, 2.3 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 4.33 (t, J = 1.9 Hz, 1H), 3.89 (d, J = 7.5 Hz, 1H), 3.71 – 3.66 (m,1H), 3.53 (dd, J = 7.6, 1.6 Hz, 1H), 2.99 (dd, J = 9.5, 1.8 Hz, 1H), 2.87 (s,2H), 2.69 (d, J = 6.9 Hz, 1H), 2.55 (s, 1H), 2.46 (s, 1H), 2.32 (d, J = 9.5 Hz,1H), 1.83 (d, J = 13.8 Hz, 8H), 1.72 (dd, J = 9.3, 2.1 Hz, 1H), 1.65 – 1.58 (m,1H), 1.55 – 1.28 (m, 2H). MS(ESI+): 622.2 (M+H).

[1437] Isomer 103-2 (21.7 mg), HPLC retention time: 17.8 min.

[1438] 1 H NMR (400MHz, DMSO -d 6 , ppm ): δ 11.11 (s, 1H), 9.29 (s, 1H), 8.63 (t,J = 6.6 Hz, 1H), 8.20 (s, 1H), 7.65 (dd, J = 13.9, 2.8 Hz, 1H), 7.45 (dd, J = 9.2,2.8 Hz, 1H), 7.39 (d, J = 2.3 Hz, 1H), 7.25 (dd, J = 8.0, 2.3 Hz, 1H), 6.96 (d, J = 8.1 Hz, 1H), 4.33 (t, J = 2.0 Hz, 1H), 3.89 (d, J = 7.5 Hz, 1H), 3.68 (d, J = 2.1Hz, 1H), 3.53 (dd, J = 7.5, 1.6 Hz, 1H), 2.99 (dd, J = 9.6, 1.8 Hz, 1H), 2.88 (s,2H), 2.68 (dt, J = 14.3, 7.9 Hz, 1H), 2.59 – 2.52 (m, 1H), 2.48 (s, 1H), 2.33(d, J = 9.4 Hz, 1H), 1.83 (d, J = 13.7 Hz, 8H), 1.72 (dd, J = 9.4, 2.1 Hz, 1H),1.61 (dd, J = 9.4, 2.4 Hz, 1H), 1.43 (s, 2H). MS(ESI+): 622.2(M+H).

[1439] Example 104 Compounds 104-1, 104-2

[1440]

[1441] Prepare according to the preparation method of Example 58, except that the (2-amino-5-fluorophenyl) dimethylphosphine oxide in step a) is replaced by (2-amino-5-trifluoromethoxyphenyl) dimethylphosphine oxide, and the 2-azabicyclo[3.1.0]hexane hydrochloride in step c) is replaced by (1 S , 4 S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride was obtained, and the crude product was purified by reverse phase high performance liquid chromatography (column: Xselect CSH OBD column, 30×150 mm, filler particle size 5um; mobile phase A: 10mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 30%B~65%B, 8 min; detection wavelength: 220 nm; isomer mixture retention time: 6.65 minutes) to obtain 75 mg of isomer mixture.

[1442] The isomer mixture was chiral separated by chiral liquid chromatography (column: CHIRALPAK ID, 2 cm x 25 cm, filler particle size 5 μm; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol; flow rate: 20 ml / min,

[1443] Gradient: 10% B in 24 min; detection wavelength 220 / 254 nm; column temperature: 25°C), after separation:

[1444] Isomer 104-1 (21.6 mg). HPLC retention time: 11.4 min.

[1445] 1 H NMR (400MHz, DMSO -d 6 , ppm ): δ 11.29 (s, 1H),,9.51 (s, 1H), 8.66 (s,1H), 8.24 (d, J = 1.4 Hz, 1H), 7.68 (dd, J = 13.8, 2.9 Hz, 1H), 7.53 – 7.47 (m,1H), 7.39 (q, J = 7.9, 6.3 Hz, 2H), 7.06 (t, J = 8.3 Hz, 1H), 4.64 (dd, J = 41.1,26.0 Hz, 2H), 4.22 (t, J = 9.7 Hz, 1H), 3.66 (dd, J = 18.8, 9.5 Hz, 1H), 3.53 –3.28 (m, 2H), 3.18 (d, J = 11.4 Hz, 1H), 2.85 – 2.66 (m, 4H), 2.27 (s, 2H), 2.17 (t, J= 9.6 Hz, 1H), 2.08 (d, J = 11.1 Hz, 1H), 1.84 (d, J = 13.7 Hz, 6H),1.66 – 1.49 (m, 1H), 1.42 (p, J = 11.7 Hz, 1H). MS(ESI+): 622.1 (M+H).

[1446] Isomer 104-2 (22.8 mg), HPLC retention time: 21.3 min.

[1447] 1 H NMR (400MHz, DMSO -d 6 , ppm ): δ 11.15 (s, 1H), 9.30 (s, 1H), 8.65 (s, 1H), 8.20 (s, 1H), 7.65 (dd, J = 13.8, 2.8 Hz, 1H), 7.47 – 7.42 (m, 1H), 7.39(d, J = 2.2 Hz, 1H), 7.26 (dd, J = 8.2, 2.3 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H), 4.33(t, J = 2.0 Hz, 1H), 3.90 (d, J = 7.5 Hz, 1H), 3.69 (d, J = 2.2 Hz, 1H), 3.53 (dd, J = 7.6, 1.7 Hz, 1H), 2.99 (dd, J = 9.4, 1.8 Hz, 1H), 2.88 (s, 2H), 2.69 (d, J =7.1 Hz, 1H), 2.55 (s, 2H), 2.32 (d, J = 9.5 Hz, 1H), 1.83 (d, J = 13.7 Hz, 8H),1.73 (d, J = 2.1 Hz, 1H), 1.65 – 1.58 (m, 1H), 1.56 – 1.33 (m, 2H). MS(ESI+):622.1(M+H).

[1448] Example 105 Compounds 105-1, 105-2

[1449]

[1450] Prepare according to the preparation method of Example 58, except that (2-amino-5-fluorophenyl)dimethylphosphine oxide in step a) is replaced by (2-amino-5-chlorophenyl)dimethylphosphine oxide, and 2-azabicyclo[3.1.0]hexane hydrochloride in step c) is replaced by (1 R , 4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride was used, and the crude product was purified by reverse phase high performance liquid chromatography (column: Xselect CSH OBD column, 30×150 mm, filler particle size 5um; mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 3%B~73%B, 6 min; detection wavelength: 220 nm; isomer mixture retention time: 7.05 minutes) to obtain 70 mg of isomer mixture.

[1451] The isomer mixture was chiral separated by chiral liquid chromatography (column: CHIRALPAK IF, 2 cm x 25 cm, filler particle size 5 μm; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol; flow rate: 15 ml / min,

[1452] Gradient: 30% B in 18 min; detection wavelength 220 / 254 nm; column temperature: 25°C), after separation:

[1453] Isomer 105-1 (26.4 mg). HPLC retention time: 11.7 min.

[1454] 1 H NMR (400MHz, DMSO -d 6 , ppm ): δ 11.10 (s, 1H), 9.31 (s, 1H), 8.56 (s, 1H), 8.19 (s, 1H), 7.69 (dd, J = 13.6, 2.6 Hz, 1H), 7.49 (dd, J = 9.0, 2.5 Hz,1H), 7.41 (d, J = 2.3 Hz, 1H), 7.28 – 7.21 (m, 1H), 6.99 (d, J = 8.1 Hz, 1H),4.34 (d, J =2.5 Hz, 1H), 3.90 (d, J = 7.5 Hz, 1H), 3.70 (s, 1H), 3.54 (dd, J = 7.5, 1.6 Hz, 1H), 3.01 (dd, J = 9.4, 1.8 Hz, 1H), 2.88 (s, 2H), 2.71 (s, 1H), 2.64 – 2.54 (m, 2H), 2.34 (d, J = 9.3 Hz, 1H), 1.82 (d, J = 13.7 Hz, 8H), 1.73(d, J = 9.9 Hz, 1H), 1.62 (d, J = 8.6 Hz, 1H), 1.41 (s, 2H). MS(ESI+): 572.10(M+H).

[1455] Isomer 105-2 (23.0 mg), HPLC retention time: 16.0 min.

[1456] 1 H NMR (400MHz, DMSO -d 6 , ppm ): δ 11.09 (s, 1H), 9.30 (s, 1H), 8.56 (s, 1H), 8.19 (s, 1H), 7.69 (dd, J = 13.6, 2.5 Hz, 1H), 7.50 (dd, J = 9.0, 2.5 Hz,1H), 7.41 (d, J = 2.3 Hz, 1H), 7.24 (dd, J = 7.7, 1.9 Hz, 1H), 6.98 (d, J = 8.1 Hz,1H), 4.33 (t, J = 1.9 Hz, 1H), 3.90 (d, J = 7.4 Hz, 1H), 3.71 (s, 1H), 3.54 (dd, J = 7.5, 1.6 Hz, 1H), 3.00 (dd, J = 9.5, 1.8 Hz, 1H), 2.85 (d, J =31.5 Hz, 2H), 2.71 (s, 1H), 2.55 (s, 2H), 2.34 (d, J = 9.4 Hz, 1H), 1.82 (d, J = 13.7 Hz, 8H),1.73 (d, J = 9.1 Hz, 1H), 1.66 – 1.59 (m, 1H), 1.43 (s, 2H). MS(ESI+):572.10(M+H).

[1457] Example 106 Compounds 106-1, 106-2

[1458]

[1459] Prepare according to the preparation method of Example 58, except that (2-amino-5-fluorophenyl)dimethylphosphine oxide in step a) is replaced by (2-amino-5-chlorophenyl)dimethylphosphine oxide, and 2-azabicyclo[3.1.0]hexane hydrochloride in step c) is replaced by (1 S , 4 S )-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride was obtained, and the crude product was purified by reverse phase high performance liquid chromatography (column: Xselect CSH OBD column, 30×150 mm, filler particle size 5um; mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 3%B~73%B, 6 min; detection wavelength: 220 nm; isomer mixture retention time: 7.05 minutes) to obtain 80 mg of isomer mixture.

[1460] The isomer mixture was chiral separated by chiral liquid chromatography (column: CHIRALPAK IF, 2 cm x 25 cm, filler particle size 5 μm; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol; flow rate: 15 ml / min,

[1461] Gradient: 30% B in 18 min; detection wavelength 220 / 254 nm; column temperature: 25°C), after separation:

[1462] Isomer 106-1 (25.6 mg). HPLC retention time: 11.7 min.

[1463] 1 H NMR (400 MHz, DMSO- d 6, ppm ): δ 11.10 (s, 1H), 9.31 (s, 1H), 8.56 (s, 1H), 8.20 (s, 1H), 7.69 (dd, J = 13.7, 2.6 Hz, 1H), 7.50 (dd, J = 9.0, 2.5 Hz, 1H), 7.42 (d, J = 2.3 Hz, 1H), 7.25 (dd, J = 8.0, 2.2 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 4.41 – 4.30 (m, 1H), 3.91 (d, J = 7.6 Hz, 1H), 3.72 (s, 1H), 3.60 – 3.50 (m, 1H), 3.01 (d, J = 9.4 Hz, 1H), 2.80 (d, J = 61.2 Hz, 3H), 2.54 (s, 2H), 2.37 - 2.33 (m, 1H), 1.82 (d, J = 13.7 Hz, 8H), 1.74 (d, J = 9.3 Hz, 1H), 1.63 (d, J = 9.3 Hz, 1H), 1.43 (s, 2H). MS(ESI+): 572.10(M + H).

[1464] Isomer 106 - 2 (27.9 mg), HPLC retention time was 16.0 min.

[1465] 1 H NMR (400 MHz, DMSO - d 6, ppm ) : δ 11.10 (s, 1H), 9.31 (s, 1H), 8.56 (s, 1H), 8.20 (s, 1H), 7.69 (dd, J = 13.7, 2.6 Hz, 1H), 7.50 (dd, J = 9.0, 2.5 Hz, 1H), 7.42 (d, J = 2.3 Hz, 1H), 7.25 (dd, J = 8.0, 2.2 Hz, 1H), 6.98 (d, J= 8.1 Hz,1H), 4.41 – 4.30 (m, 1H), 3.91 (d, J = 7.6 Hz, 1H), 3.72 (s, 1H), 3.60 – 3.50 (m, 1H), 3.01 (d, J = 9.4 Hz, 1H), 2.80 (d, J = 61.2 Hz, 3H), 2.54 (s, 2H), 2.37-2.33(m,1H),1.82 (d, J = 13.7 Hz, 8H), 1.74 (d, J = 9.3 Hz, 1H), 1.63 (d, J = 9.3Hz, 1H), 1.43 (s, 2H). MS(ESI+):572.10(M+H).

[1466] Example 107 Preparation of (S)-(4-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)dimethylphosphine oxide

[1467]

[1468] a) Preparation of 2,5-dichloro-N-(3-iodopyridin-4-yl)pyrimidin-4-amine

[1469] 2,4,5-trichloropyrimidine (200 mg), 3-iodopyridin-4-amine (254 mg), tetrahydrofuran (10 ml) were added to the reaction bottle in sequence, and lithium bis(trimethylsilyl)amide (2.2 ml, 1M) was added dropwise at -10°C for 1 hour. After the reaction was completed, saturated ammonium chloride solution (5 ml) was added to quench the reaction, and the mixture was extracted with ethyl acetate (5 ml*2). After separation, the organic layers were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol = 50 / 1) to obtain 216 mg of the title product.

[1470] b) (S)-5-chloro-N 4 -(3-iodopyridin-4-yl)-N 2 Preparation of -(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)pyrimidine-2,4-diamine

[1471] Compound 2,5-dichloro-N-(3-iodopyridin-4-yl)pyrimidin-4-amine (176 mg), (S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-amine (110 mg), n-butanol (5 ml), trifluoroacetic acid (0.1 ml) were added to the reaction bottle in sequence, and the mixture was reacted at 120°C at 400W for 5 h. After the reaction was completed, the mixture was concentrated to dryness and purified by column chromatography (mobile phase: dichloromethane / methanol = 50 / 1) to obtain 86 mg of the title product.

[1472] c) Preparation of (S)-(4-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)dimethylphosphine oxide

[1473] Add (S)-5-chloro-N 4 -(3-iodopyridin-4-yl)-N 2 -(7-(Pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)pyrimidine-2,4-diamine (40 mg), dimethylphosphine oxide (11 mg), potassium phosphate (22 mg), palladium acetate (2 mg), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (4 mg), N,N-dimethylformamide (10 ml), heated to 100°C under nitrogen atmosphere for 3 hours. After the reaction was completed, the mixture was concentrated to dryness and purified by silica gel column chromatography (dichloromethane / methanol = 20:1 v / v) to obtain 40 mg of the title product.

[1474] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 9.49 (s, 1H), 8.77 (s, 1H), 8.67 (d,J = 8.4 Hz, 1H), 8.47 (d, J = 5.6 Hz, 1H), 8.28 (s, 1H), 8.22 (s, 1H), 7.43(s, 1H), 7.34 (d, J = 7.0 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 2.83 (s, 7H), 2.62 (s, 2H), 2.04 (s, 2H), 1.88 (d, J = 13.8 Hz, 6H), 1.77 (s, 4H), 1.49(dd, J = 14.1, 3.7 Hz, 2H). MS(ESI+): 511.2(M+H).

[1475] Example 108 (S)-(4-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]amino)pyrimidin-4-yl)amino)-1,3-phenylene)bis(dimethylphosphine oxide)

[1476]

[1477] Prepare by referring to the preparation method of Example 58, except that (2-amino-5-fluorophenyl)dimethylphosphine oxide in step a) is replaced by (4-amino-1,3-phenylene)bis(dimethylphosphine oxide).

[1478] 1 H NMR (400 MHz, CDCl 3 ): δ8.81 (ddd, J = 8.7, 4.0, 2.4 Hz, 1H), 7.81(ddd, J = 13.7, 11.4, 1.9 Hz, 1H), 7.74 – 7.67 (m, 1H), 7.63 – 7.54 (m, 1H),7.33 (dd, J = 14.2, 2.3 Hz, 2H), 7.17 – 7.11 (m, 2H), 7.03 (d, J = 8.1 Hz, 1H),3.19 (m, 4H), 2.91 – 2.78 (m, 2H), 2.71 (m, 2H), 2.32 (m, 4H), 2.01 (m, 4H),1.91 (s, 3H), 1.88 (s, 3H), 1.77 (s, J = 1.7 Hz, 3H), 1.74 (s, J = 1.7 Hz, 3H),1.61 (m, 2H). MS(ESI+): 586.3(M+H).

[1479] Example 109 (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-5-(1H-tetrazol-1-yl)phenyl)dimethylphosphine oxide

[1480]

[1481] The preparation method is described in Example 1, except that the 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced with (2-amino-5-(1H-tetrazol-1-yl)phenyl)dimethylphosphine oxide.

[1482] 1 H NMR (400 MHz, CDCl 3 ): δ 11.23 (s, 1H), 9.47 (s, 1H), 8.91 (dd, J =8.9, 4.4 Hz, 1H), 8.15 (s, 1H), 7.81 – 7.66 (m, 2H), 7.43 (d, J = 2.3 Hz, 1H), 7.20 – 1.96 (s, 3H), 1.93(s, 3H), 1.66 (m, 2 H).MS(ESI+): 578.2 (M+H).

[1483] Example 110 (S)-(5-bromo-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[1484]

[1485] a) (2-amino-5-bromophenyl) dimethylphosphine oxide

[1486] The intermediate 4-bromo-2-iodoaniline (1.5 g), dimethoxyphosphine (500 mg), tris(dibenzylideneacetone)dipalladium (480 mg), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (900 mg), triethylamine (101 mg) and dioxane (30 mL) were added to a 100 mL single-mouth bottle. Under nitrogen protection, the reaction solution was placed at 60°C for 3 hours. The reaction solution was concentrated to dryness, and the residue was chromatographed on a silica gel column (dichloromethane / methanol = 20:1 v / v) to obtain 927 mg of the title product.

[1487] b) (5-bromo-2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[1488] Under nitrogen protection, the intermediate (2-amino-5-bromophenyl) dimethylphosphine oxide (1.36 g), 2,4,5-trichloropyrimidine (1.3 g), N,N- Dimethylformamide (15 mL) and N,N- Diisopropylethylamine (600 mg) was placed in a 30 mL microwave tube. The reaction solution was placed in a microwave reaction at 110°C for 1.5 hours, and then the reaction was stopped. The reaction solution was concentrated to dryness, and the residue was slurried with 10 mL of methanol and filtered to obtain 411 mg of the title product.

[1489] c) (S)-(5-bromo-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[1490] The intermediate (5-bromo-2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (120 mg), (S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-amine (69 mg), n-butanol (4 mL) and p-toluenesulfonic acid monohydrate (120 mg) were added to a 10 mL microwave tube. Under nitrogen protection, microwave reaction was carried out at 120°C for 1 h. The reaction solution was concentrated to dryness, and ethyl acetate (20 mL) was added to the residue, followed by washing with 2N sodium hydroxide (10 ml) three times. The organic layer was concentrated to dryness, and the residue was chromatographed on a silica gel column (dichloromethane / methanol = 20:1 v / v) to obtain 200 mg of the title product.

[1491] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 11.11 (s, 1H), 9.31 (s, 1H), 8.49(s, 1H), 8.19 (s, 1H), 7.79 (dd, J = 13.5, 2.4 Hz, 1H), 7.60 (dd, J = 9.0,2.4 Hz, 1H), 7.43 (d, J = 2.3 Hz, 1H), 7.22 (d, J = 8.1 Hz, 1H), 6.98 (d, J =8.1 Hz, 1H), 2.96-2.66 (m, 5H), 2.59 – 2.54 (m, 4H), 1.87 (s, 2H), 1.83 (s,3H), 1.80 (s,3H), 171-1.67 (m, 4H), 1.53 (br, 2H). MS(ESI+): 588.1 (M+H).

[1492] Example 111 (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]amino)pyrimidin-4-yl)amino)phenyl-5-deutero)dimethylphosphine oxide

[1493]

[1494] The intermediate (S)-(5-bromo-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (100 mg), deuterated methanol (0.5 mL), palladium acetate (4 mg), n-butyldi(1-adamantyl)phosphine (12 mg), potassium phosphate (72 mg) and toluene (4 mL) were added to a 25 mL single-necked bottle. Under nitrogen protection, the reaction solution was placed at 80°C for 8 hours. The reaction solution was desolventized to dryness, the reaction solution was concentrated to dryness, and the residue was chromatographed on a silica gel column (dichloromethane / methanol = 20:1 v / v) to obtain 40 mg of the title product.

[1495] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 11.10 (s, 1H), 9.27 (s, 1H), 8.57(s, 1H), 8.17 (s, 1H), 7.69-7.57 (m, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.38 (s,1H), 7.31 (d, J = 8.6 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 2.94 – 2.74 (m, 5H), 2.61 – 2.55 (m, 4H), 1.94 – 1.73 (m, 8H), 1.73 – 1.62(s, 4H),1.54-1.47 (m,2H). MS(ESI+): 511.1(M+H).

[1496] Example 112 (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]amino)pyrimidin-4-yl)amino)-5-cyclopropylphenyl)dimethylphosphine oxide

[1497]

[1498] The preparation method is described in Example 1, except that the 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced with (2-amino-5-cyclopropylphenyl) dimethylphosphine oxide.

[1499] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 10.91 (s, 1H), 9.24 (s, 1H), 8.25(s, 1H), 8.14 (s, 1H), 7.44 (d, J = 2.3 Hz, 1H), 7.31 (dd, J = 14.3, 2.2 Hz,1H), 7.25 (dd, J = 8.1, 2.3 Hz, 1H), 7.14 (dd, J = 8.6, 2.2 Hz, 1H), 6.97 (d,J = 8.2 Hz, 1H), 2.87 (m, 1H), 2.73 (m, 6H), 2.62 – 2.52 (m, 2H), 2.05 – 1.92(m, 3H), 1.77(m, 10H), 1.51 (s, 2H), 1.01 – 0.95 (m, 2H), 0.76 – 0.70 (m,2H). MS(ESI+): 550.2(M+H).

[1500] Example 113 (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]amino)pyrimidin-4-yl)amino)-6-methylphenyl)dimethylphosphine oxide

[1501]

[1502] The preparation method is described in Example 1, except that the 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced with (2-amino-6-methylphenyl) dimethylphosphine oxide.

[1503] 1 H NMR (400 MHz, Chloroform- d ) δ 11.96 (s, 1H), 8.38 (dd, J = 8.5, 3.9Hz, 1H), 8.06 (s, 1H), 7.40 – 7.33 (m, 1H), 7.31 – 7.27 (m, 2H), 7.01 (d, J =8.7 Hz, 1H), 6.93 (dd, J = 7.5, 3.9 Hz, 1H), 6.84 (s, 1H), 2.93 – 2.72 (m, 6H), 2.66 (t, J = 12.8 Hz, 2H), 2.46 (s, 3H), 2.17 (s, 2H), 1.98 (s, 3H), 1.94 (s,3H), 1.86 (s, 5H), 1.57 – 1.50 (m, 2H). MS(ESI+): 524.2(M+H).

[1504] Example 114 (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]amino)pyrimidin-4-yl)amino)-5-(isopropyloxy)phenyldimethylphosphine oxide

[1505]

[1506] The preparation method is described in Example 1, except that the 2-amino-N,N-dimethylbenzenesulfonamide in step a) is replaced with (2-amino-5-isopropoxyphenyl) dimethylphosphine oxide.

[1507] 1 H NMR (400 MHz, DMSO-d 6 , ppm ): δ 10.42 (s, 1H), 8.43 (dd, J = 9.2, 5.1Hz, 1H), 8.05 (s, 1H), 7.29 (d, J = 7.8 Hz, 2H), 7.06 – 6.98 (m, 2H), 6.89(s, 1H), 6.81 (dd, J = 15.0, 2.9 Hz, 1H), 4.54 (p, J = 6.0 Hz, 1H), 2.86 (s,7H), 2.71 – 2.63 (m, 2H), 2.19 (s, 2H), 1.88 (d, J = 6.2 Hz, 4H), 1.83 (s,3H), 1.80 (s, 3H), 1.57 (s, 2H), 1.38 (s, 3H), 1.36 (s, 3H). MS(ESI+): 568.3(M+H).

[1508] Example 115 (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]amino)pyrimidin-4-yl)amino)-5-(methoxymethyl)phenyl)dimethylphosphine oxide

[1509]

[1510] a) 2-iodo-4-(methoxymethyl)aniline

[1511] 4-(Methoxymethyl)aniline (9 g), iodine (16.65 g) and sodium bicarbonate (16.53 g) were added to a solution of dichloromethane (261 mL) / water (135 mL) and stirred at 22°C for 16 h. The reaction solution was quenched with saturated sodium thiosulfate (10 ml) at room temperature. The resulting mixture was extracted with dichloromethane (3 x 100 mL), and the combined organic layer was washed with saturated sodium chloride aqueous solution (1x100 mL), and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1 v / v) to obtain the title product (16 g). MS(ESI+): 264.0(M+H).

[1512] b) (2-amino-5-(methoxymethyl)phenyl)dimethylphosphine oxide

[1513] Under nitrogen atmosphere, dimethylphosphine oxide (5.22 g) was added to a stirred solution of 2-iodo-4-(methoxymethyl)aniline (16 g, 60.82 mmol, 1.00 equivalent), potassium phosphate (14.20 g), palladium acetate (0.68 g) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.76 g) in N,N-dimethylformamide (224 mL), and the mixture was stirred at 120°C for 2 hours. The mixture was cooled to room temperature. The obtained mixture was filtered and the filter cake was washed with N,N-dimethylformamide (3x5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1 v / v) to obtain the title product (12.9 g). MS(ESI+): 214.1(M+H).

[1514] c) (2-((2,5-dichloropyrimidin-4-yl)amino)-5-(methoxymethyl)phenyl)dimethylphosphine oxide

[1515] To N,N-dimethylformamide (22 mL) were added (2-amino-5-(methoxymethyl)phenyl)dimethylphosphine oxide (1.10 g), 2,4,5-trichloropyrimidine (1.23 g) and N,N-diisopropylethylamine (2.00 g) and stirred for 3 h at room temperature. The resulting mixture was diluted with dichloromethane (30 mL). The reaction was quenched by adding water (10 ml) at 0°C. The resulting mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with saturated sodium chloride (1x50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1 v / v) to obtain the title product (1.28 g).

[1516] MS(ESI+): 360.0(M+H).

[1517] d) (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]amino)pyrimidin-4-yl)amino)-5-(methoxymethyl)phenyl)dimethylphosphine oxide

[1518] To isopropanol (2 mL) was added (2-((2,5-dichloropyrimidin-4-yl)amino)-5-(methoxymethyl)phenyl)dimethylphosphine oxide (50.00 mg) and (S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-amine (31.98 mg), followed by a solution of hydrogen chloride in 1,4-dioxane (10 drops, 4 M), and microwave irradiation was performed at 130°C for 3.5 hours. The mixture was then cooled to room temperature and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (column: YMC ActusTriart C18, 30*150 mm, particle size: 5 μm, mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL / min, gradient: 20% B to 50% B, 8 min, wavelength: 220 nm, retention time: 6.83 min, column temperature: 25°C) to obtain the title product (20.2 mg).

[1519] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 11.07 (s, 1H), 9.26 (s, 1H), 8.52 (d, J = 4.6 Hz, 1H), 8.17 (s, 1H), 7.53 (dd, J = 14.0, 2.0 Hz, 1H), 7.44 (q, J = 3.1Hz, 2H), 7.26 (dd, J = 8.1, 2.3 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H), 4.42 (s, 2H), 3.31 (s, 3H), 3.01 – 2.75 (m, 2H), 2.55 (s, 5H), 2.50 (s, 2H), 1.84 (s, 2H), 1.81 (s, 3H), 1.77 (s, 3H), 1.70 (q, J = 3.6, 3.2 Hz, 4H), 1.54 (s, 2H). MS(ESI+): 554.2(M+H).

[1520] Example 116 Compounds 116-1, 116-2

[1521]

[1522] a) 2-[(5-chloro-4-[[2-(dimethylphosphoryl)-4-(methoxymethyl)phenyl]amino]pyrimidin-2-yl)amino]-5,6,8,9-tetrahydrobenzo[7]annulene-7-one.

[1523] To isopropanol (20 mL) was added (2-((2,5-dichloropyrimidin-4-yl)amino)-5-(methoxymethyl)phenyl)dimethylphosphine oxide (1.10 g) and 2-amino-5,6,8,9-tetrahydrobenzo[7]annulene-7-one (0.54 g), followed by a solution of hydrogen chloride in 1,4-dioxane (10 drops, 4 M) and microwave irradiation at 130°C for 0.5 h. The mixture was then cooled to room temperature, filtered, and the precipitated solid was collected and washed with isopropanol (1x10 mL) to give the title product (1 g). MS(ESI+): 499.2(M+H).

[1524] (2-((2-((7-(2-azabicyclo[2.1.1]hex-2-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)-5-chloropyrimidin-4-yl)amino)-5-(methoxymethyl)phenyl)dimethylphosphine oxide

[1525] The crude product was purified by reverse phase high performance liquid chromatography (column: XBridge-Prep-OBD C18 column, 30×150 mm, filler particle size 5 um; mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile (0.1% formic acid); flow rate: 60 mL / min; gradient: 5% B to 45% B, 8 min; detection wavelength: 220 nm; column temperature: 25°C) to obtain a mixture of isomers.

[1526] c) The isomeric mixture was chirally separated by chiral liquid chromatography (column: CHIRALPAK ID, 2x25cm, filler particle size 5 μm; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol; flow rate: 20 ml / min, gradient: 25% B in 13 min, isocratic; detection wavelength 220 / 254 nm; column temperature: 25°C), and the following was obtained after separation:

[1527] Isomer 116-1 (47.4 mg). HPLC retention time: 8.6 min.

[1528] 1 H NMR (400 MHz, DMSO- d 6, ppm ): δ 11.10 (s, 1H), 9.31 (s, 1H), 8.56 (s, 1H), 8.20 (s, 1H), 7.69 (dd, J = 13.7, 2.6 Hz, 1H), 7.50 (dd, J = 9.0, 2.5 Hz,1H), 7.42 (d, J = 2.3 Hz, 1H), 7.25 (dd, J = 8.0, 2.2 Hz, 1H), 6.98 (d, J = 8.1 Hz,1H), 4.41 – 4.30 (m, 1H), 3.91 (d, J = 7.6 Hz, 1H), 3.72 (s, 1H), 3.60 – 3.50 (m, 1H), 3.01 (d, J = 9.4 Hz, 1H), 2.80 (d, J = 61.2 Hz, 3H), 2.54 (s, 2H), 2.37-2.33(m,1H),1.82 (d, J = 13.7 Hz, 8H), 1.74 (d, J = 9.3 Hz, 1H), 1.63 (d, J = 9.3Hz, 1H), 1.43 (s, 2H). MS(ESI+): 566.2(M+H).

[1529] Isomer 116-2 (38.2 mg). HPLC retention time: 10.8 min.

[1530] 1 H NMR (400 MHz, DMSO- d 6, ppm ): δ 11.07 (s, 1H), 9.27 (s, 1H), 8.53 (d, J = 8.3 Hz, 1H), 8.18 (s, 1H), 7.54 (dd, J = 14.0, 2.0 Hz, 1H), 7.45 (dt, J = 5.0,2.6 Hz, 2H), 7.27 (d, J = 8.1 Hz, 1H), 6.98 (d, J =8.1 Hz, 1H), 4.43 (s, 2H), 3.66 (s, 1H), 3.32 (s, 3H), 2.89 (s, 2H), 2.75 – 2.62 (m, 3H), 2.52 (s, 2H), 2.50 (s, 1H), 1.91 (s, 2H), 1.79 (d, J = 13.5 Hz, 6H), 1.62 (s, 2H), 1.34 (s,4H). MS(ESI+): 566.2(M+H).

[1531] Example 117 (S)-(4-chloro-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzoannulene-2-yl)amino)pyrimidin-4-yl)amino)-6-methylphenyl)dimethylphosphine oxide

[1532]

[1533] Prepare by referring to the preparation method of Example 115, except that 4-(methoxymethyl)aniline in step a) is replaced by 5-chloro-3-methylaniline.

[1534] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 12.11 (s, 1H), 9.30 (s, 1H), 8.29(dd, J = 6.2, 3.7 Hz, 1H), 8.17 (s, 1H), 7.40 (dd, J = 8.1, 2.3 Hz, 1H), 7.22(d, J = 2.4 Hz, 1H), 7.12 (s, 1H), 6.97 (d, J = 8.2 Hz, 1H), 2.87 - 2.76 (m,2H), 2.68 (d, J = 6.0 Hz, 4H), 2.62 (s, 1H), 2.54 (s, 2H), 2.45 (s, 3H), 1.93(s, 2H), 1.90 (s, 3H), 1.87 (s, 3H), 1.78 - 1.66 (m, 4H), 1.47 (s, 2H). MS(ESI+): 558.1(M+H).

[1535] Example 118 (S)-(4-chloro-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzoannulene-2-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)dimethylphosphine oxide

[1536]

[1537] Prepare by referring to the preparation method of Example 115 (steps b to d), except that 2-iodo-4-(methoxymethyl)aniline in step b) is replaced with 5-chloro-4-fluoro-2-iodoaniline.

[1538] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ 11.09 (s, 1H), 9.36 (s, 1H), 8.70 (s,1H), 8.20 (s, 1H), 7.73 (dd, J = 13.7, 9.3 Hz, 1H), 7.36 (dd, J = 8.1, 2.2Hz, 1H), 7.26 – 7.22 (m, 1H), 7.01 (d, J = 8.2 Hz, 1H), 2.92-2.75 (m, 3H), 2.70 – 2.64 (m, 4H), 2.59-2.53 (m, 2H), 1.93 (br, 2H), 1.83 (s, 3H), 1.80 (s,3H), 1.72 (br, 4H), 1.49 (br, 2H). MS(ESI+): 562.1(M+H).

[1539] Example 119 (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)amino)pyrimidin-4-yl)amino)-5-(2-oxa-6-azaspiro[3.3]heptane-6-yl)phenyl)dimethylphosphine oxide

[1540]

[1541] To 1,4-dioxane (5 ml) were added (S)-(5-bromo-2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7] annulene-2-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (50 mg), 2-oxo-6-azaspiro[3.3]heptane (18 mg), 2-bicyclohexylphosphino-2',6'-diisopropoxybiphenyl (6 mg), tris(dibenzylideneacetone)dipalladium (6 mg) and cesium carbonate (55 mg) under nitrogen protection and reacted at 100°C for 3 h. After the reaction was completed, the solid was removed by filtration, the filter cake was washed twice with dichloromethane (10 ml x 2), the organic layers were combined, the reaction solution was desolventized to dryness, the reaction solution was concentrated to dryness, and the residue was chromatographed on a silica gel column (dichloromethane / methanol = 20:1 v / v) to obtain 35 mg of the title product.

[1542] 1 H NMR (400 MHz, DMSO -d 6 , ppm ): δ10.23 (s, 1H), 9.15 (s, 1H), 8.25 (s,1H), 8.10-8.02 (m, 1H), 7.41 (d, J = 2.3 Hz, 1H), 7.17 (d, J = 8.1 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.66 – 6.59 (m, 2H), 4.73 (s, 4H), 4.02 (s, 4H), 2.91 – 2.73 (m, 3H), 2.59 (br, 4H), 2.44 – 2.36 (m, 2H), 1.85 (br, 2H), 1.75-1.65 (m, 10H), 1.52 (br, 2H). MS(ESI+): 607.3(M+H).

[1543] Example 120 Preparation of Compounds 120-1 and 120-2

[1544]

[1545] Prepared by referring to the preparation method of Example 58, (2-amino-5-fluorophenyl) dimethylphosphine oxide in step a) was replaced by (2-amino-5-methylphenyl) dimethylphosphine oxide, and 2-azabicyclo[3.1.0]hexane hydrochloride in step c) was replaced by (3S)-pyrrolidine-3-carbonitrile hydrochloride. The crude product was purified by preparative high performance liquid chromatography under the following conditions (column: XBridgePrep OBD column 30x150mm filler particle size 5um; mobile phase A: water (10mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: 30%B~68%B in 8 minutes; wavelength: 254 / 220nm;) to obtain a mixture of two isomers.

[1546] The two isomer mixtures were purified by chiral HPLC column (column: CHIRALPAK IF, 5x25 cm, filler 5μm); mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol; flow rate: 15ml / min; gradient: 20% B in 17.5 minutes, isocratic; detection wavelength: 220 / 254 nm, column temperature: 25°C) to obtain:

[1547] Isomer 120-1 (20 mg), HPLC retention time 13.4 min:

[1548] 1 HNMR (400 MHz, DMSO- d 6 , ppm ): δ10.92 (s, 1H), 9.25 (s, 1H), 8.40 (s,1H), 8.15 (s, 1H), 7.46 – 7.39 (m, 2H), 7.34 – 7.25 (m, 2H), 6.98 (d, J = 8.2Hz, 1H), 3.29 – 3.20 (m, 1H), 2.94 – 2.69 (m, 5H), 2.62 – 2.54 (m, 3H), 2.46 (s, 1H), 2.34 (s, 3H), 2.23 – 2.11 (m, 1H), 1.99 – 1.81 (m, 3H), 1.77 (d, J =13.5 Hz, 6H), 1.52 (s, 2H). MS(ESI+): 549.2(M+H).

[1549] Isomer 120-2 (20 mg), HPLC retention time 16.2 min:

[1550] 1HNMR (400 MHz, DMSO- d 6 , ppm ): δ10.93 (s, 1H), 9.25 (s, 1H), 8.40 (s,1H), 8.15 (s, 1H), 7.47 – 7.39 (m, 2H), 7.35 – 7.25 (m, 2H), 6.98 (d, J = 8.2Hz, 1H), 3.23 – 3.25 (m, 1H), 2.95 – 2.70 (m, 5H), 2.57 (d, J = 6.7 Hz, 4H), 2.34 (s, 3H), 2.23 – 2.11 (m, 1H), 2.00 – 1.81 (m, 3H), 1.77 (d, J = 13.5 Hz, 6H), 1.51 (s, 2H). MS(ESI+): 549.2(M+H).

[1551] Example 121 Preparation of Compounds 121-1 and 121-2

[1552]

[1553] Prepared with reference to the preparation method of Example 58, (2-amino-5-fluorophenyl) dimethylphosphine oxide in step a) was replaced with (2-amino-5-methylphenyl) dimethylphosphine oxide, and 2-azabicyclo[3.1.0]hexane hydrochloride in step c) was replaced with (3R)-3-fluoropyrrolidine hydrochloride. The crude product was purified by preparative high performance liquid chromatography under the following conditions (column: XBridgePrep OBD column 30x150mm, filler particle size 5um; mobile phase A: water (10mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: 30%B~68%B in 8 minutes; wavelength: 254 / 220nm;) to obtain a mixture of two isomers.

[1554] The two isomer mixtures were purified by chiral HPLC column (column: CHIRALPAK IF, 5x25 cm, filler 5μm); mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol; flow rate: 15ml / min; gradient: 20% B in 17.5 minutes, isocratic; detection wavelength: 220 / 254 nm, column temperature: 25°C) to obtain:

[1555] Isomer 121-1 (20 mg), HPLC retention time 13.4 min:

[1556] 1HNMR (400 MHz, DMSO- d 6 , ppm ): δ10.92 (s, 1H), 9.25 (s, 1H), 8.40 (s,1H), 8.15 (s, 1H), 7.51 – 7.38 (m, 2H), 7.35 – 7.22 (m, 2H), 6.98 (d, J = 8.2Hz, 1H), 5.20 (m, 1H), 2.99 – 2.69 (m, 5H), 2.57 (s, 2H), 2.45 (s, 2H), 2.34 (s, 3H), 2.09 (ddd, J = 18.3, 14.3, 7.0 Hz, 1H), 1.91 (d, J = 26.4 Hz, 3H), 1.77(d, J = 13.5 Hz, 6H), 1.49 (s, 2H).

[1557] MS(ESI+): 542.2(M+H).

[1558] Isomer 121-2 (20 mg), HPLC retention time 16.2 min:

[1559] 1 HNMR (400 MHz, DMSO- d 6 , ppm ): δ10.92 (s, 1H), 9.25 (s, 1H), 8.40 (s,1H), 8.15 (s, 1H), 7.48 – 7.39 (m, 2H), 7.35 – 7.24 (m, 2H), 6.98 (d, J = 8.1Hz, 1H), 5.20 (d, J = 56.2 Hz, 1H), 2.97 – 2.70 (m, 5H), 2.57 (s, 3H), 2.46 (s, 1H), 2.34 (s, 3H), 2.19 – 2.04 (m, 1H), 1.87 (s, 3H), 1.77 (d, J = 13.5Hz, 6H), 1.49 (s, 2H).

[1560] MS(ESI+): 542.2(M+H).

[1561] Example 122 Preparation of Compounds 122-1 and 122-2

[1562]

[1563] Prepared by referring to the preparation method of Example 58, replacing (2-amino-5-fluorophenyl)dimethylphosphine oxide in step a) with (2-amino-5-methylphenyl)dimethylphosphine oxide, and replacing 2-azabicyclo[3.1.0]hexane hydrochloride in step c) with (3S)-3-fluoropyrrolidine hydrochloride. The crude prod...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, in, X is CH or N; R 1 for R 2 is a halogen; Ring A is phenyl, furyl, thiazolyl, pyridyl, wherein the phenyl, furyl, thiazolyl, pyridyl, Optionally one or more R 3 replace; R 3 Selected from: deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyloxy, The C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with hydroxy, halogen, cyano, C 1-3 Alkoxy or 4-7 membered heterocycloalkyl substitution; R 4 , R 5 Independently selected from C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with deuterium, hydroxyl, halogen, cyano or C 1-3 Alkoxy substitution; R 6 Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl or 4-7 membered heterocycloalkyl; R 7 , R 8 are independently selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl or 4-7 membered heterocycloalkyl, wherein the C 1-6 The alkyl group is optionally substituted with hydroxy, halogen, cyano or C 1-3 Alkoxy substitution; R 9 , R 10 Independently selected from C 1-6 Alkyl or C 3-10 Cycloalkyl; R 11 Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl or 4-7 membered heterocycloalkyl; R 12 Selected from C 3-10 Cycloalkyl, 4-7 membered heterocycloalkyl or 5-7 membered heteroaryl, which is optionally substituted by one or more hydroxyl, halogen, cyano or C 1-6 Alkyl substitution.

2. The compound of formula I according to claim 1, wherein R 1 for 3. The compound of formula I according to claim 1, wherein R 1 for 4. The compound of formula I according to claim 1, wherein R 2 For Cl.

5. The compound of formula I according to claim 1, wherein Ring A is phenyl, and the phenyl group is optionally substituted with one or more R 3 replace.

6. A compound of formula I according to any one of claims 1 to 5, wherein R 3 Selected from: deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, The C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with hydroxy, halogen, cyano, C 1-3 The group may be substituted with an alkoxy group or a 4-7 membered heterocycloalkyl group.

7. A compound of formula I according to any one of claims 1 to 5, wherein R 3 is selected from deuterium, fluorine, chlorine, bromine, methyl, trifluoromethyl, 8. A compound of formula I according to any one of claims 1 to 5, wherein R 3 Selected from fluorine, methyl, 9. A compound of formula I according to any one of claims 1 to 5, wherein R 3 Selected from 10. A compound of formula I according to any one of claims 1 to 5, wherein R 4 , R 5 Independently selected from C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with deuterium, hydroxyl, halogen, cyano or C 1-3 Alkoxy substitution.

11. A compound of formula I according to any one of claims 1 to 5, wherein R 4 , R 5 Independently selected from methyl, ethyl, n-propyl, isopropyl, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CH2CH2CD3, CH(CD3)2 or CD(CD3)2.

12. A compound of formula I according to any one of claims 1 to 5, wherein R 6 is methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

13. A compound of formula I according to any one of claims 1 to 5, wherein R 7 , R 8 independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, CH2CH2OCH3, CF3, 14. A compound of formula I according to any one of claims 1 to 5, wherein R 9 , R 10 Independently selected from C 1-6 alkyl.

15. A compound of formula I according to any one of claims 1 to 5, wherein R 9 , R 10 Independently selected from methyl, ethyl, n-propyl, isopropyl or tert-butyl.

16. A compound of formula I according to any one of claims 1 to 5, wherein R 11 It is a 4-7 membered heterocycloalkyl group.

17. A compound of formula I according to any one of claims 1 to 5, wherein R 11 It is a 5-membered heterocycloalkyl.

18. A compound of formula I according to any one of claims 1 to 5, wherein R 12 C 3-10 Cycloalkyl or 5-7 membered heteroaryl, which is optionally substituted by one or more C 1-6 Alkyl substitution.

19. A compound of formula I according to any one of claims 1 to 5, wherein R 12 is cyclopropyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or tetrazolyl, which is optionally substituted by one or more methyl groups.

20. A compound of formula I according to any one of claims 1 to 5, wherein R 12 Selected from 21. A compound of formula I according to any one of claims 1 to 5, wherein Having the structure shown in the following formula I-1 or formula I-2 compound, Among them, R 1 , R 2 , Ring A is as defined in the compound of formula I.

22. A compound represented by formula II or a pharmaceutically acceptable salt thereof, in, X is CH or N; R 1 for R 2 is a halogen; R 3 Selected from: deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyloxy, The C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with hydroxy, halogen, cyano, C 1-3 Alkoxy or 4-7 membered heterocycloalkyl substitution; n is an integer from 0 to 4; R a For deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyloxy, The C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with one or more deuterium, methoxy, hydroxy, halogen or cyano; R 4 , R 5 Independently selected from C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with deuterium, hydroxyl, halogen, cyano or C 1-3 Alkoxy substitution; R 6 Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl or 4-7 membered heterocycloalkyl; R 7 , R 8 are independently selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl or 4-7 membered heterocycloalkyl, wherein the C 1-6 The alkyl group is optionally substituted with hydroxy, halogen, cyano or C 1-3 Alkoxy substitution; R 9 , R 10 Independently selected from C 1-6 Alkyl or C 3-10 Cycloalkyl; R 11 Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl or 4-7 membered heterocycloalkyl; R 12 Selected from C 3-10 Cycloalkyl, 4-7 membered heterocycloalkyl or 5-7 membered heteroaryl, which is optionally substituted by one or more hydroxyl, halogen, cyano or C 1-6 Alkyl substitution.

23. The compound of formula II according to claim 22, wherein R 4 , R 5 Independently selected from C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with deuterium, hydroxyl, halogen, cyano or C 1-3 Alkoxy substitution.

24. The compound of formula II according to claim 22, wherein R 4 , R 5 Independently selected from methyl, ethyl, n-propyl, isopropyl, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CH2CH2CD3, CH(CD3)2 or CD(CD3)2.

25. The compound of formula II according to claim 22, wherein R 6 is methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

26. The compound of formula II according to claim 22, wherein R 7 , R 8 independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, CH2CH2OCH3, CF3, 27. The compound of formula II according to claim 22, wherein R 9 , R 10 Independently selected from C 1-6 alkyl.

28. The compound of formula II according to claim 22, wherein R 9 , R 10 Independently selected from methyl, ethyl, n-propyl, isopropyl or tert-butyl.

29. The compound of formula II according to claim 22, wherein R 11 It is a 4-7 membered heterocycloalkyl group.

30. The compound of formula II according to claim 22, wherein R 11 It is a 5-membered heterocycloalkyl.

31. The compound of formula II according to claim 22, wherein R 12 C 3-10 Cycloalkyl or 5-7 membered heteroaryl, which is optionally substituted by one or more C 1-6 Alkyl substitution.

32. The compound of formula II according to claim 22, wherein R 12 is cyclopropyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or tetrazolyl, which is optionally substituted by one or more methyl groups.

33. The compound of formula II according to claim 22, wherein R 12 Selected from 34. The compound of formula II according to claim 22, wherein R a For deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, The C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with one or more deuterium, halogen or cyano groups.

35. The compound of formula II according to claim 22, wherein R a For deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, The C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with one or more deuterium, halogen or cyano groups.

36. The compound of formula II according to claim 22, wherein R a is deuterium, fluorine, chlorine, bromine, methyl, trifluoromethyl, 37. The compound of formula II according to claim 22, wherein R a for or methyl.

38. The compound of formula II according to claim 22, wherein The compound of formula II has the structure shown in the following compound II-1, Among them, R 1 , R 2 , R 3 , R a , n are consistent with the definitions in the compound represented by formula II.

39. The compound of formula II according to claim 22, wherein Having the structure shown in the following III compound, Among them, X, R 1 , R 2 , R 3 , R a The definition of is consistent with that of the compound of formula II.

40. The compound of formula II according to claim 22, wherein The compound of formula II has the structure shown in the following compound III-1, Among them, R 1 , R 2 , R 3 , R a The definition of is the same as that of the compound represented by formula II.

41. A compound of formula II according to any one of claims 22 to 40, whereinR 1 for 42. A compound of formula II according to any one of claims 22 to 40, wherein R 1 for 43. A compound of formula II according to any one of claims 22 to 40, wherein R 2 For Cl.

44. A compound of formula II according to any one of claims 22 to 40, wherein R 3 Selected from: deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, The C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with hydroxy, halogen, cyano, C 1-3 The group may be substituted with an alkoxy group or a 4-7 membered heterocycloalkyl group.

45. A compound of formula II according to any one of claims 22 to 40, wherein R 3 is selected from deuterium, fluorine, chlorine, bromine, methyl, trifluoromethyl, 46. ​​A compound of formula II according to any one of claims 22 to 40, wherein R 3 Selected from fluorine, methyl, 47. A compound of formula II according to any one of claims 22 to 40, wherein R 3 Selected from 48. A compound of formula IV or a pharmaceutically acceptable salt thereof, Wherein X is CH or N; R 1 for R 2 is a halogen; n is an integer from 0 to 4; Ring B is phenyl, furyl, thiazolyl, pyridyl, R b For deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyloxy, The C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with one or more methoxy, hydroxy, deuterium, halogen or cyano; R 4 , R 5 Independently selected from C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with deuterium, hydroxyl, halogen, cyano or C 1-3 Alkoxy substitution; R 7 , R 8 are independently selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl or 4-7 membered heterocycloalkyl, wherein the C 1-6The alkyl group is optionally substituted with hydroxy, halogen, cyano or C 1-3 Alkoxy substitution; R 12 Selected from C 3-10 Cycloalkyl, 4-7 membered heterocycloalkyl or 5-7 membered heteroaryl, which is optionally substituted by one or more hydroxyl, halogen, cyano or C 1-6 Alkyl substitution.

49. The compound of formula IV according to claim 48, wherein R b For deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, The C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with one or more deuterium, halogen or cyano groups.

50. The compound of formula IV according to claim 48, wherein R 4 , R 5 Independently selected from C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with deuterium, hydroxyl, halogen, cyano or C 1-3 Alkoxy substitution.

51. The compound of formula IV according to claim 48, wherein R 4 , R 5 Independently selected from methyl, ethyl, n-propyl, isopropyl, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CH2CH2CD3, CH(CD3)2 or CD(CD3)2.

52. The compound of formula IV according to claim 48, wherein R 7 , R 8 independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, CH2CH2OCH3, CF3, 53. The compound of formula IV according to claim 48, wherein R 12 C 3-10 Cycloalkyl or 5-7 membered heteroaryl, which is optionally substituted by one or more C 1-6 Alkyl substitution.

54. The compound of formula IV according to claim 48, wherein R 12 is cyclopropyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or tetrazolyl, which is optionally substituted by one or more methyl groups.

55. The compound of formula IV according to claim 48, wherein R 12 Selected from 56. The compound of formula IV according to claim 48, wherein R b For deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, The C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted by one or more deuterium, halogen or cyano groups, Where R 4 , R 5 , R 7 , R 8 , R 12 The same as defined in the compound of formula IV.

57. The compound of formula IV according to claim 48, wherein R b is deuterium, fluorine, chlorine, bromine, methyl, trifluoromethyl, 58. The compound of formula IV according to claim 48, wherein R b for 59. The compound of formula IV according to claim 48, wherein It has the structure shown in the following formula IV-1: Among them, R 1 , R 2 , R b The definitions of n and ring B are consistent with those in the compound of formula IV.

60. The compound of formula IV according to claim 48, wherein It has the structure shown in the following formula V: Among them, X, R 1 , R 2 , R b The definitions of n are consistent with those in the compound of formula IV.

61. The compound of formula IV according to claim 48, wherein It has a structure as shown in Formula VI: Among them, X, R 1 , R 2 , R b The definition of is consistent with that of the compound of formula IV.

62. A compound of formula IV according to any one of claims 48 to 61, wherein R 1 for 63. A compound of formula IV according to any one of claims 48 to 61, wherein R 1 for 64. A compound of formula IV according to any one of claims 48 to 61, wherein R 2 For Cl.

65. The following compound or a pharmaceutically acceptable salt thereof:

66. A method for preparing a compound of formula I according to claim 1, comprising the steps of: Synthesis Scheme 1: Among them, R 1 , R 2 The definitions of , X and ring A are the same as those of Formula I in the general formula; The compound of formula H-1-1 is reacted with H-1-2 in a solvent and in the presence of a base to prepare the compound of formula H-1-3. The compound of formula H-1-3 and formula H-1-4 are reacted in a solvent and in the presence of an acid to prepare the compound of formula I.

67. The method for preparing the compound of formula I-1 according to claim 21 comprises the following steps: Synthesis Scheme 2: The compound of formula H-2-1 reacts with H-2-2 in a solvent and a base to prepare the compound of formula H-2-3. The compound of formula H-2-3 reacts with H-2-4 in a solvent and an acid to prepare the compound of formula H-2-5. The compound of formula H-2-5 reacts with a solvent, a reducing agent and R 1 H or its acid addition salt to obtain a compound of formula H-2-6; optionally, an optically pure target product is prepared by chiral resolution; Among them, R 2 It is a halogen.

68. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 65 or a pharmaceutically acceptable salt thereof.

69. The pharmaceutical composition according to claim 68, wherein The pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.

70. The pharmaceutical composition according to claim 68, wherein The pharmaceutical composition is administered orally.

71. The pharmaceutical composition according to claim 70, wherein The pharmaceutical composition is in the form of tablets, capsules or solutions.

72. The pharmaceutical composition according to claim 68, wherein The pharmaceutical composition is administered parenterally.

73. The pharmaceutical composition according to claim 72, wherein The pharmaceutical composition is a sterile aqueous solution, suspension or lyophilized powder.

74. Use of a compound according to any one of claims 1 to 65 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating a disease or disease state mediated by AXL protein kinase.

75. The use according to claim 74, wherein The AXL protein kinase-mediated diseases or disease states include autoimmune diseases.

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