CDK inhibitor, preparation method therefor, and use thereof

Abstract

Provided are a CDK inhibitor, a preparation method therefor, and use thereof. In particular, provided are a compound represented by formula (I), a preparation method therefor, a pharmaceutical composition comprising the compound, and use thereof as a cyclin-dependent kinase (CDK) inhibitor, especially use thereof for preventing or treating CDK-mediated diseases such as cancer.

Description

CDK inhibitors, their preparation methods, and applications Technical Field

[0001] This invention belongs to the field of biomedical technology and relates to cyclin-dependent kinase (CDK) inhibitor compounds, and their use as cyclin-dependent kinase inhibitors, particularly for the prevention or treatment of CDK2 / 4-mediated diseases such as cancer. Background Technology

[0002] Cyclin-dependent kinases (CDKs) are a family of serine / threonine protein kinases discovered for their role in regulating the cell cycle. CDKs are proteins with a molecular weight of approximately 34–40 kDa, containing only a kinase domain, and exert their effects by binding to cyclins. CDKs are ubiquitous in eukaryotes, and their regulatory function in the cell cycle is evolutionarily conserved.

[0003] The cell cycle is mainly divided into two phases: interphase and mitotic phase (M phase). Interphase is further divided into pre-DNA synthesis phase (G1 phase), DNA synthesis phase (S phase), and post-DNA synthesis phase (G2 phase). Animal cells have at least nine different CDK isoforms, among which CDK1, CDK2, CDK4, and CDK6 directly participate in cell cycle regulation. CDK1 mainly functions in the S phase and the G2 / M transition, CDK2 mainly acts in the S phase, while CDK4 / 6 mainly affects the G1 / S phase transition. Due to the important role of CDKs in cell cycle regulation, they have become important targets for cancer and other diseases caused by cell proliferation disorders. For example, the CDK4 / 6 inhibitors palbociclb, ribocicilb, and abemaciclib from Pfizer, Eli Lilly, and Novartis are widely used in the clinical treatment of breast cancer. In 2023, the total sales of these three drugs reached US$10.796 billion.

[0004] Although CDK4 / 6 inhibitors have become the standard treatment for ER+ / HER2- breast cancer, greatly changing the treatment landscape for HR+ / HER2-ABC, significant challenges remain.

[0005] First, similar to other kinase inhibitors, CDK4 / 6 inhibitors also present with primary and acquired resistance issues. Approximately 20% of patients treated with CDK4 / 6 inhibitors exhibit primary resistance (failure to respond to initial treatment), and another 50% develop resistance and disease progression within 25 months.

[0006] Second, adverse reactions in the digestive and hematologic systems during clinical application, primarily diarrhea and neutropenia. Pharmacological and biological studies of CDK4 / 6 inhibitors have revealed that inhibition of CDK6 is associated with myelotoxicity, leading to numerous hematologic adverse reactions. Inhibition of GSK3β and CDK9, on the other hand, can cause gastrointestinal adverse reactions.

[0007] To address the aforementioned issues of drug resistance and adverse reactions, there is an urgent need to develop new, highly active, and selective CDK inhibitors to better meet market demands and achieve better cancer treatment outcomes. Summary of the Invention

[0008] This invention provides a novel class of polycyclic heterocyclic compounds that can inhibit CDK activity, thereby affecting biological function.

[0009] Therefore, the present invention provides a compound of general formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0010] in:

[0011] X is selected from -O- and -NR 6 -or-CR 6a R 6b -;

[0012] Y1, Y2, Y3, and Y4 are each independently selected from N or CR. d ;

[0013] Ring A is selected from heterocyclic, heteroaryl, or aryl groups;

[0014] L is selected from the following groups: -S(O)2-, -S(O)-, -C(O)-, -S(O)2NH-, -S(O)NH-, -C(O)NH-, -CR b R c -;

[0015] R 1 Selected from hydrogen, halogen, amino, nitro, hydroxyl, mercapto, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -NR 7a R 7b -P(O)R b R c -OR c The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally selected from deuterium, halogen, amino, and -NR. 8a R 8bIt is substituted by one or more groups of nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl;

[0016] Each R 2 Each of the following groups is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, mercapto, cyano, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; or, any two R groups 2 Together with the atoms attached thereto, they form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more groups selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0017] R 3a and R 3b Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, mercapto, cyano, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -(CH2). n -R 9 -(CH2) n -NR 8a R 8b The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, methylidene, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, and -NR. 8a R 8b -S(O) v R a -COOR a -C(O)R a -P(O)R b R c -(CH2) n -R 9 -(CH2) n -NR 8a R 8b -CONR 8a R 8bThe group is substituted by one or more groups, including alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be further substituted by Q; or, R 3a and R 3b Together they form an oxygen group; or, R 3a With R 3b The atoms bonded to it together form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, -S(O). v R a -COOR a -C(O)R a -P(O)R b R c The group is substituted by one or more groups of alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl groups may optionally be further substituted by Q;

[0018] R 4a and R 4b Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, mercapto, cyano, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -(CH2). n -R 9 -(CH2) n -NR 8a R 8b The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, methylidene, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, and -NR. 8a R 8b -S(O) v R a -COOR a -C(O)R a -P(O)R b R c -(CH2) n -R 9 -(CH2) n -NR 8a R 8b -CONR 8a R 8b The group is substituted by one or more groups, including alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be further substituted by Q; or, R4a and R 4b Together they form an oxygen group; or, R 4a With R 4b The atoms bonded to it together form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, -S(O). v R a -COOR a -C(O)R a -P(O)R b R c The group is substituted by one or more groups of alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl groups may optionally be further substituted by Q;

[0019] R 5a and R 5b Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, mercapto, cyano, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -(CH2). n -R 9 -(CH2) n -NR 8a R 8b The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, methylidene, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, and -NR. 8a R 8b -S(O) v R a -COOR a -C(O)R a -P(O)R b R c -(CH2) n -R 9 -(CH2) n -NR 8a R 8b -CONR 8a R 8b The group is substituted by one or more groups, including alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be further substituted by Q; or, R 5a and R 5b Together they form an oxygen group; or, R 5a With R 5bThe atoms bonded to it together form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, -S(O). v R a -COOR a -C(O)R a -P(O)R b R c The group is substituted by one or more groups of alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl groups may optionally be further substituted by Q;

[0020] R 6a and R 6b Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, mercapto, cyano, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -(CH2). n -R 9 -(CH2) n -NR 8a R 8b The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, and -S(O). v R a -COOR a -C(O)R a -P(O)R b R c The group is substituted by one or more groups of alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl; or, R 6a and R 6b Together they form an oxygen group; or, R 6a With R 6b The atoms bonded to it together form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, -S(O). v R a -COOR a -C(O)R a -P(O)R b R c It is substituted by one or more groups, such as alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;

[0021] R 6 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, mercapto, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -(CH2). n -R 9 -(CH2) n -NR 8a R 8b The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, and -S(O). v R a -COOR a -C(O)R a -P(O)R b R c It is substituted by one or more groups, such as alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;

[0022] or,

[0023] R 3a or R 3b With R 4a or R 4b , or R 4a or R 4b With R 5a or R 5b , or R 3a or R 3b With R 5a or R 5b , or R 3a or R 3b With R 6a or R 6b , or R 4a or R 4b With R 6a or R 6b , or R 3a or R 3b With R 6 , or R 4a or R 4b With R 6 Together with the atoms they are connected to form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, -NR 7a R 7b -S(O) v Ra -COOR a -C(O)R a -P(O)R b R c The alkyl, alkoxy, alkenyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are substituted, and the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups may optionally be further substituted with Q.

[0024] R 7a and R 7b Each group is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; or, R 7a With R 7b Together with the nitrogen atom attached thereto, a heterocyclic group is formed, wherein the heterocyclic group is optionally selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, -NR. 8a R 8b It is substituted by one or more groups, including alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0025] R 8a and R 8b Each group is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; or, R 8a With R 8b Together with the nitrogen atom attached thereto, a heterocyclic group is formed, wherein the heterocyclic group is optionally replaced by one or more groups selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0026] R 9The group is selected from deuterium, halogen, amino, nitro, hydroxyl, mercapto, cyano, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0027] Q is selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0028] R a The group is selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0029] R b and R c Each group is independently selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0030] R d Selected from hydrogen, halogen, amino, cyano, alkyl, and alkoxy groups;

[0031] t is 0, 1, or 2;

[0032] m is an integer from 0 to 9;

[0033] v is 1 or 2;

[0034] n is an integer from 0 to 6.

[0035] In some embodiments, the compound represented by general formula (I) according to the present invention, or its stereoisomer or pharmaceutically acceptable salt thereof, wherein ring A is selected from 4-7-membered cycloalkyl, 4-7-membered heterocyclic, 5-10-membered heteroaryl or C 6-10 Aryl group, preferably 5-6 membered heterocyclic group, 5-6 membered heteroaryl group or phenyl group, more preferably 6 membered heterocyclic group, 6 membered heteroaryl group or phenyl group, and even more preferably piperidinyl group, tetrahydropyranyl group, morpholinyl group, piperazinyl group, pyridinyl group, pyrimidinyl group and phenyl group.

[0036] In some embodiments, the compound represented by general formula (I) according to the present invention, or its stereoisomer or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (II) or its stereoisomer or a pharmaceutically acceptable salt thereof.

[0037] Among them, X, L, R 1 R 2 R 3a R 3b R 4a R 4b R 5a R 5b , t, and m are as defined by general formula (I).

[0038] In some embodiments, the compound represented by general formula (I) according to the present invention, or its stereoisomer or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (III), or its stereoisomer or a pharmaceutically acceptable salt thereof.

[0039] Among them, X and R 1 R 2 R 3a R 3b R 4a R 4b R 5a R 5b , t, and m are as defined by general formula (I).

[0040] In some embodiments, the compound represented by general formula (I), general formula (II), or general formula (III) according to the present invention, or its stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, -NR 7a R 7b The 4-6 member heterocyclic group is optionally C 1-6 Alkyl substitution; the C1-6 Alkyl groups are optionally halogenated, C 1-6 Alkoxy, C 3-6 Cycloalkyl substitution;

[0041] R 7a and R 7b Each is independently selected from hydrogen and C. 1-6 alkyl.

[0042] In some embodiments, the compound represented by general formula (I), general formula (II), or general formula (III) according to the present invention, or its stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 6-10 Aryl or 5-10 heteroaryl; the C 6-10 Aryl or 5-10 heteroaryl groups are optionally selected from halogens, -NR 8a R 8b C 1-6 Alkoxy, cyano, C 1-6 The alkyl group is replaced by one or more groups;

[0043] R 8a and R 8b Each is independently selected from hydrogen and C. 1-6 Alkyl; or, R 8a With R 8b Together with the nitrogen atom attached thereto, a 4-7 membered heterocyclic group is formed, wherein the 4-7 membered heterocyclic group is optionally selected from C. 1-6 Alkyl substitution.

[0044] In some embodiments, the compound represented by general formula (I) or general formula (II) according to the present invention, or its stereoisomer or pharmaceutically acceptable salt thereof, wherein L is selected from -S(O)2-, -S(O)-, -C(O)-, -S(O)2NH-, -S(O)NH-, -C(O)NH-, -CR b R c -;R 1 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -NR 7a R 7b The alkyl, 4-6 membered heterocyclic, phenyl, and 5-6 membered heteroaryl groups are optionally selected from halogens and -NR. 8a R 8b , cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 One or more cycloalkyl groups are substituted;

[0045] R b Rc Each is independently selected from hydrogen and C. 1-6 alkyl;

[0046] R 7a and R 7b Each is independently selected from hydrogen and C. 1-6 alkyl;

[0047] R 8a and R 8b Each is independently selected from hydrogen and C. 1-6 Alkyl; or, R 8a With R 8b Together with the nitrogen atom attached thereto, a 4-6 membered heterocyclic group is formed, wherein the 4-6 membered heterocyclic group is optionally selected from C. 1-6 Alkyl substitution.

[0048] In some embodiments, the compound represented by general formula (I), general formula (II), or general formula (III) according to the present invention, or the stereoisomer thereof or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (IV) or the stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0049] Among them, ring B is selected from C. 6-10 Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclic or C 3-8 Cycloalkyl, preferably phenyl, 5-6 membered heteroaryl or 4-6 membered heterocyclic, more preferably phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazoleyl, thiazolyl, oxazolyl, pyrroleyl, pyrrolidinyl, cyclopropyl, azacyclobutyl, piperidinyl, piperazinyl, morpholinyl, cyclobutyl, cyclopentyl, cyclohexyl, and even more preferably phenyl, pyridinyl, pyrazolyl, imidazoleyl, thiazolyl;

[0050] Each R 10 Each is independently selected from halogen, cyano, C 1-6 alkyl;

[0051] n is 0, 1, or 2;

[0052] X, R 2 R 3a R 3b R 4a R 4b R 5a R 5b , t, and m are as defined by general formula (I).

[0053] In some embodiments, the compound represented by general formula (I), general formula (II), or general formula (III) according to the present invention, or the stereoisomer thereof or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (V), or the stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0054] R 1 Selected from hydrogen, halogen, amino, nitro, hydroxyl, mercapto, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -NR 7a R 7b The C 1-6 Alkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl are optionally selected from halogens, -NR 8a R 8b , cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 One or more cycloalkyl groups are substituted;

[0055] Each R 2 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups; preferably hydrogen, hydroxyl, halogen, and C. 1-6 alkyl;

[0056] R 3a and R 3b Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -(CH2) n -R 9 -(CH2) n -NR 8a R 8b The C 1-6 Alkyl, C 3-10 Cycloalkyl, phenyl, and 5-6 heteroaryl groups are optionally selected from deuterium, halogen, amino, hydroxyl, cyano, methyl subunit, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Haloalkoxy, -NR 8a R 8b -S(O) v R a -COOR a -C(O)Ra -P(O)R b R c -(CH2) n -R 9 -(CH2) n -NR 8a R 8b -CONR 8a R 8b C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 The alkyl group is replaced by one or more groups of cycloalkyl, phenyl, or 5-6-membered heteroaryl, wherein the C 3-6 Cycloalkyl, phenyl, or 5-6-membered heteroaryl groups may be further substituted with Q; or, R 3a and R 3b Together they form an oxygen group; or, R 3a With R 3b Together with the atoms it is connected to, they form C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -S(O) v R a -C(O)R a One or more groups are replaced;

[0057] R 4a and R 4b Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -(CH2) n -R 9 -(CH2) n -NR 8a R 8b The C 1-6 Alkyl, C 3-10 Cycloalkyl, phenyl, and 5-6 heteroaryl groups are optionally selected from deuterium, halogen, amino, hydroxyl, cyano, methyl subunit, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Haloalkoxy, -NR8a R 8b -S(O) v R a -COOR a -C(O)R a -P(O)R b R c -(CH2) n -R 9 -(CH2) n -NR 8a R 8b -CONR 8a R 8b C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 The alkyl group is replaced by one or more groups of cycloalkyl, phenyl, or 5-6-membered heteroaryl, wherein the C 3-6 Cycloalkyl, phenyl, or 5-6-membered heteroaryl groups may be further substituted with Q; or, R 4a and R 4b Together they form an oxygen group; or, R 4a With R 4b Together with the atoms it is connected to, they form C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -S(O) v R a -C(O)R a One or more groups are replaced;

[0058] R 5a and R 5b Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -(CH2) n -R 9 -(CH2) n -NR 8a R 8b The C 1-6 Alkyl, C 3-10 Cycloalkyl, phenyl, and 5-6 heteroaryl groups are optionally selected from deuterium, halogen, amino, hydroxyl, cyano, methyl subunit, and C. 1-6 Alkyl, C 1-6Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Haloalkoxy, -NR 8a R 8b -S(O) v R a -COOR a -C(O)R a -P(O)R b R c -(CH2) n -R 9 -(CH2) n -NR 8a R 8b -CONR 8a R 8b C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 The alkyl group is replaced by one or more groups of cycloalkyl, phenyl, or 5-6-membered heteroaryl, wherein the C 3-6 Cycloalkyl, phenyl, or 5-6-membered heteroaryl groups may be further substituted with Q; or, R 5a and R 5b Together they form an oxygen group; or, R 5a With R 5b Together with the atoms it is connected to, they form C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -S(O) v R a -C(O)R a One or more groups are replaced;

[0059] or,

[0060] R 3a or R 3b With R 4a or R 4b , or R 4a or R 4b With R 5a or R 5b , or R 3a or R 3b With R 5a or R 5bTogether with the atoms connected to them, they form 3-10 membered cycloalkyl, 4-10 membered heterocyclic, phenyl, or 5-6 membered heteroaryl groups, wherein the 3-10 membered cycloalkyl, 4-10 membered heterocyclic, phenyl, or 5-6 membered heteroaryl groups are optionally selected from deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-10 membered heterocyclic, 5-10 membered heteroaryl, -NR 7a R 7b -C(O)R a -S(O) v R a The C group is replaced by the group that is substituted for the C group. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic, and 5-6 membered heteroaryl groups may be further substituted by Q;

[0061] R 7a and R 7b Each is independently selected from hydrogen and C. 1-6 Alkyl; or, R 7a With R 7b Together with the nitrogen atom attached thereto, a 5-6 membered heterocyclic group is formed, wherein the 5-6 membered heterocyclic group is optionally selected from deuterium, halogen, amino, cyano, hydroxyl, mercapto, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 The alkoxy group is replaced by one or more groups of the haloalkoxy group;

[0062] R 8a and R 8b Each is independently selected from hydrogen and C. 1-6 Alkyl; or R 8a With R 8b Together with the nitrogen atom attached thereto, a 5-6 membered heterocyclic group is formed, wherein the 5-6 membered heterocyclic group is optionally C 1-6 Alkyl substitution;

[0063] R 9 Selected from hydroxyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, phenyl;

[0064] Q is selected from hydrogen, halogen, amino, C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 3-6 cycloalkyl, 4-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl group is optionally selected from deuterium, halogen, cyano, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 One or more cycloalkyl groups are substituted;

[0065] R a Selected from C 1-6 Alkyl, amino, hydroxyl;

[0066] R b and R c Each is independently selected from hydrogen and C. 1-6 alkyl;

[0067] t is 0 or 1;

[0068] m is 0 or 1;

[0069] v is 1 or 2;

[0070] n is an integer from 0 to 6.

[0071] In some embodiments, the compound represented by general formula (I), general formula (II), general formula (III), and general formula (V) according to the present invention, or its stereoisomer or pharmaceutically acceptable salt, is a compound represented by general formula (VI), or its stereoisomer or pharmaceutically acceptable salt.

[0072] R 1 Selected from hydrogen, halogen, amino, nitro, hydroxyl, mercapto, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -NR 7a R 7b The C 1-6 Alkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl are optionally selected from deuterium, halogen, -NR 8a R 8b , cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 One or more cycloalkyl groups are substituted;

[0073] Each R 2 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, and C. 1-6 Alkyl, C 1-6Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups; preferably hydrogen, hydroxyl, halogen, and C. 1-6 alkyl;

[0074] R 3a and R 3b Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -(CH2) n -R 9 -(CH2) n -NR 8a R 8b The C 1-6 Alkyl, C 3-10 Cycloalkyl, phenyl, and 5-6 heteroaryl groups are optionally selected from deuterium, halogen, amino, hydroxyl, cyano, methyl subunit, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Haloalkoxy, -NR 8a R 8b -S(O) v R a -COOR a -C(O)R a -P(O)R b R c -(CH2) n -R 9 -(CH2) n -NR 8a R 8b -CONR 8a R 8b C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 The alkyl group is replaced by one or more groups of cycloalkyl, phenyl, or 5-6-membered heteroaryl, wherein the C 3-6 Cycloalkyl, phenyl, or 5-6-membered heteroaryl groups may be further substituted with Q; or, R 3a and R 3b Together they form an oxygen group; or, R 3a With R 3b Together with the atoms it is connected to, they form C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups, wherein the C 3-10Cycloalkyl or 4-10 membered heterocyclic groups are optionally selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -S(O) v R a -C(O)R a One or more groups are replaced;

[0075] R 5a and R 5b Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -(CH2) n -R 9 -(CH2) n -NR 8a R 8b The C 1-6 Alkyl, C 3-10 Cycloalkyl, phenyl, and 5-6 heteroaryl groups are optionally selected from deuterium, halogen, amino, hydroxyl, cyano, methyl subunit, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Haloalkoxy, -NR 8a R 8b -S(O) v R a -COOR a -C(O)R a -P(O)R b R c -(CH2) n -R 9 -(CH2) n -NR 8a R 8b -CONR 8a R 8b C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 The alkyl group is replaced by one or more groups of cycloalkyl, phenyl, or 5-6-membered heteroaryl, wherein the C 3-6 Cycloalkyl, phenyl, or 5-6-membered heteroaryl groups may be further substituted with Q; or, R 5a and R 5b Together they form an oxygen group; or, R5a With R 5b Together with the atoms it is connected to, they form C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -S(O) v R a -C(O)R a One or more groups are replaced;

[0076] or,

[0077] R 3a or R 3b With R 5a or R 5b Together with the atoms connected to them, they form 3-10 membered cycloalkyl, 4-10 membered heterocyclic, phenyl, or 5-6 membered heteroaryl groups, wherein the 3-10 membered cycloalkyl, 4-10 membered heterocyclic, phenyl, or 5-6 membered heteroaryl groups are optionally selected from deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl, -NR 7a R 7b -C(O)R a -S(O) v R a The C group is replaced by the group that is substituted for the C group. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic, and 5-6 membered heteroaryl groups may be further substituted by Q;

[0078] R 7a and R 7b Each is independently selected from hydrogen and C. 1-6 Alkyl; or, R 7a With R 7b Together with the nitrogen atom attached thereto, a 5-6 membered heterocyclic group is formed, wherein the 5-6 membered heterocyclic group is optionally selected from deuterium, halogen, amino, cyano, hydroxyl, mercapto, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6The alkoxy group is replaced by one or more groups of the haloalkoxy group;

[0079] R 8a and R 8b Each is independently selected from hydrogen and C. 1-6 Alkyl; or R 8a With R 8b Together with the nitrogen atom attached thereto, a 5-6 membered heterocyclic group is formed, wherein the 5-6 membered heterocyclic group is optionally C 1-6 Alkyl substitution;

[0080] R 9 Selected from hydroxyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, phenyl;

[0081] Q is selected from hydrogen, halogen, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 4-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl group is optionally selected from deuterium, halogen, cyano, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 One or more cycloalkyl groups are substituted;

[0082] R a Selected from C 1-6 Alkyl, amino, hydroxyl;

[0083] R b and R c Each is independently selected from hydrogen and C. 1-6 alkyl;

[0084] t is 0 or 1;

[0085] m is 0 or 1;

[0086] v is 1 or 2;

[0087] n is an integer from 0 to 6.

[0088] In some embodiments, the compounds represented by general formulas (I), (II), (III), (IV), (V), and (VI) according to the present invention, or their stereoisomers or pharmaceutically acceptable salts thereof, wherein,

[0089] R 3a and R3b Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -(CH2) n -R 9 -(CH2) n -NR 8a R 8b The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, phenyl, and 5-6-membered heteroaryl groups are optionally selected from deuterium, halogen, cyano, hydroxyl, methyl subunit, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkoxy, -NR 8a R 8b -S(O) v R a -COOR a -C(O)R a -P(O)R b R c -(CH2) n -R 9 -(CH2) n -NR 8a R 8b -CONR 8a R 8b C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 The C group is replaced by one or more groups of cycloalkyl or phenyl groups, wherein the C 3-6 Cycloalkyl, phenyl, or 5-6-membered heteroaryl groups may be further substituted with Q; or, R 3a and R 3b Together they form an oxygen group; or, R 3a With R 3b Together with the atoms it is connected to, they form C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C1-6 Halogenated alkoxy groups, -S(O) v R a -C(O)R a One or more groups are replaced;

[0090] R 5a and R 5b Each is independently selected from hydrogen, deuterium, and C. 1-6 alkyl;

[0091] R 8a and R 8b Each is independently selected from hydrogen and C. 1-6 Alkyl; or R 8a With R 8b Together with the nitrogen atom attached thereto, a 5-6 membered heterocyclic group is formed, wherein the 5-6 membered heterocyclic group is optionally C 1-6 Alkyl substitution;

[0092] R 9 Selected from hydroxyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, phenyl;

[0093] Q is selected from hydrogen, halogen, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 4-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl group is optionally selected from deuterium, halogen, cyano, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 One or more cycloalkyl groups are substituted;

[0094] R a Selected from C 1-6 Alkyl, amino, hydroxyl;

[0095] R b and R c Each is independently selected from hydrogen and C. 1-6 alkyl;

[0096] v is 1 or 2;

[0097] n is an integer from 0 to 6.

[0098] In some embodiments, the compounds represented by general formulas (I), (II), (III), (IV), (V), and (VI) according to the present invention, or their stereoisomers or pharmaceutically acceptable salts thereof, wherein,

[0099] R 3a and R 3b Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The C groups described in the following groups are alkynyl, -(CH2)n-R9, and -(CH2)n-NR8aR8b'. 1-6 The alkyl group may optionally be replaced by one or more groups selected from deuterium, halogen, and hydroxyl; or, R 3a and R 3b Together they form an oxygen group;

[0100] R 5a and R 5b Each is independently selected from hydrogen, deuterium, and C. 1-6 alkyl;

[0101] R 8a and R 8b Each is independently selected from hydrogen and C. 1-6 alkyl;

[0102] R 9 Selected from hydroxyl, C 1-6 Alkoxy, phenyl.

[0103] In some embodiments, the compounds represented by general formulas (I), (II), (III), (IV), (V), and (VI) according to the present invention, or their stereoisomers or pharmaceutically acceptable salts thereof, wherein,

[0104] R 3a Selected from hydrogen;

[0105] R 3b Selected from C 3-10 cycloalkyl, 4-6 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl groups and 4-6-membered heterocyclic groups are optionally selected from cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The group is replaced by one or more haloalkoxy or phenyl groups;

[0106] R 5a and R 5b Each is independently selected from hydrogen, deuterium, and C. 1-6 alkyl.

[0107] In some embodiments, the compounds represented by general formulas (I), (II), (III), (IV), (V), and (VI) according to the present invention, or their stereoisomers or pharmaceutically acceptable salts thereof, wherein,

[0108] R 3a It is hydrogen or C 1-6 alkyl;

[0109] R 3b The group is selected from phenyl, 5-6-membered heteroaryl, wherein the phenyl, 5-6-membered heteroaryl is optionally selected from deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -S(O) v R a One or more groups are replaced;

[0110] R 5a and R 5b Each is independently selected from hydrogen, deuterium, and C. 1-6 alkyl;

[0111] R a Selected from C 1-6 alkyl;

[0112] v is 1 or 2.

[0113] In some embodiments, the compounds represented by general formulas (I), (II), (III), (IV), (V), and (VI) according to the present invention, or their stereoisomers or pharmaceutically acceptable salts thereof, wherein,

[0114] R 3a With R 3b Together with the atoms it is connected to, they form C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups;

[0115] R 5a and R 5b Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl group. In some embodiments, the compounds represented by general formulas (I), (II), (III), (IV), (V), and (VI) according to the present invention, or their stereoisomers or pharmaceutically acceptable salts thereof, wherein,

[0116] R 3a and R 3b Each is independently selected from hydrogen and C. 1-6 alkyl;

[0117] R5a and R 5b Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -CH2-R 9 The C 1-6 Alkyl groups may be optionally substituted with hydroxyl groups; or, R 5a and R 5b Together they form an oxygen group; or, R 5a With R 5b Together with the atoms it is connected to, they form C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 One or more alkoxy groups are substituted;

[0118] R 9 Selected from hydroxyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, phenyl.

[0119] In some embodiments, the compounds represented by general formulas (I), (II), (III), (IV), (V), and (VI) according to the present invention, or their stereoisomers or pharmaceutically acceptable salts thereof, wherein,

[0120] R 3a and R 3b Each is independently selected from hydrogen and C. 1-6 alkyl;

[0121] R 5a and R 5b Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -CH2-R 9 The C 1-6 Alkyl groups are replaced by hydroxyl groups;

[0122] R 9 Selected from hydroxyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, phenyl.

[0123] In some embodiments, the compounds represented by general formulas (I), (II), (III), (IV), (V), and (VI) according to the present invention, or their stereoisomers or pharmaceutically acceptable salts thereof, wherein,

[0124] R 3a and R 3b Each is independently selected from hydrogen and C. 1-6 alkyl;

[0125] R 5a With R 5b Together with the atoms it is connected to, they form C 3-6 cycloalkyl or 4-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 It is replaced by one or more alkoxy groups.

[0126] In some embodiments, the compounds represented by general formulas (I), (II), (III), (IV), (V), and (VI) according to the present invention, or their stereoisomers or pharmaceutically acceptable salts thereof, wherein,

[0127] R 3a or R 3b With R 5a or R 5b Together with the atoms they are connected to form a 5-6 membered cycloalkyl or phenyl group, wherein the 5-6 membered cycloalkyl or phenyl group is optionally selected from halogens, C-type cycloalkyl groups ... 1-6 Alkyl, C 1-6 It is replaced by one or more alkoxy groups.

[0128] In some embodiments, the compounds represented by general formulas (I), (II), (III), (IV), (V), and (VI) according to the present invention, or their stereoisomers or pharmaceutically acceptable salts thereof, wherein,

[0129] R 3a or R 3b With R 5a or R 5b Together with the atoms connected to them, they form 3-10 membered cycloalkyl, 4-10 membered heterocyclic or phenyl groups, wherein the 3-10 membered cycloalkyl, 4-10 membered heterocyclic or phenyl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-10 membered heterocyclic, 5-10 membered heteroaryl, -NR 7a R 7b -C(O)R a -S(O) v R a The C group is replaced by the group that is substituted for the C group.1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic, and 5-6 membered heteroaryl groups may be further substituted by Q;

[0130] Q is selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl groups and 4-6 membered heterocyclic groups are optionally selected from halogens, cyano groups, hydroxyl groups, and C. 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 One or more cycloalkyl groups are substituted;

[0131] R 7a and R 7b Each is independently selected from hydrogen and C. 1-6 alkyl;

[0132] R a Selected from C 1-6 Alkyl, amino, hydroxyl;

[0133] v is 1 or 2.

[0134] In some embodiments, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), and general formula (VI) according to the present invention, or the stereoisomer thereof or the pharmaceutically acceptable salt thereof, is a compound represented by general formula (VII) or the stereoisomer thereof or the pharmaceutically acceptable salt thereof.

[0135] R 1 Selected from hydrogen, halogen, amino, nitro, hydroxyl, mercapto, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -NR 7a R 7b The C 1-6 Alkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl are optionally selected from deuterium, halogen, -NR 8a R 8b , cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 One or more cycloalkyl groups are substituted;

[0136] Each R 2 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, and C. 1-6 Alkyl, C 1-6Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups; preferably hydrogen, hydroxyl, halogen, and C. 1-6 alkyl;

[0137] R 3a and R 3b Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -(CH2) n -R 9 -(CH2) n -NR 8a R 8b The C 1-6 Alkyl, phenyl, and 5-6-membered heteroaryl groups are optionally selected from deuterium, halogen, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Replaced by one or more haloalkoxy groups; or, R 3a and R 3b Together they form an oxygen group; or, R 3a With R 3b Together with the atoms it is connected to, they form C 3-6 cycloalkyl or 4-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups are optionally selected from deuterium, halogens, C 1-6 Alkyl, C 1-6 One or more alkoxy groups are substituted;

[0138] R 4a and R 4b Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -(CH2) n -R 9 -(CH2) n -NR 8a R 8b The C 1-6 Alkyl, phenyl, and 5-6-membered heteroaryl groups are optionally selected from deuterium, halogen, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C1-6 aminoalkyl, C 1-6 Replaced by one or more haloalkoxy groups; or, R 4a and R 4b Together they form an oxygen group; or, R 4a With R 4b Together with the atoms it is connected to, they form C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Replaced by one or more alkoxy or phenyl groups;

[0139] R 5a and R 5b Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -(CH2) n -R 9 -(CH2) n -NR 8a R 8b The C 1-6 Alkyl, phenyl, and 5-6-membered heteroaryl groups are optionally selected from deuterium, halogen, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Replaced by one or more haloalkoxy groups; or, R 5a and R 5b Together they form an oxygen group; or, R 5a With R 5b Together with the atoms it is connected to, they form C 3-6 cycloalkyl or 4-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups are optionally selected from deuterium, halogens, C 1-6 Alkyl, C 1-6 One or more alkoxy groups are substituted;

[0140] or,

[0141] R 3a or R 3b With R 4a or R 4b , or R 4a or R 4b With R 5a or R 5b , or R3a or R 3b With R 5a or R 5b Together with the atoms connected to them, they form 5-6 membered cycloalkyl, 5-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl groups, wherein the 5-6 membered cycloalkyl, 5-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl groups are optionally selected from deuterium, halogens, and C. 1-6 Alkyl, C 1-6 One or more alkoxy groups are substituted;

[0142] R 7a and R 7b Each is independently selected from hydrogen and C. 1-6 Alkyl; or, R 7a With R 7b Together with the nitrogen atom attached thereto, a 5-6 membered heterocyclic group is formed, wherein the 5-6 membered heterocyclic group is optionally selected from deuterium, halogen, amino, cyano, hydroxyl, mercapto, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 The alkoxy group is replaced by one or more groups of the haloalkoxy group;

[0143] R 8a and R 8b Each is independently selected from hydrogen and C. 1-6 alkyl;

[0144] R 9 Selected from hydroxyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, phenyl;

[0145] m is 0 or 1;

[0146] n is an integer from 0 to 6.

[0147] In some embodiments, the compounds represented by general formulas (I), (II), (III), (IV), (V), (VI), and (VII) according to the present invention, or their stereoisomers or pharmaceutically acceptable salts thereof, wherein,

[0148] R 3a and R 3b Each is independently selected from hydrogen and C. 1-6 alkyl;

[0149] R 4a and R 4b Each is independently selected from hydrogen, hydroxyl, and C. 1-6 Alkyl, phenyl;

[0150] R 5a and R 5b Each is independently selected from hydrogen and C. 1-6 alkyl.

[0151] In some embodiments, the compounds represented by general formulas (I), (II), (III), (IV), (V), (VI), and (VII) according to the present invention, or their stereoisomers or pharmaceutically acceptable salts thereof, wherein,

[0152] R 3a and R 3b Each is independently selected from hydrogen and C. 3-10 Cycloalkyl, 4-10 membered heterocyclic groups; or R 3a With R 3b Together with the atoms it is connected to, they form C 3-6 cycloalkyl or 4-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups are optionally selected from deuterium, halogens, C 1-6 Alkyl, C 1-6 One or more alkoxy groups are substituted;

[0153] R 4a and R 4b Each is independently selected from hydrogen, hydroxyl, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 4-6 membered heterocyclic group, phenyl, -CH2-R 9 The phenyl group is optionally substituted with one or more groups selected from halogens; or R 4a With R 4b Together with the atoms it is connected to, they form C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally selected from halogens, hydroxyl groups, C 1-6 Substituted with alkyl or phenyl groups;

[0154] R 5a and R 5b Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 cycloalkyl;

[0155] or

[0156] R 3a or R 3b With R 4a or R 4b , or R 4a or R 4b With R 5a or R5b , or R 3a or R 3b With R 5a or R 5b Together with the atoms they are connected to, they form 5-6 membered cycloalkyl groups;

[0157] R 9 Selected from C 3-6 Cycloalkyl, phenyl.

[0158] In some embodiments, the compound represented by general formula (V), general formula (VI), or general formula (VII) according to the present invention, or its stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, -NR 7a R 7b The 4-6 member heterocyclic group is optionally C 1-6 Alkyl substitution; the C 1-6 Alkyl groups are optionally halogenated, C 1-6 Alkoxy, C 3-6 Cycloalkyl substitution;

[0159] R 7a and R 7b Each is independently selected from hydrogen and C. 1-6 alkyl;

[0160] Preferably, R 1 C 1-6 alkyl.

[0161] In some embodiments, the compound represented by general formula (V), general formula (VI), or general formula (VII) according to the present invention, or its stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 6-10 Aryl or 5-10 heteroaryl; the C 6-10 Aryl or 5-10 heteroaryl groups are optionally selected from halogens, -NR 8a R 8b , cyano, C 1-6 The alkyl group is replaced by one or more groups;

[0162] R 8a and R 8b Each is independently selected from hydrogen and C. 1-6 Alkyl; or, R 8a With R 8b Together with the nitrogen atom attached thereto, a 4-7 membered heterocyclic group is formed, wherein the 4-7 membered heterocyclic group is optionally selected from C. 1-6 Alkyl substitution.

[0163] In some embodiments, the compound represented by general formula (V), general formula (VI), or general formula (VII) according to the present invention, or its stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 6-10 Aryl, 5-10-membered heteroaryl, or 4-6-membered heterocyclic group, preferably phenyl, 5-6-membered heteroaryl, or 4-6-membered heterocyclic group, more preferably phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazoleyl, thiazolyl, oxazolyl, pyrrolidinyl, pyrrolyl, azacyclic butyl, piperidinyl, piperazinyl, or morpholinyl, and even more preferably phenyl, pyridinyl, pyrazolyl, imidazoleyl, or thiazolyl; optionally selected from halogen, cyano, or C 1-6 It is replaced by one or more alkyl groups.

[0164] In some embodiments, the compound represented by general formula (I) according to the present invention, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (VIII) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0165] in,

[0166] Y1 and Y2 are each independently selected from CH or N;

[0167] L is selected from the following groups: -S(O)2-, -C(O)-, -S(O)2NH-, -CR b R c -;

[0168] R 1 Selected from hydrogen, 4-6 membered heterocyclic groups, -NR 7a R 7b -P(O)R b R c -OR c The 4-6 member heterocyclic group is optionally C 1-6 Alkyl groups are substituted;

[0169] R 7a and R 7b Each is independently selected from hydrogen and C. 1-6 Alkyl, or R 7a and R 7b Together with the nitrogen atom attached thereto, a 5-7 membered heterocyclic group is formed, wherein the 5-7 membered heterocyclic group is optionally selected from deuterium, halogen, amino, cyano, hydroxyl, mercapto, oxo, -NR. 8a R 8b C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6aminoalkyl, C 1-6 The alkoxy group is replaced by one or more groups of the haloalkoxy group;

[0170] R 8a and R 8b Each is independently selected from hydrogen and C. 1-6 alkyl;

[0171] X, R 2 R b R c R 3a R 3b R 4a R 4b R 5a R 5b , t, and m are as defined by general formula (I).

[0172] In some embodiments, the compound represented by general formula (VIII) according to the present invention, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 3a and R 3b Each independently is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; R 5a and R 5b Each is independently selected from hydrogen and C. 1-6 Alkyl, or R 5a With R 5b Together with the atoms it is connected to, they form C 3-6 cycloalkyl or 4-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 The alkoxy group is replaced by one or more groups; or R 3a and R 3b Together with the atoms it is connected to, they form C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups; t is 0.

[0173] In some embodiments, according to the invention, the general formula (I), general formula (II), general formula (III), general formula (IV), general formula (VIII) or its stereoisomers or pharmaceutically acceptable salts thereof, wherein X is -NR 6 -, R 6 Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-6 Cycloalkyl.

[0174] In some embodiments, compounds of general formulas (I), (II), (III), (IV), (V), (VI), (VII), and (VIII) according to the present invention, or their stereoisomers or pharmaceutically acceptable salts thereof, wherein each R 2 Each is independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl group, where m is 0 or 1.

[0175] In some embodiments, compounds of general formulas (I), (II), (III), (IV), (V), (VI), (VII), and (VIII) according to the present invention, or their stereoisomers or pharmaceutically acceptable salts thereof, wherein any two R 2 Together with the atoms attached thereto, they form a bridged cycloalkyl or bridged heterocyclic group, preferably, the for

[0176] Typical compounds of this invention include, but are not limited to:

[0177] The present invention also relates to a pharmaceutical composition comprising a compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof as described in the present invention, and a pharmaceutically acceptable carrier.

[0178] The present invention further provides the use of the compound or its stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound according to the present invention, in the preparation of a medicament for the prevention or treatment of CDK-mediated diseases.

[0179] The present invention further provides the use of the compound or its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound according to the present invention, in the preparation of a medicament for the prevention or treatment of cancer, preferably breast cancer, ovarian cancer, prostate cancer, lung cancer, or glioma.

[0180] The present invention further provides compounds or stereoisomers thereof or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising such compounds, for the prevention or treatment of CDK-mediated diseases.

[0181] The present invention further provides compounds or stereoisomers thereof or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising such compounds, for the prevention or treatment of cancer.

[0182] The present invention further provides a method for preventing or treating CDK-mediated diseases, comprising administering to a subject in need a compound or stereoisomer thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound according to the present invention.

[0183] The present invention further provides a method for preventing or treating cancer, comprising administering to a subject in need a compound or stereoisomer thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound according to the present invention.

[0184] In some embodiments, the CDK-mediated disease described in this invention is cancer or tumor.

[0185] In other embodiments, the cancers described in this invention are selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, colorectal cancer, prostate cancer, lung cancer, pancreatic cancer, stomach cancer, thyroid cancer, glioma, esophageal cancer, and liver cancer.

[0186] According to conventional methods in the field to which this invention pertains, the compounds of this invention can react with acids to form pharmaceutically acceptable acid addition salts. The acids include inorganic and organic acids, with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc., being particularly preferred.

[0187] According to conventional methods in the field of this invention, the compounds of this invention can react with a base to form a pharmaceutically acceptable basic addition salt. The base includes inorganic and organic bases; acceptable organic bases include diethanolamine, ethanolamine, N-methylglucosamine, triethanolamine, tromethamine, etc., and acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide, etc.

[0188] Pharmaceutical compositions containing an active ingredient can be in forms suitable for oral administration, such as tablets, sugar lozenges, tablets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from: sweeteners, flavoring agents, coloring agents, and preservatives to provide an appealing and palatable pharmaceutical formulation. Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation for mixing. These excipients can be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating agents and disintegrants such as microcrystalline cellulose, croscarmellose sodium, corn starch, or alginate; binders such as starch, gelatin, polyvinylpyrrolidone, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. These tablets may be uncoated or coated using known techniques that provide sustained release over a longer period of time by masking the taste of the drug or by delaying disintegration and absorption in the gastrointestinal tract. For example, water-soluble taste-masking substances such as hydroxypropyl methylcellulose or hydroxypropyl cellulose may be used, or time-extending substances such as ethylcellulose or cellulose acetate butyrate may be used.

[0189] Oral formulations can also be provided in hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in soft gelatin capsules in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil solvent such as peanut oil, liquid paraffin or olive oil.

[0190] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, and gum arabic; dispersants or wetting agents, which may be naturally occurring phospholipids such as lecithin, or condensation products of olefins and fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide and long-chain fatty alcohols, such as heptadeceethyleneoxy cetyl alcohol, or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitan monooleate, or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides, such as polyoxyethylene dehydrated sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more colorants, one or more flavoring agents, and one or more sweeteners, such as sucrose, saccharin, or aspartame.

[0191] Oil suspensions can be formulated by suspending the active ingredient in vegetable oils such as peanut oil, olive oil, sesame oil, or coconut oil, or mineral oils such as liquid paraffin. Oil suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavoring agents mentioned above can be added to provide a palatable formulation. These compositions can be preserved by adding antioxidants such as butylated hydroxyanisole (BHA) or α-tocopherol.

[0192] By adding water, dispersible powders and granules suitable for preparing aqueous suspensions can provide active ingredients and dispersants or wetting agents, suspending agents, or one or more preservatives for mixing. Suitable dispersants or wetting agents and suspending agents are as described above. Other excipients such as sweeteners, flavoring agents, and coloring agents may also be added. These compositions are preserved by adding antioxidants such as ascorbic acid.

[0193] The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, such as soybean lecithin, and esters or metaesters derived from fatty acids and hexitan anhydrides, such as sorbitan monooleate, and condensation products of said metaesters and ethylene oxide, such as poly(ethylene oxide) sorbitan monooleate. The emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Syrups and elixirs formulated with sweeteners such as glycerin, propylene glycol, sorbitol, or sucrose may be used. Such formulations may also contain moderating agents, preservatives, coloring agents, and antioxidants.

[0194] The pharmaceutical compositions of the present invention can be in the form of sterile injectable aqueous solutions. Acceptable solvents and media that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then treated with a mixture of water and glycerol to form a microemulsion. The injection solution or microemulsion can be injected into the patient's bloodstream by local large-volume injection. Alternatively, it is preferable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the compounds of the present invention. To maintain such a constant concentration, a continuous intravenous delivery device can be used.

[0195] The pharmaceutical compositions of the present invention can be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. The sterile injectable formulations can also be sterile injectable solutions or suspensions prepared in non-toxic, parenteral-acceptable diluents or solvents, such as solutions prepared in 1,3-butanediol. Furthermore, sterile fixative oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixative oil, including synthetic mono- or diglycerides of glycerol, can be used. Additionally, fatty acids such as oleic acid can also be used to prepare injectable formulations.

[0196] The compounds of the present invention can be administered in suppository form for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum, and thus dissolves in the rectum to release the drug. Such substances include cocoa butter, glycerin gelatin, hydrogenated vegetable oils, polyethylene glycol of various molecular weights, and mixtures of fatty acid esters of polyethylene glycol.

[0197] Those skilled in the art will recognize that the dosage of a drug depends on a variety of factors, including, but not limited to, the activity of the specific compound used, the patient's age, weight, health condition, lifestyle, diet, timing of administration, route of administration, rate of excretion, and combination of drugs. Furthermore, optimal treatment modalities, such as treatment patterns, daily dosage of general formula compounds, or types of pharmaceutically acceptable salts, can be validated based on conventional treatment protocols.

[0198] Terminology Definition

[0199] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0200] The carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen involved in the groups and compounds described in this invention all include their isotopes. That is, the carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen involved in the groups and compounds described in this invention may optionally be further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), and tritium (T, also known as superheavy hydrogen), and the isotopes of oxygen include... 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, isotopes of fluorine include 19 F, isotopes of chlorine include 35 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br.

[0201] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, an alkyl group containing 1 to 4 carbon atoms, or an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. Alkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any usable connection point. The substituents can be one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester.

[0202] The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group, as defined above, has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkylenes). The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkylenes, more preferably alkylenes containing 1 to 6 carbon atoms (i.e., C16-64 ... 1-6 Alkylenes, more preferably alkylenes containing 1 to 4 carbon atoms (i.e., C14-44 carbon atoms). 1-6Alkylenes. Non-limiting examples of alkylenes include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), and 1,4-butylene (-CH2CH2CH2CH2-). Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linking point. Substituents can be selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, and oxo.

[0203] The term "alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably an alkenyl group containing 2 to 6 carbon atoms, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. Alkenyl groups can be substituted or unsubstituted. When substituted, the substituent can be one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0204] The term "alkynyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably an alkynyl group containing 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, etc. The alkynyl group can be substituted or unsubstituted. When substituted, the substituent can be one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0205] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 6 or 5 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0206] The term "spirocycloalkyl" refers to a polycyclic group consisting of 5 to 20 quintile rings sharing a single carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6 to 14 quintiles, more preferably 7 to 10 quintiles. Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl groups being preferred. More preferably, it is a 4-quintile, 4-quintile, 4-quintile, 5-quintile, or 5-quintile / 6-quintile monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

[0207] The term "fused-ring alkyl" refers to a 5- to 20-membered polycyclic carbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused-ring alkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of fused-ring alkyl include:

[0208] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0209] The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocyclic ring, wherein the ring connected to the parent structure is a cycloalkyl group. Non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, tetrahydrobenzofuranyl, tetrahydrobenzoxazolyl, tetrahydrobenzoisoxazolyl, cyclopentothiophenyl, tetrahydrobenzothiazolyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituent may be one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0210] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m(where m is an integer from 0 to 2) heteroatoms, but excluding the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. For example, it contains 4 to 12 ring atoms, of which 1 to 4 are heteroatoms; or contains 7 to 12 ring atoms, of which 1 to 4 are heteroatoms; or contains 4 to 6 ring atoms, of which 1 to 2 are heteroatoms; or contains 7 to 10 ring atoms, of which 1 to 4 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl, or morpholinyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0211] The term "spirocyclic heterocyclic group" refers to a polycyclic heterocyclic group consisting of 5 to 20 member monocyclic rings sharing a single atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O). m The heteroatom is a carbon atom (where m is an integer from 0 to 2). It may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Preferably, it is 6 to 14-membered, more preferably 7 to 12-membered. Spirocyclic groups are classified into monospirocyclic, bispirocyclic, or multispirocyclic groups based on the number of shared spiro atoms between rings, preferably monospirocyclic and bispirocyclic groups. More preferably, they are 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic groups. Non-limiting examples of spirocyclic groups include:

[0212] The term "fused-ring heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system, and one or more ring atoms are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, it consists of 6 to 14 rings, more preferably 7 to 12 rings. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

[0213] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group with 5 to 14 members in which any two rings share two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are selected from nitrogen, oxygen, or S(O). m(where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, it consists of 6 to 14 rings, more preferably 7 to 12 rings. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0214] The heterocyclic ring can be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group.

[0215] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent can be one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0216] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. Phenyl is more preferred. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples include:

[0217] The aryl group can be substituted or unsubstituted. When substituted, the substituent can be one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0218] The term "heteroaryl" or "aromatic heterocycle" refers to a heteroaromatic system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered, containing 1 to 3 heteroatoms; more preferably 5- or 6-membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrrololyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazolyl, pyrazinyl, etc., and most preferably imidazolyl, thiazolyl, pyrazolyl, or pyrimidinyl, thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0219] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent can be one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0220] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent can be one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester.

[0221] The term "subunit A" refers to Group.

[0222] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0223] The term "haloalkoxy" refers to an alkoxy group that is substituted with one or more halogens, wherein the alkoxy group is as defined above.

[0224] The term "hydroxyalkyl" refers to an alkyl group that has been substituted with a hydroxyl group, wherein the alkyl group is as defined above.

[0225] The term "aminoalkyl" refers to an alkyl group that has been substituted with an amino group, wherein the alkyl group is as defined above.

[0226] The term "hydroxyl group" refers to the -OH group.

[0227] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0228] The term "amino" refers to -NH2.

[0229] The term "cyano" refers to -CN.

[0230] The term "nitro" refers to -NO2.

[0231] The term "oxo" refers to =O.

[0232] The term "carboxyl group" refers to -C(O)OH.

[0233] The term "thiol" refers to -SH.

[0234] The term "ester group" refers to -C(O)O (alkyl) or -C(O)O (cycloalkyl), where alkyl and cycloalkyl are as defined above.

[0235] The compounds disclosed herein can exist in specific stereoisomer forms. The term "stereoisomer" refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, blocked isomers, conformational isomers, and mixtures thereof (such as racemic mixtures and mixtures of diastereomers). Substituents in the compounds disclosed herein may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this disclosure. Optically active (-)- and (+)- isomers, (R)- and (S)- enantiomers, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. This disclosure discloses an isomer of a compound, which can be prepared by asymmetric synthesis or with chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, followed by diastereomer resolution using conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is typically performed by chromatography.

[0236] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations. In the chemical structure of the compounds described in this disclosure, the bonds... The configuration is not specified, meaning it can be Z-configuration, E-configuration, or both. For all carbon-carbon double bonds, even if only one configuration is named, both Z-type and E-type are included; No configuration is specified, meaning it can be Z configuration, E configuration, or both configurations.

[0237] In the compounds disclosed herein, when a position is specifically designated as "deuterium" or "D", that position should be understood to indicate that the abundance of deuterium is at least 1000 times greater than the native abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium doping). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 1000 times greater than the native abundance of deuterium (i.e., at least 15% deuterium doping). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 2000 times greater than the native abundance of deuterium (i.e., at least 30% deuterium doping). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3000 times greater than the native abundance of deuterium (i.e., at least 45% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3340 times greater than the natural deuterium abundance (i.e., at least 50.1% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3500 times greater than the natural deuterium abundance (i.e., at least 52.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4000 times greater than the natural deuterium abundance (i.e., at least 60% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4500 times greater than the natural deuterium abundance (i.e., at least 67.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5000 times greater than the natural deuterium abundance (i.e., at least 75% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5500 times greater than the natural deuterium abundance (i.e., at least 82.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6000 times greater than the natural deuterium abundance (i.e., at least 90% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6333.3 times greater than the natural deuterium abundance (i.e., at least 95% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6466.7 times greater than the natural deuterium abundance (i.e., at least 97% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6600 times greater than the natural deuterium abundance (i.e., at least 99% deuterium doping). In some implementations, the abundance of deuterium in each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium doping).

[0238] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0239] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0240] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0241] "Pharmaceutical-acceptable salt" or "pharmaceutically acceptable salt" refers to salts of the compounds of this invention that are safe and effective in mammalian use and possess the desired biological activity. These salts can be prepared either during the final isolation and purification of the compound or by reacting suitable groups with suitable bases or acids. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include both inorganic and organic acids.

[0242] "Pharmaceutical acceptable" means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0243] "Carrier" refers to a carrier or diluent that does not cause significant stimulation to an organism and does not eliminate the biological activity and properties of the given compound. Detailed Implementation

[0244] Further examples are provided to illustrate the compounds of the present invention and their preparation, and these examples demonstrate methods for preparing or using said compounds. However, it is to be understood that these examples do not limit the scope of the invention. Variations of the invention now known or further developed are considered to fall within the scope of the invention described and claimed herein.

[0245] The compounds of this invention are prepared using convenient starting materials and common preparation steps. Typical or preferred reaction conditions are provided, such as reaction temperature, time, solvent, pressure, and molar ratio of reactants. However, unless otherwise specified, other reaction conditions may also be adopted. Optimal conditions may vary depending on the specific reactants or solvents used, but in general, the optimal reaction steps and conditions can be determined.

[0246] In addition, some protecting groups may be used in this invention to protect certain functional groups from unnecessary reactions. Suitable protecting groups for various functional groups and their protection or deprotection conditions are well known to those skilled in the art. For example, TW Greene and GMWuts' "Protecting Groups in Organic Preparations" (3rd edition, Wiley, New York, 1999 and cited references in the book) describes in detail a large number of protecting or deprotecting groups.

[0247] The separation and purification of compounds and intermediates are carried out using appropriate methods and procedures depending on specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer chromatography, preparative high-performance liquid chromatography, or a combination of the above methods. Specific methods can be found in the examples described in this invention. Of course, other similar separation and purification methods can also be used. Conventional methods (including physical constants and spectroscopic data) can be used for characterization.

[0248] The structure of the compounds was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts are given in units of 10⁻⁶ (ppm). NMR measurements were performed using a Zhongke Oxford WNMR-I-400MHz NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃), and deuterated methanol (CD₃OD) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0249] MS analysis was performed using a 1260Infinity II 6125B single quadrupole LC-MS system (manufacturer: Agilent Technologies), with a Kinetex XB-C18 100A 1.7μm (30×3mm) column (manufacturer: Finomer), and the mobile phase was acetonitrile / water (0.1% FA).

[0250] Preparative liquid chromatography was performed using a 1260 Infinity II preparative liquid chromatogram (manufacturer: Agilent Technologies), an Xtimate C18 5μm (21.2×250mm) column (manufacturer: Yuexu Technology), and a mobile phase of acetonitrile / water.

[0251] Thin-layer chromatography (TLC) uses Qingdao Ocean Chemical GF254 silica gel plates. The silica gel plates used for reaction monitoring in TLC have a diameter of 0.20 mm to 0.25 mm, while those used for separation and purification have a diameter of 0.5 mm.

[0252] Silica gel column chromatography uses Qingdao marine silica gel of 100-200 mesh, 200-300 mesh, and 300-400 mesh as carriers.

[0253] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as NetEase Mall, Exploration Platform, Booker Mall, Lanbo.com, Beijing Ouhe, Sigma, Bailingwei, Yishiming, Shanghai Shuya, Shanghai Inokai, Anaiji Chemical, Shanghai Bide, Shanghai Leyan, Nanjing Yaoshi, etc.

[0254] Unless otherwise specified in the examples, all reactions can be carried out under a nitrogen atmosphere.

[0255] Argon atmosphere, nitrogen atmosphere, or hydrogen atmosphere refers to a reaction flask connected to a balloon of argon, nitrogen, or hydrogen with a volume of approximately 1L.

[0256] The terms "reaction solvent," "organic solvent," or "inert solvent" each refer to solvents that do not participate in the reaction under the described reaction conditions. These include solvents such as benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane (DCM), diethyl ether, methanol (MeOH), ethanol (EtOH), dimethyl sulfoxide (DMSO), 1,4-dioxane, N-methylpyrrolidone (NMP), pyridine, and water. Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0257] The chemical reactions described in this invention are generally carried out under normal pressure. The reaction time and conditions are, for example, at one atmosphere, between -78°C and 200°C, and are completed in approximately 1 to 24 hours. If the reaction is carried out overnight, the reaction time is generally 16 hours. Unless otherwise specified in the examples, the reaction temperature is room temperature, between 20°C and 30°C.

[0258] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent systems used in the reactions were: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, and C: acetone. The volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0259] The eluent system for column chromatography and the developing solvent system for thin-layer chromatography used to purify the compound include: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound. Small amounts of basic or acidic reagents such as triethylamine and trifluoroacetic acid can also be added for adjustment.

[0260] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention.

[0261] Example

[0262] Example 1: Synthesis of N-(1-(methanesulfonyl)piperidin-4-yl)-2-phenyl-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-9-amine (1)

[0263] Step 1: Preparation of 2-((5-bromo-2-(methylthio)pyrimidin-4-yl)amino)-1-phenylethanol (1-2)

[0264] 5-Bromo-4-chloro-2-(methylthio)pyrimidine (1-1, 1 g, 4.18 mmol), 2-amino-1-phenylethyl-1-ol (0.72 g, 5.22 mmol), and DIEA (1.08 g, 8.35 mmol) were sequentially added to DMSO (10.0 mL), and the mixture was stirred at 100 °C for 4 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 1-2 (1.4 g, 98% yield, pale yellow solid).

[0265] LC-MS (ESI) + ): 340.0 / 342.1m / z [M+H] + .

[0266] Step 2: Preparation of 2-((5-(3-chloro-2-fluoropyridin-4-yl)-2-(methylthio)pyrimidin-4-yl)amino)-1-phenylethanol (1-3)

[0267] Compounds 1-2 (0.5 g, 1.47 mmol), (3-chloro-2-fluoropyridin-4-yl)boronic acid (0.5 g, 2.94 mmol), Pd(dtbpf)Cl2 (94.9 mg, 0.15 mmol), and potassium fluoride (256 mg, 4.41 mmol) were sequentially added to a mixed solvent of 1,4-dioxane (5.5 mL) / H2O (1.0 mL). The mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 1-3 (0.6 g, 100% yield, pale yellow solid).

[0268] LC-MS (ESI) + ):391.1m / z[M+H] + .

[0269] Step 3: Preparation of 9-(methylthio)-2-phenyl-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluorene (1-4)

[0270] Compounds 1-3 (80 mg, 0.20 mmol), Pd-PEPPSI-IPentCl (19.9 mg, 0.02 mmol), and sodium tert-butoxide (49.2 mg, 0.51 mmol) were sequentially added to anhydrous 1,4-dioxane (2.0 mL), and stirred at 100 °C for 4 hours under a nitrogen atmosphere. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (dichloromethane / methanol = 10 / 1) to give compounds 1-4 (28 mg, yield 40.9%, yellow solid).

[0271] LC-MS (ESI) + ): 335.2 m / z [M+H] + .

[0272] Step 4: Preparation of 9-(methyl sulfoxide)-2-phenyl-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene (1-5)

[0273] m-CPBA (14.4 mg, 0.08 mmol) was slowly added to a DCM (2.0 mL) solution of compounds 1-4 (28 mg, 0.08 mmol), and the mixture was stirred at room temperature for half an hour. Sodium bicarbonate aqueous solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compounds 1-5 (29 mg, 99% yield, yellow solid).

[0274] LC-MS (ESI) + ): 351.1 m / z [M+H] + .

[0275] Step 5: Preparation of N-(1-(methanesulfonyl)piperidin-4-yl)-2-phenyl-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-9-amine (1)

[0276] Compounds 1-4 (29 mg, 0.08 mmol), 1-(methanesulfonyl)piperidin-4-amine (22 mg, 0.12 mmol), and DIEA (32 mg, 0.25 mmol) were sequentially added to DMSO (0.5 mL), and the mixture was stirred at 100 °C for 1.5 h. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (water / acetonitrile = 95% / 5%-10% / 90%) to give compound 1 (2.4 mg, 100% purity, 6.2% yield, white solid).

[0277] LC-MS (ESI) + ): 465.2 m / z [M+H] + .

[0278] 1 H NMR(400MHz, DMSO-d6)δ9.10(s,1H),7.95(s,1H),7.60–7.69(m,3H),7.56(d,J=5.5Hz,1H),7.52–7.46(m,3H),5.74–5.67(m,1H),4.7 0–4.55(m,1H),4.24(t,J=11.2Hz,1H),4.03(s,1H),3.55(d,J=11.8Hz,2H),2.97–2.81(m,5H),2.09–1.97(m,2H),1.66–1.55(m,2H).

[0279] The following compounds were synthesized using the corresponding starting materials according to the method in Example 1:

[0280] Example 37: N-(1-(methanesulfonyl)piperidin-4-yl)-2',3'-dihydro-3',4',8',10',10b'-pentazaspiro[cyclohexane-1,1'-fluoranthene]-3a',3a 1 Synthesis of '(6a'),5',6b',8',10'-hexene-9'-amine(37)

[0281] 9'-((1-(methanesulfonyl)piperidin-4-yl)amino)-3',4',8',10',10'-pentazaspiro[cyclohexane-1,1'-fluoranthene]-3a',3a 1 '(6a'),5',6b',8',10'-hexene-3'(2'H)-carboxylic acid tert-butyl ester (synthesized according to Example 1, using (1-aminocyclohexyl)methyl)carbamate tert-butyl ester instead of 2-amino-1-phenylethanol-1-ol) (37-1, 90 mg) was dissolved in DCM (10 mL), and TFA (10 mL) was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and DCM (50 mL) was added. The pH was adjusted to >7 with saturated Na2CO3 aqueous solution, and the mixture was extracted with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by high performance liquid chromatography (water / acetonitrile = 95% / 5%-10% / 90%) to give compound 37 (20 mg, yield 27%, white solid).

[0282] LC-MS (ESI) + ): 456.2 m / z [M+H] + .

[0283] 1 H NMR (400MHz, DMSO-d6) δ8.94(s,1H),7.72(d,J=5.6Hz,1H),7.41(s,1H),7.10(d,J=5.6Hz,1H),6.86(s,1H), 3.82(s,1H),3.65–3.51(m,4H),2.97–2.84(m,5H),2.81–2.69(m,2H),2.17–1.97(m,2H),1.85–1.28(m,10H).

[0284] Example 38: 3'-Methyl-N-(1-(methanesulfonyl)piperidin-4-yl)-2',3'-dihydro-3',4',8',10',10b'-pentazaspiro[cyclohexane-1,1'-fluoranthene]-3a',3a 1 Synthesis of '(6a'),5',6b',8',10'-hexene-9'-amine(38)

[0285] Step 1: Preparation of tert-butyl carbamate (38-1)

[0286] Compound 1-1 (2.0 g, 8.35 mmol), tert-butyl ((1-aminocyclohexyl)methyl)carbamate (2.08 g, 9.10 mmol), and DIEA (1.51 g, 11.69 mmol) were dissolved in 1,4-dioxane / DMSO (6 mL / 6 mL), and the mixture was heated to 100 °C and stirred for 5 days. The reaction mixture was concentrated, diluted with ethyl acetate and water, and extracted with ethyl acetate. The combined organic phases were washed with saturated brine. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / PE = 0%–20%) to give compound 38-1 (2.59 g, 72% yield, white solid).

[0287] LC-MS (ESI) + ): 431.2 / 433.2m / z[M+H] + .

[0288] Step 2: Preparation of ((1-((5-bromo-2-(methylthio)pyrimidin-4-yl)amino)cyclohexyl)methyl)(methyl)carbamate tert-butyl ester (38-2)

[0289] At 0 °C, LiHMDS (1 M THF solution, 5 mL, 5.00 mmol) was added to a THF (21 mL) solution of compound 38-1 (1.8 g, 4.17 mmol), and the mixture was stirred for 40 minutes. MeI (0.29 mL, 4.29 mmol) was added dropwise, and the mixture was slowly heated to room temperature and stirred for 10 minutes. The reaction mixture was heated to 40 °C and stirred for 15 hours. The reaction mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The organic phases were combined, washed with water and saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / PE = 0%–16%) to give compound 38-2 (955 mg, 40% yield, colorless gelatinous solid).

[0290] LC-MS (ESI) + ): 445.2 / 447.2m / z [M+H] + .

[0291] 1 H NMR (400MHz, DMSO-d6) δ8.20(s,1H),3.64(s,2H),2.75(s,3H),2.45–2.39(m,5H),1.61–1.22(m,19H).

[0292] Step 3: Preparation of ((1-((5-(3-chloro-2-fluoropyridin-4-yl)-2-(methylthio)pyrimidin-4-yl)amino)cyclohexyl)methyl)(methyl)tert-butyl carbamate (38-3)

[0293] Compound 38-2 (430 mg, 0.97 mmol), 3-chloro-2-fluoropyridine-4-boronic acid (339 mg, 1.93 mmol), KF (168 mg, 2.90 mmol), and Pd(dtbpf)Cl2 (93 mg, 0.14 mmol) were dissolved in 1,4-dioxane / water (10.0 mL / 2.0 mL). The mixture was heated to 100 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / PE = 4%-30%) to give compound 38-3 (420 mg, 78% yield, yellow gelatinous solid).

[0294] LC-MS (ESI) + ): 496.2 / 498.2m / z [M+H] + .

[0295] Step 4: Preparation of ((1-(8-fluoro-2-(methylthio)-9H-pyridyl[4',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)cyclohexyl)methyl)(methyl)tert-butyl carbamate (38-4)

[0296] Compound 38-3 (420 mg, 0.85 mmol), Pd-PEPPSI-IPentCl (73 mg, 0.085 mmol), and cesium carbonate (828 mg, 2.54 mmol) were dissolved in 1,4-dioxane (8.5 mL). The mixture was heated to 120 °C and stirred for 21 hours under a nitrogen atmosphere. After cooling, the mixture was transferred to a microwave-safe tube, and Pd-PEPPSI-IPentCl (73 mg, 0.085 mmol) and cesium carbonate (414 mg, 1.27 mmol) were added. The mixture was then microwave-safe at 120 °C for 6 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (MeOH / DCM = 0.4%) to give compound 38-4 (200 mg, 51% yield, yellow gelatinous solid).

[0297] LC-MS (ESI) + ): 460.2 m / z [M+H]+ .

[0298] Step 5: Preparation of 1-(1-(8-fluoro-2-(methylthio)-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)cyclohexyl)-N-methylmethylamine (38-5)

[0299] TFA (1.5 mL) was added to dichloromethane (9 mL) containing 200 mg (0.43 mmol) of compound 38-4, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give compound 38-5 (TFA salt, 156 mg, 100% yield, yellow gelatinous solid).

[0300] LC-MS (ESI) + ): 360.2 m / z [M+H] + .

[0301] Step 6: 3'-Methyl-9'-(methylthio)-2',3'-dihydro-3',4',8',10',10b'-pentazaspiro[cyclohexane-1,1'-fluoranthene]-3a',3a 1 Preparation of (6a'),5',6b',8',10'-hexene(38-6)

[0302] Cesium carbonate (708 mg, 2.17 mmol) was added to a 1,4-dioxane (8.7 mL) solution of compound 38-6 (TFA salt, 156 mg, 0.43 mmol), and the mixture was stirred at 100 °C for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / DCM = 3%–35%) to give compound 38-6 (27 mg, 18% yield, yellow solid).

[0303] LC-MS (ESI) + ): 340.2 m / z [M+H] + .

[0304] Compound 38 was synthesized by replacing steps 1-4 with compound 38-6 according to steps 4 and 5 of Example 1.

[0305] LC-MS (ESI) + ): 470.2 m / z [M+H] + .

[0306] 1H NMR (400MHz, DMSO-d6) δ8.95(s,1H),7.81(d,J=5.5Hz,1H),7.44(s,1H),7.14(d,J=5.5Hz,1H),4.01–3.72(m ,5H),3.13(s,3H),2.90(s,5H),2.84–2.70(m,2H),2.23–1.93(m,2H),1.85–1.52(m,9H),1.39–1.24(m,1H).

[0307] Example 39: Synthesis of 1,1-dimethyl-N-(1-(methanesulfonyl)piperidin-4-yl)-2-phenyl-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-9-amine (39)

[0308] Step 1: Preparation of (1-hydroxy-2-methyl-1-phenylprop-2-yl) tert-butyl carbamate (39-2)

[0309] At room temperature, magnesium phenyl bromide (7.6 mL, 2.8 mmol / L) was added to a tetrahydrofuran solution (20 mL) of (1,1-dimethyl-2-oxoethyl)carbamate tert-butyl ester (39-1, 2 g, 10.6 mmol). The reaction mixture was stirred at 25 °C for 12 hours under a nitrogen atmosphere. After the reaction was complete, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to give compound 39-2 (900 mg, yield 31%).

[0310] LC-MS (ESI) + ):266.2m / z[M+H] + .

[0311] Step 2: Preparation of 2-amino-2-methyl-1-phenylprop-1-ol (39-3)

[0312] At room temperature, trifluoroacetic acid (1 mL) was added to a 3 mL solution of compound 39-2 (800 mg, 3 mmol) in dichloromethane. The reaction mixture was stirred at 25 °C for 1 hour until the starting material disappeared. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give compound 39-3 (TFA salt, 400 mg, 80% yield).

[0313] LC-MS (ESI) + ): 166.2m / z [M+H] + .

[0314] Compound 39 was prepared by replacing 2-amino-1-phenylethyl-1-ol with compound 39-3 according to the method in Example 1.

[0315] LC-MS (ESI) + ): 493.4 m / z [M+H] + .

[0316] 1 H NMR (400MHz, DMSO-d6) δ9.12 (s, 1H), 7.96 (d, J = 5.6Hz, 1H), 7.71 (s, 1H), 7.58-7.56 (m, 3H), 7.49-7.46 (m, 3H), 5. 56(s,1H),3.58-3.55(m,2H),2.93-2.89(m,5H),2.09-2.01(m,2H),1.93(s,3H),1.64-1.59(m,2H),1.30(s,3H).

[0317] The following compounds were synthesized using the corresponding starting materials according to the method of Example 39:

[0318] Example 40: 4-Methoxy-N-(1-(methanesulfonyl)piperidin-4-yl)-2'H-3'-oxa-4',8',10',10b'-tetraazaspiro[cyclohexane-1,1'-fluoranthene]-3a',3a 1 Synthesis of '(6a'),5',6b',8',10'-hexene-9'-amine(40)

[0319] Step 1: Preparation of (1-amino-4-methoxycyclohexyl)methanol (40-2)

[0320] Under ice bath conditions, 1-amino-4-methoxycyclohexanecarboxylic acid (40-1, 300 mg, 1.73 mmol) was dissolved in THF (5 mL), and boranetetrahydrofuran (2 mL, 3.5 mmol, 1 mmol / L) was added dropwise at 0 °C. The mixture was then slowly heated to room temperature and stirred for 2 h. MeOH (20 mL) was added to the reaction mixture, and the mixture was stirred at 60 °C for 1 h. The reaction mixture was concentrated under reduced pressure to obtain crude product 40-2, which was directly used in the next reaction step (300 mg, yellow oily liquid).

[0321] LC-MS (ESI) + ): 160.1 m / z [M+H] + .

[0322] Following the route of Example 1, compound 40 was prepared by replacing 2-amino-1-phenylethyl-1-ol with compound 40-2.

[0323] LC-MS (ESI) + ): 487.2 m / z [M+H] + .

[0324] The following compounds were synthesized using the corresponding starting materials according to the method described in Example 40:

[0325] Example 43: Synthesis of 1-(cyclopropylmethyl)-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (43)

[0326] Step 1: Preparation of 2-amino-3-cyclopropylprop-1-ol (43-2)

[0327] Under ice bath conditions, 2-amino-3-cyclopropylpropionic acid (43-1, 1 g, 7.74 mmol) was dissolved in tetrahydrofuran (10 mL), and a tetrahydrofuran solution of lithium aluminum hydride (15.5 mmol, 2.5 M) was added dropwise. The reaction mixture was stirred for 10 minutes. The resulting mixture was stirred at 70 °C for 12 hours. Under ice bath conditions, an aqueous solution of NH4Cl (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (petroleum ether / ethyl acetate = 0 / 1) to give compound 43-2 (0.8 g, 89% yield, white liquid).

[0328] LC-MS (ESI) + ): 116.2 m / z [M+H] + .

[0329] Following the route of Example 1, compound 43 was prepared by replacing 2-amino-1-phenylethyl-1-ol with compound 43-2.

[0330] LC-MS (ESI) + ): 443.2 m / z [M+H] + .

[0331] Example 44: Synthesis of 2-methyl-N-(1-(methanesulfonyl)piperidin-4-yl)-2-phenyl-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-9-amine (44)

[0332] Step 1: Preparation of 1-amino-2-phenylprop-2-ol (44-2)

[0333] 2-Methyl-2-phenylethylene oxide (44-1, 0.5 g, 3.72 mmol) was dissolved in methanol (10 mL) and water (2 mL) at room temperature. Ammonium formate (0.47 g, 7.45 mmol) and ammonia (0.65 g, 18.6 mmol) were added, and the mixture was stirred at 50 °C for 12 hours in a sealed tube. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with DCM (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (petroleum ether / ethyl acetate = 0 / 1) to give compound 44-2 (0.3 g, 53% yield, pale yellow liquid).

[0334] LC-MS (ESI) + ): 152.2 m / z [M+H] + .

[0335] Following the route of Example 1, compound 44 was prepared by replacing 2-amino-1-phenylethyl-1-ol with compound 44-2.

[0336] LC-MS (ESI) + ): 479.2 m / z [M+H] + .

[0337] 1 H NMR(400MHz,DMSO-d6)δ9.04(s,1H),8.20(s,1H),7.61-7.55(m,3H),7.33( t,J=8.0Hz,2H),7.29(d,J=4.0Hz,1H),7.23(t,J=8.0Hz,1H),7.05(d,J=8.0 Hz,1H),4.86(d,J=16.0Hz,1H),4.68(d,J=12.0Hz,1H),3.91(s,1H),3.60(s ,2H),3.01-2.87(m,5H),2.05-2.02(m,2H),1.70–1.56(m,2H),1.35(s,3H).

[0338] Example 45: Synthesis of N-(1-(methanesulfonyl)piperidin-4-yl)-1-(pyridin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-9-amine (45)

[0339] Step 1: Preparation of 9-(methylthio)-1-(pyridin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene (45-2)

[0340] Under ice bath conditions, 2-(8-fluoro-2-(methylthio)-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2-(pyridin-4-yl)ethane-1-ol (prepared according to Example 1 using 2-amino-2-(pyridin-4-yl)ethane-1-ol instead of 2-amino-1-phenylethyl-1-ol) (45-1, 15 mg, 0.04 mmol) was dissolved in tetrahydrofuran (10 mL), and sodium hydrogen (60%, 5 mg, 0.12 mmol) was added. The reaction mixture was stirred for 10 minutes. The resulting mixture was stirred at 60 °C for 2 hours. After the reaction mixture was cooled to room temperature, it was quenched with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (dichloromethane / methanol = 10 / 1) to give compound 45-2 (14 mg, 98% yield, white solid).

[0341] LC-MS (ESI) + ): 336.1 m / z [M+H] + .

[0342] Compound 45 was prepared by replacing compounds 1-4 with compound 45-2 according to the method in Example 1.

[0343] LC-MS (ESI) + ): 466.2 m / z [M+H] + .

[0344] Example 46: Synthesis of 2-isopropyl-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-9-amine (46)

[0345] Step 1: Preparation of 2-isopropyl-9-(methylthio)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene (46-2)

[0346] Under ice bath conditions, 1-(8-fluoro-2-(methylthio)-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-3-methylbut-2-ol (prepared according to Example 1 using 1-amino-3-methylbut-2-ol instead of 2-amino-1-phenylethyl-1-ol) (46-1, 400 mg, 1.25 mmol) was dissolved in dioxane (6 mL), and sodium hydroxide (200 mg, 4.99 mmol) was added. The reaction mixture was stirred for 10 minutes, and the resulting mixture was stirred at 100 °C for 4 hours. After the reaction mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (dichloromethane / methanol = 10 / 1) to give compound 46-2 (300 mg, yield 80%, white solid).

[0347] LC-MS (ESI) + ): 301.1m / z [M+H] + .

[0348] Following the method of Example 1, compound 46 was synthesized by replacing compound 1-4 with compound 46-2.

[0349] LC-MS (ESI) + ): 431.2 m / z [M+H] + .

[0350] Example 47: Synthesis of (S)-N-(1-(methanesulfonyl)piperidin-4-yl)-2-phenyl-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-9-amine (47)

[0351] Step 1: Preparation of (S)-2-((5-bromo-2-chloropyrimidin-4-yl)amino)-1-phenylethyl-1-ol (47-2)

[0352] 5-Bromo-2,4-Dichloropyrimidine (compound 47-1, 500 mg, 2.20 mmol) was dissolved in isopropanol (6 mL), and (S)-2-amino-1-phenylethyl-1-ol (299 mg, 2.20 mmol) and DIEA (709 mg, 5.50 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 47-2 (700 mg, 93% yield, yellow oil).

[0353] LC-MS (ESI) + ): 340.2 m / z [M+H] + .

[0354] Step 2: Preparation of (S)-2-((5-bromo-2-((1-(methanesulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)amino)-1-phenylethyl-1-ol (47-3)

[0355] Compound 47-2 (700 mg, 2.06 mmol) was dissolved in DMSO (8 mL), and 1-(methanesulfonyl)piperidin-4-amine (299 mg, 3.09 mmol) and DIEA (797 mg, 6.18 mmol) were added at room temperature. The resulting reaction solution was stirred at 120 °C for 16 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (dichloromethane / methanol = 20 / 1) to give compound 47-3 (700 mg, 72% yield, yellow solid).

[0356] LC-MS (ESI) + ): 470.2 m / z [M+H] + .

[0357] Step 3: Preparation of (S)-2-((5-(3-chloro-2-fluoropyridin-4-yl)-2-((1-(methanesulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)amino)-1-phenylethyl-1-ol (47-4)

[0358] Compound 47-3 (700 mg, 1.49 mmol) was dissolved in a mixed solvent of 1,4-dioxane and water (10 mL / 1 mL). At room temperature, (3-chloro-2-fluoropyridin-4-yl)boronic acid (339 mg, 1.94 mmol), Pd(dtbpf)Cl2 (97 mg, 0.15 mmol), and KF (259 mg, 4.47 mmol) were added. The resulting reaction mixture was stirred at 95 °C for 3 hours under a nitrogen atmosphere. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (dichloromethane / methanol = 20 / 1) to give compound 47-4 (600 mg, 77% yield, yellow solid).

[0359] LC-MS (ESI) + ): 521.2 m / z [M+H] + .

[0360] Step 4: Preparation of (S)-N-(1-(methanesulfonyl)piperidin-4-yl)-2-phenyl-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (47)

[0361] Compound 47-4 (300 mg, 0.57 mmol) was dissolved in 1,4-dioxane (10 mL), and Pd-Peppsi-IpentCl (58 mg, 0.06 mmol) and cesium carbonate (557 mg, 1.71 mmol) were added at room temperature. The resulting reaction solution was stirred at 120 °C for 16 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (dichloromethane / methanol = 20 / 1) to obtain a crude product, which was then purified by high performance liquid chromatography (water / acetonitrile = 95% / 5%-10% / 90%) to obtain compound 47 (20.6 mg, yield 8%, white solid).

[0362] LC-MS (ESI) + ): 465.2 m / z [M+H] + .

[0363] 1 H NMR (400MHz, DMSO-d6) δ9.10(s,1H),8.46(s,1H),7.95(d,J=5.2Hz,1H),7.67-7.60(m,2H),7.56(d,J=5.6Hz,1H),7.54-7.44(m,3H),5.71(dd,J =9.2,2.4Hz,1H),4.64(s,1H),4.36-4.17(m,1H),4.03(s,1H),3.56(d, J=12.0Hz,2H),2.97-2.85(m,5H),2.13-1.92(m,2H),1.71-1.53(m,2H).

[0364] The following compounds were synthesized using the corresponding starting materials according to the method described in Example 47:

[0365] Example 70: Synthesis of (8aS,12aR)-N-(1-(methanesulfonyl)piperidin-4-yl)-8a,9,10,11,12,12a-hexahydro-8-oxa-1,3,7,12b-tetraazabenzo[a]acetylanthraene-2-amine (70)

[0366] In a sealed tube, (1S,2R)-2-(8-fluoro-2-((1-(methanesulfonyl)piperidin-4-yl)amino)-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)cyclohexyl-1-ol (synthesized according to Example 1 by replacing (S)-2-amino-1-phenylethyl-1-ol with (1S,2R)-2-aminocyclohexyl-1-ol) (70-1, 100 mg, 0.21 mmol) was dissolved in 1,4-dioxane (5 mL), and t-BuOK (36 mg, 0.32 mmol) was added. The resulting mixture was stirred at 100 °C for 2 hours. Ethyl acetate (20 mL) was added to the reaction mixture, and the mixture was washed with saturated brine (5 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid preparative chromatography (water / acetonitrile = 95% / 5%-10% / 90%) and freeze-dried to give compound 70 (14.1 mg, yield 15%, white solid).

[0367] LC-MS (ESI) + ): 443.2 m / z [M+H] + .

[0368] 1 H NMR (400MHz, DMSO-d6) δ9.04(s,1H),7.88(d,J=5.6Hz,1H),7.61(d,J=7.6Hz,1H),7.47(d,J=5.6Hz,1H),4.67-4.59(m,2H),4. 02(s,1H),3.65–3.49(m,2H),2.97-2.88(m,2H),2.89(s,3H),2.21(s,1H),2.06–1.86(m,4H),1.71(s,1H),1.68–1.39(m,6H).

[0369] The following compounds were synthesized using the corresponding starting materials according to the method of Example 70:

[0370] Example 72: N-(1-(methanesulfonyl)piperidin-4-yl)-2'H-3'-oxa-4',8',10',10b'-tetraazaspiro[cyclohexane-1,1'-fluoranthene]-3a',3a 1 Synthesis of '(6a'),5',6b',8',10'-hexene-9'-amine(72)

[0371] Step 1: N-(piperidin-4-yl)-2'H-3'-oxa-4',8',10',10b'-tetraazaspiro[cyclohexane-1,1'-fluoranthene]-3a',3a 1 Preparation of (6a'),5',6b',8',10'-hexene-9'-amine (72-2)

[0372] 4-((2'H-3'-oxa-4',8',10',10b'-tetraazaspiro[cyclohexane-1,1'-fluoranthene]-3a',3a 1 '(6a'),5',6b',8',10'-hexene-9'-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (synthesized according to Example 1, using (1-aminocyclohexyl)methanol instead of (S)-2-amino-1-phenylethyl-1-ol and 4-aminopiperidine-1-carboxylic acid tert-butyl ester instead of 1-(methanesulfonyl)piperidine-4-amine) (72-1, 2.0 g, 4.18 mmol) was dissolved in DCM (20 mL), and TFA (20 mL) was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and DCM (100 mL) was added. The pH was adjusted to >7 with saturated Na2CO3 aqueous solution, and the mixture was extracted with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 72-2 (1.5 g, 94% yield, white solid).

[0373] LC-MS (ESI) + ): 319.1 m / z [M+H] + .

[0374] Step 2: N-(1-(methanesulfonyl)piperidin-4-yl)-2'H-3'-oxa-4',8',10',10b'-tetraazaspiro[cyclohexane-1,1'-fluoranthene]-3a',3a 1 Preparation of '(6a'),5',6b',8',10'-hexene-9'-amine(72)

[0375] Compound 72-2 (0.6 g, 1.58 mmol) was dissolved in DCM (10 mL), and DIEA (613 mg, 4.75 mmol) and methanesulfonic anhydride (331 mg, 1.9 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 2 hours. DCM (20 mL) was added to the reaction mixture, and the solution was washed with saturated brine (5 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (water / acetonitrile = 95% / 5%-10% / 90%), and lyophilized to give compound 72 (424 mg, 58% yield, white solid).

[0376] LC-MS (ESI)+ ): 457.2 m / z [M+H] + .

[0377] 1 H NMR(400MHz, DMSO-d6)δ9.06(s,1H),7.88(d,J=5.6Hz,1H),7.67(s,1H),7.50(d,J=5.2Hz,1H),4.64(s,2H),4.06-3.83( m,1H),3.60(d,J=11.6Hz,2H),2.92(s,5H),2.70(t,J=13.6Hz,2H),2.18–1.94(m,2H),1.94–1.48(m,11H),1.34(s,1H).

[0378] The following compounds were synthesized using the corresponding starting materials according to the method of Example 72:

[0379] Example 87: N-(1-(azacyclobutane-3-ylsulfonyl)piperidin-4-yl)-2'H-3'-oxa-4',8',10',10b'-tetraazaspiro[cyclohexane-1,1'-fluoranthene]-3a',3a 1 Synthesis of '(6a'),5',6b',8',10'-hexene-9'-amine(87)

[0380] According to step 2 of Example 72, tert-butyl 3-(chlorosulfonyl)azacyclobutane-1-carboxylate was used to replace methanesulfonic anhydride to obtain compound 87-1. Then, according to step 1 of Example 72, compound 87 was synthesized by replacing compound 72-1 with compound 87-1.

[0381] LC-MS (ESI) + ): 498.2 m / z [M+H] + .

[0382] 1H NMR (400MHz, DMSO-d6) δ9.04(s,1H),8.25(s,1H),7.87(d,J=5.6Hz,1H),7.65(s,1H),7.49(d,J=5.6Hz,1H),4.62(s,2H),4.41(s,1H),4.15– 3.96(m,1H),3.94–3.69(m,6H),2.95(s,2H),2.82–2.60(m,2H),2.15- 1.92(m,2H),1.89–1.69(m,5H),1.64-1.45(m,4H),1.41-1.25(m,1H).

[0383] Example 88: Synthesis of 2-(tert-butyl)-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (88)

[0384] Step 1: Preparation of 1-amino-3,3-dimethylbutane-2-ol (88-2)

[0385] 2-Hydroxy-3,3-dimethylbutyronitrile (88-1, 400 mg, 3.5 mmol) was dissolved in THF (20 mL). A tetrahydrofuran solution of lithium aluminum hydride (5.3 mmol) was slowly added dropwise under ice bath conditions. After stirring for 1 hour under ice bath conditions, the mixture was brought to room temperature and stirred overnight. Ice water (1.2 mL) and a 15% sodium hydroxide aqueous solution (1 mL) were slowly added to the reaction mixture under ice bath conditions. The mixture was stirred at room temperature for 15 minutes, filtered through diatomaceous earth, dried over anhydrous sodium sulfate, filtered again, and the filtrate was concentrated under reduced pressure to give compound 88-2 (250 mg, 59% yield, colorless oil).

[0386] LC-MS (ESI) + ): 118.2 m / z [M+H] + .

[0387] Compound 88 was synthesized by replacing (S)-2-amino-1-phenylethyl-1-ol with compound 88-2 according to the method of Example 47.

[0388] LC-MS (ESI) + ): 445.2 m / z [M+H] + .

[0389] 1H NMR(400MHz, DMSO-d6)δ9.07(s,1H),7.89(d,J=5.5Hz,1H),7.70–7.54(m,1H),7.49(d,J=5.5Hz,1H),4.48(s,1H),4.29(dd,J=10.0,1.4Hz,1H),4.13 –4.03(m,1H),3.95(t,J=11.4Hz,1H),3.57(d,J=11.6Hz,2H),3.02–2.93(m ,2H),2.91(s,3H),2.01(d,J=10.0Hz,2H),1.69–1.51(m,2H),1.17(s,9H).

[0390] Example 89: Synthesis of 1-ethyl-1-methyl-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (89)

[0391] Following step 1 of Example 40, 2-amino-2-methylbutyric acid (89-1) was used to replace 40-1 to obtain 2-amino-2-methylbut-1-ol (89-2). Then, following the method of step 47 of Example, compound 89 was synthesized by replacing (S)-2-amino-1-phenylethyl-1-ol with compound 89-2.

[0392] LC-MS (ESI) + ): 431.2 m / z [M+H] + .

[0393] 1 H NMR (400MHz, DMSO-d6) δ9.07 (s, 1H), 7.90 (d, J = 5.4Hz, 1H), 7.66 (s, 1H), 7.52 (d, J=5.4Hz,1H),4.53(d,J=11.6Hz,1H),4.29(d,J=11.6Hz,1H),3.94–3.82(m,1H),3 2.99–2.86(m,5H),2.19–1.92(m,4H),1.74(s,3H),1.71–1.56(m,2H),0.87(t,J=7.5Hz,3H).

[0394] Example 90: Synthesis of 2-(aminomethyl)-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (90)

[0395] At room temperature, tert-butyl (9-((1-(methanesulfonyl)piperidin-4-yl)amino)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-2-yl)methyl)carbamate (synthesized according to Example 47 using (3-amino-2-hydroxypropyl)carbamate instead of (S)-2-amino-1-phenylethyl-1-ol)) (90-1, 50 mg, 0.09 mmol) was dissolved in DCM (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (water / acetonitrile = 95% / 5%-10% / 90%) to give compound 90 (2.0 mg, 5% yield, white solid).

[0396] LC-MS (ESI) + ): 418.2 m / z [M+H] + .

[0397] 1 H NMR (400MHz, DMSO-d6) δ9.06(s,1H),7.91(d,J=4.0Hz,1H),7.67(s,1H),7.52(d,J=4.0Hz,1H),4.67-4.60(m,2 H),4.09–3.94(m,3H),3.56(d,J=12.0Hz,2H),3.31-3.22(m,2H),2.93-2.89(s,5H),2.01(s,2H),1.62(s,2H).

[0398] The following compounds were synthesized using the corresponding starting materials according to the method of Example 90:

[0399] Example 92: Synthesis of 2-(azacyclobutane-3-yl)-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (92)

[0400] Step 1: Preparation of tert-butyl 3-(1-hydroxy-2-nitroethyl)azacyclobutane-1-carboxylic acid (92-2)

[0401] 3-Formylazetidine-1-carboxylic acid tert-butyl ester (92-1, 1 g, 5.4 mmol) was dissolved in methanol (20 mL) under ice bath conditions. Nitromethane (980 mg, 16.3 mmol) and triethylamine (1.3 g, 13.5 mmol) were slowly added dropwise under ice bath conditions. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure. The residue was purified by rapid column chromatography (petroleum ether: ethyl acetate 20:1-3:1) to give compound 92-2 (400 mg, yield 30%, colorless oily liquid).

[0402] LC-MS (ESI) + ): 191.2 m / z [M-55] + .

[0403] Step 2: Preparation of tert-butyl 3-(2-amino-1-hydroxyethyl)azacyclobutane-1-carboxylic acid (92-3)

[0404] Compound 92-2 (300 mg, 1.2 mmol) was dissolved in MeOH (5 mL), and Pd / C (20%, 30 mg) and acetic acid (5 mg) were added. The resulting reaction solution was stirred overnight at room temperature under a hydrogen atmosphere. After filtration, the solution was concentrated under reduced pressure to give compound 92-3 (acetate, 200 mg, 76% yield, colorless oily liquid).

[0405] LC-MS (ESI) + ): 161.2 m / z [M+H] + .

[0406] According to the method of Example 90, compound 92 was synthesized by replacing (3-amino-2-hydroxypropyl) tert-butyl carbamate with compound 92-3.

[0407] LC-MS (ESI) + ): 444.2 m / z [M+H] + .

[0408] Example 93: 1'-Methyl-N-(1-(methanesulfonyl)piperidin-4-yl)-2H-3-oxa-4,8,10,10b-tetraazaspiro[fluoranthene-1,4'-piperidin]-3a,3a 1 Synthesis of (6a), 5,6b, 8,10-hexene-9-amine (93)

[0409] Compound 91 (50.0 mg, 0.11 mmol) was dissolved in MeOH (2 mL), followed by the addition of formaldehyde aqueous solution (0.1 mL) and NaBH3CN (13 mg, 0.22 mmol). The resulting mixture was stirred at room temperature for 1 hour. Ethyl acetate (20 mL) was added to the reaction mixture, and the solution was washed with saturated brine (5 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (water / acetonitrile = 95% / 5%-10% / 90%), and lyophilized to give compound 93 (3.5 mg, 7% yield, white solid).

[0410] LC-MS (ESI) + ): 472.2 m / z [M+H] + .

[0411] Example 94: N-(1-((1-methylazacyclobutane-3-yl)sulfonyl)piperidin-4-yl)-2'H-3'-oxa-4',8',10',10b'-tetraazaspiro[cyclohexane-1,1'-fluoranthene]-3a',3a 1 Synthesis of '(6a'),5',6b',8',10'-hexene-9'-amine(94)

[0412] Compound 94 was synthesized from compound 87 according to the method of Example 93.

[0413] LC-MS (ESI) + ): 512.2 m / z [M+H] + .

[0414] Example 95: N-(1-((4-((3S,5S)-3,5-dimethylpiperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)-2'H-3'-oxa-4',8',10',10b'-tetraazaspiro[cyclohexane-1,1'-fluoranthene]-3a',3a 1 Synthesis of '(6a'),5',6b',8',10'-hexene-9'-amine(95)

[0415] Step 1: Synthesis of (2S,6S)-tert-butoxycarbonyl-4-(4-((4-((2H-spiro[3-oxa-4,8,10,10b-tetraazafluoranthene-1,1'-cyclohexane]-9-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2,6-dimethylpiperazine (95-1)

[0416] At room temperature, Pd-PEPPSI-IHept-Cl (7 mg, 0.008 mmol) and cesium carbonate (54 mg, 0.17 mmol) were added to a dioxane solution (1 mL) of compound 79 (50 mg, 0.08 mmol) and (2S,6S)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (36 mg, 0.16 mmol). The reaction mixture was stirred at 100 °C for 12 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 10) to give compound 95-1 (50 mg, 81% yield).

[0417] LC-MS (ESI) + ): 731.2 m / z [M+H] + .

[0418] Step 2: N-(1-((4-((3S,5S)-3,5-dimethylpiperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)-2'H-3'-oxa-4',8',10',10b'-tetraazaspiro[cyclohexane-1,1'-fluoranthene]-3a',3a 1 Synthesis of '(6a'),5',6b',8',10'-hexene-9'-amine(95)

[0419] At room temperature, trifluoroacetic acid (0.2 mL) was added to a 1 mL solution of compound 95-1 (50 mg, 0.7 mmol) in dichloromethane. The reaction mixture was stirred at 25 °C for 1 hour until the starting material disappeared. The resulting residue was purified by reversed-phase high-performance liquid chromatography (water / acetonitrile = 95% / 5%-10% / 90%) to give compound 95 (17.7 mg, yield 41%).

[0420] LC-MS (ESI) + ):631.4m / z[M+H] + .

[0421] 1H NMR (400MHz, DMSO-d6) δ9.00 (s, 1H), 7.85 (d, J = 5.6Hz, 1H), 7.63 (s, 1H), 7. 52-7.45(m,3H),7.05(d,J=9.2Hz,2H),4.60(s,2H),3.82-3.80(m,1H),3.39 -3.36(m,4H),3.23-3.19(m,2H),3.04-2.99(m,2H),2.67-2.56(m,2H),2.44 -2.33(m,2H),2.06-1.93(m,2H),1.82-1.57(m,10H),1.09(d,J=6.4Hz,6H).

[0422] Example 96: Synthesis of (3R,4R)-4-((2-isopropyl-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-9-yl)amino)-1-(methanesulfonyl)piperidine-3-ol (96)

[0423] Step 1: Preparation of (3R,4R)-4-((5-bromo-4-((2-hydroxy-3-methylbutyl)amino)pyrimidin-2-yl)amino)piperidin-3-ol (96-2)

[0424] (3R,4R)-4-((5-bromo-4-((2-hydroxy-3-methylbutyl)amino)pyrimidin-2-yl)amino)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (synthesized according to Example 47, using 1-amino-3-methylbut-2-ol instead of (S)-2-amino-1-phenylethyl-1-ol and (3R,4R)-4-amino-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester instead of 1-(methanesulfonyl)piperidine-4-amine) (96-1, 0.13 mg, 0.27 mmol) was dissolved in DCM (2 mL), and TFA (0.5 mL) was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give compound 96-2 (0.1 g, 97% yield, brown oil).

[0425] LC-MS (ESI) + ): 374.1 m / z [M+H] + .

[0426] Step 2: Preparation of (3R,4R)-4-((5-bromo-4-((2-hydroxy-3-methylbutyl)amino)pyrimidin-2-yl)amino)-1-(methanesulfonyl)piperidin-3-ol (96-3)

[0427] Compound 96-2 (0.1 g, 0.267 mmol) was dissolved in DCM (3 mL), and DIEA (0.17 g, 1.33 mmol) and methanesulfonic anhydride (51 mg, 0.29 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 1 hour. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with DCM (100 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 97 / 3) to give compound 96-3 (120 mg, 99% yield, yellow oil).

[0428] LC-MS (ESI) + ): 452.1 m / z [M+H] + .

[0429] Step 3: Preparation of (3R,4R)-4-((5-(3-chloro-2-fluoropyridin-4-yl)-4-(2-hydroxy-3-methylbutyl)amino)pyrimidin-2-yl)amino)-1-(methanesulfonyl)piperidin-3-ol (96-4)

[0430] Compound 96-3 (0.12 g, 0.26 mmol) was dissolved in 1,4-dioxane (5 mL) / H₂O (0.5 mL), and (3-chloro-2-fluoropyridin-4-yl)boronic acid (82 mg, 0.32 mmol), Pd(dtbpf)Cl₂ (17 mg, 0.026 mmol), and KF (77 mg, 1.32 mmol) were added sequentially. The resulting mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 95 / 5) to give compound 96-4 (0.1 g, 75% yield, yellow solid).

[0431] LC-MS (ESI) + ): 503.2 m / z [M+H] + .

[0432] Step 4: Preparation of (3R,4R)-4-((2-isopropyl-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-9-yl)amino)-1-(methanesulfonyl)piperidin-3-ol (96)

[0433] Compound 96-4 (100 mg, 0.19 mmol) was dissolved in a sealed tube containing 3 mL of 1,4-dioxane. Xphos Pd G3 (17.00 mg, 0.02 mmol) and Cs₂CO₃ (323 mg, 0.99 mmol) were added sequentially. The resulting mixture was stirred at 120 °C for 12 hours under a nitrogen atmosphere. Ethyl acetate (20 mL) was added to the reaction mixture, and the solution was washed with saturated brine (5 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (water / acetonitrile = 95% / 5%-10% / 90%), and lyophilized to give compound 96 (1.4 mg, 2% yield, white solid).

[0434] LC-MS (ESI) + ): 447.2 m / z [M+H] + .

[0435] Example 97: (4-((2'H-3'-oxa-4',8',10',10b'-tetraazaspiro[cyclohexane-1,1'-fluoranthene]-3a',3a) 1 Synthesis of '(6a'),5',6b',8',10'-hexen-9'-yl)amino)phenyl)(piperidin-1-yl)methyl ketone (97)

[0436] Step 1: Preparation of tert-butyl 4-(4-iodobenzoyl)piperazine-1-carboxylate (97-2)

[0437] 4-Iodobenzoic acid (97-1, 3.0 g, 12.1 mmol) was dissolved in DMF (30 mL), and DIEA (4.68 g, 36.3 mmol), piperazine-1-carboxylate tert-butyl ester (2.2 g, 12.1 mmol), and HATU (6.90 g, 18.1 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 18 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 97-2 (4 g, 79% yield, white solid).

[0438] LC-MS (ESI) + ): 417.1 m / z [M+H] + .

[0439] Step 2: 2'H-3'-oxa-4',8',10',10'-tetraazaspiro[cyclohexane-1,1'-fluoranthene]-3a',3a 1Preparation of '(6a'),5',6b',8',10'-hexene-9'-amine (97-4)

[0440] 9'-(methylsulfinyl)-2'H-3'-oxa-4',8',10',10'-tetraazaspiro[cyclohexane-1,1'-fluoranthene]-3a',3a 1 '(6a'),5',6b',8'-10'-hexene (synthesized according to Example 1 route, replacing 2-amino-1-phenylethyl-1-ol with (1-aminocyclohexyl)methanol) (97-3, 90 mg, 0.26 mmol) was dissolved in 1,4-dioxane (2 mL), and NH3·H2O (0.5 mL) was added. The resulting mixture was stirred at 100 °C for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 92 / 8) to give compound 97-4 (70 g, 90% yield, white solid).

[0441] LC-MS (ESI) + ):296.1m / z[M+H] + .

[0442] Step 3: 4-(4-((2'H-3'-oxa-4',8',10',10b'-tetraazaspiro[cyclohexane-1,1'-fluoranthene]-3a',3a 1 Preparation of tert-butyl piperazine-1-carboxylate (97-5) (6a'), 5', 6b', 8'-10'-hexen-9'-yl)amino)benzoyl)piperazine-1-carboxylate

[0443] Compound 97-4 (30 mg, 0.1 mmol) was dissolved in 1,4-dioxane (2 mL), followed by the sequential addition of compound 97-2 (42 mg, 0.1 mmol), Brettphos Pd G3 (9 mg, 0.01 mmol), and K2CO3 (42 mg, 0.3 mmol). The mixture was stirred at 90 °C for 2 hours under a nitrogen atmosphere. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 92 / 8) to give compound 97-5 (30 mg, 50% yield, white solid).

[0444] LC-MS (ESI) + ): 584.2m / z [M+H] + .

[0445] Step 4: (4-((2'H-3'-oxa-4',8',10',10b'-tetraazaspiro[cyclohexane-1,1'-fluoranthene]-3a',3a) 1 Preparation of '(6a'),5',6b',8',10'-hexene-9'-yl)amino)phenyl)(piperidin-1-yl)methyl ketone (97)

[0446] Compound 97-5 (30.0 mg, 0.05 mmol) was dissolved in DCM (2 mL), and TFA (0.5 mL) was added. The resulting mixture was stirred at room temperature for 1 hour. DCM (20 mL) was added to the reaction mixture, and the pH was adjusted to >7 with Na₂CO₃ aqueous solution. Extraction was performed using DCM. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (water / acetonitrile = 95% / 5%-10% / 90%), and lyophilized to give compound 97 (6.2 mg, 25% yield, white solid).

[0447] LC-MS (ESI) + ): 484.2 m / z [M+H] + .

[0448] 1 H NMR (400MHz, DMSO-d6) δ10.15(s,1H),9.28(s,1H),7.98–7.88(m,3H),7.61(d,J=5.6Hz,1H),7.41–7.35(m,2 H), 4.69 (s, 2H), 3.47 (s, 4H), 2.75 (t, J = 6.8Hz, 6H), 2.02–1.73 (m, 5H), 1.73–1.51 (m, 2H), 1.46–1.30 (m, 1H).

[0449] The following compounds were synthesized using the corresponding starting materials according to the method of Example 97:

[0450] Example 102: (R)-4-((2'H-3'-oxa-4',8',10',10b'-tetraazaspiro[cyclohexane-1,1'-fluoranthene]-3a',3a 1 Synthesis of (6a'),5',6b',8',10'-hexene-9'-yl)amino)-N-(1-methylpiperidin-3-yl)benzenesulfonamide (102)

[0451] Step 1: Synthesis of (R)-3-((4-iodophenyl)sulfonamido)piperidine-1-carboxylic acid tert-butyl ester (102-2)

[0452] At room temperature, (R)-1-tert-butoxycarbonyl-3-aminopiperidine (348 mg, 1.74 mmol) and TEA (500 mg, 4.96 mmol) were added to a solution of 4-iodobenzenesulfonyl chloride (1-2-1, 500 mg, 1.65 mmol) in dichloromethane (8 mL), and the mixture was stirred for 4 hours. The reaction solution was diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted again with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtrate was collected and the solvent was removed under reduced pressure to give compound 102-2 (794 mg, 100% yield, white solid).

[0453] LC-MS (ESI) + ): m / z 411.0, [M- t Bu+H] + 489.0, [M+Na] + .

[0454] Following the route method of Example 97, compound 102-3 was synthesized by replacing compound 97-2 with compound 102-2. Compound 102 was synthesized using compound 102-3 according to step 1 of Example 93.

[0455] LC-MS (ESI) + ): 548.3 m / z [M+H] + .

[0456] 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),9.32(s,1H),8.04(d,J=8.9Hz,2H),7.97(d,J= 5.5Hz,1H),7.77(d,J=8.9Hz,2H),7.63(d,J=5.5Hz,1H),7.58(d,J=7.4Hz,1H),4.71 (s,2H),3.01(s,1H),2.82–2.68(m,2H),2.61–2.55(m,1H),2.49–2.44(m,1H),2.06( s,3H),1.98–1.59(m,10H),1.58–1.47(m,2H),1.45–1.21(m,2H),1.11–0.96(m,1H).

[0457] Example 103: 4-((2'H-3'-oxa-4',8',10',10b'-tetraazaspiro[cyclohexane-1,1'-fluoranthene]-3a',3a 1 Synthesis of '(6a'),5',6b',8',10'-hexene-9'-yl)amino)benzenesulfonamide (103)

[0458] Step 1: Preparation of (4-iodophenyl)sulfonyl)carbamate tert-butyl ester (103-2)

[0459] 4-Iodobenzenesulfonamide (103-1, 0.1 g, 0.35 mmol) was dissolved in DCM (2 mL), and DIEA (0.13 g, 1.0 mmol), DMAP (4 mg, 0.03 mmol), and Boc2O (0.15 g, 0.7 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 1 hour. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with DCM (100 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 103-2 (0.13 g, 96% yield, white solid).

[0460] LC-MS (ESI) + ): 383.9 m / z [M+H] + .

[0461] Compound 103 was synthesized by replacing compound 97-2 with compound 103-2 according to the method of Example 97.

[0462] LC-MS (ESI) + ): 451.2 m / z [M+H] + .

[0463] 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),9.31(s,1H),8.09–8.00(m,2H),7.96(d,J=5.6Hz,1H),7.84–7.75(m,2H),7.62(d,J=5 .6Hz,1H),7.24(s,2H),4.71(s,2H),2.76(td,J=13.6,4.4Hz,2H),2.00–1.75(m,5H),1.73–1.55(m,2H),1.46-1.26(m,1H).

[0464] Example 104: 1-(6-((2'H-3'-oxa-4',8',10',10b'-tetraazaspiro[cyclohexane-1,1'-fluoranthene]-3a',3a 1 Synthesis of '(6a'),5',6b',8',10'-hexene-9'-yl)amino)pyridin-3-yl)-4-(dimethylamino)piperidin-2-one (104)

[0465] Step 1: Synthesis of (1-((5-bromo-2-chloropyrimidin-4-yl)amino)cyclohexyl)methanol (104-1)

[0466] At room temperature, diisopropylethylamine (2 mL) was added to a 1,4-dioxane solution (10 mL) of compound 47-1 (1 g, 4.4 mmol) and (1-aminocyclohexyl)methanol (850 mg, 6.6 mmol). The reaction mixture was stirred at 100 °C for 12 hours. After the reaction was complete, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to give compound 104-1 (700 mg, 50% yield).

[0467] LC-MS (ESI) + ): 321.2 m / z [M+H] + .

[0468] Step 2: Synthesis of (1-((2-chloro-5-(3-chloro-2-fluoropyridin-4-yl)pyrimidin-4-yl)amino)cyclohexyl)methanol (104-2)

[0469] At room temperature, (3-chloro-2-fluoropyridin-4-yl)boronic acid (426 mg, 2.4 mmol), [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (120 mg, 0.19 mmol), and potassium fluoride (326 mg, 5.6 mmol) were added to a mixed solvent of 1,4-dioxane solution (10 mL) and water (3 mL) of compound 104-1 (600 mg, 1.9 mmol). The reaction mixture was stirred at 100 °C for 1 hour under a nitrogen atmosphere. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to give compound 104-2 (600 mg, 86% yield).

[0470] LC-MS (ESI) + ): 372.2 m / z [M+H] + .

[0471] Step 3: Synthesis of (1-(6-((2H-spiro[3-oxa-4,8,10,10b-tetraazafluoranthene-1,1'-cyclohexane]-9-yl)amino)pyridin-3-yl)-2-oxoperidin-4-yl)tert-butyl carbamate (104-3)

[0472] At room temperature, tert-butyl 1-(6-aminopyridin-3-yl)-2-oxopiperidin-4-yl)carbamate (165 mg, 0.54 mmol), tris(dibenzylacetone)palladium (45 mg, 0.05 mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (50 mg, 0.1 mmol), and cesium carbonate (700 mg, 2 mmol) were added to a 5 mL solution of dioxane containing compound 104-2 (200 mg, 0.54 mmol). The reaction mixture was stirred at 100 °C for 12 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 10) to give compound 104-3 (100 mg, 32% yield).

[0473] LC-MS (ESI) + ):315.2m / z[M+H] + .

[0474] Step 4: Synthesis of 1-(6-((2H-spiro[3-oxa-4,8,10,10b-tetraazafluoranthene-1,1'-cyclohexane]-9-yl)amino)pyridin-3-yl)-4-aminopiperidin-2-one (104-4)

[0475] At room temperature, 0.2 mL of trifluoroacetic acid was added to a 1 mL solution of compound 104-3 (100 mg, 0.17 mmol) in dichloromethane. The reaction mixture was stirred at 25 °C for 1 hour until the starting material disappeared. After the reaction was complete, the reaction mixture was concentrated to dryness under reduced pressure to give compound 104-4 (80 mg, 96% yield).

[0476] LC-MS (ESI) + ): 485.2m / z [M+H] + .

[0477] Step 5: 1-(6-((2'H-3'-oxa-4',8',10',10b'-tetraazaspiro[cyclohexane-1,1'-fluoranthene]-3a',3a 1 Synthesis of '(6a'),5',6b',8',10'-hexene-9'-yl)amino)pyridin-3-yl)-4-(dimethylamino)piperidin-2-one (104)

[0478] At room temperature, formaldehyde aqueous solution (0.1 mL, 33%) and sodium triacetoxyborohydride (70 mg, 0.3 mmol) were added to a methanol solution (1 mL) of compound 104-4 (80 mg, 0.16 mmol). The reaction mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 10) to give compound 104 (20.3 mg, yield 24%).

[0479] LC-MS (ESI) + ): 513.4m / z [M+H] + .

[0480] 1 H NMR (400MHz, DMSO-d6) δ10.24(s,1H),9.33(s,1H),8.37(d,J=8.8Hz,1H),8.27(s,1 H),7.98(d,J=5.4Hz,1H),7.77(d,J=7.2Hz,1H),7.66(d,J=5.4Hz,1H),4.72(s,2H) ,2.80-2.74(m,3H),2.61-2.56(m,1H),2.47-2.41(m,1H),2.25(s,6H),2.16-2.07( m,1H),1.96-1.93(m,2H),1.88-1.77(m,4H),1.66-1.62(m,2H),1.42-1.32(m,1H).

[0481] The following compounds were synthesized using the corresponding starting materials according to the method of Example 104:

[0482] Example 124: Synthesis of N-(1-(methanesulfonyl)piperidin-4-yl)-2-(tetrahydrofuran-3-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-9-amine (124)

[0483] Following the steps of Example 92, compound 92-1 was synthesized by replacing compound 92-1 with tetrahydrofuran-3-carboxaldehyde (compound 124-1). Then, following the method of Example 1, compound 124 was synthesized by replacing 2-amino-1-phenylethyl-1-ol with compound 124-3.

[0484] LC-MS (ESI) + ): 459.2 m / z [M+H]+ .

[0485] 1 H NMR (400MHz, DMSO-d6) δ9.04(s,1H),7.87(dd,J=4.0,2.0Hz,1H),7.60(s,1H),7.48(d,J=8.0Hz,1H),4.53(t,J=8.0Hz,2H),4.04(s,1H),3.98-3.6 6(m,5H),3.56-3.53(m,2H),2.96-2.88(m,5H),2.77-2.72(m,1H),2.19- 2.07(m,1H),2.00-1.97(m,2H),1.88(s,1H),1.64-1.56(d,J=8.0Hz,2H).

[0486] The following compounds were synthesized using the corresponding starting materials according to the method described in Example 124:

[0487] Example 126: Synthesis of 2-(1-methylcyclopropyl)-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (126)

[0488] (1-Methylcyclopropyl)methanol (126-1, 1 g, 11.6 mmol) was dissolved in dichloromethane (20 mL) under ice bath conditions, and pyridinium chlorochromate (3.75 g, 17.4 mmol) was added. The resulting mixture was stirred at room temperature for 5 hours. After cooling the reaction solution to room temperature, it was quenched with saturated sodium bicarbonate aqueous solution (20 mL) and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 126-2 (900 mg, 92% yield, white solid).

[0489] Compound 126-4 was synthesized by replacing compound 92-1 with compound 126-2 according to the method of Example 92. Compound 126 was synthesized by replacing 2-amino-1-phenylethyl-1-ol with compound 126-4 according to the method of Example 1.

[0490] LC-MS (ESI) + ): 443.2 m / z [M+H] + .

[0491] The following compounds were synthesized using the corresponding starting materials according to the method described in Example 126:

[0492] Example 128: Synthesis of 2-(1-fluoro-2-methylpropyl-2-yl)-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (128)

[0493] Step 1: Preparation of 3-hydroxy-N-methoxy-N,2,2-trimethylpropionamide (128-2)

[0494] At room temperature, 3-hydroxy-2,2-dimethylpropionic acid (128-1, 2 g, 16.9 mmol) was dissolved in N,N-dimethylformamide (20 mL), and N,O-dimethylhydroxylamine (1.5 g, 25.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.8 g, 25.4 mmol), 1-hydroxybenzotriazole (3.4 g, 25.4 mmol), and N,N-diisopropylethylamine (6.5 g, 50.79 mmol) were added. The resulting mixture was stirred at room temperature for 12 hours. After the reaction solution was cooled to room temperature, water (100 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 128-2 (1 g, yield 36%, white solid).

[0495] LC-MS (ESI) +) 162.1 m / z [M+H] + .

[0496] Step 2: Preparation of 3-fluoro-N-methoxy-N,2,2-trimethylpropionamide (128-3)

[0497] Compound 128-2 (1 g, 6.2 mmol) was dissolved in dichloromethane (10 mL) at -78 °C, and diethylaminotrifluoride (1.5 g, 9.3 mmol) was slowly added dropwise at this temperature. The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 128-3 (1 g, 98% yield, white solid).

[0498] LC-MS (ESI) + ): 164.1 m / z [M+H] + .

[0499] Step 3: Preparation of 3-fluoro-2,2-dimethylpropionaldehyde (128-4)

[0500] Compound 128-3 (1 g, 6.1 mmol) was dissolved in tetrahydrofuran (10 mL) under ice bath conditions. Lithium aluminum hydride (349 mg, 9.2 mmol, 2.5 M) was slowly added dropwise at this temperature. The resulting mixture was stirred under ice bath conditions for 1 hour. After cooling to room temperature, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 128-4 (600 mg, 94% yield, white solid).

[0501] LC-MS (ESI) + ): 105.1 m / z [M+H] + .

[0502] Compound 128 was synthesized by replacing compound 126-2 with compound 128-4 according to the method of Example 126.

[0503] LC-MS (ESI) + ): 463.2 m / z [M+H] + .

[0504] 1 H NMR(400MHz, DMSO-d6)δ9.05(s,1H),7.87(d,J=4.0Hz,1H),7.59(s,1H),7.49(d,J=8.0Hz,1H),4.62–4.35(m,4H),4.06 -4.01(m,2H),3.55(d,J=12.0Hz,2H),2.95-2.88(m,5H),1.99(d,J=8.0Hz,2H),1.65-1.57(m,2H),1.16(s,3H),1.14(s,3H).

[0505] Example 129: Synthesis of 2-(3-fluorobicyclo[1.1.1]pent-1-yl)-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-9-amine (129) (10158)

[0506] Compound 129 was synthesized by replacing compound 128-1 with 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (129-1) according to steps 1 and 3 of Example 128 and the method of Example 126.

[0507] LC-MS (ESI) + ): 499.1 m / z [M+H] + .

[0508] The following compounds were synthesized using the corresponding starting materials according to the method described in Example 129:

[0509] Example 131: Synthesis of 1-methyl-N-(1-(methanesulfonyl)piperidin-4-yl)-1-phenyl-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-9-amine (131)

[0510] Step 1: Preparation of 3,3,3-trifluoro-2,2-dimethylprop-1-ol (131-2)

[0511] Under ice bath conditions, 3,3,3-trifluoro-2,2-dimethylpropionic acid (131-1, 1.5 g, 9.6 mmol) was dissolved in THF (15 mL). Under a nitrogen atmosphere, a THF solution of LiAlH4 (7.68 mL, 19.2 mmol, 2.5 mmol / L) was added dropwise at 0 °C. After the addition was complete, the mixture was slowly brought to room temperature and stirred for 2 h. Sodium sulfate decahydrate (540 mg, 3.84 mmol / L) was added to the reaction solution at 0 °C, and the mixture was stirred at room temperature for 2 h. The mixture was then filtered, and the filter cake was washed with (DCM:MeOH = 10:1) (10 mL × 3). The filtrate was concentrated under reduced pressure and used directly in the next reaction step.

[0512] Step 2: Preparation of 3,3,3-trifluoro-2,2-dimethylpropanal (131-3)

[0513] Under ice bath conditions, the crude product from the previous step was dissolved in DCM (15 mL), and DMP (4.8 g, 11.52 mmol) was added at 0 °C. After the addition was complete, the mixture was brought to room temperature and stirred for 2 h. Saturated Na2SO3 solution and saturated Na2CO3 solution were added to the reaction solution at 0 °C, and the mixture was stirred before DCM extraction. The solution was dried, concentrated under reduced pressure, and the crude product was used directly in the next reaction step.

[0514] Step 3: Preparation of 4,4,4-trifluoro-2-hydroxy-3,3-dimethylbutyronitrile (131-4)

[0515] Under ice bath conditions, the crude product from the previous step was dissolved in DMSO (15 mL) / H2O (3 mL), and TMSCN (1.24 g, 12.48 mmol) was added at 0 °C. After the addition was complete, the temperature was raised to 50 °C and stirred for 12 h. The reaction solution was quenched with water at 0 °C, extracted with ethyl acetate, dried, concentrated under reduced pressure, and the residue was used directly in the next reaction step.

[0516] Step 4: Preparation of 1-amino-4,4,4-trifluoro-3,3-dimethylbutane-2-ol (131-5)

[0517] Under ice bath conditions, the crude product from the previous step was dissolved in anhydrous THF (15 mL), and a LiAlH4 THF solution (7.68 mL, 19.2 mmol, 2.5 mmol / L) was added dropwise at 0 °C. After the addition was complete, the mixture was slowly brought to room temperature and stirred for 2 h. Sodium sulfate decahydrate (540 mg, 3.84 mmol / L) was added to the reaction solution at 0 °C, and the mixture was stirred at room temperature for 2 h. The mixture was then filtered, and the filter cake was washed with DCM:MeOH = 10:1 (10 mL × 3). The filtrate was concentrated under reduced pressure, and the crude product (730 mg) was used directly in the next reaction step.

[0518] LC-MS (ESI) + ): 172.1 m / z [M+H] + .

[0519] Following the method of Example 47, compound 131 was synthesized by replacing (S)-2-amino-1-phenylethyl-1-ol with compound 131-5.

[0520] LC-MS (ESI) + ): 499.1 m / z [M+H] + .

[0521] 1 H NMR (400MHz, DMSO-d6) δ9.09(s,1H),7.91(d,J=5.6Hz,1H),7.65(s,1H),7.54(d,J=5.6Hz,1H),4.77(d,J=9.2Hz,1H),4.53 (s,1H),4.19–4.04(m,2H),3.57(d,J=12.0Hz,2H),2.94-2.91(m,5H),2.02(s,2H),1.64(s,2H),1.42(s,3H),1.38(s,3H).

[0522] Example 132: Synthesis of 2-methyl-N-(1-(methanesulfonyl)piperidin-4-yl)-2-(2,2,2-trifluoroethyl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (132)

[0523] Following the method of Example 131, compound 132 was synthesized by replacing compound 131-3 with compound 4,4,4-trifluorobut-2-one (132-1).

[0524] LC-MS (ESI) + ): 485.1 m / z [M+H]+ .

[0525] 1 H NMR(400MHz,DMSO-d6)δ9.08(s,1H),7.94(d,J=5.2Hz,1H),7.70(s,1H),7.53(d,J=5.2Hz,1H), 4.24(s,2H),4.07(s,1H),3.58(d,J=11.6Hz,2H),3.09–2.91(m,7H),2.01(s,2H),1.60(m,5H).

[0526] The following compounds were synthesized using the corresponding starting materials according to the method described in Example 132:

[0527] Example 136: Synthesis of 2-(bicyclo[2.2.2]octane-1-yl)-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-9-amine (136)

[0528] Following the method of Example 131, compound 136-5 was synthesized by replacing compound 131-1 with bicyclo[2.2.2]octane-1-carboxylic acid (compound 136-1). Then, following the method of Example 1, compound 136 was synthesized by replacing 2-amino-1-phenylethyl-1-ol with compound 136-5.

[0529] LC-MS (ESI) + ): 497.1 m / z [M+H] + .

[0530] 1 H NMR(400MHz, DMSO-d6)δ9.04(s,1H),7.86(d,J=5.6Hz,1H),7.58(s,1H),7.46(d,J=5.6Hz,1H),4.38(s,1H),4.16(d,J=9.6Hz,1H), 4.05(s,1H),3.93(d,J=12.0Hz,1H),3.56(d,J=12.0Hz,2H),2.95-2.89(m,5H),1.99(s,2H),1.75-1.73(m,3H),1.66–1.54(m,12H).

[0531] Example 137: Synthesis of 2-(tert-butyl)-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-1,1-d2-9-amine (137)

[0532] At 0 °C, LiAlD4 (245 mg, 5.83 mmol) was added to an anhydrous THF (4.0 mL) solution of 2-hydroxy-3,3-dimethylbutyronitrile (137-1, 330 mg, 2.92 mmol). The mixture was stirred at room temperature for 5 hours. Na2SO4·10H2O (3.6 g) was added to the mixture at room temperature. The mixture was filtered, and the filtrate was concentrated to give compound 137-2 (340 mg, 98% yield).

[0533] LC-MS (ESI+): 120.2 m / z [M+H] + .

[0534] According to the method of Example 47, compound 137 was synthesized by replacing (S)-2-amino-1-phenylethyl-1-ol with compound 137-2.

[0535] LC-MS (ESI) + ): 447.2 m / z [M+H] + .

[0536] 1 H NMR (400MHz, DMSO-d6) δ9.05(s,1H),7.87(d,J=5.6Hz,1H),7.65–7.53(m,1H),7.48(d,J=5.6Hz,1H),4.26(s,1 H),4.20–3.93(m,1H),3.67–3.47(m,2H),3.05–2.83(m,5H),2.08–1.92(m,2H),1.72–1.52(m,2H),1.15(s,9H).

[0537] Example 138: Synthesis of 2-(tert-butyl)-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-2d-9-amine (138)

[0538] Step 1: Synthesis of 2,2-dimethylprop-1,1-d2-1 alcohol (138-2)

[0539] At 0 °C, LiAlD4 (723 mg, 17.2 mmol) was added to methyl neopentanoate (138-1, 1000 mg, 8.61 mmol) in anhydrous THF (6.0 mL). The mixture was stirred at room temperature for 3 hours. Sodium sulfate decahydrate (4500 mg) was added to the mixture at room temperature. The mixture was filtered, and the filtrate was concentrated to give compound 138-2 (crude product, 800 mg, 100% yield).

[0540] Step 2: Synthesis of 2,2-dimethylpropionaldehyde-1-d(138-3)

[0541] At room temperature, PCC (5.74 g, 26.6 mmol) was added to a solution of compound 138-2 (800 mg, 8.87 mmol) in DCM (6.0 mL). The resulting mixture was stirred at room temperature for 10 hours. The reaction mixture was filtered, and the filtrate was concentrated at low temperature (10 °C) to give compound 138-3 (crude product, 700 mg, 90% yield, oily).

[0542] According to the method of Example 47, compound 138 was synthesized by replacing (S)-2-amino-1-phenylethyl-1-ol with compound 138-3.

[0543] LC-MS (ESI) + ): 446.2 m / z [M+H] + .

[0544] 1 H NMR(400MHz, DMSO-d6)δ9.05(s,1H),7.87(d,J=5.6Hz,1H),7.67–7.51(m,1H),7.47(d,J=5.6Hz,1H),4.50–4.38(m,1H),4.1 1–4.00(m,1H),3.97–3.85(m,1H),3.59–3.49(m,2H),2.96–2.84(m,5H),2.07–1.93(m,2H),1.68–1.53(m,2H),1.15(s,9H).

[0545] Example 139: Synthesis of 4-(9-((1-(methanesulfonyl)piperidin-4-yl)amino)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-2-yl)benzonitrile (139)

[0546] Step 1: Preparation of 4-glycerobenzonitrile (139-2)

[0547] Under ice bath conditions, tert-butyl (2-(4-cyanophenyl)-2-oxoethyl)carbamate (139-1, 500 mg, 1.92 mmol) was dissolved in DCM (10 mL), and 4 M HCl (2 mL) was slowly added at 0 °C. The resulting reaction solution was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure to give compound 139-2 (hydrochloride, 0.5 g, 100% yield, white solid).

[0548] LC-MS (ESI) + ): 161.0 m / z [M+H] + .

[0549] Step 2: Preparation of 4-(2-amino-1-hydroxyethyl)benzonitrile (139-3)

[0550] Compound 139-2 (0.5 g, 3.12 mmol) was dissolved in MeOH (15 mL), and sodium borohydride (0.17 g, 4.68 mmol) was slowly added at 0 °C. The resulting reaction solution was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction solution, and the mixture was extracted with DCM (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 139-3 (450 mg, 90% yield, white solid).

[0551] LC-MS (ESI) + ):163.0m / z[M+H] + .

[0552] Following the method of Example 1, compound 139 was synthesized by replacing 2-amino-1-phenylethyl-1-ol with compound 139-3.

[0553] LC-MS (ESI) + ): 490.0 m / z [M+H] + .

[0554] 1 H NMR(400MHz,DMSO-d6)δ9.09(s,1H),7.98(d,J=8.0Hz,2H),7.95(d,J=5.6Hz ,1H),7.84(d,J=8.0Hz,2H),7.67(s,1H),7.56(d,J=5.6Hz,1H),5.82(dd,J= 9.0,2.8Hz,1H),4.70(s,1H),4.21(dd,J=12.6,9.2Hz,1H),4.03(s,1H),3.5 5(d,J=12.0Hz,2H),2.94–2.84(m,5H),2.00–1.96(m,2H),1.65–1.55(m,2H).

[0555] Example 140: 2-(4-(methanesulfonyl)phenyl)-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (140)

[0556] Following the method of Example 139, compound 140 was synthesized by replacing compound 139-2 with 2-amino-1-(4-(methanesulfonyl)phenyl)ethyl-1-one.

[0557] LC-MS (ESI) + ): 543.0 m / z [M+H] + .

[0558] 1 H NMR (400MHz, DMSO-d6) δ9.09 (s, 1H), 8.05 (d, J = 8.0Hz, 2H), 7.95 (d, J = 5.6Hz ,1H),7.91(d,J=8.0Hz,2H),7.67(s,1H),7.57(d,J=5.6Hz,1H),5.86(dd,J=9 .0,2.8Hz,1H),4.71(s,1H),4.26-4.23(m,1H),4.02(s,1H),3.55(d,J=12.0H z,2H),3.26(s,3H),2.91-2.87(m,5H),2.00-1.97(m,2H),1.65-1.58(m,2H).

[0559] Example 141: Synthesis of 2-(2-chloro-4-fluorophenyl)-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (141)

[0560] Step 1: Preparation of 2-bromo-1-(2-chloro-4-fluorophenyl)ethane-1-ol (141-2)

[0561] Under ice bath conditions, sodium borohydride (185 mg, 4.90 mmol) was slowly added to a MeOH (8 mL) solution of 2-bromo-1-(2-chloro-4-fluorophenyl)ethyl-1-one (141-1, 880 mg, 3.5 mmol), and the mixture was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 141-2 (940 mg, yield >100%, colorless oil).

[0562] Step 2: Preparation of 2-amino-1-(2-chloro-4-fluorophenyl)ethanol-1-ol (141-3)

[0563] Compound 141-2 (940 mg, 3.5 mmol) was added to a methanol solution of NH3 (6.0 mL), and stirred at room temperature for 16 hours, then at 85 °C for 2 hours. The reaction solution was concentrated under reduced pressure to give compound 141-3 (crude product, 890 mg, white solid).

[0564] LC-MS (ESI) + ): 190.1m / z [M+H] + .

[0565] Following the method of Example 1, compound 141 was synthesized by replacing 2-amino-1-phenylethyl-1-ol with compound 141-3.

[0566] LC-MS (ESI) + ): 517.2 m / z [M+H] + .

[0567] 1 H NMR (400MHz, DMSO-d6) δ9.10 (s, 1H), 8.35 (s, 1H), 7.95 (d, J = 5.5Hz, 1H), 7.81 (s, 1H), 7.67(s,1H),7.64(dd,J=8.8,2.6Hz,1H),7.58(d,J=5.5Hz,1H),7.43(td,J=8.5,2.7H z,1H),5.91(dd,J=9.6,3.0Hz,1H),4.62(s,1H),4.24(s,1H),4.03(s,1H),3.55(d,J= 11.6Hz, 2H), 2.93-2.88 (m, 5H), 1.99 (d, J = 11.9Hz, 2H), 1.60 (q, J = 11.2, 10.2Hz, 2H).

[0568] Example 142: Synthesis of 2-ethyl-1,1-dimethyl-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (142)

[0569] Compound 142-2 was synthesized by replacing phenyl magnesium bromide with ethyl magnesium bromide according to the method of Example 39. Then, compound 142 was synthesized by replacing (S)-2-amino-1-phenylethyl-1-ol with compound 142-2 according to the method of Example 47.

[0570] LC-MS (ESI) +): 445.1 m / z [M+H] + .

[0571] 1 H NMR (400MHz, DMSO-d6) δ9.06(s,1H),7.89(d,J=5.4Hz,1H),7.66(s,1H),7.50(d,J=5.4Hz,1H),4.24(d,J=9.2Hz,1H),3.90(s,1H ), 3.58 (d, J = 12.0Hz, 2H), 2.98-2.91 (m, 5H), 2.07 (s, 2H), 1.94 (s, 4H), 1.63 (d, J = 8.0Hz, 3H), 1.43 (s, 3H), 1.17 (t, J = 7.2Hz, 3H).

[0572] The following compounds were synthesized using the corresponding starting materials according to the method of Example 142:

[0573] Example 144: Synthesis of 2-((methylamino)methyl)-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (144)

[0574] Compound 90-1 (20 mg, 0.04 mmol) was dissolved in acetonitrile (3 mL) at room temperature, and iodomethane (16.4 mg, 0.11 mmol) and potassium carbonate (16 mg, 0.11 mmol) were added. The resulting mixture was stirred in an oil bath at 50 °C for 12 hours. After cooling the reaction solution to room temperature, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 144-1 (20 mg, 97% yield, white solid).

[0575] LC-MS (ESI) + ): 532.2 m / z [M+H] + .

[0576] Compound 144 was synthesized by replacing compound 90-1 with compound 144-1 according to the method of Example 90.

[0577] LC-MS (ESI) + ): 432.2 m / z [M+H] + .

[0578] Examples 145 and 146: Synthesis of (R)-2-ethyl-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthen-9-amine (145) and (S)-2-ethyl-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthen-9-amine (146)

[0579] Compound 17 was resolved chirally (chiral column: AD-3, 0.46 cm × 5 cm; mobile phase: CO2:EtOH (0.05% DEA) = 40:40; flow rate: 2.5 mL / min; column temperature: 25 °C) to give compound A (retention time: 1.42 min), which was randomly defined as -2-Ethyl-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (145) and compound B (retention time: 2.44 min) were randomly defined as (S)-2-ethyl-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (146).

[0580] Compound 145:

[0581] LC-MS (ESI) + ): 417.2 m / z [M+H] + .

[0582] 1H NMR(400MHz, DMSO-d6)δ9.04(s,1H),7.87(d,J=5.5Hz,1H),7.58(s,1H),7.48(d,J=5.5Hz,1H),4.53–4.47(m,2H),4.04–4.02(m,1H),3 .91–3.86(m,1H),3.57–3.53(m,2H),2.95–2.89(m,5H),2.01–1.99(m,2H),1.92–1.85(m,2H),1.65–1.57(m,2H),1.12(t,J=7.4Hz,3H).

[0583] Compound 146:

[0584] LC-MS (ESI) + ): 417.2 m / z [M+H] + .

[0585] 1H NMR(400MHz, DMSO-d6)δ9.04(s,1H),7.87(d,J=5.5Hz,1H),7.58(s,1H),7.47(d,J=5.5Hz,1H),4.53–4.47(m,2H),4.05–4.02(m,1H),3 .91–3.86(m,1H),3.58–3.54(m,2H),2.95–2.89(m,5H),2.01–1.98(m,2H),1.91–1.85(m,2H),1.64–1.56(m,2H),1.12(t,J=7.4Hz,3H).

[0586] Example 147: Synthesis of (R)-2-tert-butyl-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthen-9-amine (147) and (S)-2-tert-butyl-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthen-9-amine (148)

[0587] Compound 88 was chirally resolved (chiral column: AD-3, 0.46 cm × 5 cm; mobile phase: CO2:EtOH (0.05% DEA) = 40:40; flow rate: 2.5 mL / min; column temperature: 25 °C) to give compound C (retention time: 3.62 min), randomly defined as (R)-2-tert-butyl-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthen-9-amine (147) and compound D (retention time: 3.90 min), randomly defined as (S)-2-tert-butyl-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthen-9-amine (148).

[0588] Compound 147:

[0589] LC-MS (ESI) + ): 445.2 m / z [M+H] + .

[0590] 1H NMR (400MHz, DMSO-d6) δ9.05(s,1H),7.87(d,J=5.5Hz,1H),7.59(s,1H),7.48(d,J=5.5Hz,1H),4.45(s,1H),4.27(d,J=10.0Hz,1H),4.09 –4.03(m,1H),3.93(t,J=11.4Hz,1H),3.55(d,J=11.6Hz,2H),2.96–2.89(m,5H),2.00(d,J=10.0Hz,2H),1.64–1.60(m,2H),1.15(s,9H).

[0591] Compound 148:

[0592] LC-MS (ESI) + ): 445.2 m / z [M+H] + .

[0593] 1 H NMR(400MHz, DMSO-d6)δ9.05(s,1H),7.87(d,J=5.5Hz,1H),7.63–7.55(m,1H),7.48(d,J=5.5Hz,1H),4.47(s,1H),4.29(dd,J=10.0,1.4Hz,1H) ,4.13–4.03(m,1H),3.95(t,J=11.4Hz,1H),3.56(d,J=11.6Hz,2H),2.9 6–2.91(m,5H),2.00(d,J=10.0Hz,2H),1.65–1.57(m,2H),1.15(s,9H).

[0594] Example 159: Synthesis of 2-(3,3-dimethylcyclobutyl)-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (159)

[0595] Compound 159 was synthesized by replacing compound 129-1 with compound 159-1 according to the method of Example 129.

[0596] LC-MS (ESI) + ): 471.4 m / z [M+H] + .

[0597] 1H NMR(400MHz, DMSO-d6)δ9.06(s,1H),7.89(d,J=5.6Hz,1H),7.49(d,J=5.6Hz,1H),4.56-4.51(m,1H),4.39-4.36(m,1H),4.07-4.05(m,1H), 3.75-3.72(m,1H),3.59-3.56(m,2H),2.97-2.91(m,5H),2.73-2.71(m ,1H),2.02-1.85(m,6H),1.64-1.61(m,2H),1.21(s,3H),1.13(s,3H).

[0598] The following compounds were synthesized using the corresponding starting materials according to Example 159:

[0599] Example 160: Synthesis of 2-(tert-butyl)-N-((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (160)

[0600] Step 1: Preparation of 2-hydroxy-3,3-dimethylbutyronitrile (160-2)

[0601] Neopentanal 160-1 (6.50 g, 75.4 mmol) was dissolved in chloroform (80 mL), and zinc iodide (62.5 g, 0.196 mmol) and trimethylcyanosilane (8.96 g, 90.5 mmol) were added sequentially at 0 °C, and the mixture was stirred at 0 °C for 2 hours. The reaction solution was concentrated under reduced pressure to give compound 160-2 (8.5 g, 99% yield, colorless oil). The crude product was used directly in the next step.

[0602] Step 2: Preparation of 1-amino-3,3-dimethylbut-2-ol (160-3)

[0603] Compound 160-2 (8.5 g, 75.1 mmol) was dissolved in tetrahydrofuran (100 mL), and LiAlH4 (50.8 mL, 127.7 mmol) was added dropwise at 0 °C, with stirring at 0 °C for 2 hours. The reaction was quenched by slowly adding sodium sulfate decahydrate at 0 °C. After quenching, the reaction solution was filtered through diatomaceous earth, and the filtrate was added to 4 M HCl dioxane (20 mL), stirred for 0.5 h, and then concentrated under reduced pressure to give compound 160-3 (8.0 g, 90% yield, white solid).

[0604] LC-MS (ESI) + ): 118.2m / z [M+H] + .

[0605] Step 3: Preparation of 1-((5-bromo-2-(methylthio)pyrimidin-4-yl)amino)-3,3-dimethyl-2-butanol (160-4)

[0606] Compound 160-3 (6 g, 39.2 mmol) and compound 1-1 (9.4 g, 39.1 mmol) were dissolved in dioxane (60 mL), and DIPEA (10.2 g, 78.4 mmol) was added at room temperature. The mixture was stirred at 100 °C for 3 hours. The reaction solution was concentrated under reduced pressure. Water (40 mL) was added to the reaction solution, and the mixture was extracted with EA (40 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 160-4 (8.6 g, 69% yield, white solid).

[0607] LC-MS (ESI) + ):320.2m / z[M+H] + .

[0608] Step 4: Preparation of 1-((5-(3-chloro-2-fluoropyridin-4-yl)-2-(methylthio)pyrimidin-4-yl)amino)-3,3-dimethyl-2-butanol (160-5)

[0609] Compound 160-4 (8.6 g, 27 mmol), (3-chloro-2-fluoropyridin-4-yl)boronic acid (7.1 g, 40.5 mmol), Pd(dtbpf)Cl2 (1.75 g, 2.7 mmol), and KF (3.2 g, 54 mmol) were dissolved in dioxane (60 mL) and water (15 mL) and stirred at 100 °C for 1 hour. The reaction mixture was concentrated under reduced pressure. Water (40 mL) was added to the reaction mixture, and the mixture was extracted with EA (40 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 160-5 (8 g, 80% yield, white solid).

[0610] LC-MS (ESI) + ):371.2m / z[M+H] + .

[0611] Step 5: Preparation of 2-(tert-butyl)-9-(methylthio)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene (160-6)

[0612] Compound 160-5 (2.8 g, 7.56 mmol), XPhos-Pd-G3 (680 mg, 0.8 mmol), and Cs₂CO₃ (12.3 g, 37.8 mmol) were dissolved in dioxane (30 mL) and stirred at 120 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. Water (40 mL) was added to the reaction mixture, and the mixture was extracted with EA (40 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 5) to give compound 160-6 (1.7 g, 71% yield, white solid).

[0613] LC-MS (ESI) + ):315.2m / z[M+H] + .

[0614] Step 6: Preparation of 2-(tert-butyl)-9-(methyl sulfoxide)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene (160-7)

[0615] Compound 160-6 (700 mg, 2.23 mmol) was dissolved in dichloromethane (10 mL), and m-CPBA (500 mg, 2.45 mmol) was added at 0 °C. The mixture was then transferred to room temperature and stirred for 1 hour. Sodium sulfite aqueous solution (5 mL) and sodium bicarbonate aqueous solution (5 mL) were added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was not purified to give crude compound 160-7 (730 mg, white solid).

[0616] LC-MS (ESI) + ):331.2m / z[M+H] + .

[0617] Step 7: Preparation of (3R,4R)-4-((2-(tert-butyl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-9-yl)amino)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (160-8)

[0618] Compound 160-7 (730 mg, 2.23 mmol), (3R,4R)-4-amino-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (972 mg, 4.46 mmol), and DIPEA (576 mg, 4.46 mmol) were dissolved in dimethyl sulfoxide (10 mL) and stirred at 120 °C for 16 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give compound 160-8 (550 mg, 51% yield, white solid).

[0619] LC-MS (ESI) + ): 485.2m / z [M+H] + .

[0620] Step 8: Preparation of 2-(tert-butyl)-N-((3R,4R)-3-fluoropiperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (160-9)

[0621] Compound 160-8 (1.4 g, 2.9 mmol) was dissolved in dichloromethane (7 mL), and TFA (7 mL) was added at 0 °C. The mixture was then transferred to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure. Dichloromethane was added, followed by an aqueous sodium bicarbonate solution (10 mL), and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give compound 160-9 (1 g, 90% yield, white solid).

[0622] LC-MS (ESI) + ):385.2m / z[M+H] + .

[0623] Step 9: Preparation of 2-(tert-butyl)-N-((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (160)

[0624] Compound 160-9 (1 g, 2.6 mmol) was dissolved in dichloromethane (10 mL), and DIPEA (672 mg, 5.2 mmol) and Ms₂O (498 mg, 2.86 mmol) were added at 0 °C. The mixture was then stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) and prep-HPLC (water / acetonitrile = 95% / 5%-10% / 90%, gradient elution) to give compound 160 (592 mg, 49% yield, white solid).

[0625] LC-MS (ESI) + ):463.2m / z[M+H] + .

[0626] The following compounds were synthesized using the corresponding starting materials according to the method described in Example 160:

[0627] Examples 161 and 162: Synthesis of (S)-2-(tert-butyl)-N-((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthen-9-amine (161) and (R)-2-(tert-butyl)-N-((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthen-9-amine (162)

[0628] Compound 160 was chirally resolved (chiral column: OD-3, 0.46 cm × 5 cm; mobile phase: CO2:EtOH (0.05% DEA) = 70:30; flow rate: 2.5 mL / min; column temperature: 25 °C) to give fraction 1 (retention time: 2.872 min), randomly defined as (S)-2-(tert-butyl)-N-((3R,4R)-3-fluoro-1-(methanesulfonyl)piperidine-4- (R)-2-(tert-butyl)-N-((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (161) and fraction 2 (retention time: 2.998 min), randomly defined as (R)-2-(tert-butyl)-N-((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (162).

[0629] Compound 161:

[0630] LC-MS (ESI) + ):m / z 463.2,[M+H] + .

[0631] 1 H NMR (400MHz, DMSO-d6) δ9.07 (s, 1H), 7.88 (d, J = 5.5Hz, 1H), 7.76 (s, 1H), 7.49 (d, J = 5. 5Hz,1H),4.70(d,J=47.7Hz,1H),4.44(d,J=38.5Hz,2H),4.27(dd,J=10.3,2.7Hz,1H) ,3.95(dd,J=12.6,10.3Hz,1H),3.79–3.67(m,1H),3.52–3.46(m,1H),3.22–3.16(m,1 H),3.14–3.07(m,1H),2.96(s,3H),2.16–2.04(m,1H),1.75–1.60(m,1H),1.15(s,9H).

[0632] Compound 162:

[0633] LC-MS (ESI) + ):m / z 463.2,[M+H] + .

[0634] 1H NMR (400MHz, DMSO-d6) δ9.10 (s, 1H), 7.91 (d, J = 5.5Hz, 1H), 7.78 (s, 1H), 7.52 (d, J = 5 .5Hz,1H),4.73(d,J=47.4Hz,1H),4.57–4.37(m,2H),4.30(dd,J=10.3,2.7Hz,1H),3 .98(dd,J=12.6,10.3Hz,1H),3.80–3.70(m,1H),3.55–3.51(m,1H),3.25–3.21(m,1H ),3.18–3.11(m,1H),2.99(s,3H),2.18–2.03(m,1H),1.77–1.61(m,1H),1.18(s,9H).

[0635] Example 163: Synthesis of (3R,4R)-4-((2-(tert-butyl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-9-yl)amino)-1-(methylsulfonyl)piperidine-3-ol (163)

[0636] Step 1: Preparation of (3R,4R)-4-((2-(tert-butyl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluorene-9-yl)amino)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (163-1)

[0637] Compound 160-7 (50 mg, 0.15 mmol), (3R,4R)-4-amino-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (49 mg, 0.22 mmol), and DIPEA (58 mg, 0.46 mmol) were dissolved in dimethyl sulfoxide (2 mL) and stirred at 100 °C for 16 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give compound 163-1 (30 mg, 41% yield, white solid).

[0638] LC-MS (ESI) + ): 483.2m / z [M+H] + .

[0639] Step 2: Preparation of (3R,4R)-4-((2-(tert-butyl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-9-yl)amino)piperidin-3-ol (163-2)

[0640] Compound 163-1 (30 mg, 0.062 mmol) was dissolved in dichloromethane (1 mL), and TFA (0.5 mL) was added at 0 °C. The mixture was then transferred to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure. Dichloromethane was added, followed by an aqueous sodium bicarbonate solution (10 mL), and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give compound 163-2 (20 mg, 84% yield, white solid).

[0641] LC-MS (ESI) + ):383.2m / z[M+H] + .

[0642] Step 3: Preparation of (3R,4R)-4-((2-(tert-butyl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluorene-9-yl)amino)-1-(methanesulfonyl)piperidine-3-ol (163)

[0643] Compound 163-2 (20 mg, 0.052 mmol) was dissolved in dichloromethane (2 mL), and DIPEA (20 mg, 0.157 mmol) and Ms2O (10 mg, 0.052 mmol) were added at 0 °C. The mixture was then stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction mixture, and the solution was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) and prep-HPLC (water / acetonitrile = 95% / 5%-10% / 90%, gradient elution) to give compound 163 (14.8 mg, 61% yield, white solid).

[0644] LC-MS (ESI) + ):461.2m / z[M+H] + .

[0645] 1 H NMR(400MHz, DMSO-d6)δ9.20(s,1H),7.99(d,J=5.6Hz,1H),7.61(d,J=5.6Hz,1H),4.38(d,J=9.6Hz,2H),4.08-3.93(m,3H ),3.66(d,J=10.0Hz,3H),3.56(s,1H),2.93(s,3H).2.77-2.64(m,1H),2.17-2.04(m,1H),1.71-1.52(m,1H),1.17(s,9H).

[0646] The following compounds were synthesized using the corresponding starting materials according to the method described in Example 163:

[0647] Example 164: Synthesis of 2-(5-fluoropyridin-2-yl)-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (164)

[0648] Steps 1 to 6 are performed according to the method of Example 160, except that 5-fluoropyridine-2-aldehyde is used instead of 160-1, wherein step 5 is performed using Pd-Peppsi- i Compound 164-7 was synthesized using HeptCl as a catalyst.

[0649] Step 7: Following Step 1 of Example 163, compound 164 was synthesized by replacing compound 160-7 with compound 164-7.

[0650] LC-MS (ESI) + ): 484.1 m / z [M+H] + .

[0651] The following compounds were synthesized using the corresponding starting materials according to the method described in Example 164:

[0652] Example 165: Synthesis of 9,13,13-trimethyl-N-(1-(methanesulfonyl)piperidin-4-yl)-8a,9,10,11,12,12a-hexahydro-8-oxa-1,3,7,12b-tetraaza-9,12-methylbenzo[a]acetylanthraene-2-amine (165)

[0653] Following the synthesis method of Example 1, 3-amino-1,7,7-trimethylbicyclo[2.2.1]heptane-2-ol (purchased from...) was used. ) replaces 2-amino-1-phenylethyl-1-ol in step 1, wherein step 3 is carried out according to step 5 of Example 160, and the catalyst is XPhos-Pd-G3 or Pd-Peppsi- i HeptCl, with cesium carbonate as the base, was used to synthesize compound 165.

[0654] LC-MS (ESI) + ): 497.0 m / z [M+H] + .

[0655] The following compounds were synthesized using the corresponding starting materials according to steps 7-9 of Examples 165 and 160 and the method of Example 163:

[0656] Example 347: Synthesis of 2-(tert-butyl)-N-((3R,4R)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (346)

[0657] Following the method of Example 160, in step 7, (3R,4R)-4-amino-3-methylpiperidine-1-carboxylic acid tert-butyl ester was used instead of (3R,4R)-4-amino-3-fluoropiperidine-1-carboxylic acid tert-butyl ester to synthesize compound 347.

[0658] LC-MS (ESI) + ):459.2m / z[M+H] + .

[0659] Examples 348 and 349: Synthesis of (S)-2-(tert-butyl)-2-methyl-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthen-9-amine (348) and (R)-2-(tert-butyl)-2-methyl-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthen-9-amine (349)

[0660] Compound 266 was chirally resolved (chiral column: AD-3, 0.46 cm × 5 cm; mobile phase: CO2:EtOH (0.05% DEA) = 70:30; flow rate: 2.5 mL / min; column temperature: 25 °C) to give fraction 1 (retention time: 2.850 min), randomly defined as (S)-2-(tert-butyl)-2-methyl-N-(1-(methanesulfonyl)piperidine-4- (R)-2-(tert-butyl)-2-methyl-N-(1-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (348) and fraction 2 (retention time: 3.270 min), randomly defined as (R)-2-(tert-butyl)-2-methyl-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (349).

[0661] Compound 348:

[0662] LC-MS (ESI) + ):459.2m / z[M+H] + .

[0663] 1 H NMR(400MHz, DMSO-d6)δ9.04(s,1H),7.88(d,J=5.5Hz,1H),7.71–7.48(m,1H),7.46(d,J=5.5Hz,1H),4.29–4 .00(m,3H),3.63–3.46(m,2H),2.99–2.82(m,5H),2.04–1.93(m,2H),1.69–1.53(m,2H),1.21–1.13(m,12H).

[0664] Compound 349:

[0665] LC-MS (ESI) + ):459.2m / z[M+H] + .

[0666] 1 H NMR(400MHz, DMSO-d6)δ9.04(s,1H),7.88(d,J=5.5Hz,1H),7.71–7.49(m,1H),7.46(d,J=5.5Hz,1H),4.32–3 .99(m,3H),3.61–3.49(m,2H),3.00–2.83(m,5H),2.05–1.93(m,2H),1.74–1.53(m,2H),1.21–1.12(m,12H).

[0667] Example 350: Synthesis of N-(1-(methanesulfonyl)piperidin-4-yl)-2-(4-(1-(trifluoromethyl)-1H-pyrazol-4-yl)phenyl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (350)

[0668] Step 1: Preparation of tert-butyl (2-(4-bromophenyl)-2-oxoethyl)carbamate (350-1)

[0669] Compound 350-1 (3000 mg, 14 mmol) was dissolved in DCM (50 mL), and DIEA (5.42 g, 42 mmol) and di-tert-butyl dicarbonate (3.67 g, 16.8 mmol) were added. The mixture was stirred at room temperature for 2 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with EA (100 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 350-2 (4 g, 90% yield, yellow oil).

[0670] LC-MS (ESI) + ):314.1 316.1m / z[M+H] + .

[0671] Step 2: Preparation of tert-butyl (2-(4-bromophenyl)-2-oxoethyl)carbamate (350-3)

[0672] Compound 350-2 (3000 mg, 9.55 mmol) was dissolved in MeOH (50 mL), and NaBH4 (1.72 g, 42.96 mmol) was added. The mixture was stirred at room temperature for 2 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with EA (100 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 97 / 3) to give compound 350-3 (2.2 g, 72% yield, yellow oil).

[0673] LC-MS (ESI) + ):316.1 318.1m / z[M+H] + .

[0674] Step 3: Preparation of tert-butyl (2-hydroxy-2-(4-(1-(trifluoromethyl)-1H-pyrazol-4-yl)phenyl)ethyl)carbamate (350-4)

[0675] Compound 350-3 (2.2 g, 6.98 mmol) was dissolved in 1,4-dioxane / H₂O (50 / 5 mL), and (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1-(trifluoromethyl)-1H-pyrazole (2.2 g, 8.3 mmol), Pd(dppf)Cl₂ (0.51 g, 0.698 mmol), and K₂CO₃ (2.89 g, 20.9 mmol) were added. The resulting mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 97 / 3) to give compound 350-4 (1.5 g, 58% yield, brown solid).

[0676] LC-MS (ESI) + ):372.1m / z[M+H] + .

[0677] Step 4: Preparation of 2-amino-1-(4-(1-(trifluoromethyl)-1H-pyrazol-4-yl)phenyl)ethanol-1-ol (350-5)

[0678] Compound 350-4 (500 mg, 1.34 mmol) was dissolved in dichloromethane (3 mL), and TFA (3 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give compound 350-5 (350 mg, 95% yield, yellow oil).

[0679] LC-MS (ESI) + ):272.1m / z[M+H] + .

[0680] According to Example 164, compound 350 was synthesized by replacing compound 164-3 with 2-amino-1-(4-(1-(trifluoromethyl)-1H-pyrazol-4-yl)phenyl)ethanol-1-ol (350-5).

[0681] LC-MS (ESI) + ):599.2m / z[M+H] + .

[0682] Example 351: Synthesis of (3R,4R)-1-(methanesulfonyl)-4-((2-(4-(1-(trifluoromethyl)-1H-pyrazol-4-yl)phenyl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-9-yl)amino)piperidin-3-ol (351)

[0683] Compound 351-1 was synthesized according to the method of Example 350. Then, compound 351 was synthesized by replacing compound 160-7 with compound 351-1 according to the method of Example 163.

[0684] LC-MS (ESI) + ): 615.2m / z [M+H] + .

[0685] Example 352: Synthesis of 2-(4-((3S,5S)-3,5-dimethylpiperazin-1-yl)phenyl)-N-(1-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (352)

[0686] Compound 352-1 (300 mg, 2.41 mmol) was dissolved in DMSO (10 mL), and (2S,6S)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (518 mg, 2.41 mmol) and K2CO3 (1 g, 7.25 mmol) were added. The mixture was stirred at 120 °C for 12 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with EA (100 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 352-2 (400 mg, yield 52%, yellow oil).

[0687] LC-MS (ESI) + ):319.2m / z[M+H] + .

[0688] Following the method of Example 164, compound 352-3 was synthesized by replacing compound 164-1 with (2S,6S)-4-(4-formylphenyl)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (352-2). Then, following step 4 of Example 104, compound 352-3 was replaced with compound 104-3, and the mixture was purified by prep-HPLC (water / acetonitrile = 95% / 5%-10% / 90%, gradient elution) to obtain compound 352.

[0689] LC-MS (ESI) + ): 577.2m / z [M+H] + .

[0690] Example 353: Synthesis of 1-methyl-4-(9-(1-(methanesulfonyl)piperidin-4-yl)amino)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-2-yl)cyclohexyl-1-ol (353)

[0691] Following the method of step 1 in Example 39, compound 353-2 was synthesized by replacing compound 39-1 with compound 353-1 and replacing phenyl magnesium bromide with methyl magnesium bromide.

[0692] Following the method in step 2 of Example 131, compound 353-3 was synthesized by replacing compound 131-2 with compound 353-2.

[0693] Following the method of Example 164, compound 353 was synthesized by replacing compound 164-1 with compound 353-3.

[0694] LC-MS (ESI) + ): 501.2m / z [M+H] + .

[0695] Example 354: Synthesis of (3-(9-((1-(methanesulfonyl)piperidin-4-yl)amino)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-2-yl)bicyclo[1.1.1]pent-1-yl)methanol (354)

[0696] Step 1: Preparation of methyl 3-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentane-1-carboxylate (354-2)

[0697] Compound 354-1 (1000 mg, 6.4 mmol) was dissolved in DMF (20 mL), and TBSCl (1.1 g, 7.68 mmol) and imidazole (2.17 g, 32 mmol) were added. The mixture was stirred at room temperature for 2 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with EA (100 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give compound 354-2 (1 g, 58% yield, yellow oil).

[0698] LC-MS (ESI) + ): 501.2m / z [M+H] + .

[0699] Step 2: Preparation of (3-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pent-1-yl)methanol (354-3)

[0700] Compound 354-2 (1.6 g, 5.91 mmol) was dissolved in THF (50 mL), and a 2.5 M LiAlH4 THF solution (3.5 mL, 8.87 mmol) was added at 0 °C. The mixture was stirred at room temperature for 2 hours. Sodium sulfate decahydrate was added to the reaction solution, and after stirring for half an hour, the mixture was filtered directly. The filtrate was used directly in the next step to obtain compound 354-3 (1.4 g, 97% yield, yellow oil).

[0701] LC-MS (ESI) + ): 501.2m / z [M+H] + .

[0702] Step 3: Preparation of 3-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentan-1-carboxaldehyde (354-4)

[0703] Compound 354-3 (1.2 g, 4.94 mmol) was dissolved in DCM (20 mL), and Dess-Martin reagent (3.14 g, 7.42 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. NaHCO3 aqueous solution (100 mL) was added to the reaction mixture, and the mixture was extracted with DCM (100 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 354-4 (1 g, 84% yield, yellow oil).

[0704] LC-MS (ESI) + ): 501.2m / z [M+H] + .

[0705] Step 4: Preparation of 3-(3-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pent-1-yl)-3-hydroxypropionitrile (354-5)

[0706] Compound 354-4 (1000 mg, 4.15 mmol) was dissolved in DMSO / H2O (10 / 2 mL), and TMSCN (617 mg, 6.23 mmol) was added. The mixture was stirred at 50 °C for 12 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with EA (100 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 354-5 (1 g, 85% yield, yellow oil).

[0707] LC-MS (ESI) +): 501.2m / z [M+H] + .

[0708] Step 5: Preparation of 2-amino-1-(3-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pent-1-yl)ethanol-1-ol (354-6)

[0709] Compound 354-5 (1 g, 3.55 mmol) was dissolved in THF (20 mL), and a 2.5 M LiAlH4 THF solution (2 mL, 5.3 mmol) was added at 0 °C. The mixture was stirred at room temperature for 2 hours. Sodium sulfate decahydrate was added to the reaction solution, and after stirring for half an hour, the mixture was filtered directly. The filtrate was used directly in the next step to obtain compound 354-6 (800 mg, 83% yield, yellow oil).

[0710] LC-MS (ESI) + ): 501.2m / z [M+H] + .

[0711] In steps 6-10, following the method of Example 165, 2-amino-1-(3-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pent-1-yl)ethanol-1-ol (354-6) was used instead of 3-amino-1,7,7-trimethylbicyclo[2.2.1]heptane-2-ol to synthesize compound 354-11.

[0712] Step 11: Compound 354 was synthesized according to the method of Example 90.

[0713] LC-MS (ESI) + ): 485.2m / z [M+H] + .

[0714] Example 355: Synthesis of 2-(3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl)-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-9-amine (355)

[0715] Step 1: Preparation of 3-(((tert-Butoxycarbonyl)amino)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid (355-2)

[0716] At room temperature, Boc₂O (405 mg, 1.86 mmol) was added to a solution of 3-(aminomethyl)bicyclo[1.1.1]pentane-1-carboxylate (355-1, 300 mg, 1.69 mmol) and triethylamine (512 mg, 5.07 mmol) in dichloromethane (17 mL), and the mixture was stirred for 16 hours. The reaction solution was concentrated to obtain crude product 355-2, which was used directly in the next step without purification.

[0717] Steps 2-5: Following the method of Example 129, compound 355-2 was used to replace compound 129-1 to synthesize compound 355-6.

[0718] In steps 6-10, following the method of Example 165, compound 354-11 was synthesized by replacing 3-amino-1,7,7-trimethylbicyclo[2.2.1]heptane-2-ol with compound 355-6.

[0719] Step 11: Compound 355 was synthesized according to the method of Example 90.

[0720] LC-MS (ESI) + ):m / z 484.2,[M+H] + .

[0721] 1 H NMR(400MHz, DMSO-d6)δ9.05(s,1H),7.88(d,J=5.5Hz,1H),7.58(s,1H),7.48(d,J=5.5Hz,1H),4.71(s,1H),4.43–4.26(m,1H), 4.07–3.97(m,2H),3.59–3.53(m,3H),2.99–2.91(m,2H),2.89(s,3H),2.83–2.76(m,2H),2.06–1.95(m,2H),1.80–1.53(m,9H).

[0722] Example 356: Synthesis of 2-(3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl)-N-((3R,4R)-3-fluoro-1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-9-amine (356)

[0723] Step 1: Preparation of (3R,4R)-4-(((benzyloxy)carbonyl)amino)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (356-2)

[0724] At room temperature, (3R,4R)-4-amino-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (356-1, 30 g, 0.14 mol) was dissolved in DCM (200 mL), DIEA (35.5 g, 0.28 mol) was added, followed by dropwise addition of a DCM solution of Cbz-OSu (34 g, 0.14 mol) (added over 20 min), and the mixture was stirred at room temperature for 0.5 h. Citric acid monohydrate (3 g, 0.1 eq) and water (200 mL) were added to the reaction mixture, and the organic phase was separated. The aqueous phase was then extracted with DCM (100 mL). The combined organic phases were washed with saturated brine and water, and concentrated to dryness to give compound 356-2 (crude product, brown oil, 54.5 g, purity 90.5%, yield >100%), which was used directly in the next reaction step.

[0725] Step 2: Preparation of ((3R,4R)-3-fluoropiperidin-4-yl)carbamate benzyl ester (356-3)

[0726] Compound 356-2 (crude product, brown oil, 54.5 g, purity 90.5%, 0.14 mol) was dissolved in 250 mL of MeOH (250 mL), and then 4 M HCl / dioxane (172 mL) was added dropwise. After the addition was complete, the reaction solution was directly concentrated under reduced pressure to obtain compound 356-3 (crude product, brown oil, 48.2 g, purity 73%, yield >100%), which was used directly in the next reaction.

[0727] Step 3: Preparation of ((3R,4R)-3-fluoro-1-(methanesulfonyl)piperidin-4-yl)carbamate benzyl ester (356-4)

[0728] Compound 356-3 (crude product, brown oil, 48.2 g, purity 73%, yield >100%) was dissolved in 2-methyltetrahydrofuran (400 mL), and DIEA (35.5 g, 0.28 mmol) was added at room temperature. Ms2O (28.6 g, 0.16 mol.) was added in portions, and the mixture was stirred at room temperature for 1 hour. The reaction solution was heated to 50 °C, and hot water (50 °C, 200 mL) was added. Extraction was performed while hot, and the mixture was separated. The organic phase was washed with hot water (50 °C, 200 mL) and 2M hydrochloric acid (20 mL), and concentrated to dryness to give compound 356-4 (crude product, 50.2 g, purity 90.4%, yield >100%, white solid), which was used directly in the next reaction.

[0729] Step 4: Preparation of (3R,4R)-3-fluoro-1-(methanesulfonyl)piperidine-4-amine (356-5)

[0730] Crude product 356-4 (50.2 g, purity 90.4%, 0.14 mol) was added to glacial acetic acid (251 mL), followed by acetic acid solution of 33% HBr (126 mL). The reaction was carried out at room temperature for 2 hours. Ethyl acetate (2500 mL) was added at 0 °C, precipitating a white solid. The mixture was stirred for 30 minutes, filtered, and concentrated to dryness to give compound 356-5 (24.3 g, total yield of four steps 64%, white solid).

[0731] In steps 5-6, following steps 7-8 of Example 160, compound 160-7 was replaced with compound 356-5, and (3R,4R)-3-fluoro-1-(methanesulfonyl)piperidine-4-amine (356-5) was replaced with (3R,4R)-4-amino-3-fluoropiperidine-1-carboxylic acid tert-butyl ester to synthesize compound 356.

[0732] LC-MS (ESI) + ):m / z 502.2,[M+H] + .

[0733] Example 357: Synthesis of 2-(3-((dimethylamino)methyl)bicyclo[1.1.1]pentan-1-yl)-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-9-amine (357)

[0734] Following step 5 of Example 104, compound 357 was obtained by replacing compound 104-4 with compound 355.

[0735] LC-MS (ESI) + ): 512.2m / z [M+H] + .

[0736] 1 H NMR(400MHz,DMSO-d6)δ9.04(s,1H),8.18(s,1H,1.0mol FA),7.87(d,J=5.5Hz,1H),7.60(s,1H),7.47(d,J=5.5Hz,1H),4.70–4.62(m,1H),4.44–4.22(m,1H),4.11–4.00(m,1H),3.99–3 .91(m,1H),3.57–3.54(m,2H),3.02–2.91(m,2H),2.89(s,3H),2.39(s,2H),2.18(s,6H),2.07–1.93(m,2H),1.86–1.50(m,8H).

[0737] Examples 358 and 359: Synthesis of (3aS,11cS)-3a-methyl-N-(1-(methanesulfonyl)piperidin-4-yl)-2,3,3a,11c-tetrahydro-1H-4-oxa-5,9,11,11b-tetraazacyclopentane[a]fluoranthene-10-amine (358) and (3aR,11cS)-3a-methyl-N-(1-(methanesulfonyl)piperidin-4-yl)-2,3,3a,11c-tetrahydro-1H-4-oxa-5,9,11,11b-tetraazacyclopentane[a]fluoranthene-10-amine (359)

[0738] Following the method of Example 142, compounds 358 and 359 were synthesized by replacing compound 39-1 with (S)-N-tert-butoxycarbonyl-2-aminocyclopentanone.

[0739] Compound 358:

[0740] LC-MS (ESI) + ):443.2m / z[M+H]+.

[0741] 1 H NMR (400MHz, DMSO-d6) δ9.25(s,1H),8.08(d,J=5.6Hz,1H),7.64(d,J=5.6Hz,1H),4.38–4.10(m,1H),3.99(s,1H),3.60(dd ,J=11.2,5.2Hz,2H),3.05-2.93(m,2H),2.92(s,3H),2.73-2.62(m,1H),2.22–1.88(m,7H),1.75–1.58(m,2H),1.18(s,3H)

[0742] Compound 359:

[0743] LC-MS (ESI) + ):443.2m / z[M+H]+.

[0744] Example 360: Synthesis of 2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxo-4,8,10,10b-tetraazafluoroanthracene-9-amine (360)

[0745] At room temperature, 2-(4-chlorophenyl)-9-(methylthio)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene

[0746] Compound 360-1 (synthesized according to Example 1, using 2-amino-1-(4-chlorophenyl)ethane-1-ol instead of 2-amino-1-phenylethyl-1-ol, 30 mg, 0.08 mmol) was dissolved with 1-methylpyrazole-4-boronic acid linalool ester (34 mg, 0.16 mmol) in a mixed solvent of dried 1,4-dioxane (1 mL) and water (0.1 mL), and Pd-PEPPSI- i PentCl (8 mg, 0.008 mmol) and potassium phosphate (34 mg, 0.16 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 2 hours under a nitrogen atmosphere. After the reaction was complete, the crude product was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 10) to give 2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-9-(methylthio)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene (30 mg, yield: 89%).

[0747] LC-MS (ESI) + ): 415.4 m / z [M+H] + .

[0748] Following steps 6-7 of Example 164, compound 360 was synthesized by replacing compound 164-6 with compound 360-2.

[0749] LC-MS (ESI) + ): 545.4 m / z [M+H] + .

[0750] The following compounds were synthesized using the corresponding starting materials according to the method of Example 360:

[0751] Example 364: Synthesis of 2-(3-(9-((1-(methanesulfonyl)piperidin-4-yl)amino)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-2-yl)bicyclo[1.1.1]pentan-1-yl)prop-2-ol (364)

[0752] Step 1: Preparation of methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate (364-2)

[0753] 4 g (25 mmol) of methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylic acid ester 364-1 was dissolved in dichloromethane (30 mL), and pyridinium chlorochromate (8.3 g, 38 mmol) was added. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with water (20 mL) and then extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give 364-2 (2 g, yield 51%).

[0754] Step 2: Preparation of methyl 3-(1-hydroxy-2-nitroethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (364-3)

[0755] Compound 364-2 (2 g, 13 mmol) was dissolved in triethylamine (5 mL), and nitromethane (4 mL) was added. The reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was quenched with water (20 mL) and then extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to give compound 364-3 (1.6 g, yield 57%).

[0756] Step 3: Preparation of methyl 3-(1-hydroxy-2-aminoethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (364-4)

[0757] Compound 364-3 (1.6 g, 7.4 mmol) was dissolved in methanol (10 mL) at room temperature, and 5% palladium on carbon (100 mg) was added. The reaction mixture was stirred at 25 °C for 12 hours under a hydrogen atmosphere. After the reaction was complete, the palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting crude product (1.3 g) did not require purification and was used directly in the next reaction.

[0758] LC-MS (ESI) + ): 186.2m / z[M+H]+.

[0759] Step 4: Preparation of (2-((5-bromo-2-(methylthio)pyrimidin-4-yl)amino)-1-hydroxyethyl)bicyclo[1.1.1]pentane-1-carboxylic acid methyl ester (364-5)

[0760] At room temperature, 364-4 (450 mg, 2.5 mmol) and 2-methylthio-4-chloro-5-bromopyrimidine (600 mg, 2.5 mmol) were dissolved in DMF (10 mL), and triethylamine (1 mL) was added. The reaction mixture was stirred at 60 °C for 12 hours. After the reaction was complete, the reaction mixture was quenched with water (10 mL) and then extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 364-5 (200 mg, yield 20%).

[0761] LC-MS (ESI) + ): 389.2 m / z [M+H] + .

[0762] Step 5: Preparation of 2-(3-(2-((5-bromo-2-(methylthio)pyrimidin-4-yl)amino)-1-hydroxyethyl)bicyclo[1.1.1]pent-1-yl)prop-2-ol (364-6)

[0763] Compound 364-5 (150 mg, 0.4 mmol) was dissolved in tetrahydrofuran (2 mL), and methyllithium (1 mL, 1.6 mol / L) was added at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was quenched with water (10 mL), and then extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound 364-6 (50 mg, 33% yield).

[0764] LC-MS (ESI) + ): 389.2 m / z [M+H] + .

[0765] According to Example 164, compound 364 was synthesized by replacing compound 164-4 with compound 364-6.

[0766] LC-MS (ESI) + ): 513.5 m / z [M+H] + .

[0767] Example 365: Synthesis of (3aR,11cR)-3,3-dimethyl-N-(1-(methanesulfonyl)piperidin-4-yl)-2,3,3a,11c-tetrahydro-1H-4-oxa-5,9,11,11b-tetraazacyclopentadien[a]fluorane-10-amine (365)

[0768] Step 1: Preparation of 5-((2,4-dimethoxyphenylmethyl)amino)-2,2-dimethylcyclopentanone (365-2)

[0769] At room temperature, 5-bromo-2,2-dimethylcyclopentanone (365-1, 1.5 g, 7.8 mmol) and 2,4-dimethoxybenzylamine (2 g, 11.8 mmol) were dissolved in acetonitrile (10 mL), and triethylamine (3 mL) was added. The reaction mixture was stirred at 25 °C for 4 hours. The reaction mixture was quenched with water (10 mL) and then extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 365-2 (1.1 g, 50% yield).

[0770] LC-MS (ESI) + ): 278.4 m / z [M+H] + .

[0771] Step 2: Preparation of 5-((2,4-dimethoxyphenylmethyl)amino)-2,2-dimethylcyclopentanol (365-3)

[0772] 365-2 (1.1 g, 4 mmol) was dissolved in methanol (5 mL), and sodium borohydride (150 mg, 4 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was quenched with water (10 mL) and then extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The organic phase was concentrated under reduced pressure to give compound 365-3 (1 g, 90% yield).

[0773] LC-MS (ESI) + ): 280.2 m / z [M+H] + .

[0774] Step 3: Preparation of 5-((5-bromo-2-(methylthio)pyrimidin-4-yl)(2,4-dimethoxybenzyl)amino)-2,2-dimethylcyclopentanol (365-4)

[0775] At room temperature, 365-3 (1 g, 4.2 mmol) and 2-methylthio-4-chloro-5-bromopyrimidine (1.2 g, 4.2 mmol) were dissolved in DMF (10 mL), and triethylamine (1.2 mL) was added. The reaction mixture was stirred at 100 °C for 12 hours. After the reaction was complete, the reaction mixture was quenched with water (10 mL) and then extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give compound 365-4 (1.1 g, yield 54%).

[0776] LC-MS (ESI) + ): 483.2 m / z [M+H] + .

[0777] Step 4: Preparation of 5-((5-bromo-2-methylthiopyrimidin-4-yl)amino)-2,2-dimethylcyclopentanol (365-5)

[0778] Compound 365-4 (1.1 g, 2.3 mmol) was dissolved in dichloromethane (5 mL) at room temperature, and trifluoroacetic acid (0.4 mL) was added. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), and then extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound 365-5 (400 mg, yield 53%).

[0779] LC-MS (ESI) + ): 333.4 m / z [M+H] + .

[0780] According to Example 164, compound 365 was synthesized by replacing compound 164-4 with compound 365-5.

[0781] LC-MS (ESI) + ): 457.4 m / z [M+H] + .

[0782] The following compounds were synthesized using the corresponding starting materials according to steps 7-9 of Example 365, Example 160, and the method of Example 163:

[0783] Example 374: Synthesis of (8aS,12aS)-10,10-dimethyl-N-(1-(methanesulfonyl)piperidin-4-yl)-9,10,12,12a-tetrahydro-8aH-8,11-dioxa-1,3,7,12b-tetraazabenzo[a]acetylanthraene-2-amine (374)

[0784] Step 1: Preparation of 5-bromo-2,2-dimethyldihydro-2H-pyran-4(3H)-one (374-2)

[0785] At room temperature, 3.3 g (25 mmol) of 2,2-dimethyldihydro-2H-pyran-4(3H)-one was dissolved in 20 mL of dichloromethane, and N-bromosuccinimide (13 g, 77 mmol) was added. The reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was quenched with 30 mL of water and then extracted with 30 mL x 3 of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 10) to give compound 374-2 (1.4 g, yield: 26%).

[0786] Step 2: Preparation of (4S,5R)-5-bromo-2,2-dimethyltetrahydro-2H-pyran-4-ol (374-3)

[0787] Compound 374-2 (1.2 g, 5.8 mmol) was dissolved in methanol (5 mL) at room temperature, and sodium borohydride (0.4 g, 11 mmol) was added. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with water (10 mL) and then extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 374-3 (1.2 g, yield: 99%).

[0788] Step 3: Preparation of (4S,5S)-5-azido-2,2-dimethyltetrahydro-2H-pyran-4-ol (374-4) 374-3 (900 mg, 4.3 mmol) was dissolved in DMF (10 mL), and lithium azide aqueous solution (1 mL) was added. The reaction mixture was stirred at 100 °C for 12 hours until the starting material disappeared. After the reaction was complete, water (20 mL) was added to quench the reaction mixture, and then it was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to give compound 374-4 (300 mg, yield 40%).

[0789] Step 4: Preparation of (4S,5S)-5-amino-2,2-dimethyltetrahydro-2H-pyran-4-ol (374-5) At room temperature, 374-4 (300 mg, 1.7 mmol) was dissolved in methanol (5 mL), and 5% palladium on carbon (20 mg) was added. The reaction mixture was stirred at 25 °C for 12 hours under a hydrogen atmosphere. After the reaction was complete, the palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure to give compound 374-5 (250 mg, 99% yield).

[0790] LC-MS (ESI) + ): 146.2 m / z [M+H] + .

[0791] Following the method of Example 164, compound 374 was synthesized by replacing 164-4 with compound 374-5.

[0792] LC-MS (ESI) + ): 473.2 m / z [M+H] + .

[0793] The following compounds were synthesized using the corresponding starting materials according to steps 7-9 of Examples 374 and 160:

[0794] Example 376: Synthesis of (8aR,12aS)-9,9-dimethyl-N-(1-(methanesulfonyl)piperidin-4-yl)-8a,11,12,12a-tetrahydro-9H-8,10-dioxa-1,3,7,12b-tetraazabenzo[a]acetylanthraene-2-amine (376)

[0795] Step 1: Preparation of 6,6-dimethyl-3,6-dihydro-2H-pyran (376-2)

[0796] At room temperature, 5-methyl-3,4-hexadien-1-ol (800 mg, 7 mmol) was dissolved in dichloromethane (10 mL), and silver oxide (800 mg, 3.5 mmol) was added. The reaction mixture was stirred at 25 °C for 24 hours until the starting material disappeared. The reaction mixture was concentrated under reduced pressure to give compound 376-2 (750 mg, 94% yield).

[0797] Step 2: Preparation of 2,2-dimethyl-3,7-dioxabicyclo[4.1.0]heptane (376-3)

[0798] Compound 376-2 (750 mg, 6.7 mmol) was dissolved in dichloromethane (10 mL) at room temperature, and m-chloroperoxybenzoic acid (3400 mg, 20 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours until the starting material disappeared. The reaction mixture was quenched with saturated sodium hydroxide aqueous solution (30 mL), and then extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 376-3 (750 mg, 87% yield).

[0799] Step 3: Preparation of (3R,4S)-4-((2,4-dimethoxybenzyl)amino)-2,2-dimethyltetrahydro-2H-pyran-3-ol (376-4)

[0800] Compound 376-3 (800 mg, 6.2 mmol) and 2,4-dimethoxybenzylamine (3100 mg, 18.6 mmol) were dissolved in toluene (10 mL). The reaction mixture was stirred at 100 °C for 12 hours. After the starting material disappeared, the reaction mixture was quenched with water (10 mL) and then extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 10) to give compound 376-4 (1500 mg, yield: 81%).

[0801] Following the method of Example 365, compound 376 was synthesized by replacing compound 365-3 with compound 376-4.

[0802] LC-MS (ESI) + ): 473.2 m / z [M+H] + .

[0803] 1 H NMR(400MHz, DMSO-d6)δ9.07(s,1H),7.90(d,J=5.6Hz,1H),7.53(d,J=5.6Hz,1H),4.60-4.57(m,1H),4.09(d,J=9.2Hz,1H) ,3.88-3.85(m,3H),3.59-3.56(m,3H),2.96-2.92(m,5H),2.06-2.02(m,3H),1.65-1.61(m,2H),1.45(s,3H),1.38(s,3H).

[0804] The following compounds were synthesized using the corresponding starting materials according to Example 375:

[0805] Example 378: Synthesis of (3aS,11cS)-2,2-difluoro-N-(1-(methanesulfonyl)piperidin-4-yl)-2,3,3a,11c-tetrahydro-1H-4-oxa-5,9,11,11b-tetraazacyclopentadien[a]fluorane-10-amine (378)

[0806] Step 1: Preparation of tert-butyl(cyclopent-3-en-1-yloxy)diphenylsilane (378-2)

[0807] At room temperature, cyclopent-3-enol (5 g, 59 mmol) and imidazole (8 g, 118 mmol) were dissolved in dichloromethane (100 mL), and tert-butyldiphenylchlorosilane (18 g, 65 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with water (50 mL) and then extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to give compound 378-2 (16 g, yield: 83%).

[0808] Step 2: Preparation of (6-oxabicyclo[3.1.0]hexane-3-yloxy)(tert-butyl)diphenylsilane (378-3)

[0809] Compound 378-2 (6 g, 19 mmol) was dissolved in dichloromethane (50 mL) at room temperature, and m-chloroperoxybenzoic acid (6 g, 38 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours until the starting material disappeared. The reaction mixture was quenched with saturated sodium hydroxide aqueous solution (30 mL), and then extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 378-3 (6 g, 90% yield).

[0810] Step 3: Preparation of (1S,2S)-4-((tert-butyldiphenylsilyl)oxy)-2-((2,4-dimethoxybenzyl)amino)cyclopentanol (378-4)

[0811] Compound 378-3 (6 g, 17 mmol) and 2,4-dimethoxybenzylamine (3.1 g, 18.6 mmol) were dissolved in toluene (50 mL). The reaction mixture was stirred at 100 °C for 12 hours. After the starting material disappeared, the reaction mixture was quenched with water (30 mL) and then extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 10) to give compound 378-4 (8 g, yield: 89%).

[0812] LC-MS (ESI) + ): 506.6 m / z [M+H] + .

[0813] Step 4: Preparation of (1S,2S)-2-((5-bromo-2-(methylthio)pyrimidin-4-yl)(2,4-dimethoxybenzyl)amino)-4-((tert-butyldiphenylsilyl)oxy)cyclopentanol (378-5)

[0814] Compound 378-4 (8 g, 16 mmol) was dissolved in DMF (50 mL) with 5-bromo-4-chloro-2-methylthiopyrimidine (5.7 g, 23 mmol), and triethylamine (6 mL) was added. The reaction mixture was stirred at 100 °C for 12 hours. After the starting material disappeared, the reaction mixture was quenched with water (30 mL) and then extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 10) to give compound 378-5 (10 g, yield: 89%).

[0815] LC-MS (ESI) + ): 679.2 m / z [M+H] + .

[0816] Step 5: Preparation of (1S,2S)-2-((5-bromo-2-(methylthio)pyrimidin-4-yl)amino)-4-((tert-butyldiphenylsilyl)oxy)cyclopentanol (378-6)

[0817] Compound 378-5 (10 g, 14 mmol) was dissolved in dichloromethane (50 mL) at room temperature, and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (50 mL), and then extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound 378-6 (5 g, 63% yield).

[0818] LC-MS (ESI) + ): 559.4 m / z [M+H] + .

[0819] Step 6: Preparation of (1S,2S)-2-((5-bromo-2-(methylthio)pyrimidin-4-yl)amino)-4-((tert-butyldiphenylsilyl)oxy)cyclopentyl4-nitrobenzene (378-7)

[0820] Compound 378-6 (5 g, 9 mmol) and 4-nitrobenzyl chloride (2.5 g, 13 mmol) were dissolved in dichloromethane (50 mL), and triethylamine (4 mL) was added. The reaction mixture was stirred at 25 °C for 2 hours. After the starting material disappeared, the reaction mixture was quenched with water (30 mL) and then extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to give compound 378-7 (6 g, yield: 95%).

[0821] LC-MS (ESI) + ): 708.6 m / z [M+H] + .

[0822] Step 7: Preparation of (1S,2S)-2-((5-bromo-2-(methylthio)pyrimidin-4-yl)amino)-4-hydroxycyclopentyl 4-nitrobenzene ester (378-8)

[0823] Compound 378-7 (6 g, 8.4 mmol) was dissolved in dichloromethane (50 mL), and tetrabutylammonium fluoride (17 mL, 1 mol / L THF solution) was added. The reaction mixture was stirred at 25 °C for 2 hours. After the starting material disappeared, the reaction mixture was quenched with water (30 mL), and then extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to give compound 378-8 (2.4 g, yield: 60%).

[0824] LC-MS (ESI) + ): 470.2 m / z [M+H] + .

[0825] Step 8: Preparation of (1S,2S)-2-((5-bromo-2-(methylthio)pyrimidin-4-yl)amino)-4-oxocyclopentyl 4-nitrobenzene ester (378-9)

[0826] Compound 378-8 (1.3 g, 2.8 mmol) was dissolved in dichloromethane (10 mL), and Dys-Martin oxidant (2.3 g) was added. The reaction mixture was stirred at 25 °C for 2 hours. After the starting material disappeared, the reaction mixture was quenched with water (20 mL), and then extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 378-9 (1.2 g, yield: 95%).

[0827] LC-MS (ESI) +): 468.2 m / z [M+H] + .

[0828] Step 9: Preparation of (1S,2S)-2-((5-bromo-2-(methylthio)pyrimidin-4-yl)amino)-4,4-difluorocyclopentyl 4-nitrobenzene ester (378-10)

[0829] Compound 378-9 (1.2 g, 2.6 mmol) was dissolved in dichloromethane (10 mL), and diethylaminosulfur trifluoride (1.8 mL) was added. The reaction mixture was stirred at 25 °C for 2 hours. After the starting material disappeared, the reaction mixture was quenched with water (30 mL), and then extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound 378-10 (0.5 g, yield: 35%).

[0830] LC-MS (ESI) + ): 490.2 m / z [M+H] + .

[0831] Step 10: Preparation of (1S,2S)-2-((5-bromo-2-(methylthio)pyrimidin-4-yl)amino)-4,4-difluorocyclopentanol (378-11)

[0832] Compound 378-10 (500 mg, 1 mmol) was dissolved in a mixture of methanol (5 mL) and water (5 mL), and lithium hydroxide monohydrate (85 mg, 2 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours. After the starting material disappeared, the reaction mixture was quenched with water (10 mL) and then extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 378-11 (300 mg, yield: 86%).

[0833] LC-MS (ESI) + ): 341.2 m / z [M+H] + .

[0834] Following the method of Example 164, compound 378 was synthesized by replacing 164-4 with compound 378-11.

[0835] LC-MS (ESI) + ): 465.2 m / z [M+H] + .

[0836] The following compounds were synthesized using the corresponding starting materials according to the method described in Example 378:

[0837] Example 380: Synthesis of 2-(1,1-difluoro-2-methylpropyl-2-yl)-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (380)

[0838] Following the method of Example 131, compound 380 was synthesized by replacing 3,3,3-trifluoro-2,2-dimethylpropionic acid with 3,3-difluoro-2,2-dimethylpropionic acid.

[0839] LC-MS (ESI) + ): 481.2 m / z [M+H] + .

[0840] 1 H NMR(400MHz, DMSO-d6)δ9.06(s,1H),7.88(d,J=4.0Hz,1H),7.51(d,J=8.0Hz,1H),6.37-6.09(m,1H),4.57-4.49(m,2H),4.07–4 .02(m,2H),3.55(d,J=12.0Hz,2H),2.95–2.89(m,5H),1.99(d,J=12.0Hz,2H),1.61(d,J=8.0Hz,2H),1.23(s,3H),1.19(s,3H).

[0841] The following compounds were synthesized using the corresponding starting materials according to the method of Example 380:

[0842] Example 385: Synthesis of (3R,4R)-3-fluoro-1-(methanesulfonyl)piperidin-4-yl-2-methyl-2-(1-(trifluoromethyl)cyclobutyl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (385)

[0843] Step 1: Preparation of N-methoxy-N-methyl-1-(trifluoromethyl)cyclobutane-1-carboxamide (385-2)

[0844] 1-(trifluoromethyl)cyclobutane-1-carboxylic acid (3.0 g, 17.86 mmol) was dissolved in DCM (35 mL). Oxaloyl chloride (2.72 g, 21.43 mmol) and 2 drops of DMF were added at 0 °C. The mixture was stirred at room temperature for 4 hours. After the reaction was complete, a solution (40 mL) of N,O-dimethylhydroxylamine hydrochloride (2.66 g, 26.79 mmol) and diisopropylethylamine (3.02 mL, 17.3 mmol) in DCM (5 mL) was slowly added. The mixture was stirred at room temperature for 1.5 h, and then extracted with DCM (40 mL × 3). The organic phases were combined and washed successively with 1 M dipotassium hydrogen phosphate solution (2 × 30 mL), saturated sodium bicarbonate aqueous solution (30 mL), and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 385-2 (2 g, 53% yield, colorless oil).

[0845] LC-MS (ESI) + ):212.2m / z[M+H] + .

[0846] Step 2: Preparation of 1-(1-(trifluoromethyl)cyclobutyl)ethane-1-one (385-3)

[0847] N-methoxy-N-methyl-1-(trifluoromethyl)cyclobutane-1-carboxamide (2.0 g, 9.43 mmol) was dissolved in THF (25 mL), and methyl magnesium bromide (1 M THF solution, 14 mL, 14.15 mmol) was added at 0 °C. The resulting mixture was stirred at 0–5 °C for 2 hours. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution and then extracted with EA (40 mL × 3). The organic phases were combined, washed successively with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 385-3, which could be directly added to the next step without further purification.

[0848] LC-MS (ESI+): 167.2 m / z [M+H] + .

[0849] Following the method of Example 160, compound 385 was synthesized by replacing 160-1 with compound 385-3.

[0850] LC-MS (ESI) + ): 543.2 m / z [M+H] + .

[0851] The following compounds were synthesized using the corresponding starting materials according to the method of Example 385:

[0852] Example 389: Synthesis of 3-(9-((1-(methanesulfonyl)piperidin-4-yl)amino)-1,2-dihydro-3-oxo-4,8,10,10b-tetraazafluorenyl-2-yl)bicyclo[1.1.1]pentane-1-nitrile (389)

[0853] Step 1: Preparation of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (389-2)

[0854] Oxaloyl chloride (722 mg, 5.69 mmol) was slowly added to a DCM (5 mL) solution of compound 389-1 (440 mg, 2.58 mmol) and DMF (19 mg, 0.26 mmol) under ice bath conditions, and the mixture was stirred at 0 °C for 2.0 h. The reaction solution was concentrated under reduced pressure and dissolved in THF / MeCN. TMSN2 was slowly added at 0 °C, and the mixture was stirred at 0 °C for 1.5 h. HBr (1.3 g, 48% aqueous solution, 7.76 mmol) was added to the reaction solution under ice bath conditions and stirred for 10 min. The mixture was quenched with NaHCO3 and extracted with EtOAc (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 389-2 (400 mg, yield 62.6%, white solid).

[0855] Step 2: Preparation of methyl 3-(2-bromo-1-hydroxyethyl)tricyclo[1.1.1]pentane-1-carboxylic acid (389-3)

[0856] NaBH4 (73 mg, 1.94 mmol) was slowly added to a MeOH (4 mL) solution of compound 389-2 (400 mg, 1.62 mmol) under ice bath conditions, and the mixture was stirred at 0 °C for 1.0 h. After quenching with water, the mixture was extracted with EtOAc (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 389-3 (400 mg, 99.2% yield, white solid).

[0857] Step 3: Preparation of 3-(2-amino-1-hydroxyethyl)bicyclo[1.1.1]pentane-1-carboxamide (389-4)

[0858] Compound 3 (400 mg, 1.60 mmol) was added to a 7 M ammonia-methanol solution (4.0 mL), and stirred at 80 °C for 16 hours. The reaction solution was concentrated under reduced pressure to give compound 389-4 (300 mg, 100% yield, white solid).

[0859] Steps 4-8: Following the method of Example 165, 3-(2-amino-1-hydroxyethyl)bicyclo[1.1.1]pentane-1-carboxamide (389-4) was used instead of 3-amino-1,7,7-trimethylbicyclo[2.2.1]heptane-2-ol to synthesize compound 389-9.

[0860] Step 9: Preparation of 3-(9-((1-(methanesulfonyl)piperidin-4-yl)amino)-1,2-dihydro-3-oxo-4,8,10,10b-tetraazafluorenyl-2-yl)bicyclo[1.1.1]pentane-1-nitrile (389)

[0861] Compound 389-9 (24 mg, 0.05 mmol) and Burgess reagent (69 mg, 0.29 mmol) were added to THF (0.5 mL) and stirred at 30 °C for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by prep-HPLC to give compound 389 (6.6 mg, 100% purity, 28.5% yield, white solid).

[0862] LC-MS (ESI) + ): 480.2 m / z [M+H] + .

[0863] 1 H NMR (400MHz, DMSO-d6) δ9.07(s,1H),7.90(d,J=5.5Hz,1H),7.51(d,J=5.5Hz,1H),4.70(d,J=8.3Hz,1H),3.93(dd,J=12.7, 8.6Hz, 1H), 3.58 (d, J = 11.8Hz, 2H), 2.96 (d, J = 11.8Hz, 2H), 2.91 (s, 3H), 2.36 (d, J = 12.4Hz, 6H), 2.02 (s, 2H), 1.64 (s, 2H).

[0864] Example 390: Synthesis of N-(1-(methylsulfonyl)piperidin-4-yl)-2-(tetrahydrofuran-3-yl)-2-(trifluoromethyl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (390)

[0865] Step 1: Preparation of 2-(aminomethyl)-1,1,3,3-hexafluoroprop-2-ol (390-2)

[0866] At room temperature and under a nitrogen atmosphere, CF3TMS (3.28 g, 23 mmol, 2.0 eq.) was slowly added to a toluene (50.0 mL) solution of compound 390-1 (1.5 g, 11.5 mmol, 1.0 eq.). The reaction solution was cooled to -78 °C, and TBAF (1.0 M, 1.15 mL, 1.15 mmol, 0.1 eq.) was slowly added. The reaction solution was stirred at -78 °C for 0.5 h, then heated to room temperature and stirred for 16 h. 9 mL of 2N HCl was added to the reaction solution, and the mixture was stirred at room temperature for 2 h. Then, an aqueous solution of NaHCO3 was added to adjust the pH to >7. Water and ethyl acetate were added, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was used directly in the next reaction step.

[0867] Step 2: Preparation of 3,3,3-trifluoro-2-hydroxy-2-(tetrahydrofuran-3-yl)propionitrile (390-3)

[0868] At 0 °C, TMSCN (1.49 g, 15 mmol, 1.3 eq.) was slowly added to a mixed solution of compound 390-2 (1.94 g, 11.5 mmol, 1.0 eq.) in toluene (1.0 mL), DMSO (15.0 mL), and H₂O (3.0 mL). The reaction mixture was stirred at 50 °C for 16 hours. After cooling to room temperature, water and ethyl acetate were added. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was used directly in the next reaction step.

[0869] Step 3: Preparation of 3-amino-1,1,1-trifluoro-2-(tetrahydrofuran-3-yl)prop-2-ol (390-4) At 0°C, LiAlH4 (2.5 M, 9.2 mL, 23 mmol, 2.0 eq.) was slowly added to a THF (18.0 mL) solution of compound 390-3 (2.25 g, 11.5 mmol, 1.0 eq.). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled to 0°C, and sodium sulfate decahydrate was slowly added until no more bubbles were generated. The mixture was then stirred at room temperature for 20 minutes, filtered, and the filter cake was washed with DCM:CH3OH = 4:1. The filtrates were combined and concentrated under reduced pressure. The crude product was used directly in the next reaction step.

[0870] Following the method of Example 164, compound 390 was synthesized by replacing 164-3 with compound 390-4.

[0871] LC-MS (ESI) + ): 527.2 m / z [M+H] + .

[0872] 1H NMR (400MHz, DMSO-d6) δ9.09 (s, 1H), 7.94 (dd, J = 5.4, 2.1Hz, 1H), 7.76 (s, 1H), 7. 58(d,J=5.5Hz,1H),4.77(s,1H),4.33(dd,J=45.6,14.5Hz,1H),4.14–4.01(m,1H) ,3.94–3.83(m,2H),3.71–3.63(m,1H),3.56(d,J=11.9Hz,2H),3.21–3.13(m,1H) ,2.93(s,2H),2.89(s,3H),2.27–2.06(m,2H),1.99(s,3H),1.62(d,J=9.3Hz,2H).

[0873] The following compounds were synthesized using the corresponding starting materials according to the method of Example 390:

[0874] Example 392: Synthesis of N-(1-(methylsulfonyl)piperidin-4-yl)-2,2-bis(trifluoromethyl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (392)

[0875] Step 1: Preparation of 2-(aminomethyl)-1,1,3,3-hexafluoroprop-2-ol (392-2)

[0876] At room temperature, 2,2-bis(trifluoromethyl)ethylene oxide (1 g, 5.55 mmol) was dissolved in amine methanol (20 mL), and the resulting mixture was stirred at 25 °C for 2 hours in a sealed tube. The reaction solution was concentrated under reduced pressure and used directly in the next step to give compound 392-2 (1 g, yield 91.36%).

[0877] LC-MS (ESI) + ): 198.2 m / z [M+H] + .

[0878] Compound 392 was synthesized by replacing 3-amino-1,7,7-trimethylbicyclo[2.2.1]heptane-2-ol with compound 392-2.

[0879] LC-MS (ESI) + ): 525.2 m / z [M+H] + .

[0880] 1H NMR(400MHz, DMSO-d6)δ9.13(s,1H),8.03(d,J=4.0Hz,1H),7.71(d,J=8.0Hz,1H),4.96-4.86(m,2 H),4.09–4.07(m,1H),3.57(d,J=12.0Hz,2H),2.94-2.89(m,5H),2.01(s,2H),1.67–1.58(m,2H).

[0881] The following compounds were synthesized using the corresponding starting materials according to steps 7, 8, and 9 of Examples 392 and 160, and the method of Example 163:

[0882] Example 395: Synthesis of 2-(tert-butyl)-N-(1-(methanesulfonyl)piperidin-4-yl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-1,1,2,3,9-amine (395)

[0883] Step 1: Preparation of sodium 2,2-dimethylvalproate-1-d(395-2)

[0884] At 0 °C, LiAlD4 (867 mg, 20.7 mmol) was added to a solution of methyl pentanoate (2000 mg, 17.2 mmol) in anhydrous THF (8.0 mL). The mixture was stirred at room temperature for 5 hours. Sodium sulfate decahydrate (9000 mg) was added to the mixture at room temperature. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 395-2 (1200 mg, yield 77.3%).

[0885] Step 2: Preparation of 2,2-dimethylpropane-1,1-d2-1-ol (395-3)

[0886] At room temperature, PCC (4590 mg, 21.3 mmol) was added to a solution of compound 395-2 (1200 mg, 13.3 mmol) in DCM (9.0 mL). The resulting mixture was stirred at room temperature for 10 hours. The mixture was filtered and concentrated under reduced pressure to give compound 395-3 (1000 mg, oil, crude product).

[0887] Step 3: Preparation of 2-hydroxy-3,3-dimethylbutyronitrile-2-d(395-4)

[0888] At room temperature, TMSCN (854 mg, 8.61 mmol) was added to a solution of compound 395-3 (1000 mg, 5.748 mmol) in MeOH (10 mL). The resulting mixture was stirred at 50 °C for 18 hours. The mixture was concentrated under reduced pressure to give compound 395-4 (900 mg, oil, crude product).

[0889] Step 4: Preparation of 1-amino-3,3-dimethylbut-1,1,2-d3-2-ol (395-5)

[0890] At 0 °C, LiAlD4 (166 mg, 3.94 mmol) was added to 5.0 mL of anhydrous THF solution of compound 395-4 (450 mg, 1.97 mmol). The mixture was stirred at room temperature for 6 hours. Sodium sulfate decahydrate (2100 mg) was added to the mixture at room temperature. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 395-5 (400 mg, solid, crude).

[0891] LC-MS (ESI) + ): 121.2m / z [M+H] + .

[0892] Following the method of Example 47, compound 395 was synthesized by replacing (S)-2-amino-1-phenylethyl-1-ol with compound 395-5.

[0893] LC-MS (ESI) + ): 448.2 m / z [M+H] + .

[0894] 1 H NMR(400MHz,DMSO-d6)δ9.07(s,1H),7.89(d,J=5.6Hz,1H),7.75–7.53(m,1H),7.49(d,J=5.6Hz,1H),4.2 3–3.94(m,1H),3.70–3.50(m,2H),3.03–2.80(m,5H),2.14–1.88(m,2H),1.81–1.48(m,2H),1.17(s,9H).

[0895] The following compounds were synthesized using the corresponding starting materials according to the methods described in Examples 395, 160, and 163:

[0896] Examples 403 and 404: Synthesis of 4-(9-((1-(methanesulfonyl)piperidin-4-yl)amino)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-2-yl)benzoic acid (403) and 4-(9-((1-(methanesulfonyl)piperidin-4-yl)amino)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-2-yl)benzamide (404)

[0897] Step 1: Preparation of 4-(9-((1-(methylsulfonyl)piperidin-4-yl)amino)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-2-yl)benzoic acid (403)

[0898] At room temperature, LiOH·H₂O (68.7 mg, 2.871 mmol) was added to a solution of methyl 4-(9-((1-(methanesulfonyl)piperidin-4-yl)amino)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-2-yl)benzoate (300 mg, 0.57 mmol, synthesized from the corresponding starting material according to Example 47) in MeOH (4.0 mL). The resulting mixture was stirred at room temperature for 8 hours. HCl (2 mol / L) was added to the mixture until pH = 5. The mixture was concentrated under reduced pressure. Water (10 mL) was added to the residue, the mixture was filtered, and the filter cake was dried to give compound 403 (160 mg, yield 54.8%).

[0899] LC-MS (ESI+): 509.2 m / z [M+H] + .

[0900] Step 2: Preparation of 4-(9-((1-(methylsulfonyl)piperidin-4-yl)amino)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthracene-2-yl)benzamide (404)

[0901] HATU (89.7 mg, 0.24 mmol) was added to a THF (2.0 mL) solution of compound 403 (80 mg, 0.16 mmol), NH4Cl (10.1 mg, 0.19 mmol), and DIPEA (0.08 mL, 0.47 mmol). The resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (0.1% NH3H2O ​​aqueous solution / CH3CN) to give compound 404 (2.0 mg, yield 2.5%).

[0902] LC-MS (ESI) + ): 508.2m / z [M+H]+ .

[0903] According to the method of Example 404, the following was synthesized using the corresponding raw materials:

[0904] Example 406: 3,3-Dimethyl-N-(1-(methylsulfonyl)piperidin-4-yl)-1'H-3'-oxo-4',8',10',10b'-tetraazaspiro[cyclobutane-1,2'-fluorene]-3a',3a 1 Synthesis of '(6a'),5',6b',8',10'-hexene-9'-amine (406)

[0905] Step 1: Preparation of 1-bromo-3,3-dimethylcyclobutane-1-carboxylic acid (406-2)

[0906] Under ice bath conditions, PBr3 (422 mg, 1.56 mmol) was slowly added to a bromine solution (1.9 g, 11.70 mmol) containing compound 406-1 (1 g, 7.80 mmol), and the mixture was stirred at 100 °C for 16 hours. The reaction mixture was then poured into an aqueous solution of NaHSO3 (20 mL) under ice bath conditions and extracted with EtOAc (20 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 406-2 (1.7 g, yield >100%, pale yellow solid).

[0907] Step 2: Preparation of 1-hydroxy-3,3-dimethylcyclobutane-1-carboxylic acid (406-3)

[0908] LiOH·H₂O (448 mg, 10.67 mmol) was added to a THF / H₂O (10.0 mL / 2.0 mL) solution of compound 406-2 (1.7 g, 8.21 mmol) and stirred at 80 °C for 4 hours. The pH of the reaction mixture was adjusted to 1 with 2 M HCl, and the mixture was extracted with EtOAc (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 406-3 (1.2 g, yield >100%, pale yellow solid).

[0909] Step 3: Preparation of methyl 1-hydroxy-3,3-dimethylcyclobutane-1-carboxylate (406-4)

[0910] Under ice bath conditions, SOCl2 (422 mg, 1.56 mmol) was slowly added to a MeOH (10.0 mL) solution of compound 406-3 (1.2 g, 8.32 mmol), and the mixture was stirred at 80 °C for 5 hours. The reaction solution was then concentrated under reduced pressure to give compound 406-4 (1.0 g, yield 75.9%, pale yellow solid).

[0911] Step 4: Preparation of 1-hydroxy-3,3-dimethylcyclobutane-1-carboxamide (406-5)

[0912] Compound 406-4 (1.0 g, 6.32 mmol) was added to a 7 M ammonia-methanol solution (30.0 mL) and stirred at 80 °C for 16 hours. The reaction solution was concentrated under reduced pressure to give compound 406-5 (790 mg, yield 87.3%, white solid).

[0913] Step 5: Preparation of 1-(aminomethyl)-3,3-dimethylcyclobutane-1-ol (406-6)

[0914] Under ice bath conditions, 2.5 M LiAlH4 (6.62 mL, 16.5 mmol) was slowly added to a THF (5.0 mL) solution of compound 406-5 (790 mg, 5.52 mmol), and the mixture was stirred at room temperature for 16 hours. Sodium sulfate decahydrate was then added under ice bath conditions, and the mixture was stirred for 1 hour. The reaction solution was filtered through diatomaceous earth, washed with DCM / MeOH (v / v: 3 / 1), and the filtrate was concentrated under reduced pressure to give compound 406-6 (700 mg, 98.2% yield, pale yellow oil).

[0915] Compound 406 was synthesized by replacing 3-amino-1,7,7-trimethylbicyclo[2.2.1]heptane-2-ol with compound 406-6 according to the method of Example 165.

[0916] LC-MS (ESI) + ): 457.2m / z[M+H]+.

[0917] 1 H NMR (400MHz, DMSO-d6) δ9.07(s,1H),7.92(d,J=5.5Hz,1H),7.52(t,J=5.6Hz,1H),4.27(s,2H),4.08(d,J=9.7Hz,1H),3.58(dd,J= 10.5, 6.3Hz, 2H), 2.86–2.98 (m, 5H), 2.17 (d, J = 13.1Hz, 2H), 2.10–1.99 (m, 4H), 1.64 (d, J = 11.7Hz, 3H), 1.34 (s, 3H), 1.25 (s, 3H).

[0918] Following steps 7-9 of Example 406, Example 160, and the method of Example 163, the following was synthesized using the corresponding raw materials:

[0919] Examples 409, 410 and 411: N-((3R,4R)-3-fluoro-1-(methanesulfonyl)piperidin-4-yl)-2-(2-(methyl-d3)prop-2-yl-1,1,1,3,3,3-d6)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (409), (S)-N-((3R,4R)-3-fluoro-1-(methanesulfonyl)piperidin-4-yl)-2-(2-(methyl-d3)prop- Synthesis of 2-yl-1,1,1,3,3,3-d6)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthen-9-amine (410) and (R)-N-((3R,4R)-3-fluoro-1-(methanesulfonyl)piperidin-4-yl)-2-(2-(methyl-d3)propyl-2-yl-1,1,1,3,3,3-d6)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthen-9-amine (411)

[0920] Step 1: Preparation of N-methoxy-N-methyl-2,2-bis(methyl-d3)propionamide-3,3,3-d3 (409-2)

[0921] At 0 °C, HATU (94.38 g, 248 mmol) was slowly added to a DCM (500 mL) solution of compound 409-1 (23 g, 206.8 mmol), dimethylhydroxylamine hydrochloride (30.3 g, 310 mmol), and DIPEA (110 mL, 621 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was cooled to 0 °C and washed successively with saturated NaHCO3 solution, 1N HCl aqueous solution, and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0–8%) to give compound 409-2 (32 g, 100% yield).

[0922] Step 2: Preparation of 2,2-bis(methyl-d3)propionaldehyde-3,3,3-d3 (409-3)

[0923] At 0°C, LiAlH4 (2.5M, 125mL, 310mmol) was slowly added to a THF (380mL) solution of compound 409-2 (32g, 206.8mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0°C, and sodium sulfate decahydrate was slowly added until no more bubbles were generated. The mixture was then stirred at room temperature for 20 minutes, filtered, and the filter cake was washed with THF. The combined filtrates were used directly for the next reaction step.

[0924] Step 3: Preparation of 2-hydroxy-3,3-bis(methyl-d3)butyronitrile-4,4,4-d3 (409-4)

[0925] At 0°C, TMSCN (30.8 g, 310 mmol) was slowly added to a mixed solution of compound 409-3 (19.7 g, 207 mmol) in 1200 mL of THF, 200 mL of DMSO, and 120 mL of H₂O. The reaction mixture was stirred at 50°C for 16 hours. After cooling to room temperature, water and ethyl acetate were added, and the mixture was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used directly in the next reaction step.

[0926] Step 4: Preparation of 1-amino-3,3-bis(methyl-d3)butane-4,4,4-d3-2-ol (409-5)

[0927] At 0°C, LiAlH4 (2.5 M, 166 mL, 415 mmol) was slowly added to a THF (400 mL) solution of compound 409-4 (25.3 g, 207 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled to 0°C, and sodium sulfate decahydrate was slowly added until no more bubbles were generated. The mixture was then stirred at room temperature for 20 minutes, filtered, and the filter cake was washed with THF. The filtrates were combined and concentrated under reduced pressure. The residue was used directly in the next reaction step.

[0928] Step 5: Preparation of 1-((5-bromo-2-(methylthio)pyrimidin-4-yl)amino)-3,3-bis(methyl-d3)butane-4,4,4-d3-2-ol (409-6)

[0929] At room temperature, compound 409-5 (22 g, 173 mmol), compound 1-1 (23 g, 96 mmol), and DIPEA (37 g, 288 mmol) were sequentially added to dioxane (60 mL) and DMSO (120 mL). The reaction mixture was stirred at 70 °C for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and water and ethyl acetate were added. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-19%) to give compound 409-6 (10 g, total yield of 14.7% in four steps).

[0930] Step 6: Preparation of 1-((5-(3-chloro-2-fluoropyridin-4-yl)-2-(methylthio)pyrimidin-4-yl)amino)-3,3-bis(methyl-d3)butane-4,4,4-d3-2-ol (409-7)

[0931] At room temperature, compound 409-6 (10 g, 30.5 mmol), (3-chloro-2-fluoropyridin-4-yl)boronic acid (9.6 g, 54.9 mmol), Pd(dtbpf)Cl2 (2.98 g, 4.6 mmol), and KF (5.3 g, 91.6 mmol) were successively added to dioxane (150 mL) and H2O (30 mL). The reaction mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography ((dichloromethane:methanol = 4:1) / dichloromethane = 0-19%) to give compound 409-7 (10.1 g, yield 87.5%).

[0932] Steps 7 and 8: Preparation of 2-(2-(methyl-d3)propyl-2-yl-1,1,1,3,3,3-d6)-9-(methylthio)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene (409-9)

[0933] Compound 409-7 (10.1 g, 26.6 mmol), Xphos Pd G3 (4.5 g, 5.3 mmol), and Cs₂CO₃ (25.9 g, 79.8 mmol) were added sequentially to dioxane (250 mL) at room temperature. The reaction mixture was stirred at 100 °C for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and t-BuOK (4.5 g, 39.9 mmol) was added. The reaction mixture was stirred at 100 °C for 50 minutes. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with DCM. The filtrates were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0-18%) to give compound 409-9 (6.32 g, total yield of 73.5%).

[0934] Step 9: Preparation of 2-(2-(methyl-d3)propyl-2-yl-1,1,1,3,3,3-d6)-9-(methylsulfinyl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene (409-10)

[0935] At 0°C, m-CPBA (85%, 4.05 g, 19.9 mmol) was slowly added to a DCM (160 mL) solution of compound 409-9 (6.32 g, 19.5 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C, and the pH was adjusted to >7 with saturated sodium bicarbonate solution. Extraction was performed with DCM, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used directly in the next reaction step.

[0936] Step 10: Preparation of (3R,4R)-3-fluoro-4-((2-(2-(methyl-d3)propyl-2-yl-1,1,1,3,3,3-d6)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (409-11)

[0937] Compound 409-10 (6.65 g, 19.5 mmol), (3R,4R)-4-amino-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (12.8 g, 58.6 mmol), and DIPEA (7.6 g, 58.6 mmol) were added sequentially to DMSO (90 mL) at room temperature. The reaction mixture was stirred at 120 °C for 16 hours. The reaction solution was cooled to room temperature, and EA and H2O were added. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0-13%) to give compound 409-11 (8.45 g, total yield of 87.6% in both steps).

[0938] Step 11: Preparation of N-((3R,4R)-3-fluoropiperidin-4-yl)-2-(2-(methyl-d3)propyl-2-yl-1,1,1,3,3,3-d6)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (409-12)

[0939] At room temperature, 30 mL of TFA was slowly added to a 90 mL solution of compound 409-11 (8.45 g, 17.1 mmol) in DCM. The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the resulting residue was dissolved in DCM. The pH was adjusted to >7 with an aqueous sodium bicarbonate solution, and the mixture was extracted with DCM. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was used directly in the next reaction.

[0940] Step 12: Preparation of N-((3R,4R)-3-fluoro-1-(methanesulfonyl)piperidin-4-yl)-2-(2-(methyl-d3)propyl-2-yl-1,1,1,3,3,3-d6)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthene-9-amine (409)

[0941] At 0 °C, Ms₂O (3.13 g, 18 mmol) was slowly added to a DCM (90 mL) solution of compound 409-11 (6.7 g, 17 mmol) and triethylamine (3.44 g, 34 mmol). The reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was cooled to 0 °C, and DCM and H₂O were added. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (water / acetonitrile = 95% / 5%-10% / 90%, gradient elution) to give compound 409 (5.15 g, total yield of 64% in two steps, purity 99.9%).

[0942] Step 13: Preparation of (S)-N-((3R,4R)-3-fluoro-1-(methanesulfonyl)piperidin-4-yl)-2-(2-(methyl-d3)propyl-2-yl-1,1,1,3,3,3-d6)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthen-9-amine (410) and (R)-N-((3R,4R)-3-fluoro-1-(methanesulfonyl)piperidin-4-yl)-2-(2-(methyl-d3)propyl-2-yl-1,1,1,3,3,3-d6)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoranthen-9-amine (411)

[0943] Compound 409 (1670 mg) was separated and purified by SFC (column: OD-3, mobile phase: CO2:EtOH = 70:30, flow rate: 2.5 mL), with chirality randomly assigned, to obtain compound 410 (705 mg, ee value: 99.4%, purity 99.63%) and compound 411 (658 mg, ee value: 99.24%, purity 100%).

[0944] LC-MS (ESI) + ): 472.2 m / z [M+H] + .

[0945] 1H NMR (400MHz, DMSO-d6) δ9.08 (s, 1H), 7.88 (d, J = 5.5Hz, 1H), 7.77 (s, 1H), 7.49 (d ,J=5.5Hz,1H),4.70(d,J=49.7Hz,1H),4.43(d,J=28.3Hz,2H),4.27(d,J=10.2Hz ,1H),3.95(t,J=11.5Hz,1H),3.72(t,J=13.5Hz,1H),3.49(d,J=12.2Hz,1H),3.2 1(s,1H),3.12(d,J=8.8Hz,1H),2.96(s,3H),2.07(s,1H),1.67(d,J=9.6Hz,1H).

[0946] The following compounds were synthesized using the corresponding starting materials according to Examples 409, 165, and 163:

[0947] Example 425: Synthesis of (3R,4R)-4-(((8aR,11aS)-10,10-dimethyl-8,8a,9,10,11,11-hexahydro-12-oxa-1,5,7,7b-tetraazazolino[5,6,7-jk]fluorene-6-yl)amino)-1-(methanesulfonyl)piperidine-3-ol (425)

[0948] Step 1: Preparation of methyl 2-hydroxy-4,4-dimethylcyclopentane-1-carboxylate (425-2)

[0949] 4,4-Dimethyl-2-oxocyclopentane-1-carboxylate 425-1 (200 mg, 1.17 mmol) was dissolved in ethanol (5 mL) at room temperature, and sodium borohydride (66.97 mg, 1.76 mmol) was added under ice bath conditions. The resulting mixture was stirred at 0 °C for 1 hour. The reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 425-2 (200 mg, 98.8% yield).

[0950] Step 2: Preparation of 2-hydroxy-4,4-dimethylcyclopentane-1-carboxamide (425-3)

[0951] Compound 425-2 (200 mg, 1.16 mmol) was dissolved in ammonia-methanol solution (5 mL), and the resulting mixture was stirred at 50 °C for 21 hours in a sealed tube. The mixture was quenched with an aqueous solution (50 mL) and extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 425-3 (150 mg, yield 82.2%).

[0952] Step 3: Preparation of 2-(aminomethyl)-4,4-dimethylcyclopentan-1-ol (425-4)

[0953] Compound 425-3 (150 mg, 0.95 mmol) was dissolved in tetrahydrofuran (3 mL), and lithium aluminum hydride (0.76 mL, 2.5 M) was added under ice bath conditions. The resulting mixture was stirred at 70 °C for 12 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give compound 425-4 (100 mg, 73.5% yield).

[0954] LC-MS (ESI) + ): 144.2 m / z [M+H] + .

[0955] Compound 425 was synthesized using the corresponding raw materials according to steps 3-6 of Example 160 and the method of Example 163.

[0956] LC-MS (ESI) + ): 487.2 m / z [M+H] + .

[0957] 1 H NMR (400MHz, DMSO-d6) δ9.06 (s, 1H), 7.91 (d, J = 4.0Hz, 1H), 7.62 (d, J = 4.0Hz ,1H),7.47(s,1H),5.25(s,1H),4.72-4.66(m,2H),3.96(s,1H),3.64-3.60(m ,3H),3.51-3.48(m,1H),2.91(s,4H),2.79–2.72(m,2H),2.22-2.17(m,1H), 2.10(s,1H),1.97–1.87(m,2H),1.56–1.44(m,2H),1.18(s,3H),1.12(s,3H).

[0958] The following compounds were synthesized using the corresponding starting materials according to steps 7-9 of Examples 425 and 160:

[0959] Examples 427 and 428: Synthesis of (8aS,11aS)-8a-methyl-N-(1-(methanesulfonyl)piperidin-4-yl)-8,8a,9,10,11,11-hexahydro-12-oxa-1,5,7,7b-tetraazazolino[5,6,7-jk]fluorene-6-amine (427) and (8aS,11aR)-8a-methyl-N-(1-(methanesulfonyl)piperidin-4-yl)-8,8a,9,10,11,11-hexahydro-12-oxa-1,5,7,7b-tetraazazolino[5,6,7-jk]fluorene-6-amine (428)

[0960] Step 1: Preparation of 1-methyl-2-oxocyclopentane-1-onitrile (427-2)

[0961] At room temperature, with stirring, 5 mL of an aqueous solution of lithium hydroxide (290 mg, 12.1 mmol) and iodomethane (0.75 mL, 12.1 mmol) were added to a methanol solution of 2-oxocyclopentanonitrile (1100 mg, 10.1 mmol) (5 mL). The resulting mixture was heated to 50 °C and stirred for 1.5 hours. The methanol solvent was removed under vacuum. The aqueous residue was extracted with EA (2 x 25 mL). The combined extracts were dried (Na₂SO₄), decantated, and concentrated to give compound 427-2 (1000 mg, 81% yield).

[0962] Step 2: Preparation of 2-(aminomethyl)-2-methylcyclopentan-1-ol (427-3)

[0963] At 0 °C, LiAlH4 (200 mg, 5.28 mmol) was added to an anhydrous THF (5.0 mL) solution of compound 427-2 (500 mg, 4.06 mmol). The mixture was stirred at room temperature for 16 hours. Sodium sulfate decahydrate (1800 mg) was added to the mixture at room temperature. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 427-3 (300 mg, 57% yield).

[0964] LC-MS (ESI) + ): 130.2m / z [M+H] + .

[0965] Following the method of Example 47, compound 427 (fraction 1, cis-trans randomly specified) and compound 428 (fraction 2, cis-trans randomly specified) were synthesized by replacing (S)-2-amino-1-phenylethyl-1-ol with compound 427-3.

[0966] Compound 427:

[0967] LC-MS (ESI) + ): 457.2 m / z [M+H] + .

[0968] 1 H NMR (400MHz, DMSO-d6) δ9.17–9.00(m,1H),8.28–8.11(m,1H),7.94(d,J=5.2Hz,1H),7.64(d,J=5.2Hz,1H),4.75–4.4 1(m,2H),4.13–3.95(m,1H),3.69–3.48(m,4H),3.04–2.79(m,5H),2.42–2.23(m,1H),2.04–1.57(m,8H),0.98(s,3H).

[0969] Compound 428:

[0970] LC-MS (ESI) + ): 457.2m / z[M+H]+.

[0971] 1 H NMR(400MHz, DMSO-d6)δ9.21–8.86(m,1H),7.91(d,J=5.2Hz,1H),7.66(d,J=5.2Hz,1H),7.63–7.47(m,1H),4.55–4.35(m,1H), 4.32–4.17(m,2H),4.16–3.94(m,1H),3.67–3.52(m,3H),3.03–2.85(m,5H),2.38–2.20(m,1H),2.03–1.58(m,8H),0.95(s,3H).

[0972] The following compounds were synthesized using the corresponding starting materials according to steps 7-9 of Example 427, Example 160, and the method of Example 163:

[0973] Examples 433 and 434: Synthesis of (9aS,12aR)-9a-methyl-N-(1-(methanesulfonyl)piperidin-4-yl)-9,9a,10,11,12,12a-hexahydro-8-oxa-1,3,7,12b-tetraazaazolo[6,5,4-jk]fluorene-2-amine (433) and (9aR,12aR)-9a-methyl-N-(1-(methanesulfonyl)piperidin-4-yl)-9,9a,10,11,12,12a-hexahydro-8-oxa-1,3,7,12b-tetraazaazolo[6,5,4-jk]fluorene-2-amine (434)

[0974] Step 1: Preparation of (E)-2-(hydroxyimino)-1-methylcyclopentane-1-carboxylic acid ethyl ester (433-2)

[0975] At room temperature, NH₂OH·HCl (225 mg, 3.23 mmol) was added to a mixture of ethyl 1-methyl-2-oxocyclopentane-1-carboxylate (500 mg, 2.94 mmol) in ethanol / water (4 mL / 1 mL). The resulting mixture was stirred at room temperature for 6 hours. Then, it was concentrated under reduced pressure to give compound 433-2 (530 mg, crude product).

[0976] LC-MS (ESI) + ): 186.2m / z [M+H] + .

[0977] Step 2: Preparation of ethyl 2-amino-1-methylcyclopentane-1-carboxylate (433-3)

[0978] At room temperature, Raney nickel (100 mg) was added to a 5.0 mL ethanol solution of compound 433-2 (530 mg, 2.86 mmol). The resulting mixture was heated to 100 °C and stirred for 5 hours under a hydrogen atmosphere. The mixture was filtered and concentrated under reduced pressure to give compound 433-3 (oil, 400 mg, yield 82%).

[0979] LC-MS (ESI) + ): 172.2 m / z [M+H] + .

[0980] Step 3: Preparation of (2-amino-1-methylcyclopentyl)methanol (433-4)

[0981] At 0 °C, LiAlH4 (115.3 mg, 3.04 mmol) was added to a solution of compound 433-3 (400 mg, 2.34 mmol) in anhydrous THF (3.0 mL). The mixture was stirred at room temperature for 16 hours. Na2SO4·10H2O (1800 mg) was added to the mixture at room temperature. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 433-4 (solid, 300 mg, 99% yield).

[0982] LC-MS (ESI) + ): 130.2 m / z [M+H] + .

[0983] Following the method of Example 47, (S)-2-amino-1-phenylethyl-1-ol was replaced with compound 433-4 to synthesize compound 433 (fraction 1, cis-trans randomly specified) and compound 434 (fraction 2, cis-trans randomly specified).

[0984] Compound 433:

[0985] LC-MS (ESI) + ): 457.2 m / z [M+H] + .

[0986] 1 H NMR (400MHz, DMSO-d6) δ9.15–8.98(m,1H),8.39–8.15(m,1H),7.96(d,J=5.2Hz,1H),7.64(d,J=5.2Hz,1H),4.41–4.27(m,1H), 4.18–4.05(m,1H),4.03–3.80(m,2H),3.61–3.49(m,4H),2.99–2.80(m,5H),2.08–1.74(m,4H),1.65–1.46(m,4H),0.94(s,3H).

[0987] Compound 434:

[0988] LC-MS (ESI) + ): 457.2 m / z [M+H] + .

[0989] 1H NMR(400MHz, DMSO-d6)δ9.16–8.97(m,1H),7.90(d,J=5.2Hz,1H),7.62(d,J=5.2Hz,1H),7.59–7.43(m,1H),4.84–4.72(m,1H), 4.50–4.28(m,1H),4.18–3.97(m,2H),3.60–3.51(m,3H),2.94–2.81(m,5H),2.12–1.95(m,4H),1.77–1.51(m,5H),1.20(s,3H).

[0990] The following compounds were synthesized using the corresponding starting materials according to steps 7-9 of Example 433, Example 160, and the method of Example 163:

[0991] Examples 448, 449 and 450: (8aS,12aS)-12,12-dimethyl-N-(1-(methanesulfonyl)piperidin-4-yl)-8a,9,10,11,12,12a-hexahydro-8-oxo-1,3,7,12b-tetraazabenzo[a]acetylanthralen-2-amine (448), (8aS,12aR)-12,12-dimethyl-N-(1-(methanesulfonyl)piperidin-4-yl)-8a Synthesis of 9,10,11,12,12a-hexahydro-8-oxo-1,3,7,12b-tetraazabenzo[a]acetanelenolin-2-amine (449) and (8aR,12aS)-12,12-dimethyl-N-(1-(methanesulfonyl)piperidin-4-yl)-8a,9,10,11,12,12a-hexahydro-8-oxo-1,3,7,12b-tetraazabenzo[a]acetanelenoxazol-2-amine (450)

[0992] Step 1: Preparation of (E)-2-(hydroxyimino)-3,3-dimethylcyclohexanone (448-2)

[0993] Under ice bath conditions, t-BuOK (1.3 g, 11.9 mmol) and tert-butyl nitrite (899 mg, 8.72 mmol) were added separately to a t-BuOH (10 mL) solution of compound 448-1 (1.0 g, 7.92 mmol), and stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted to 5 with 2 M HCl, and extracted with DCM (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 448-2 (400 mg, yield 32.5%, pale yellow solid).

[0994] Step 2: Preparation of 2-amino-3,3-dimethylcyclohexanol (448-3)

[0995] Under ice bath conditions, 2.5 M LiAlH4 (3.61 mL, 9.02 mmol) was slowly added to a THF (5.0 mL) solution of compound 448-2 (350 mg, 2.25 mmol), and the mixture was stirred at 80 °C for 4 hours. Under ice bath conditions, Na2SO4·10H2O was added and the mixture was stirred for 1 hour. The reaction solution was filtered through diatomaceous earth, washed with DCM / MeOH (v / v: 3 / 1), and the filtrate was concentrated under reduced pressure to give compound 448-3 (320 mg, 99.1% yield, a pale yellow oil).

[0996] Following the method of Example 165, 3-amino-1,7,7-trimethylbicyclo[2.2.1]heptane-2-ol was replaced with compound 448-3 to synthesize compound 448 (fraction 1, cis-trans randomly specified), compound 449 (fraction 2, cis-trans randomly specified) and compound 450 (fraction 3, cis-trans randomly specified).

[0997] Compound 448:

[0998] LC-MS (ESI) + ): 471.2 m / z [M+H] + .

[0999] 1 H NMR(400MHz, DMSO-d6)δ9.08(s,1H),7.90(d,J=5.5Hz,1H),7.50(d,J=5.5Hz,1H),4.80(s,1H),4.63(s,1H),3.95(s,1H),3.63–3.55(m,2H),2 .92–2.97(m,5H),2.57(s,1H),2.02(t,J=16.3Hz,4H),1.79(s,1H),1.6 9–1.52(m,2H),1.45(dd,J=22.0,7.9Hz,2H),1.27(s,1H),1.06(s,6H).

[1000] Compound 449:

[1001] LC-MS (ESI) + ): 471.2 m / z [M+H] + .

[1002] 1H NMR (400MHz, DMSO-d6) δ9.09(s,1H),7.90(d,J=5.5Hz,1H),7.51(d,J=5.5Hz,1H),4.74(s,1H),4.33(s,1H),4.01(dd,J=9.2,1. 4Hz,1H),3.70(s,2H),3.13(s,2H),2.98(d,J=1.1Hz,3H),2.11(s,1H),1.71(s,5H),1.64–1.45(m,2H),1.18(d,J=44.7Hz,8H).

[1003] Compound 450:

[1004] LC-MS (ESI) + ): 471.2 m / z [M+H] + .

[1005] 1 H NMR(400MHz, DMSO-d6)δ9.09(s,1H),7.90(d,J=5.5Hz,1H),7.51(d,J=5.5Hz,1H),4.80(s,1H),4.63(s,1H),3.95(s,1H),3.63–3.55(m,2 H),2.91(s,6H),2.56(s,1H),2.02(s,3H),1.77(s,1H),1.59–1.65(m,2H),1.54(d,J=7.0Hz,1H),1.46(s,2H),1.25(s,1H),1.05(s,6H).

[1006] The following compounds were synthesized using the corresponding starting materials according to steps 7-9 of Example 448, Example 160, and the method of Example 163:

[1007] Example 466: Synthesis of (3R,4R)-1-(methylsulfoxide)-4-((2-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluoreneanthracene-9-yl)amino)piperidine-3-ol (466)

[1008] Step 1: Preparation of 4,4,4-trifluoro-2-hydroxybutyronitrile (466-2)

[1009] Compound 466-1 (5.0 g, 44.6 mmol) and TMSCN (5.7 g, 58.0 mmol) were added sequentially to a DMSO / H₂O solution (50.0 / 10.0 mL), and stirred at 50 °C for 16 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 466-2 (6.2 g, 99.9% yield, pale yellow solid).

[1010] Step 2: Preparation of 1-amino-4,4,4-trifluorobut-2-ol (466-3)

[1011] Under ice bath conditions, 2.5 M LiAlH4 (35.6 mL, 89.1 mmol) was slowly added to a THF (60.0 mL) solution of compound 466-2 (6.2 g, 5.52 mmol), and the mixture was stirred at room temperature for 2 hours. Then, under ice bath conditions, Na2SO4·10H2O was added and the mixture was stirred for 1 hour. The reaction solution was filtered through diatomaceous earth, washed with DCM / MeOH (v / v: 3 / 1), and the filtrate was concentrated under reduced pressure to give compound 466-3 (5.2 g, yield 81.5%, a pale yellow oil).

[1012] Step 3: Preparation of 1-((5-bromo-2-(methylthio)pyrimidin-4-yl)amino)-4,4,4-trifluoro-2-butanol (466-4)

[1013] Compound 1-1 (7.0 g, 29.2 mmol), compound 466-3 (5.2 g, 35.1 mmol), and DIEA (11.3 g, 87.7 mmol) were sequentially added to a 50.0 mL solution of dioxane and stirred at 100 °C for 2 hours. Water (70 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (70 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 466-4 (7.0 g, yield 69.2%, pale yellow solid).

[1014] Step 4: Preparation of 1-((5-(3-chloro-2-fluoropyridin-4-yl)-2-(methylthio)pyrimidin-4-yl)amino)-4,4,4-trifluorobut-2-ol (466-5)

[1015] Compound 466-4 (6.5 g, 18.78 mmol), (3-chloro-2-fluoropyridin-4-yl)boronic acid (6.6 g, 37.5 mmol), Pd(dtbpf)Cl2 (1.2 g, 1.88 mmol), and potassium fluoride (3.3 g, 56.3 mmol) were added sequentially to a dioxane (50.0 mL) / H2O (10.0 mL) solution. The mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. Water (60 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (60 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 466-5 (7.4 g, 99.3% yield, pale yellow solid).

[1016] Step 5: Preparation of N-(2-((tert-butyldimethylsilyl)oxy)-4,4,4-trifluorobutyl)-5-(3-chloro-2-fluoropyridin-4-yl)-2-(methylthio)pyrimidine-4-amine (466-6)

[1017] Under ice bath conditions, TBSOTf (7.4 g, 28.0 mmol) was added to a DCM (50 mL) solution of compound 466-5 (7.4 g, 18.6 mmol) and 2,6-dimethylpyridine (4.0 g, 37.3 mmol), and the mixture was stirred at room temperature for 2 hours. An aqueous solution (50 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 466-6 (8.3 g, 87.1% yield, pale yellow solid).

[1018] Step 6: Preparation of 9-(2-((tert-butyldimethylsilyl)oxy)-4,4,4-trifluorobutyl)-8-fluoro-2-(methylthio)-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine (466-7)

[1019] Compound 466-6 (5.0 g, 9.78 mmol), XPhos Pd G3 (1.24 g, 1.47 mmol), and cesium carbonate (9.56 g, 29.3 mmol) were sequentially added to a 50.0 mL solution of dioxane. The mixture was stirred at 100 °C for 2.0 h under a nitrogen atmosphere. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 466-7 (4.6 g, 99.1% yield, pale yellow solid).

[1020] Step 7: Preparation of 4,4,4-trifluoro-1-(8-fluoro-2-(methylthio)-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)but-2-ol (466-8)

[1021] Under ice bath conditions, 1 M TBAF (10.7 mL, 10.7 mmol) was slowly added to a THF (2.0 mL) solution of compound 466-7 (4.6 g, 9.69 mmol), and the mixture was stirred at 0°C for half an hour. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 466-8 (2.6 g, yield 74.4%, pale yellow solid).

[1022] Step 8: Preparation of 4,4,4-trifluoro-1-(8-fluoro-2-(methylthio)-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)but-2-one (466-9)

[1023] DMP (6.1 g, 14.4 mmol) was added to a DCM (30.0 mL) solution of compound 466-8 (2.6 g, 7.21 mmol) and stirred at room temperature for 2.5 hours. Sodium bicarbonate aqueous solution (20 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 466-9 (2.6 g, 100% yield, pale yellow solid).

[1024] Step 9: Preparation of 1,1,1,4,4,4-hexafluoro-2-((8-fluoro-2-(methylthio)-9H-pyridopyrrolopyrimidin-9-yl)methyl)but-2-ol (466-10)

[1025] Under ice bath conditions, TMSCF3 (595 mg, 4.18 mmol) was slowly added to a THF (20.0 mL) solution of compound 466-9 (1.0 g, 2.79 mmol), and the mixture was stirred at 0°C for half an hour. A sodium bicarbonate aqueous solution (50 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 466-10 (240 mg, yield 20.1%, pale yellow solid).

[1026] Step 10: Preparation of 9-(methylthio)-2-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1,2-dihydro-3-oxo-4,8,10,10b-tetraazafluoroanthracene (466-11)

[1027] Compound 466-10 (240.0 mg, 0.56 mmol) and cesium carbonate (326 mg, 1.12 mmol) were slowly added to a solution of dioxane (3.0 mL), and the mixture was stirred at 40 °C for 3 hours. A sodium bicarbonate aqueous solution (20 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 466-11 (234 mg, 100% yield, yellow solid).

[1028] Step 11: Preparation of 9-(methylsulfoxide)-2-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1,2-dihydro-3-oxo-4,8,10,10b-tetraazafluoranthene (466-12)

[1029] m-CPBA (109 mg, 0.63 mmol) was slowly added to a DCM (3.0 mL) solution of compound 466-11 (234 mg, 0.57 mmol), and the mixture was stirred at 0 °C for half an hour. Sodium bicarbonate aqueous solution (20 mL) was added to the reaction mixture, and the solution was extracted with EtOAc (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 466-12 (245 mg, 100% yield, pale yellow solid).

[1030] Step 12: Preparation of (3R,4R)-1-(methylsulfoxide)-4-((2-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1,2-dihydro-3-oxa-4,8,10,10b-tetraazafluorene-9-yl)amino)piperidine-3-ol (466)

[1031] Compound 466-12 (90 mg, 0.21 mmol), (3R,4R)-4-amino-1-(methanesulfonyl)piperidine-3-ol (compound 466-13, synthesized according to steps 1-3 of Example 356 and step 2 of Example 92, 82 mg, 0.42 mmol), and DIEA (82 mg, 0.64 mmol) were sequentially added to DMSO (1.0 mL), and stirred at 100 °C for 2.0 h. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (water / acetonitrile = 95% / 5%-10% / 90%, gradient elution) to give compound 466 (17.0 mg, 100% purity, 14.4% yield, white solid).

[1032] LC-MS (ESI) + ): 555.2 m / z [M+H] + .

[1033] 1 H NMR(400MHz,DMSO-d6)δ11.71(s,1H),9.09(s,1H),8.43(d,J=1.9Hz,1H),7 .26(d,J=6.7Hz,1H),6.91(d,J=6.7Hz,1H),5.28(s,1H),4.18(s,1H),4.01 –3.87(m,1H),3.62(s,3H),3.52(d,J=11.9Hz,1H),2.92(s,3H),2.83(s,1H ), 2.63 (s, 1H), 2.02 (d, J = 12.3Hz, 1H), 1.56 (d, J = 12.3Hz, 1H), 1.24 (s, 1H).

[1034] The following compounds were synthesized using the corresponding starting materials according to steps 7-9 of Example 466 and Example 160 and step 5 of Example 1:

[1035] Example 469: 3-Fluoro-N-(1-(methanesulfonyl)piperidin-4-yl)-1'H-3'-oxa-4',8',10',10b'-tetraazaspiro[cyclobutane-1,2'-fluoranthene]-3a',3a 1 Synthesis of '(6a'),5',6b',8',10'-hexene-9'-amine (469)

[1036] Following the method of Example 164, compound 469-1 was synthesized by replacing compound 164-1 with 3-((tert-butyldimethylsilyl)oxy)cyclobutane-1-one. Compound 469 was then synthesized by following step 7 of Example 466 and step 2 of Example 128.

[1037] LC-MS (ESI) + ): 447.2 m / z [M+H] + .

[1038] 1 H NMR (400MHz, DMSO-d6) δ9.21–8.95(m,1H),8.52–8.28(m,1H),7.93(d,J=5.6Hz,1H),7.54(d,J=5.6Hz,1H),5.62–5.37(m,1H),4.4 9–4.34(m,2H),4.14–4.02(m,1H),3.64–3.54(m,4H),3.00–2.88(m,5H),2.73–2.65(m,2H),2.13–1.95(m,2H),1.71–1.57(m,2H).

[1039] The following compounds were synthesized using the corresponding starting materials according to the methods of Examples 160, 163, and 469:

[1040] Example 472: Synthesis of 6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-4-oxa-3,7a,8,10-tetraazacycloheptane[jk]fluorene-9-amine (472)

[1041] Step 1: Preparation of ethyl 2-cyano-2-(tetrahydro-2H-pyran-4-yl)propionate (472-2).

[1042] Ethyl 2-cyanopropionate (1.54 g, 12.1 mmol) was dissolved in DMF (3 mL) under ice bath conditions, followed by the addition of NaH (60%, 1.45 g, 36.26 mmol). The resulting reaction mixture was stirred at room temperature for 0.5 hours. Then, 4-bromotetrahydropyran (compound 472-1, 2 g, 12.12 mmol) was added under ice bath conditions, and the resulting reaction mixture was stirred at room temperature for 2 hours. Extraction was performed using DCM (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give compound 472-2 (1.9 g, 74.2% yield, yellow solid).

[1043] LC-MS (ESI) + ): 212.2 m / z [M+H] + .

[1044] Step 2: Preparation of 3-amino-2-methyl-2-(tetrahydro-2H-pyran-4-yl)prop-1-ol (472-3)

[1045] Compound 472-2 (1.9 g, 8.96 mmol) was dissolved in THF (20 mL), and lithium aluminum hydride (14.3 mL, 35.8 mmol) was slowly added at 0 °C. The resulting reaction solution was stirred at room temperature for 3 hours. The reaction was quenched by adding sodium sulfate decahydrate, filtered, and the filtrate was diluted with water and extracted with DCM (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 472-3, which was used directly in the next reaction.

[1046] LC-MS (ESI) + ):174.2m / z[M+H] + .

[1047] Compound 472 was synthesized by replacing 3-amino-1,7,7-trimethylbicyclo[2.2.1]heptane-2-ol with compound 472-3 according to the method of Example 165.

[1048] LC-MS (ESI) + ): 501.0 m / z [M+H] + .

[1049] 1H NMR (400MHz, DMSO-d6) δ9.00(s,1H),7.87(d,J=5.2Hz,1H),7.56(d,J=5.2Hz,2H ),4.51–4.44(m,1H),4.28(d,J=12.8Hz,1H),4.12(d,J=12.8Hz,1H),3.98–3.95 (s,1H),3.83–3.75(m,2H),3.59–3.44(m,3H),3.06(dt,J=31.2,11.6Hz,2H),2. 82(s,5H),2.00–1.92(m,2H),1.71–1.48(m,4H),1.46–1.30(m,3H),0.90(s,3H).

[1050] The following compounds were synthesized using the corresponding starting materials according to steps 7, 8, and 9 of Example 472, Example 160, and the method of Example 163:

[1051] Example 481: N-(1-(methylsulfonyl)piperidin-4-yl)-5H,7H-4-oxa-3,7a,8,10-tetraazabispiro[cycloheptane[jk]fluorene-6,1'-cyclobutane-3',3'-oxacyclobutane]-1,3,3a 1 Synthesis of (11b),7b,9,11-hexen-9-amine (481)

[1052] Step 1: Preparation of ethyl 6-cyano-2-oxaspiro[3.3]heptane-6-carboxylic acid (481-2).

[1053] At room temperature, 3,3-bis(bromomethyl)oxetane (compound 481-1, 2.0 g, 8.2 mmol) and ethyl cyanoacetate (927.4 mg, 8.2 mmol) were dissolved in DMF (10 mL), followed by the addition of potassium carbonate (3.4 g, 24.6 mmol). The resulting reaction mixture was stirred at 80 °C for 16 hours. The resulting reaction mixture was extracted with DCM (50 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 482-2 (1.4 g, yield 87.5%, yellow solid).

[1054] LC-MS (ESI) + ): 196.2 m / z [M+H] + .

[1055] Step 2: Preparation of (6-(aminomethyl)-2-oxaspiro[3.3]heptane-6-yl)methanol (481-3)

[1056] Compound 481-2 (1.4 g, 7.14 mmol) was dissolved in THF (20 mL), and lithium aluminum hydride (8.7 mL, 21.4 mmol) was slowly added at 0 °C. The resulting reaction solution was stirred at room temperature for 3 hours. The reaction was quenched by adding sodium sulfate decahydrate, and extracted with DCM (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 481-3, which was used directly in the next reaction.

[1057] LC-MS (ESI) + ): 158.2m / z [M+H] + .

[1058] According to the method of Example 165, compound 481 was synthesized by replacing 3-amino-1,7,7-trimethylbicyclo[2.2.1]heptane-2-ol with compound 481-3.

[1059] LC-MS (ESI) + ): 485.2 m / z [M+H] + .

[1060] 1 H NMR (400MHz, DMSO-d6) δ9.09(s,1H),7.94(d,J=5.2Hz,1H),7.63(d,J=5.2Hz,2H),4.66(s,4H),4.34(s,2H),4.15(s,2H),4.06(s,1 H), 3.59-3.56 (m, 3H), 2.91-2.85 (m, 4H), 2.36 (d, J = 12.4Hz, 2H), 2.13 (d, J = 12.4Hz, 2H), 2.04 (s, 2H), 1.65-1.62 (d, J = 12.0Hz, 2H).

[1061] The following compounds were synthesized using the corresponding starting materials according to steps 7, 8, and 9 of Examples 481 and 160, and the method of Example 163:

[1062] Example 484: Synthesis of (3R,4R)-4-[(4',4'-difluoro-5H,7H-4-oxa-3,7a,8,10-tetraazaspiro[cycloheptane[jk]fluorene-6,1'-cyclohexane]-1,3,3a1(11b),7b,9,11-hexen-9-yl)amino]-1-(methanesulfonyl)piperidine-3-ol (484)

[1063] Step 1: Preparation of ethyl 1-cyano-4,4-difluorocyclohexane-1-carboxylate (484-2)

[1064] Under a nitrogen atmosphere, LDA (1 M THF solution, 15.61 mL, 15.61 mol) was added to a tetrahydrofuran (20 mL) solution of ethyl 4,4-difluorocyclohexane-1-carboxylate (compound 484-1, 2.0 g, 10.41 mol) at -70 °C. The mixture was stirred at -70 °C for 1 hour. Then, 4-methylbenzenesulfonyl cyanide (2.8 g, 15.61 mol) dissolved in tetrahydrofuran (30 mL) was added, and the mixture was stirred at -70 °C for 1 hour. The reaction mixture was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give compound 484-2 (800 mg, 35% yield, white solid).

[1065] LC-MS (ESI) + ):218.2m / z[M+H] + .

[1066] Step 2: Preparation of (1-(aminomethyl)-4,4-difluorocyclohexyl)methanol (484-3)

[1067] Compound 484-2 (800 mg, 3.69 mmol) was dissolved in THF (15 mL), and then LiAlH4 (2.5 M THF solution, 6 mL, 14.76 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with Na2SO4·10H2O, filtered with diatomaceous earth, and compound 484-3 (crude product) was obtained, which was used directly in the next step without purification.

[1068] LC-MS (ESI) + ): 180.2m / z [M+H] + .

[1069] Following steps 3-6 of Example 160 and the method of Example 163, compound 484 was synthesized by replacing compound 160-3 with compound 484-3.

[1070] LC-MS (ESI) + ): 523.2 m / z [M+H] + .

[1071] Examples 485 and 486: Synthesis of 9-(((3R,4R)-3-hydroxy-1-methanesulfonylpiperidin-4-yl)amino)-4'-methyl-5H,7H-4-oxa-3,7a,8,10-tetraazaspiro[cycloheptan[jk]fluorene-6,1'-cyclohexane]-1,3,3a1(11b),7b,9,11-hexen-4'-ol (485) and 9-(((3R,4R)-3-hydroxy-1-methanesulfonylpiperidin-4-yl)amino)-4'-methyl-5H,7H-4-oxa-3,7a,8,10-tetraazaspiro[cycloheptan[jk]fluorene-6,1'-cyclohexane]-1,3,3a1(11b),7b,9,11-hexen-4'-ol (486)

[1072] Following the method of Example 484, compound 485-1 was replaced with compound 484-1 to synthesize 485-3.

[1073] Following steps 3-5 of Example 160, compound 485-3 was replaced with compound 160-3 to synthesize compound 485-4.

[1074] Step 6: 9-(methylthio)-5H,7H-4-oxa-3,7a,8,10-tetraazaspiro[cycloheptano[jk]fluorene-6,1'-cyclohexane]-1,3,3a 1 Preparation of (11b),7b,9,11-hexen-4'-one (485-5)

[1075] Dissolve 485-4 (300 mg, 0.75 mmol) in acetonitrile (4 mL), and add hydrochloric acid aqueous solution (4 mL, 4 M) at room temperature. After the addition is complete, stir the resulting mixture at 50 °C for 16 hours. Add ice water (10 mL) to the reaction solution and extract with ethyl acetate (10 mL × 3). Combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude 485-5, which can be used directly in the next step without purification.

[1076] LC-MS (ESI) + ): 355.2 m / z [M+H] + .

[1077] Step 7: 4'-Methyl-9-(methylthio)-5H,7H-4-oxa-3,7a,8,10-tetraazaspiro[cycloheptano[jk]fluorene-6,1'-cyclohexane]-1,3,3a 1 Preparation of (11b),7b,9,11-hexen-4'-ol (485-6)

[1078] 485-5 (approximately 0.75 mmol crude) was dissolved in tetrahydrofuran (6 mL), and methylmagnesium chloride (1.5 mL, 1.5 mmol in 1 M THF solution) was added at 0 °C. The mixture was stirred at 0 °C for 2 hours, and then quenched with saturated ammonium chloride solution at 0 °C. The resulting mixture was extracted with ethyl acetate. Ice water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 485-6, which could be used directly in the next step without purification.

[1079] LC-MS (ESI) + ):371.2m / z[M+H] + .

[1080] Following step 6 of Example 160 and Example 163, compound 485 was synthesized by replacing compound 160-6 with compound 485-6.

[1081] LC-MS (ESI) + ): 517.2 m / z [M+H] + .

[1082] Example 487: N-(1-(methylsulfonyl)piperidin-4-yl)-2”,3”,5”,6”-tetrahydro-5H,7H-4-oxa-3,7a,8,10-tetraazabispiro[cycloheptane[jk]fluorene-6,1'-cyclopropane-2',4”-pyran]-1,3,3a 1 Synthesis of (11b),7b,9,11-hexen-9-amine (487)

[1083] Step 1: Preparation of methyl 2-cyano-2-(tetrahydro-4H-pyran-4-yl)acetate (487-2)

[1084] At room temperature, methyl 2-cyanoacetate (2 g, 20.18 mmol) was dissolved in toluene (20 mL), and tetrahydro-4H-pyran-4-one (compound 487-1, 2.42 g, 24.22 mmol), ammonium acetate (404 mg, 5.25 mmol), and acetic acid (0.2 mL) were added. The resulting mixture was stirred at 110 °C for 12 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 487-2 (2.2 g, 60% yield).

[1085] Step 2: Preparation of methyl 1-cyano-6-oxaspiro[2.5]octane-1-carboxylate (487-3)

[1086] Compound 487-2 (500 mg, 2.76 mmol) was dissolved in acetonitrile (10 mL), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (420 mg, 2.76 mmol) and nitromethane (841 mg, 13.8 mmol) were added. The mixture was stirred at 25 °C for 12 hours. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 487-3 (300 mg, yield 55.69%).

[1087] Step 3: Preparation of (1-(aminomethyl)-6-oxaspiro[2.5]octane-1-yl)methanol (487-4)

[1088] Compound 487-3 (360 mg, 1.84 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium aluminum hydride (2.21 mL, 2.5 M) was added under ice bath conditions. The resulting mixture was stirred at 25 °C for 2 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give compound 487-4 (300 mg, 95% yield).

[1089] LC-MS (ESI) + ): 172.2 m / z [M+H] + .

[1090] Compound 487 was synthesized by replacing 3-amino-1,7,7-trimethylbicyclo[2.2.1]heptane-2-ol with compound 487-4.

[1091] LC-MS (ESI) + ): 499.2 m / z [M+H] + .

[1092] 1H NMR (400MHz, DMSO-d6) δ9.08(s,1H),7.96(d,J=4.0Hz,1H),7.64(d,J=4.0Hz,1H),4.73(s, 1H),4.45(d,J=12.0Hz,1H),4.34(s,1H),4.21(d,J=12.0Hz,1H),4.02(s,1H),3.54(d,J=12 .0Hz,3H),3.45(t,J=8.0Hz,1H),3.34(s,1H),3.21(s,1H),2.92-2.88(m,5H),1.98(s,2H), 1.75-1.73(m,1H),1.59(t,J=12.0Hz,3H),1.30(s,2H),0.96(d,J=4.0Hz,1H),0.85(s,1H).

[1093] The following compounds were synthesized using the corresponding starting materials according to steps 7, 8, and 9 of Example 487, Example 160, and the method of Example 163:

[1094] Example 490: N-(1-(methylsulfonyl)piperidin-4-yl)-2'-phenyl-5H,7H-4-oxa-3,7a,8,10-tetraazaspiro[cycloheptane[jk]fluorene-6,1'-cyclopropane]-1,3,3a 1 Synthesis of (11b),7b,9,11-hexen-9-amine (490)

[1095] Step 1: Preparation of methyl 1-cyano-2-phenylcyclopropane-1-carboxylate (490-2)

[1096] Under ice bath conditions, trimethyl sulfoxide (1.76 g, 8.01 mmol) was dissolved in DMSO (5 mL), followed by the addition of NaH (480.6 mg, 12.0 mmol). The resulting reaction mixture was stirred at room temperature for 0.5 h. Then, methyl (Z)-2-cyano-3-phenylacrylate (500 mg, 2.67 mmol) was added, and the reaction mixture was stirred at room temperature for 3 h. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give compound 490-2 (340 mg, yield 63.4%, yellow solid).

[1097] LC-MS (ESI+): 202.2 m / z [M+H] + .

[1098] Step 2: Preparation of (1-(aminomethyl)-2-phenylcyclopropyl)methanol (490-3)

[1099] Compound 490-2 (340 mg, 1.68 mmol) was dissolved in THF (5 mL), and lithium aluminum hydride (2.7 mL, 6.72 mmol) was slowly added at 0 °C. The resulting reaction solution was stirred at room temperature for 3 hours. The reaction was quenched by adding decahydrate and sodium sulfate, and extracted with DCM (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 490-3, which was used directly in the next reaction.

[1100] LC-MS (ESI+): 178.2 m / z [M+H] + .

[1101] Compound 490 was synthesized by replacing 3-amino-1,7,7-trimethylbicyclo[2.2.1]heptane-2-ol with compound 490-3.

[1102] LC-MS (ESI) + ): 505.2 m / z [M+H] + .

[1103] The following compounds were synthesized using the corresponding starting materials according to steps 7, 8, and 9 of Examples 490 and 160, and the method of Example 163:

[1104] Example 493: Synthesis of 6-(2,4-difluorophenyl)-N-(1-(methylsulfonyl)piperidin-4-yl)-6,7-dihydro-5H-4-oxa-3,7a,8,10-tetraazacycloheptane[jk]fluorene-9-amine (493)

[1105] Step 1: Preparation of ethyl 2-cyano-2-(2,4-difluorophenyl)acetate (493-2)

[1106] At room temperature, ethyl 2-cyanoacetate (2 g, 17.7 mmol) was dissolved in dimethyl sulfoxide (30 mL), and 2,4-difluoro-1-iodobenzene (493-1, 5.09 g, 21.21 mmol), cuprous iodide (337 mg, 1.77 mmol), L-proline (407 mg, 3.54 mmol), and potassium carbonate (7.32 g, 53.0 mmol) were added. The mixture was stirred at 100 °C for 12 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 493-2 (890 mg, yield 22.4%).

[1107] Step 2: Preparation of 3-amino-2-(2,4-dif...

Claims

1. A compound of general formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in: X is selected from -0-, -S-, -NR 6 - or -CR 6a R 6b -; Y1, Y2, Y3, Y4are each independently selected from N or CR d ; Ring A is selected from cycloalkyl, heterocyclic, heteroaryl, or aryl groups; L is selected from the following groups: -S(O)2-, -S(O)-, -C(O)-, -S(O)2NH-, -S(O)NH-, -C(O)NH-, -CR b R c -; R 1 Selected from hydrogen, halogen, amino, nitro, hydroxyl, mercapto, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -NR 7a R 7b -P(O)R b R c -OR c The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally selected from deuterium, halogen, amino, and -NR. 8a R 8b It is substituted by one or more groups of nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; Each R 2 Each of the following groups is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, mercapto, cyano, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; or, any two R groups 2 Together with the atoms attached thereto, they form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more groups selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl. R 3a and R 3b Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, mercapto, cyano, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -(CH2). n -R 9 -(CH2) n -NR 8a R 8b The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, methylidene, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, and -NR. 8a R 8b -S(O) v R a -COOR a -C(O)R a -P(O)R b R c -(CH2) n -R 9 -(CH2) n -NR 8a R 8b -CONR 8a R 8b The group is substituted by one or more groups, including alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be further substituted by Q; or, R 3a and R 3b Together they form an oxygen group; or, R 3a With R 3b The atoms bonded to it together form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, -S(O). v R a -COOR a -C(O)R a -P(O)R b R c The group is substituted by one or more groups of alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl groups may optionally be further substituted by Q; R 4a and R 4b Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, mercapto, cyano, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -(CH2). n -R 9 -(CH2) n -NR 8a R 8b The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, methylidene, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, and -NR. 8a R 8b -S(O) v R a -COOR a -C(O)R a -P(O)R b R c -(CH2) n -R 9 -(CH2) n -NR 8a R 8b -CONR 8a R 8b The group is substituted by one or more groups, including alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be further substituted by Q; or, R 4a and R 4b Together they form an oxygen group; or, R 4a With R 4b The atoms bonded to it together form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, -S(O). v R a -COOR a -C(O)R a -P(O)R b R c The group is substituted by one or more groups of alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl groups may optionally be further substituted by Q; R 5a and R 5b Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, mercapto, cyano, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -(CH2). n -R 9 -(CH2) n -NR 8a R 8b The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, methylidene, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, and -NR. 8a R 8b -S(O) v R a -COOR a -C(O)R a -P(O)R b R c -(CH2) n -R 9 -(CH2) n -NR 8a R 8b -CONR 8a R 8b The group is substituted by one or more groups, including alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally further substituted by Q; or, R 5a and R 5b Together they form an oxygen group; or, R 5a With R 5b The atoms bonded to it together form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, -S(O). v R a -COOR a -C(O)R a -P(O)R b R c The group is substituted by one or more groups of alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl groups may optionally be further substituted by Q; R 6a and R 6b Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, mercapto, cyano, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -(CH2). n -R 9 -(CH2) n -NR 8a R 8b The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, and -S(O). v R a -COOR a -C(O)R a -P(O)R b R c The group is substituted by one or more groups of alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl; or, R 6a and R 6b Together they form an oxygen group; or, R 6a With R 6b The atoms bonded to it together form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, -S(O). v R a -COOR a -C(O)R a -P(O)R b R c It is substituted by one or more groups, such as alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl; R 6 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, mercapto, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -(CH2). n -R 9 -(CH2) n -NR 8a R 8b The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, and -S(O). v R a -COOR a -C(O)R a -P(O)R b R c It is substituted by one or more groups, such as alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl; or, R 3a or R 3b With R 4a or R 4b , or R 4a or R 4b With R 5a or R 5b , or R 3a or R 3b With R 5a or R 5b , or R 3a or R 3b With R 6a or R 6b , or R 4a or R 4b With R 6a or R 6b , or R 3a or R 3b With R 6 , or R 4a or R 4b With R 6 Together with the atoms they are connected to form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, -NR 7a R 7b -S(O) v R a -COOR a -C(O)R a -P(O)R b R c The alkyl, alkoxy, alkenyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are substituted, and the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups may optionally be further substituted with Q. R 7a and R 7b Each group is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; or, R 7a With R 7b Together with the nitrogen atom attached thereto, a heterocyclic group is formed, wherein the heterocyclic group is optionally selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, -NR. 8a R 8b It is substituted by one or more groups, including alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; R 8a and R 8b Each group is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; or, R 8a With R 8b Together with the nitrogen atom attached thereto, a heterocyclic group is formed, wherein the heterocyclic group is optionally replaced by one or more groups selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl. R 9 The group is selected from deuterium, halogen, amino, nitro, hydroxyl, mercapto, cyano, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; Q is selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; R a The group is selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; R b and R c Each group is independently selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; R d selected from hydrogen, halogen, amino, cyano, alkyl, alkoxy; t is 0, 1, or 2; m is an integer from 0 to 9; v is 1 or 2; n is an integer from 0 to 6.

2. The compound of formula (I) according to claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, Ring A is selected from 4-7 membered cycloalkyl, 4-7 membered heterocyclic, 5-10 membered heteroaryl, or C. 6-10 Aryl group, preferably 5-6 membered heterocyclic group, 5-6 membered heteroaryl group or phenyl group, more preferably 6 membered heterocyclic group, 6 membered heteroaryl group or phenyl group, and even more preferably piperidinyl group, tetrahydropyranyl group, morpholinyl group, piperazinyl group, pyridinyl group, pyrimidinyl group and phenyl group.

3. The compound of general formula (I) according to claim 1 or 2, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of general formula (II) is a stereoisomer thereof or a pharmaceutically acceptable salt thereof. in, X, L, R 1 , R 2 , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , t, m are as defined in claim 1.

4. The compound of general formula (I) according to any one of claims 1 to 3, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of general formula (III) is a stereoisomer thereof or a pharmaceutically acceptable salt thereof. in, X, R 1 , R 2 , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , t, m are as defined in claim 1.

5. The compound of general formula (I) according to any one of claims 1 to 4, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, -NR 7a R 7b The 4-6 member heterocyclic group is optionally C 1-6 Alkyl or oxo-substituted; the C 1-6 Alkyl groups are optionally halogenated, C 1-6 Alkoxy, C 3-6 Cycloalkyl substitution; R 7a and R 7b each independently is selected from the group consisting of hydrogen and C 1-6 alkyl.

6. The compound of general formula (I) according to any one of claims 1 to 4, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 1 selected from C 6-10 aryl or 5-10 membered heteroaryl; said C 6-10 aryl or 5-10 membered heteroaryl is optionally substituted with one or more groups selected from halo, -NR 8a R 8b , C 1-6 alkoxy, cyano, C 1-6 alkyl; R 8a and R 8b each independently is selected from hydrogen, C 1-6 alkyl; or, R 8a and R 8b together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclyl group, optionally substituted with a member selected from C 1-6 alkyl.

7. The compound of formula (I) according to any one of claims 1 to 3, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, L is selected from -S(O)2-, -S(O)-, -C(O)-, -S(O)2NH-, -S(O)NH-, -C(O)NH-, -CR b R c -; R 1 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -NR 7a R 7b The C 1-6 Alkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl are optionally selected from halogens, -NR 8a R 8b , cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 One or more cycloalkyl groups are substituted; R b R c Each is independently selected from hydrogen and C. 1-6 alkyl; R 7a and R 7b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl; R 8a and R 8b are each independently selected from hydrogen, C 1-6 alkyl; or, R 8a and R 8b together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl group, optionally substituted with a C 1-6 alkyl group.

8. The compound of formula (I) according to claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of formula (IV) is a stereoisomer thereof or a pharmaceutically acceptable salt thereof. in, Ring B is selected from C 6-10 Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclic or C 3-8 Cycloalkyl, preferably phenyl, 5-6 membered heteroaryl or 4-6 membered heterocyclic, more preferably phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazoleyl, thiazolyl, oxazolyl, pyrroleyl, pyrrolidinyl, cyclopropyl, azacyclobutyl, piperidinyl, piperazinyl, morpholinyl, cyclobutyl, cyclopentyl, cyclohexyl, and even more preferably phenyl, pyridinyl, pyrazolyl, imidazoleyl, thiazolyl; each R is independently selected from halogen, cyano, C 10 each R is independently selected from halogen, cyano, C 1-6 alkyl; n is 0, 1, or 2; X, R 2 , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , t, m are as defined in claim 1.

9. The compound of formula (I) according to claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of formula (V) is a stereoisomer thereof or a pharmaceutically acceptable salt thereof. R 1 Selected from hydrogen, halogen, amino, nitro, hydroxyl, mercapto, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -NR 7a R 7b The C 1-6 Alkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl are optionally selected from halogens, -NR 8a R 8b , cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 One or more cycloalkyl groups are substituted; Each R 2 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups; preferably hydrogen, hydroxyl, halogen, and C. 1-6 alkyl; R 3a and R 3b Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -(CH2) n -R 9 -(CH2) n -NR 8a R 8b The C 1-6 Alkyl, C 3-10 Cycloalkyl, phenyl, and 5-6-membered heteroaryl groups are optionally selected from deuterium, halogen, amino, hydroxyl, cyano, methyl subunit, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Haloalkoxy, -NR 8a R 8b -S(O) v R a -COOR a -C(O)R a -P(O)R b R c -(CH2) n -R 9 -(CH2) n -NR 8a R 8b -CONR 8a R 8b C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 The C group is substituted by one or more groups of cycloalkyl, phenyl, or 5-6-membered heteroaryl, wherein the C 3-6 Cycloalkyl, phenyl, or 5-6-membered heteroaryl groups may be further substituted with Q; or, R 3a and R 3b Together they form an oxygen group; or, R 3a With R 3b Together with the atoms it is connected to, they form C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -S(O) v R a , -C(O)R a one or more groups of R1A; R 4a and R 4b Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -(CH2) n -R 9 -(CH2) n -NR 8a R 8b The C 1-6 Alkyl, C 3-10 Cycloalkyl, phenyl, and 5-6 heteroaryl groups are optionally selected from deuterium, halogen, amino, hydroxyl, cyano, methyl subunit, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Haloalkoxy, -NR 8a R 8b -S(O) v R a -COOR a -C(O)R a -P(O)R b R c -(CH2) n -R 9 -(CH2) n -NR 8a R 8b -CONR 8a R 8b C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 The alkyl group is replaced by one or more groups of cycloalkyl, phenyl, or 5-6-membered heteroaryl, wherein the C 3-6 Cycloalkyl, phenyl, or 5-6-membered heteroaryl groups may be further substituted with Q; or, R 4a and R 4b Together they form an oxygen group; or, R 4a With R 4b Together with the atoms it is connected to, they form C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -S(O) v R a -C(O)R a One or more groups are replaced; R 5a and R 5b Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -(CH2) n -R 9 -(CH2) n -NR 8a R 8b The C 1-6 Alkyl, C 3-10 Cycloalkyl, phenyl, and 5-6 heteroaryl groups are optionally selected from deuterium, halogen, amino, hydroxyl, cyano, methyl subunit, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Haloalkoxy, -NR 8a R 8b -S(O) v R a -COOR a -C(O)R a -P(O)R b R c -(CH2) n -R 9 -(CH2) n -NR 8a R 8b -CONR 8a R 8b C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 The alkyl group is replaced by one or more groups of cycloalkyl, phenyl, or 5-6-membered heteroaryl, wherein the C 3-6 Cycloalkyl, phenyl, or 5-6-membered heteroaryl groups may be further substituted with Q; or, R 5a and R 5b Together they form an oxygen group; or, R 5a With R 5b Together with the atoms it is connected to, they form C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -S(O) v R a -C(O)R a One or more groups are replaced; or, R 3a or R 3b With R 4a or R 4b , or R 4a or R 4b With R 5a or R 5b , or R 3a or R 3b With R 5a or R 5b Together with the atoms connected to them, they form 3-10 membered cycloalkyl, 4-10 membered heterocyclic, phenyl, or 5-6 membered heteroaryl groups, wherein the 3-10 membered cycloalkyl, 4-10 membered heterocyclic, phenyl, or 5-6 membered heteroaryl groups are optionally selected from deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-10 membered heterocyclic, 5-10 membered heteroaryl, -NR 7a R 7b -C(O)R a -S(O) v R a The C group is replaced by the group that is substituted for the C group. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic, and 5-6 membered heteroaryl groups may be further substituted by Q; R 7a and R 7b Each is independently selected from hydrogen and C. 1-6 Alkyl; or, R 7a With R 7b Together with the nitrogen atom attached thereto, a 5-6 membered heterocyclic group is formed, wherein the 5-6 membered heterocyclic group is optionally selected from deuterium, halogen, amino, cyano, hydroxyl, mercapto, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 The alkoxy group is replaced by one or more groups of the haloalkoxy group; R 8a and R 8b Each is independently selected from hydrogen and C. 1-6 Alkyl; or R 8a With R 8b Together with the nitrogen atom attached thereto, a 5-6 membered heterocyclic group is formed, wherein the 5-6 membered heterocyclic group is optionally C 1-6 Alkyl substitution; R 9 Selected from hydroxyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, phenyl; Q is selected from hydrogen, halogen, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 4-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl group is optionally selected from deuterium, halogen, cyano, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 One or more cycloalkyl groups are substituted; R a Selected from C 1-6 Alkyl, amino, hydroxyl; R b and R c Each is independently selected from hydrogen and C. 1-6 alkyl; t is 0 or 1; m is 0 or 1; v is 1 or 2; n is an integer from 0 to 6.

10. The compound of formula (I) according to claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of formula (VI) is a stereoisomer thereof or a pharmaceutically acceptable salt thereof. R 1 Selected from hydrogen, halogen, amino, nitro, hydroxyl, mercapto, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -NR 7a R 7b The C 1-6 Alkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl are optionally selected from deuterium, halogen, -NR 8a R 8b , cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 One or more cycloalkyl groups are substituted; Each R 2 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups; preferably hydrogen, hydroxyl, halogen, and C. 1-6 alkyl; R 3a and R 3b Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -(CH2) n -R 9 -(CH2) n -NR 8a R 8b The C 1-6 Alkyl, C 3-10 Cycloalkyl, phenyl, and 5-6 heteroaryl groups are optionally selected from deuterium, halogen, amino, hydroxyl, cyano, methyl subunit, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Haloalkoxy, -NR 8a R 8b -S(O) v R a -COOR a -C(O)R a -P(O)R b R c -(CH2) n -R 9 -(CH2) n -NR 8a R 8b -CONR 8a R 8b C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 The alkyl group is replaced by one or more groups of cycloalkyl, phenyl, or 5-6-membered heteroaryl, wherein the C 3-6 Cycloalkyl, phenyl, or 5-6-membered heteroaryl groups may be further substituted with Q; or, R 3a and R 3b Together they form an oxygen group; or, R 3a With R 3b Together with the atoms it is connected to, they form C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -S(O) v R a -C(O)R a One or more groups are replaced; R 5a and R 5b Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -(CH2) n -R 9 -(CH2) n -NR 8a R 8b The C 1-6 Alkyl, C 3-10 Cycloalkyl, phenyl, and 5-6 heteroaryl groups are optionally selected from deuterium, halogen, amino, hydroxyl, cyano, methyl subunit, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Haloalkoxy, -NR 8a R 8b -S(O) v R a -COOR a -C(O)R a -P(O)R b R c -(CH2) n -R 9 -(CH2) n -NR 8a R 8b -CONR 8a R 8b C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 The alkyl group is replaced by one or more groups of cycloalkyl, phenyl, or 5-6-membered heteroaryl, wherein the C 3-6 Cycloalkyl, phenyl, or 5-6-membered heteroaryl groups may be further substituted with Q; or, R 5a and R 5b Together they form an oxygen group; or, R 5a With R 5b Together with the atoms it is connected to, they form C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -S(O) v R a -C(O)R a One or more groups are replaced; or, R 3a or R 3b With R 5a or R 5b Together with the atoms connected to them, they form 3-10 membered cycloalkyl, 4-10 membered heterocyclic, phenyl, or 5-6 membered heteroaryl groups, wherein the 3-10 membered cycloalkyl, 4-10 membered heterocyclic, phenyl, or 5-6 membered heteroaryl groups are optionally selected from deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl, -NR 7a R 7b -C(O)R a -S(O) v R a The C group is replaced by the group that is substituted for the C group. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-10 membered heterocyclic, and 5-10 membered arylheteroaryl groups may be further substituted with Q; R 7a and R 7b Each is independently selected from hydrogen and C. 1-6 Alkyl; or, R 7a With R 7b Together with the nitrogen atom attached thereto, a 5-6 membered heterocyclic group is formed, wherein the 5-6 membered heterocyclic group is optionally selected from deuterium, halogen, amino, cyano, hydroxyl, mercapto, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 The alkoxy group is replaced by one or more groups of the haloalkoxy group; R 8a and R 8b Each is independently selected from hydrogen and C. 1-6 Alkyl; or R 8a With R 8b Together with the nitrogen atom attached thereto, a 5-6 membered heterocyclic group is formed, wherein the 5-6 membered heterocyclic group is optionally C 1-6 Alkyl substitution; R 9 Selected from hydroxyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, phenyl; Q is selected from hydrogen, halogen, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 4-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl group is optionally selected from deuterium, halogen, cyano, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 One or more cycloalkyl groups are substituted; R a Selected from C 1-6 Alkyl, amino, hydroxyl; R b and R c Each is independently selected from hydrogen and C. 1-6 alkyl; t is 0 or 1; m is 0 or 1; v is 1 or 2; n is an integer from 0 to 6.

11. The compound of formula (I) according to claim 9 or 10, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 3a and R 3b Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -(CH2) n -R 9 -(CH2) n -NR 8a R 8b The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, phenyl, and 5-6-membered heteroaryl groups are optionally selected from deuterium, halogen, cyano, hydroxyl, methyl subunit, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkoxy, -NR 8a R 8b -S(O) v R a -COOR a -C(O)R a -P(O)R b R c -(CH2) n -R 9 -(CH2) n -NR 8a R 8b -CONR 8a R 8b C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 The C group is replaced by one or more groups of cycloalkyl or phenyl groups, wherein the C 3-6 Cycloalkyl, phenyl, or 5-6-membered heteroaryl groups may be further substituted with Q; or, R 3a and R 3b Together they form an oxygen group; or, R 3a With R 3b Together with the atoms it is connected to, they form C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -S(O) v R a -C(O)R a One or more groups are replaced; R 5a and R 5b Each is independently selected from hydrogen, deuterium, and C. 1-6 alkyl; R 8a and R 8b Each is independently selected from hydrogen and C. 1-6 Alkyl; or R 8a With R 8b Together with the nitrogen atom attached thereto, a 5-6 membered heterocyclic group is formed, wherein the 5-6 membered heterocyclic group is optionally C 1-6 Alkyl substitution; R 9 Selected from hydroxyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, phenyl; Q is selected from hydrogen, halogen, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 4-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl group is optionally selected from deuterium, halogen, cyano, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 One or more cycloalkyl groups are substituted; R a Selected from C 1-6 Alkyl, amino, hydroxyl; R b and R c Each is independently selected from hydrogen and C. 1-6 alkyl; v is 1 or 2; n is an integer from 0 to 6.

12. The compound of formula (I) according to claim 9 or 10, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 3a and R 3b Each is independently selected from hydrogen and C. 1-6 alkyl; R 5a and R 5b Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -CH2-R 9 The C 1-6 Alkyl groups may be optionally substituted with hydroxyl groups; or, R 5a and R 5b Together they form an oxygen group; or, R 5a With R 5b Together with the atoms it is connected to, they form C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 One or more alkoxy groups are substituted; R 9 Selected from hydroxyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, phenyl.

13. The compound of formula (I) according to claim 9 or 10, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 3a or R 3b With R 5a or R 5b Together with the atoms connected to them, they form 3-10 membered cycloalkyl, 4-10 membered heterocyclic or phenyl groups, wherein the 3-10 membered cycloalkyl, 4-10 membered heterocyclic or phenyl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-10 membered heterocyclic, 5-10 membered heteroaryl, -NR 7a R 7b -C(O)R a -S(O) v R a The C group is replaced by the group that is substituted for the C group. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic, and 5-6 membered heteroaryl groups may be further substituted by Q; Q is selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl groups and 4-6 membered heterocyclic groups are optionally selected from halogens, cyano groups, hydroxyl groups, and C. 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 One or more cycloalkyl groups are substituted; R 7a and R 7b Each is independently selected from hydrogen and C. 1-6 alkyl; R a Selected from C 1-6 Alkyl, amino, hydroxyl; v is 1 or 2.

14. The compound of formula (I) according to claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of formula (VII) is a stereoisomer thereof or a pharmaceutically acceptable salt thereof. R 1 Selected from hydrogen, halogen, amino, nitro, hydroxyl, mercapto, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -NR 7a R 7b The C 1-6 Alkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl are optionally selected from deuterium, halogen, -NR 8a R 8b , cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 One or more cycloalkyl groups are substituted; Each R 2 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups; preferably hydrogen, hydroxyl, halogen, and C. 1-6 alkyl; R 3a and R 3b Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -(CH2) n -R 9 -(CH2) n -NR 8a R 8b The C 1-6 Alkyl, phenyl, and 5-6-membered heteroaryl groups are optionally selected from deuterium, halogen, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Replaced by one or more haloalkoxy groups; or, R 3a and R 3b Together they form an oxygen group; or, R 3a With R 3b Together with the atoms it is connected to, they form C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups are optionally selected from deuterium, halogens, C 1-6 Alkyl, C 1-6 One or more alkoxy groups are substituted; R 4a and R 4b Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -(CH2) n -R 9 -(CH2) n -NR 8a R 8b The C 1-6 Alkyl, phenyl, and 5-6-membered heteroaryl groups are optionally selected from deuterium, halogen, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Replaced by one or more haloalkoxy groups; or, R 4a and R 4b Together they form an oxygen group; or, R 4a With R 4b Together with the atoms it is connected to, they form C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Replaced by one or more alkoxy or phenyl groups; R 5a and R 5b Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -(CH2) n -R 9 -(CH2) n -NR 8a R 8b The C 1-6 Alkyl, phenyl, and 5-6-membered heteroaryl groups are optionally selected from deuterium, halogen, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Replaced by one or more haloalkoxy groups; or, R 5a and R 5b Together they form an oxygen group; or, R 5a With R 5b Together with the atoms it is connected to, they form C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups are optionally selected from deuterium, halogens, C 1-6 Alkyl, C 1-6 One or more alkoxy groups are substituted; or, R 3a or R 3b With R 4a or R 4b , or R 4a or R 4b With R 5a or R 5b , or R 3a or R 3b With R 5a or R 5b Together with the atoms connected to them, they form 5-6 membered cycloalkyl, 5-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl groups, wherein the 5-6 membered cycloalkyl, 5-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl groups are optionally selected from deuterium, halogens, and C. 1-6 Alkyl, C 1-6 One or more alkoxy groups are substituted; R 7a and R 7b Each is independently selected from hydrogen and C. 1-6 Alkyl; or, R 7a With R 7b Together with the nitrogen atom attached thereto, a 5-6 membered heterocyclic group is formed, wherein the 5-6 membered heterocyclic group is optionally selected from deuterium, halogen, amino, cyano, hydroxyl, mercapto, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 The alkoxy group is replaced by one or more groups of the haloalkoxy group; R 8a and R 8b Each is independently selected from hydrogen and C. 1-6 alkyl; R 9 Selected from hydroxyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, phenyl; m is 0 or 1; n is an integer from 0 to 6.

15. The compound of formula (I) according to claim 14, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 3a and R 3b Each is independently selected from hydrogen and C. 1-6 alkyl; R 4a and R 4b Each is independently selected from hydrogen, hydroxyl, and C. 1-6 Alkyl, phenyl; R 5a and R 5b Each is independently selected from hydrogen and C. 1-6 alkyl.

16. The compound of formula (I) according to claim 14, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 3a and R 3b Each is independently selected from hydrogen and C. 3-10 Cycloalkyl, 4-10 membered heterocyclic groups; or R 3a With R 3b Together with the atoms it is connected to, they form C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups are optionally selected from deuterium, halogens, C 1-6 Alkyl, C 1-6 One or more alkoxy groups are substituted; R 4a and R 4b Each is independently selected from hydrogen, hydroxyl, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 4-6 membered heterocyclic group, phenyl, -CH2-R 9 The phenyl group is optionally substituted with one or more groups selected from halogens; or R 4a With R 4b Together with the atoms it is connected to, they form C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups, wherein the C 3-10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally selected from halogens, hydroxyl groups, C 1-6 Substituted with alkyl or phenyl groups; R 5a and R 5b Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 cycloalkyl; or R 3a or R 3b With R 4a or R 4b , or R 4a or R 4b With R 5a or R 5b , or R 3a or R 3b With R 5a or R 5b Together with the atoms they are connected to, they form 5-6 membered cycloalkyl groups; R 9 Selected from C 3-6 Cycloalkyl, phenyl.

17. The compound of formula (I) according to any one of claims 9 to 16, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, -NR 7a R 7b The 4-6 member heterocyclic group is optionally C 1-6 Alkyl substitution; the C 1-6 Alkyl groups are optionally halogenated, C 1-6 Alkoxy, C 3-6 Cycloalkyl substitution; R 7a and R 7b Each is independently selected from hydrogen and C. 1-6 alkyl; Preferably, R 1 C 1-6 alkyl.

18. The compound of formula (I) according to any one of claims 9 to 16, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 1 Selected from C 6-10 Aryl or 5-10 heteroaryl; the C 6-10 Aryl or 5-10 heteroaryl groups are optionally selected from halogens, -NR 8a R 8b , cyano, C 1-6 The alkyl group is replaced by one or more groups; R 8a and R 8b Each is independently selected from hydrogen and C. 1-6 Alkyl; or, R 8a With R 8b Together with the nitrogen atom attached thereto, a 4-7 membered heterocyclic group is formed, wherein the 4-7 membered heterocyclic group is optionally selected from C. 1-6 Alkyl substitution.

19. The compound of formula (I) according to any one of claims 9 to 16, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 1 Selected from C 6-10 Aryl, 5-10-membered heteroaryl, or 4-6-membered heterocyclic group, preferably phenyl, 5-6-membered heteroaryl, or 4-6-membered heterocyclic group, more preferably phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazoleyl, thiazolyl, oxazolyl, pyrrolidinyl, pyrrolyl, azacyclic butyl, piperidinyl, piperazinyl, or morpholinyl, and even more preferably phenyl, pyridinyl, pyrazolyl, imidazoleyl, or thiazolyl; optionally selected from halogen, cyano, or C 1-6 It is replaced by one or more groups of alkyl.

20. The compound of formula (I) according to claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of formula (VIII) is a stereoisomer thereof or a pharmaceutically acceptable salt thereof. in, Y1 and Y2 are each independently selected from CH or N; L is selected from the following groups: -S(O)2-, -C(O)-, -S(O)2NH-, -CR b R c -; R 1 Selected from hydrogen, C 1-6 Alkyl, 4-6 membered heterocyclic groups, -NR 7a R 7b -P(O)R b R c -OR c The 4-6 member heterocyclic group is optionally C 1-6 Alkyl groups are substituted; R 7a and R 7b Each is independently selected from hydrogen and C. 1-6 Alkyl, or R 7a and R 7b Together with the nitrogen atom attached thereto, a 5-7 membered heterocyclic group is formed, wherein the 5-7 membered heterocyclic group is optionally selected from deuterium, halogen, amino, cyano, hydroxyl, mercapto, oxo, -NR. 8a R 8b C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 The alkoxy group is replaced by one or more groups of the haloalkoxy group; R 8a and R 8b Each is independently selected from hydrogen and C. 1-6 alkyl; X, R 2 R b R c R 3a R 3b R 4a R 4b R 5a R 5b , t, and m are as defined in claim 1.

21. The compound of formula (I) according to claim 20, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 3a and R 3b Each independently is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; R 5a and R 5b Each is independently selected from hydrogen and C. 1-6 Alkyl; or R 5a With R 5b Together with the atoms it is connected to, they form C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 The alkoxy group is replaced by one or more groups; or R 3a and R 3b Together with the atoms it is connected to, they form C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups; t is 0.

22. The compound of formula (I) according to any one of claims 1 to 8, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, X is -NR 6 -, R 6 Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-6 Cycloalkyl.

23. The compound of formula (I) according to any one of claims 1 to 22, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, Each R 2 Each is independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl group, where m is 0 or 1.

24. The compound of formula (I) according to any one of claims 1 to 22, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, Any two R 2 Together with the atoms attached thereto, they form a bridged cycloalkyl or bridged heterocyclic group, preferably, the for 25. The compound of formula (I) according to any one of claims 1 to 24, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from:

26. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 25, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

27. Use of the compound of general formula (I) according to any one of claims 1 to 25, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 26, in the preparation of a medicament for the prevention or treatment of a CDK-mediated disease, preferably cancer or tumor.

28. Use of the compound of general formula (I) according to any one of claims 1 to 25, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 26, in the preparation of a medicament for the prevention or treatment of cancer, wherein the cancer is preferably breast cancer, ovarian cancer, bladder cancer, uterine cancer, colorectal cancer, prostate cancer, lung cancer, pancreatic cancer, gastric cancer, thyroid cancer, glioma, esophageal cancer, or liver cancer.

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