BRM selective degradation agent compound and application thereof

Abstract

The invention discloses a BRM selective degradation agent compound, and particularly provides a compound as shown in a formula (I), a formula (I)-1, a formula (I)-2 or a formula (II) or a stereoisomer or a pharmaceutically acceptable salt thereof, and the compound has a substituent group and structural characteristics described in the application. Also described are pharmaceutical compositions comprising a compound of Formula (I), Formula (I)-1, Formula (I)-2, or Formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the use of the compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in medicine.

Description

BRM selective degradation agent compound and its application

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to the following five Chinese invention patent applications, the entire contents of which are hereby incorporated by reference in their entirety:

[0003] Patent application No. 202311212766.1 submitted to the State Intellectual Property Office on September 19, 2023,

[0004] Patent application No. 202311627127.1 submitted to the State Intellectual Property Office on November 29, 2023,

[0005] Patent application No. 202410117813.2 filed with the International Intellectual Property Office on January 26, 2024,

[0006] Patent application No. 202410612111.1 filed with the State Intellectual Property Office on May 15, 2024, and

[0007] Patent application No. 202411243441.4 submitted to the State Intellectual Property Office on September 5, 2024. Technical Field

[0008] The present disclosure relates to compounds or stereoisomers or pharmaceutically acceptable salts thereof that are selective degraders of BRMs, methods for preparing the same, pharmaceutical compositions containing the same, and uses of the same in preventing or treating diseases or conditions mediated by BRMs. Background Art

[0009] SWI / SNF is a crucial nucleosome remodeling complex that hydrolyzes ATP to generate energy, which is used to break down the interactions between DNA and histones within nucleosomes, thereby regulating gene expression and repairing genetic damage. Epigenetic abnormalities have been shown to be a major cause of the development and progression of many chronic diseases, such as cancer. Mutations in SWI / SNF complex components are found in approximately 20% of cancers. BRM (SMARCA2) and BRG1 (SMARCA4) are both ATPase subunits of the SWI / SNF complex and are core components. Their primary function is to hydrolyze ATP to provide energy for nucleosome mobilization, regulating gene transcription, DNA replication, and DNA damage repair. The two proteins share the same but mutually exclusive functions within the complex and cannot coexist in the same SWI / SNF complex. Simultaneous inhibition of BRM and BRG1 protein function leads to cell death, a phenomenon known as synthetic lethality. BRG1 deficiency occurs in a variety of tumors, including lung, gastric, and pancreatic cancers, which are highly malignant and have limited therapeutic options. For example, BRG1 mutations occur in 5-10% of non-small cell lung cancer (NSCLC) and are mutually exclusive with the most prevalent driver genes in NSCLC, such as EGFR, ALK, MET, ROS1, and RET. Tumor cells with BRG1 mutations or functional loss are highly dependent on BRMs and are therefore more sensitive to BRM inhibitors, resulting in a synergistic lethal effect. Normal cells, however, are well-tolerated by BRM inhibitors, making BRMs a potential specific tumor target.

[0010] Proteolysis-Targeting Chimeras (PROTACs) are an emerging technology with great prospects, which are expected to turn many "undruggable" potential targets into "druggable". Traditional small molecule drugs are often powerless against proteins without enzyme functions, which account for about 80% of human proteins, because these drugs usually need to bind to enzymes or receptors to work. PROTACs are composed of three parts: a ligand (anchor) that recruits E3 ubiquitin ligase, a ligand molecule (warhead) that binds to the target protein (protein of interest, POI), and a linker (linker) that connects the two parts. Traditional small molecules need to exert their pharmacological effects by occupying key sites of the target protein (i.e., occupancy-driven), so a certain drug concentration in the body needs to be maintained, and the requirements for small molecule binding sites are high. PROTACs achieve pharmacodynamic effects by degrading the target protein, and theoretically do not require very high drug concentrations.

[0011] BRM and BRG1 proteins have two main functional regions: the ATPase domain and the bromodomain. The amino acid residues in these two functional regions share greater than 90% homology. Small molecule inhibitors struggle to achieve selectivity for BRM and BRG1, and therefore have a strong killing ability against normal cells. There is an urgent clinical need for BRM protein degraders with excellent stability and activity, as well as good selectivity for BRG1.

[0012] Summary of the Invention

[0013] The present disclosure relates to a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0014] in:

[0015] Indicates a single bond or a double bond;

[0016] X is selected from -NR 4 (CH2) r -、-O(CH2) r -or-S(CH2) r -;

[0017] Y 1 、Y 2 Independently selected from C, CR 5 or N;

[0018] Z is selected from C1-C3 alkylene, C2-C3 alkenylene, C2-C3 alkynylene, O, OCHR q , S, SCHR q NR q NR q CHR q ', C(O) or C(O)NR q The C1-C3 alkylene, C2-C3 alkenylene or C2-C3 alkynylene is optionally substituted by one or more R 6a replace;

[0019] Ring A is a benzene ring or a 5-6 membered heteroaromatic ring;

[0020] Ring B is a benzene ring, a 5-6 membered heteroaromatic ring or a 5-6 membered heterocyclic ring;

[0021] R q 、R q 'Independently selected from H, deuterium, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group is optionally replaced by one or more R 7a replace;

[0022] R 1 Selected from deuterium, OH, halogen, CN, COOH, NO2, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl or 4-8 membered heterocyclic group, the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl or 4-8 membered heterocyclic group is optionally substituted by one or more R 1a replace;

[0023] R 2 Selected from deuterium, halogen, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -C(O)R a 、-C(O)OR a 、-C(O)NHR a OR-P(O)(OR b )2, wherein the OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl is optionally replaced by one or more R 2a Replacement, R a and R b Each of the above-mentioned C1-C6 alkyl, NH2, C3-C6 cycloalkyl or 4-8 membered heterocyclic group is independently selected from H, C1-C6 alkyl, NH2, C3-C6 cycloalkyl or 4-8 membered heterocyclic group, wherein the C1-C6 alkyl, NH2, C3-C6 cycloalkyl or 4-8 membered heterocyclic group is optionally replaced by one or more R 2a replace;

[0024] R 3 Selected from C3-C6 cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group, the C3-C6 cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group is optionally substituted by one or more R 3a replace;

[0025] Alternatively, when t is 1 or 2, R 3 With an R 2 and their respective atoms together form a 5-10 membered heteroaromatic ring or a 5-14 membered heterocyclic ring, wherein the 5-10 membered heteroaromatic ring or the 5-14 membered heterocyclic ring is optionally replaced by one or more R 3b replace;

[0026] R 4 Selected from hydrogen, C1-C6 alkyl, C(O)(C1-C6 alkyl), C3-C6 cycloalkyl, C(O)(C3-C6 cycloalkyl), C6-C 10 Aryl, C(O)-(C6-C 10aryl), 5-10 membered heteroaryl, C(O)-(5-10 membered heteroaryl), 4-8 membered heterocyclic group or C(O)-4-8 membered heterocyclic group, the C1-C6 alkyl, C(O)(C1-C6 alkyl), C3-C6 cycloalkyl, C(O)(C3-C6 cycloalkyl), C6-C 10 Aryl, C(O)-(C6-C 10 aryl), 5-10 membered heteroaryl, C(O)-(5-10 membered heteroaryl), 4-8 membered heterocyclyl or C(O)-4-8 membered heterocyclyl optionally substituted with one or more R 4a replace;

[0027] R 5 is selected from hydrogen, deuterium, halogen, NH2, C1-C6 alkyl, C1-C6 alkyl-O-, C3-C6 cycloalkyl-O- or 4-8 membered heterocyclyl-O-, wherein said NH2, C1-C6 alkyl, C1-C6 alkyl-O-, C3-C6 cycloalkyl-O- or 4-8 membered heterocyclyl-O- is optionally replaced by one or more R 5a replace;

[0028] R 1a 、R 2a 、R 3a 、R 3b 、R 4a 、R 5a 、R 6a 、R 7a are independently selected from deuterium, OH, CN, halogen, =O, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclyl, C6-C 10 Aryl or 5-10 membered heteroaryl, the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more R c replace;

[0029] R c is selected from halogen, OH, NH2, =O, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl or 4-8 membered heterocyclyl;

[0030] r, t are independently selected from 0, 1 or 2;

[0031] f is selected from 0 or 1;

[0032] n is selected from 0, 1, 2, 3 or 4.

[0033] In some embodiments, Ring A is a benzene ring or a 6-membered heteroaromatic ring. In some embodiments, Ring A is a benzene ring.

[0034] In some embodiments, For double bonds.

[0035] In some embodiments, is a single bond, ring B is selected from a 5-6 membered heteroaromatic ring or a 5-6 membered heterocyclic ring, Y 1 and Y 2 One is N and the other is C or CR 5 In some embodiments, is a single bond, ring B is selected from a 5-6 membered heteroaromatic ring or a 5-6 membered heterocyclic ring, Y 1 N, Y 2 C or CR 5 In some embodiments, is a single bond, ring B is selected from a 5-membered heteroaromatic ring or a 5-6-membered heterocyclic ring, Y 1 N, Y 2 C or CR 5 In some embodiments, is a single bond, ring B is a 5-6 membered heteroaromatic ring, and Y 1 N, Y 2 is C, or ring B is a 5-6 membered heteroaromatic ring, and Y 1 C, Y 2 is N. In some embodiments, is a single bond, ring B is a 5-6 membered heteroaromatic ring, and Y 1 N, Y 2 is C. In some embodiments, is a single bond, ring B is a 5-membered heteroaromatic ring, and Y 1 N, Y 2 is C. In some embodiments, is a single bond, ring B is a pyrazole ring, and Y 1 N, Y 2 For C.

[0036] In some embodiments, is a double bond, Y 1 、Y 2 In some embodiments, is a double bond, ring B is a benzene ring or a 6-membered heteroaromatic ring, and Y 1 、Y 2 In some embodiments, is a double bond, ring B is a 6-membered heteroaromatic ring, and Y 1 、Y 2 In some embodiments, is a double bond, ring B is a pyridine ring, and Y 1 、Y 2 Both are C.

[0037] In some embodiments, is a double bond, is a double bond, Y 1 、Y 2 Both are C.

[0038] In some embodiments, is a double bond, is a double bond, ring A is a benzene ring, ring B is a pyridine ring, and Y 1 、Y 2 Both are C.

[0039] In some embodiments, R 5 Selected from hydrogen, deuterium, halogen or optionally replaced by one or more R 5a Substituted from the following groups: NH2, C1-C6 alkyl or C1-C6 alkyl-O-.

[0040] In some embodiments, R 5a is selected from deuterium, OH, halogen, =O, NH2 or C1-C6 alkyl, wherein the OH, NH2 or C1-C6 alkyl is optionally replaced by one or more R c replace.

[0041] In some embodiments, R 5a Selected from deuterium, OH, halogen, =O, NH2, C1-C6 alkyl, C1-C6 alkyl-O-, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0042] In some embodiments, R 5 Selected from hydrogen, deuterium, halogen or C1-C6 alkyl.

[0043] In some embodiments, R 5 Selected from hydrogen.

[0044] In some embodiments, r is selected from 0 or 1. In some embodiments, r is 0, that is, X is selected from NR 4 , O or S.

[0045] In some embodiments, X is selected from NR 4 , O or S, R 4 selected from hydrogen or optionally replaced by one or more R 4a Substituted groups: C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl or 4-8 membered heterocyclic group.

[0046] In some embodiments, X is selected from NR 4 , O or S, R 4 selected from hydrogen or optionally replaced by one or more R 4aSubstituted C1-C6 alkyl.

[0047] In some embodiments, R 4a is selected from deuterium, OH, halogen, =O, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group is optionally replaced by R c replace.

[0048] In some embodiments, R 4a Selected from deuterium, OH, halogen, =O, NH2, C1-C6 alkyl, C1-C6 alkyl-O-, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0049] In some embodiments, X is selected from NR 4 , O or S, R 4 Selected from hydrogen or C1-C6 alkyl.

[0050] In some embodiments, X is selected from NH, NCH 3 , O, or S.

[0051] In some embodiments, X is selected from NH, O, or S.

[0052] In some embodiments, X is selected from NH or O.

[0053] In some embodiments, X is selected from O.

[0054] In some embodiments, Z is selected from O, OCHR q , S, SCHR q NR q NR q CHR q ', C(O) or C(O)NR q .

[0055] In some embodiments, Z is selected from O or NR q .

[0056] In some embodiments, R q 、R q ' is independently selected from H, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclic group, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more R 7a replace.

[0057] In some embodiments, R q 、R q 'Independently selected from H, deuterium or C1-C6 alkyl, the C1-C6 alkyl is optionally replaced by one or more R 7areplace.

[0058] In some embodiments, R q 、R q ' is independently selected from H or deuterium.

[0059] In some embodiments, Z is selected from O or NR q , R q Selected from H, deuterium or C1-C6 alkyl.

[0060] In some embodiments, Z is selected from O.

[0061] In some embodiments, f is 0.

[0062] In some embodiments, R 1 is selected from deuterium, OH, halogen, CN, COOH, NO2, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group is optionally replaced by one or more R 1a replace.

[0063] In some embodiments, R 1 is selected from deuterium, OH, halogen, NH2 or C1-C6 alkyl, wherein the OH, NH2 or C1-C6 alkyl is optionally replaced by one or more R 1a replace.

[0064] In some embodiments, R 1a is selected from deuterium, OH, halogen, =O, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally replaced by one or more R c replace.

[0065] In some embodiments, R 1 Selected from deuterium, OH, halogen, NH2, C1-C6 alkyl, C1-C6 alkyl-O-, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0066] In some embodiments, R 1 Selected from OH, NH2 or halogen such as F, Cl, Br.

[0067] In some embodiments, R 1 Selected from halogens such as F, Cl, Br.

[0068] In some embodiments, n is selected from 0, 1, or 2. In some embodiments, n is selected from 0 or 1. In some embodiments, n is selected from 1.

[0069] In some embodiments, R 2 Selected from deuterium, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, -C(O)R a OR-P(O)(OR b )2, wherein the OH, NH2, C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by one or more R 2a Replacement, R a and R b independently selected from H or optionally one or more R 2a Substituted C1-C6 alkyl; R 3 Selected from optionally one or more R 3a Substituted with the following groups: C3-C6 cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group; or, when t is 1 or 2, R 3 With an R 2 and their respective atoms together form a group optionally substituted by one or more R 3b substituted 5-6 membered heteroaryl ring or 5-14 membered heterocyclic ring.

[0070] In some embodiments, R 2 Selected from deuterium, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, -C(O)R a OR-P(O)(OR b )2, wherein the NH2, C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by one or more R 2a Replacement, R a and R b independently selected from H or optionally one or more R 2a Substituted C1-C6 alkyl; R 3 Selected from optionally one or more R 3a Substituted with the following groups: C3-C6 cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group; or, when t is 1 or 2, R 3 With an R 2 and their respective atoms together form a group optionally substituted by one or more R 3b substituted 5-6 membered heteroaryl ring or 5-14 membered heterocyclic ring.

[0071] In some embodiments, R 2 Selected from deuterium, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, -C(O)R a OR-P(O)(OR b)2, wherein the OH, NH2, C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by one or more R 2a Replacement, R a and R b independently selected from H or optionally one or more R 2a Substituted C1-C6 alkyl; R 3 Selected from optionally one or more R 3a Substituted with the following groups: C3-C6 cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl.

[0072] In some embodiments, R 2 Selected from deuterium, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, -C(O)R a OR-P(O)(OR b )2, wherein the NH2, C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by one or more R 2a Replacement, R a and R b independently selected from H or optionally one or more R 2a Substituted C1-C6 alkyl; R 3 Selected from optionally one or more R 3a Substituted with the following groups: C3-C6 cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl.

[0073] In some embodiments, R a and R b Each independently selected from H, NH2 or C1-C6 alkyl, wherein the C1-C6 alkyl or NH2 is optionally replaced by one or more R 2a replace.

[0074] In some embodiments, R 2a is selected from halogen, OH, NH2, =O, C1-C3 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclic group, wherein the OH, NH2, C1-C3 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclic group is optionally replaced by one or more R c replace.

[0075] In some embodiments, R 2a Selected from optionally one or more R c Substituted C1-C3 alkyl.

[0076] In some embodiments, R 2a Selected from methyl or propyl.

[0077] In some embodiments, R3a Selected from OH, halogen, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more R c replace.

[0078] In some embodiments, R 3a Selected from optionally one or more R c Substituted groups: C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl.

[0079] In some embodiments, R 3a Selected from optionally one or more R c Substituted: C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group.

[0080] In some embodiments, R 3a Selected from optionally one or more R c Substituted: C1-C6 alkyl or 4-8 membered heterocyclic group.

[0081] In some embodiments, R 3a selected from halogen or optionally replaced by one or more R c Substituted from the following groups: OH, methyl, piperazinyl or piperidinyl.

[0082] In some embodiments, R 3a Selected from optionally one or more R c Substituted from the following groups: methyl, piperazinyl or piperidinyl.

[0083] In some embodiments, R 3a Selected from optionally one or more R c Substituted piperazinyl.

[0084] In some embodiments, R c Selected from halogen, OH, NH2, =O, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl or 4-6 membered heterocyclyl.

[0085] In some embodiments, R c Selected from halogen, OH, NH2, =O, C1-C3 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl.

[0086] In some embodiments, Rc Selected from C1-C3 alkyl or 4-6 membered heterocyclic group.

[0087] In some embodiments, R c Selected from C1-C3 alkyl or piperidinyl.

[0088] In some embodiments, R c Selected from C1-C3 alkyl, such as methyl.

[0089] In some embodiments, R 3a Selected from halogen, methyl, methoxy,

[0090] In some embodiments, t is 0 or 1. In some embodiments, t is 1.

[0091] In some embodiments, R 2 is selected from deuterium, OH, NH2, C1-C6 alkyl or C3-C6 cycloalkyl, wherein the OH, NH2, C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by one or more R 2a Replacement; R 3 Selected from optionally one or more R 3a Substituted with the following groups: C6-C 10 aryl or 5-10 membered heteroaryl.

[0092] In some embodiments, R 2 is selected from deuterium, OH, NH2 or C1-C6 alkyl, wherein the OH, NH2 or C1-C6 alkyl is optionally replaced by one or more R 2a Replacement; R 3 Selected from optionally one or more R 3a Substituted with the following groups: C6-C 10 aryl or 5-10 membered heteroaryl.

[0093] In some embodiments, R 2 Selected from deuterium, NH2, C1-C6 alkyl, the C1-C6 alkyl optionally replaced by one or more R 2a Replacement; R 3 Selected from optionally one or more R 3a Substituted with the following groups: C6-C 10 aryl or 5-10 membered heteroaryl.

[0094] In some embodiments, R 2 is selected from NH2, NHCH3, NHEt, NHPr, CH3, OCH3, ethyl, isopropyl or cyclopropyl.

[0095] In some embodiments, R 2is selected from NH2, NHCH3, NHEt, NHPr, CH3 or OCH3.

[0096] In some embodiments, R 2 Selected from NH2 or NHCH3.

[0097] In some embodiments, R 2 Selected from NH2.

[0098] In some embodiments, R 3 Selected from optionally one or more R 3a Substituted: phenyl, 5-6 membered heteroaryl or 5-10 membered heterocyclyl.

[0099] In some embodiments, R 3 Selected from optionally one or more R 3a Substituted groups: phenyl, pyridyl, pyrimidinyl, pyrazolyl,

[0100] In some embodiments, R 3 Selected from optionally one or more R 3a Substituted: phenyl, pyridyl or pyrimidinyl.

[0101] In some embodiments, R 3 Selected from optionally one or more R 3a Substituted: phenyl or pyridyl.

[0102] In some embodiments, (R 2 ) t is selected from H, NH2, NHCH3, NHCH2CH3, NHCH2CH2CH3, CH3, OCH3, ethyl, isopropyl or cyclopropyl.

[0103] In some embodiments, (R 2 ) t is selected from H, NH2, NHCH3, NHCH2CH3, NHCH2CH2CH3, CH3 or OCH3.

[0104] In some embodiments, (R 2 ) t is selected from H, NH2 or NHCH3. In some embodiments, (R 2 ) t is NH2.

[0105] In some embodiments, R 3 Selected from Phenyl, pyridyl,

[0106] In some embodiments, R 3 Selected from Phenyl, pyridyl,

[0107] In some embodiments, R 3 Selected from Phenyl, pyridyl,

[0108] In some embodiments, R 3 Selected from Phenyl or pyridyl.

[0109] In some embodiments, t is 1 or 2, R 3 With an R 2 and their respective atoms together form a group optionally substituted by one or more R 3b substituted 5-6 membered heteroaryl ring or 5-14 membered heterocyclic ring.

[0110] In some embodiments, t is 1 or 2, R 3 With an R 2 and their respective atoms together form a group optionally substituted by one or more R 3b substituted 5-6 membered heteroaryl ring or 5-10 membered heterocyclic ring.

[0111] In some embodiments, t is 1 or 2, R 3 With an R 2 and their respective atoms together form a group optionally substituted by one or more R 3b Substituted 5-10 membered heterocycle.

[0112] In some embodiments, t is 1, R 3 With R 2 and their respective atoms together form a group optionally substituted by one or more R 3b Substituted 5-10 membered heterocycle.

[0113] In some embodiments, R 3b Selected from deuterium, OH, halogen, =O, NH2, C1-C6 alkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the OH, NH2, C1-C6 alkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more R c replace.

[0114] In some embodiments, R 3b is selected from deuterium, OH, halogen, =O, NH2 or C1-C6 alkyl, wherein the OH, NH2 or C1-C6 alkyl is optionally replaced by one or more R c replace.

[0115] In some embodiments, R 3b Selected from deuterium, OH, halogen, =O, NH2, C1-C6 alkyl, C1-C6 alkyl-O-, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0116] In some embodiments, the compound of formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound of formula (I)-1 or its stereoisomer or its pharmaceutically acceptable salt:

[0117] Among them, ring A, R 1 、R 2 、R 3 , X, Z, n, t and f are as defined above.

[0118] In some embodiments, the compound of formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound of formula (I)-2 or its stereoisomer or its pharmaceutically acceptable salt:

[0119] Among them, ring A, R 1 、R 2 、R 3 , X, Z, n, t and f are as defined above.

[0120] In some embodiments, the compound of Formula (I) or Formula (I)-1 or Formula (I)-2, or its stereoisomers, or its pharmaceutically acceptable salts are selected from the following compounds, or their stereoisomers, or their pharmaceutically acceptable salts:

[0121] In some embodiments, the compound of Formula (I) or Formula (I)-1 or Formula (I)-2, or its stereoisomers, or its pharmaceutically acceptable salts are selected from the following compounds, or their stereoisomers, or their pharmaceutically acceptable salts:

[0122] On the other hand, the present application also provides a compound represented by formula (II) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0123] TL-Linker-DIM

[0124] (II)

[0125] Wherein, TL is the residue formed after the compound of the above formula (I) loses one hydrogen atom, that is, described Ring A, Ring B, X, Y 1 、Y 2 , Z, R 1 、R 2 、R 3 , n, t and f are as defined in formula (I);

[0126] The DIM is a ligand compound capable of binding to E3 ubiquitin ligase;

[0127] The Linker is a connecting group that covalently binds a TL and a DIM;

[0128] Provided that: the compound of formula (II) or its stereoisomer or its pharmaceutically acceptable salt does not include the following compound or its stereoisomer or its pharmaceutically acceptable salt:

[0129] In some embodiments, the TL is a residue formed after the compound of formula (I)-1 loses one hydrogen atom, that is, The ring A, R 1 、R 2 、R 3 , X, Z, n, t and f are as defined in formula (I)-1. In some embodiments, the TL is a residue formed after the compound of formula (I)-2 loses one hydrogen atom, i.e. The ring A, R 1 、R 2 、R 3 , X, Z, n, t and f are as defined in formula (I)-2.

[0130] In some embodiments, the TL is expressed by R 3 Connected to Linker, that is, TL is Alternatively, the TL is passed through R 2 、R 3 The ring atoms of the ring formed by the atoms to which they are attached or through the substituents R on the ring 3b Connected to Linker, Ring A, Ring B, X, Y 1 、Y 2 , Z, R 1 、R 2 、R 3 ,n,t,f,R3b As defined in formula (I).

[0131] In some embodiments, the TL is described Ring A, Ring B, X, Y 1 、Y 2 , Z, R 1 、R 2 、R 3 , n, t and f are as defined in formula (I).

[0132] In some embodiments, the TL is expressed by R 3 Connected to Linker, and TL is The ring A, R 1 、R 2 、R 3 , X, Z, n, t and f are as defined in formula (I)-1.

[0133] In some embodiments, the TL is expressed by R 3 Connected to Linker, and TL is The ring A, R 1 、R 2 、R 3 , X, Z, n, t and f are as defined in formula (I)-2.

[0134] In some embodiments, the TL is described Ring B, X, Y 1 、Y 2 、R 1 、R 2 、R 3 , n and t are as defined in formula (I).

[0135] In some embodiments, the TL is The R 1 、R 2 、R 3 , X, n and t are as defined in formula (I)-1.

[0136] In some embodiments, the TL is The R 1 、R 2 、R 3 , X, n and t are as defined in formula (I)-2.

[0137] In some embodiments, the TL is

[0138]

[0139] In some embodiments, the TL is

[0140] In some embodiments, the TL is

[0141] In some embodiments, the TL is

[0142] In some embodiments, the TL is expressed by R 2 、R 3 The ring atoms of the ring formed by the atoms to which they are attached or through the substituents R on the ring 3b Connected to Linker.

[0143] In some embodiments, the Linker is selected from: A -、-L B -、-R 1L -、-R 2L -、-Q 1 -、-Q 2 -、

[0144] Where: -L A -、-L B - independently selected from a bond, -O-, -S-, -NR 3’ -、-CR 4’ R 5’ -、-CR 4’ R 5’ -NR 3’ -、-CR 4’ R 5’ -O-, -C(O)-, -CR 4’ R 5’ -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -C(O)O- or -C(O)NR 6’ -;

[0145] R 1L and R 2Lare independently selected from a bond, -C(O)-, alkylene, heteroalkylene, alkenylene and alkynylene, wherein said alkylene, heteroalkylene, alkenylene and alkynylene are optionally substituted with a group selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =O, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0146] Q 1 , Q 2 , Q 3 and Q 4 are independently selected from cycloalkyl, heterocyclyl, aryl, heteroaryl or cycloalkenyl, wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl and cycloalkenyl are each independently optionally substituted by a group selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =O, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0147] R 3’ is selected from H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0148] R 4’ and R 5’ Each is independently selected from H, halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =O, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0149] R 6’ is selected from H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

[0150] In some embodiments, the Linker is selected from

[0151] In some embodiments, R 1L is selected from a bond, -C(O)- or C1-C3 alkylene, said C1-C3 alkylene being optionally substituted with C1-C3 alkyl.

[0152] In some embodiments, Q 1 , Q 2 Independently selected from C3-C8 cycloalkyl or 5-10 membered heterocyclyl, said C3-C8 cycloalkyl or 5-10 membered heterocyclyl being optionally substituted by a group selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, OH, C1-C3 hydroxyalkyl or NH2.

[0153] In some embodiments, the linker is selected from the following structures: a bond,

[0154] In some embodiments, the linker is selected from the following structures: a bond,

[0155] In some embodiments, the linker is selected from the following structures: a bond,

[0156] In some embodiments, the linker is selected from the following structures:

[0157] In some embodiments, the linker is selected from the following structures:

[0158] In some embodiments, the linker is selected from the following structures:

[0159] In some embodiments, the DIM is selected from a CRBN ligand, ie, a binding portion that binds a cereblon-type E3 ubiquitin ligase; or a VHL ligand, ie, a binding portion that binds a Von Hippel-Lindau-type E3 ubiquitin ligase.

[0160] In some embodiments, the DIM is selected from CRBN ligands.

[0161] In some embodiments, the DIM is selected from the structure shown in formula (DIM-1) or (DIM-2):

[0162] in:

[0163] Selected from

[0164] Y is a bond, or Y is selected from Y A 、O、NH、NR E 、C(O)O、C(O)NR E '、NR E 'C(O), Y A -NH, Y A -NR E 、Y A-C(O), Y A -C(O)O、Y A -OC(O),Y A -C(O)NR E ' or Y A -NR E 'C(O), wherein the Y A is selected from C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene;

[0165] X' is selected from C(O) or C(R A )2;X A -X B Selected from C(R A )=N or C(R A )2-C(R A )2;

[0166] Every R A independently selected from H or C1-C3 alkyl, said C1-C3 alkyl being optionally replaced by C6-C 10 substituted with aryl or 5-10 membered heteroaryl;

[0167] Every R A 'Independently selected from C1-C3 alkyl;

[0168] Every R B are independently selected from H or C1-C3 alkyl, or two R B Together with the atoms to which it is attached, it forms a C(O), a C3-C6 cycloalkyl, a C3-C6 cycloalkenyl, or a 4-6 membered heterocyclyl;

[0169] R C Selected from H, halogen or C1-C3 alkyl;

[0170] Every R D Independently selected from halogen, NO2, NH2, OH, COOH, C1-C6 alkyl or C1-C6 alkoxy;

[0171] Every R E independently selected from C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C(O)-C1-C6 alkyl, C(O)-C2-C6 alkenyl, C(O)-C3-C8 cycloalkyl or C(O)-3-8 membered heterocycloalkyl, wherein R E Optionally substituted by a group selected from the group consisting of halogen, N(R a )2、NHC(O)R a 、NHC(O)OR a , OR b , C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C10 aryl or 5-10 membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 The aryl or 5-10 membered heteroaryl is optionally further substituted by a group selected from the group consisting of halogen, NH2, CN, NO2, OH, COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0172] R E ' is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted by a group selected from the following: halogen, N (R a )2、NHC(O)R a 、NHC(O)OR a , OR b , C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 The aryl or 5-10 membered heteroaryl is optionally further substituted by a group selected from the group consisting of halogen, NH2, CN, NO2, OH, COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;

[0173] Every R a Independently selected from H or C1-C6 alkyl;

[0174] R b Selected from H or p-toluenesulfonyl;

[0175] t' is selected from 0 or 1;

[0176] m is selected from 0, 1, 2 or 3;

[0177] p is selected from 0, 1 or 2.

[0178] In some embodiments, the DIM is further selected from the structure represented by formula (DIM-3) or (DIM-4):

[0179] Wherein, the rings A, Y, and R A 、R A '、R B 、R C 、R D , m and p are as defined above.

[0180] In some embodiments, the DIM is further selected from the structure represented by formula (DIM-5), (DIM-6), (DIM-7) or (DIM-8):

[0181] Wherein, the Y, X', X A -X B 、R A 、R A '、R B 、R C 、R D , m and p are as defined above.

[0182] In some embodiments, the DIM is further selected from the structure represented by formula (DIM-9) or (DIM-10):

[0183] Wherein, the Y, X', X A -X B 、R A 、R A '、R B 、R C 、R D , m and p are as defined above.

[0184] In some embodiments, the DIM is selected from the structure shown in formula (DIM-11):

[0185] in:

[0186] X C Selected from bonds, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R'-, -P(O)(OR')-, -P(O)(NR'2)-, -C(O)-, -C(S)-

[0187] X D selected from C, N or Si;

[0188] X E is selected from a bond, -C(R')2-, -NR'-, -O-, -S- or -Si(R')2-;

[0189] R F Does not exist, or R Fis selected from H, deuterium, halogen, CN, -OR', -SR', -S(O)R', -S(O)2R', -N(R')2, -P(O)(OR')2, -P(O)(N(R')2)OR', -P(O)(N(R')2)2, -Si(OH)2R', -Si(OH)(R')2, -Si(R')3 or C1-C4 alkyl;

[0190] Every R G independently selected from H, deuterium, R H , Halogen, CN, -NO2, -OR', -SR', -N(R')2, -Si(R')3, -S(O)2R', -S(O)2N(R')2, -S(O)R', -C(O)R', -C(O)OR', -C(O)N (R')2, -C(O)N(R')OR', -C(R')2N(R')C(O)R', -C(R')2N(R')C(O)N(R')2, -OC(O)R', -OC(O)N(R')2, -OP(O)(R ')2, -OP(O)(OR')2, -OP(O)(OR')N(R')2, -OP(O)(N(R')2)2, -N(R')C(O)OR', -N(R')C(O)R', -N(R')C(O)N(R' )2, -N(R')S(O)2R', -N(R')P(O)(R')2, -N(R')P(O)(OR')2, -N(R')P(O)(OR')N(R')2 or -N(R')P(O)(N(R')2)2;

[0191] Every R H Independently selected from C1-C6 alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl;

[0192] Ring E, Ring F, and Ring G are independently selected from phenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl, 5-7 membered heterocyclyl, or 5-6 membered heteroaryl, wherein Ring E, Ring F, and Ring G are each optionally further substituted with =O;

[0193] L 1 is selected from a bond, C1-C3 alkylene, C2-C3 alkenylene or C2-C3 alkynylene, wherein any one or two methylene groups in the C1-C3 alkylene, C2-C3 alkenylene or C2-C3 alkynylene are optionally replaced by -O-, -C(O)-, -C(S)-, -C(R')2-, -CH(R')-, -C(F)2-, -N(R')-, -S- or -S(O)2-;

[0194] Each R' is independently selected from H, C1-C6 alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, or two R' and the atoms to which they are attached together form a 4-7 membered heterocyclyl or 5-6 membered heteroaryl;

[0195] q is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

[0196] In some embodiments, the DIM is selected from the structure shown in formula (DIM-11'):

[0197] wherein X C 、R F 、R G , q, ring E, ring F and ring G are as defined in formula (DIM-11).

[0198] In some embodiments, the DIM is selected from the structure shown in formula (DIM-12):

[0199] wherein: Ring H is selected from C5-C9 cycloalkyl, C5-C9 cycloalkenyl or 5-9 membered heterocyclyl, wherein said C5-C9 cycloalkyl, C5-C9 cycloalkenyl or 5-9 membered heterocyclyl is optionally substituted with ═O; k is selected from 0, 1, 2, 3 or 4; X C 、X D 、X E 、R F 、R G , L 1 and Ring E are as defined in Formula (DIM-11).

[0200] In some embodiments, the DIM is selected from the structure shown in (DIM-12'):

[0201] Wherein, the X C 、R F 、R G , k, ring E and ring H are as defined in formula (DIM-12).

[0202] In some embodiments, the DIM is selected from the structure shown in formula (DIM-13):

[0203] Wherein, the X C 、X D 、X E 、R F 、R G , L 1 , Ring E and k are as defined in Formula (DIM-12).

[0204] In some embodiments, the DIM is selected from the structure shown in (DIM-13'):

[0205] Wherein, the X C 、R F 、R G , Ring E and k are as defined in Formula (DIM-13).

[0206] In some embodiments, the DIM is selected from the structure represented by Formula (DIM-1), Formula (DIM-3), Formula (DIM-5), Formula (DIM-12) or Formula (DIM-12').

[0207] In some embodiments, the DIM is selected from the structure represented by Formula (DIM-3), Formula (DIM-5), Formula (DIM-12), or Formula (DIM-12').

[0208] In some embodiments, the DIM is selected from VHL ligands.

[0209] In some embodiments, the DIM is selected from the structures represented by formula (DIM-14), (DIM-15), (DIM-16), (DIM-17), or (DIM-18):

[0210] in:

[0211] R J Selected from optionally substituted C1-C6 alkyl, optionally substituted -(CH2) j OH, optionally substituted -(CH2) j SH, optionally substituted -(CH2) j -O-(C1-C6)alkyl, optionally substituted -(CH2) j -CH2OCH2-(C0-C6)alkyl, optionally substituted-(CH2) j COOH, optionally substituted -(CH2) j C(O)-(C1-C6 alkyl), optionally substituted-(CH2) j NR c R d , optionally substituted -(CH2) j NHC(O)-R c , optionally substituted -(CH2) j C(O)-NR c R d , optionally substituted -(CH2) j OC(O)-NR c R d 、-(CH2O)j H, optionally substituted -(CH2) j OC(O)-(C1-C6 alkyl), optionally substituted-(CH2) j C(O)-O-(C1-C6 alkyl), optionally substituted-(CH2O) j COOH, optionally substituted -(OCH2) j O-(C1-C6 alkyl), optionally substituted-(CH2O) j C(O)-(C1-C6 alkyl), optionally substituted-(OCH2) j NHC(O)-R c , optionally substituted -(CH2O) j C(O)-NR c R d 、-(CH2CH2O) j H, optionally substituted -(CH2CH2O) j COOH, optionally substituted -(OCH2CH2) j O-(C1-C6 alkyl), optionally substituted-(CH2CH2O) j C(O)-(C1-C6 alkyl), optionally substituted-(OCH2CH2) j NHC(O)-R c , optionally substituted -(CH2CH2O) j C(O)-NR c R d , optionally substituted -SO2R s , optionally substituted -S(O)R s , NO2, CN or halogen;

[0212] R c and R d are independently selected from H or C1-C6 alkyl, which is optionally substituted by OH or halogen;

[0213] R s is selected from C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl or -(CH2) g NR c R d ;

[0214] X F and X G are independently selected from C=O, C=S, S(O) or S(O)2;

[0215] R L Selected from optionally substituted -(CH2) j -(C=O)u (NR c ) v (SO2) w (C1-C6 alkyl), optionally substituted -(CH2) j -(C=O) u (NR c ) v (SO2) w NR 1N R 2N , optionally substituted -(CH2) j -(C=O) u (NR c ) v (SO2) w -aryl, optionally substituted-(CH2) j -(C=O) u (NR c ) v (SO2) w -heteroaryl, optionally substituted-(CH2) j -(C=O) v NR c (SO2) w -heterocyclyl, optionally substituted -NR e -(CH2) j -C(O) u (NR c ) v (SO2) w -C1-C6 alkyl, optionally substituted -NR e -(CH2) j -C(O) u (NR c ) v (SO2) w -NR 1N R 2N , optionally substituted -NR e -(CH2) j -C(O) u (NR c ) v (SO2) w -NR c C(O)R 1N , optionally substituted -NR e -(CH2) j -(C=O) u (NR c ) v (SO2) w -aryl, optionally substituted -NR e -(CH2)j -(C=O) u (NR c ) v (SO2) w -heteroaryl or optionally substituted -NR e -(CH2) j -(C=O) v NR c (SO2) w -heterocyclyl, optionally substituted -X R2’ -C1-C6 alkyl, optionally substituted -X R2’ -aryl, optionally substituted-X R2’ -heteroaryl or optionally substituted-X R2’ -heterocyclic group;

[0216] R M Selected from optionally substituted C1-C6 alkyl, optionally substituted -(CH2) j -C(O) u (NR c ) v (SO2) w -C1-C6 alkyl, optionally substituted -(CH2) j -C(O) u (NR c ) v (SO2) w -NR 1N R 2N , optionally substituted -(CH2) j -C(O) u (NR c ) v (SO2) w -NR c C(O)R 1N , optionally substituted -(CH2) j -C(O) u (NR c ) v (SO2) w -C(O)NR c R d , optionally substituted -(CH2) j -C(O) u (NR c ) v (SO2) w -aryl, optionally substituted-(CH2) j -C(O) u (NR c ) v (SO2) w-heteroaryl, optionally substituted-(CH2) j -C(O) u (NR c ) v (SO2) w -heterocycle, optionally substituted-NR e -(CH2) j -C(O) u (NR c ) v (SO2) w -C1-C6 alkyl, optionally substituted -NR e -(CH2) j -C(O) u (NR c ) v (SO2) w -NR 1N R 2N , optionally substituted -NR e -(CH2) j -C(O) u (NR c ) v (SO2) w -NR c C(O)R 1N , optionally substituted -NR e -(CH2) j -C(O) u (NR c ) v (SO2) w -aryl, optionally substituted -NR e -(CH2) j -C(O) u (NR c ) v (SO2) w -heteroaryl, optionally substituted -NR e -(CH2) j -C(O) u (NR c ) v (SO2) w -heterocyclic, optionally substituted-O-(CH2) j -(C=O) u (NR c ) v (SO2) w -C1-C6 alkyl, optionally substituted -O-(CH2) j -(C=O) u (NR c ) v(SO2) w -NR 1N R 2N , optionally substituted -O-(CH2) j -(C=O) u (NR c ) v (SO2) w -NR c C(O)R 1N , optionally substituted -O-(CH2) j -(C=O) u (NR c ) v (SO2) w -aryl, optionally substituted -O-(CH2) j -(C=O) u (NR c ) v (SO2) w -heteroaryl or optionally substituted -O-(CH2) j -(C=O) u (NR c ) v (SO2) w -heterocyclic, optionally substituted-(CH2) j -(V) n’ -(CH2) j -(V) n’ -C1-C6 alkyl, optionally substituted -(CH2) j -(V) n’ -(CH2) j -(V) n’ -aryl, optionally substituted-(CH2) j -(V) n’ -(CH2) j -(V) n’ -heteroaryl, optionally substituted-(CH2) j -(V) n’ -(CH2) j -(V) n’ -heterocyclyl, optionally substituted-(CH2) j -N(R e )(C=O) m’ -(V) n’ -C1-C6 alkyl, optionally substituted -(CH2) j -N(R e )(C=O) m’ -(V) n’ -aryl, optionally substituted -(CH2) j -N(Re )(C=O) m’ -(V) n’ -heteroaryl, optionally substituted-(CH2) j -N(R e )(C=O) m’ -(V) n’ -heterocyclyl, optionally substituted -X R3’ -C1-C6 alkyl, optionally substituted -X R3’ -aryl, optionally substituted-X R3’ -heteroaryl or optionally substituted-X R3’ -heterocyclic group;

[0217] where R 1N and R 2N are each independently H, C1-C6 alkyl optionally substituted with OH and halogen, or optionally substituted -(CH2) j -aryl, -(CH2) j -heteroaryl or -(CH2) j -heterocyclic group;

[0218] V is O, S, or NR c ;

[0219] R e Independently selected from H or C1-C3 alkyl;

[0220] X R2’ and X R3’ are each independently selected from optionally substituted -(CH2) j -、-(CH2) j -C(X v )=C(X v )-、-(CH2) j -C≡C-, -(CH2CH2O) j - or C3-C6 cycloalkylene, wherein X v is H, halogen or optionally substituted C1-C3 alkyl;

[0221] g is independently 0, 1, 2, 3, 4, 5, 6; j is independently 0, 1, 2, 3, 4, 5, or 6; m' is independently 0 or 1; n' is independently 0 or 1; u is independently 0 or 1; v is independently 0 or 1; and w is independently 0 or 1.

[0222] In some embodiments, R in the formula (DIM-14), (DIM-15), (DIM-16), (DIM-17), or (DIM-18) J All are OH.

[0223] In some embodiments, X in the formula (DIM-14), (DIM-15) or (DIM-18) F and X G All are C=O.

[0224] In some embodiments, the DIM is selected from the structure shown in formula (DIM-14), (DIM-15) or (DIM-18), and X F and X G All are C=O.

[0225] In some embodiments, the DIM is selected from the structure shown in formula (DIM-15), and R J OH, X F and X G All are C=O.

[0226] In some embodiments, the DIM is selected from the following structures:

[0227] In some embodiments, the DIM is selected from the following structures:

[0228] In some embodiments, the DIM is selected from the following structures:

[0229] In some embodiments, the DIM is selected from the following structures:

[0230] In some embodiments, the compound of formula (II) of the present disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from the following compounds, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0231] On the other hand, the present disclosure provides a pharmaceutical composition comprising a compound represented by formula (I), formula (I)-1, formula (I)-2 or (II) of the present disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0232] On the other hand, the present disclosure provides a method for treating a disease mediated by BRM in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment, a therapeutically effective amount of a compound represented by Formula (I), Formula (I)-1, Formula (I)-2 or (II) of the present disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0233] On the other hand, the present disclosure provides a method for treating tumors in mammals, comprising administering a therapeutically effective amount of a compound represented by Formula (I), Formula (I)-1, Formula (I)-2 or (II) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0234] On the other hand, the present disclosure provides the use of a compound represented by Formula (I), Formula (I)-1, Formula (I)-2 or (II) or its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for preventing or treating BRM-mediated diseases.

[0235] On the other hand, the present disclosure provides the use of a compound represented by formula (I), formula (I)-1, formula (I)-2 or (II) or its stereoisomer or pharmaceutically acceptable salt, or a pharmaceutical composition thereof in the preparation of a drug for preventing or treating tumors.

[0236] On the other hand, the present disclosure provides the use of a compound represented by Formula (I), Formula (I)-1, Formula (I)-2 or (II) or its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in preventing or treating BRM-mediated diseases.

[0237] On the other hand, the present disclosure provides the use of a compound represented by Formula (I), Formula (I)-1, Formula (I)-2 or (II) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating tumors.

[0238] In another aspect, the present disclosure provides a compound of Formula (I), Formula (I)-1, Formula (I)-2 or (II) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating BRM-mediated diseases.

[0239] On the other hand, the present disclosure provides compounds of formula (I), formula (I)-1, formula (I)-2 or (II) or their stereoisomers or pharmaceutically acceptable salts, or pharmaceutical compositions thereof for preventing or treating tumors.

[0240] In some embodiments, the BRM-mediated disease is selected from a tumor.

[0241] In some embodiments, the tumor is selected from cancer.

[0242] On the other hand, the present disclosure also provides the use of a compound of formula (I), formula (I)-1 or formula (I)-2 or a stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of a target protein degradation drug.

[0243] On the other hand, the present disclosure also provides the use of a compound of formula (I), formula (I)-1 or formula (I)-2 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an intermediate in the preparation of a target protein degradation drug.

[0244] Definitions and Explanations of Terms

[0245] Unless otherwise indicated, the terms used in this disclosure have the following meanings. The definitions of groups and terms described in this disclosure, including their exemplary definitions, preferred definitions, definitions described in tables, and definitions of specific compounds in the Examples, may be combined and coupled with each other in any manner. A particular term should not be considered undefined or unclear unless specifically defined, but should be understood according to its common meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0246] In this article Indicates the connection site. of when When not connected to a fixed ring or atom, it means that it can be connected to a group after losing the hydrogen atom at any position in the molecule enclosed by "[]" (including hydrogen atoms directly connected to ring atoms, hydrogen atoms on non-hydrogen substituents of ring atoms, and hydrogen atoms in further substituents on substituents), for example middle The connection position includes but is not limited to R 1 and its substituents, ring A, ring B, R 2 and its substituents, R 3 and its substituents, R 2 With R 3 The rings formed by the atoms to which they are attached and their substituents, etc. middle The connection position includes R 3 and R 3 The substituent R 3a wait.

[0247] The term "capable of binding" means capable of measurably binding to a target (eg, a ligand of an E3 ubiquitin ligase is capable of forming a covalent bond with a cysteine ​​of an E3 ubiquitin ligase, etc.).

[0248] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, targeting them for degradation. E3 ubiquitin ligases, alone or in complex with E2 ubiquitin ligases, are responsible for transferring ubiquitin to target proteins. Typically, ubiquitin ligases participate in polyubiquitination, where a second ubiquitin is attached to the first; a third ubiquitin is attached to the second, and so on. Polyubiquitination marks proteins for degradation by the proteasome. However, there are some ubiquitination events that are limited to monoubiquitination, in which the ubiquitin ligase only adds a single ubiquitin to the substrate molecule. Monoubiquitinated proteins are not targeted for degradation by the proteasome, but can instead change their cellular location or function, for example, by binding to other proteins with domains capable of binding ubiquitin. Further complicating matters, E3 ubiquitin ligases can target different lysines on ubiquitin to create chains.

[0249] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Compounds of the present disclosure may exhibit tautomerism. Tautomeric compounds may exist as two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer typically result in a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present disclosure encompasses all tautomeric forms of the compounds.

[0250] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0251] The compounds of the present disclosure may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, and thus the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the definition of compounds of the present disclosure and mixtures thereof. Substituents such as alkyl groups may have additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms, and all of these isomers and mixtures thereof involved in the substituents are also within the definition of compounds of the present disclosure. Compounds of the present disclosure containing an asymmetric atom can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.

[0252] Asterisk "*" herein represents a chiral center, indicating that the absolute configuration of the position is either S-configuration or R-configuration.

[0253] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo does not occur on aromatic groups.

[0254] The term "optional" or "optionally" refers to that the event or situation described subsequently may or may not occur, and the description includes that the event or situation occurs and that the event or situation does not occur. For example, an ethyl group is "optionally" substituted with halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (CH2CH2F, CH2CH2Cl, etc.), polysubstituted (CHFCH2F, CH2CHF2, CHFCH2Cl, CH2CHCl2, etc.), or fully substituted (CF2CF3, CF2CCl3, CCl2CCl3, etc.). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, any sterically impossible and / or incomposable replacement or substitution pattern will not be introduced.

[0255] The term "optionally substituted" means that the group may be substituted or not substituted. Unless otherwise specified, the type and amount of the substituents may be any based on chemical practicability.

[0256] The term "substituted" means that a specific atom or group can be replaced by another specified atom or group. For example, the CH2 in -CH2CH2CH2- can be replaced by O, S or NH to obtain -CH2OCH2-, -OCH2CH2-, -CH2SCH2-, -SCH2CH2-, -CH2NHCH2- or -NHCH2CH2-, etc.

[0257] When any variable (such as R a 、R b ) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is represented by two R b is replaced, then each R b There are independent options; for the group N (C1-C6 alkyl) 2, when the C1-C6 alkyl is R b When substituted, the two C1-C6 alkyl groups have independent R b options.

[0258] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a bond.

[0259] When one of the variables is selected from a bond or is absent, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a bond, it means that the structure is actually AZ.

[0260] When the linking group mentioned in this article does not specify its connection direction, its connection direction is arbitrary. For example, when X in formula (I) is selected from "-NR 4 (CH2) r -", X can connect ring A and ring B from left to right, and the formula (I) is: Ring A and Ring B can also be connected from right to left. In this case, Formula (I) is formed.

[0261] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. Represents R 1 Substitution can occur at any of the 1, 2, 3 or 4 positions on the benzene ring.

[0262] In this article, C m -C n It means having mn or an integer number of carbon atoms in the range of m to n. For example, "C1-C 10" means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms. Similarly, m-membered to n-membered means that the number of ring atoms is m to n, for example, 5-14 membered ring includes 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, 12-membered ring, 13-membered ring and 14-membered ring, and also includes any range from n to m, for example, 5-14 membered ring includes 6-14 membered ring, 6-11 membered ring, 5-10 membered ring, 6-10 membered ring, 6-8 membered ring, etc.

[0263] The term "alkyl" refers to a group of the formula C n H 2n+1 The term "C1-C 10 The term "alkyl" is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of such alkyl radicals include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1, The term "C1-C6 alkyl" can be understood to mean an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, and specific examples include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc. The term "C1-C4 alkyl" can be understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3 or 4 carbon atoms. The term "C1-C3 alkyl" can be understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2 or 3 carbon atoms. The "C1-C 10The term "alkyl" may include "C1-C6 alkyl", "C1-C4 alkyl" or "C1-C3 alkyl", and the "C1-C6 alkyl" may further include "C1-C4 alkyl" or "C1-C3 alkyl", and the "C1-C4 alkyl" may further include "C1-C3 alkyl". The C0 alkyl group herein represents a hydrogen atom H, such as "(C0-C6)alkyl" includes H and C1-C6 alkyl, which may further include C1-C6 alkyl.

[0264] The term "heteroalkyl" refers to an alkyl group in which one or more -CH2- are replaced by a heteroatom selected from NH, O and S, or one or more -CH- are replaced by N; wherein the alkyl group is as defined above.

[0265] The term "haloalkyl" refers to a group obtained by further replacing the alkyl group with a halogen, such as "C1-C6 haloalkyl" refers to a C1-C6 alkyl group further replaced with a halogen. The term "hydroxyalkyl" refers to a group obtained by further replacing the alkyl group with an OH group.

[0266] The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon radical, i.e., a residue derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane, and is a straight or branched group containing 1 to 20 carbon atoms, preferably an alkylene radical containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably an alkylene radical containing 1 to 6 carbon atoms. Non-limiting examples of alkylene radicals include, but are not limited to, methylene, -CH(CH3)-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. The term "C1-C6 alkylene radical" may be understood to mean an alkylene radical having 1, 2, 3, 4, 5, or 6 carbon atoms. The term "C1-C3 alkylene radical" may be understood to mean an alkylene radical having 1, 2, or 3 carbon atoms. Preferably, "C1-C6 alkylene" may include "C1-C3 alkylene". The term "heteroalkylene" refers to an alkylene group in which one or more -CH2- groups are substituted by a heteroatom selected from N, O and S; wherein the alkylene group is as defined above.

[0267] The term "alkoxy" refers to a monovalent group generated by the loss of a hydrogen atom from a hydroxyl group of a straight-chain or branched alcohol, which can be understood as "alkyloxy" or "alkyl-O-", wherein the definition of alkyl is as described above. 10 "Alkoxy" can be understood as "C1-C 10 Alkyloxy" or "C1-C 10The term "C1-C6 alkoxy" can be understood as "C1-C6 alkyloxy" or "C1-C6 alkyl-O-". "C1-C3 alkoxy" can be understood as "C1-C3 alkyloxy" or "C1-C3 alkyl-O-". The "C1-C 10 The term "alkoxy" may include "C1-C6 alkoxy" and "C1-C3 alkoxy", and the "C1-C6 alkoxy" may further include "C1-C3 alkoxy".

[0268] The term "haloalkoxy" refers to a group obtained by further substituted alkoxy with halogen, such as "C1-C6 haloalkoxy" refers to a C1-C6 alkoxy further substituted with halogen.

[0269] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, which is a straight or branched chain containing 2 to 20 carbon atoms and has at least one double bond. 10 The term "alkenyl" is understood to mean a linear or branched unsaturated monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, and the term "C2-C6 alkenyl" is understood to mean a linear or branched unsaturated monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5 or 6 carbon atoms. 10 "Alkenyl" is preferably "C2-C6 alkenyl" or "C2-C4 alkenyl", "C2-C6 alkenyl" is further preferably "C2-C4 alkenyl", and further preferably C2 or C3 alkenyl. It should be understood that when the alkenyl contains more than one double bond, the double bonds may be separated from each other or conjugated. Specific examples of the alkenyl include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl or (Z)-1-methylprop-1-enyl, etc.

[0270] The term "alkenylene" refers to a residue derived from the same or two different carbon atoms of a parent alkene, wherein alkenyl is as defined above. The term "C2-C6 alkenylene" is understood to mean an alkenylene having 2 to 6 carbon atoms. The term "C2-C3 alkenylene" is understood to mean an alkenylene having 2 or 3 carbon atoms. Preferably, "C2-C6 alkenylene" includes "C2-C3 alkenylene".

[0271] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, containing 2 to 20 carbon atoms and having at least one triple bond. 10 “Alkynyl” is understood to mean a linear or branched unsaturated monovalent hydrocarbon radical containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The term “C2-C6 alkynyl” is understood to mean a linear or branched unsaturated monovalent hydrocarbon radical containing one or more triple bonds and having 2, 3, 4, 5 or 6 carbon atoms. Examples of “C2-C6 alkynyl” include, but are not limited to, ethynyl (-C≡CH3), propynyl (-C≡CCH3, -CH2C≡CH3), but-1-ynyl, but-2-ynyl or but-3-ynyl. “C2-C 10 "Alkynyl" may include "C2-C6 alkynyl" or "C2-C3 alkynyl", and "C2-C6 alkynyl" may include "C2-C3 alkynyl". Examples of "C2-C3 alkynyl" include ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH3) or prop-2-ynyl (propargyl).

[0272] The term "alkynylene" refers to a residue derived from the same carbon atom or two different carbon atoms of a parent alkyne by removing two hydrogen atoms, wherein the definition of alkynyl is as given above. The term "C2-C6 alkynylene" is understood to mean an alkynylene having 2 to 6 carbon atoms. The term "C2-C3 alkynylene" is understood to mean an alkynylene having 2 or 3 carbon atoms. Preferably, "C2-C6 alkynylene" includes "C2-C3 alkynylene".

[0273] The term "cycloalkyl" refers to a fully saturated carbon ring that exists in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 10-membered ring. The term "C3-C 10The term "cycloalkyl" shall be understood to mean a saturated monovalent monocyclic, cyclic, spirocyclic or bridged ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The term "C3-C8 cycloalkyl" shall be understood to mean a saturated monovalent monocyclic, cyclic, spirocyclic or bridged ring having 3, 4, 5, 6, 7 or 8 carbon atoms. The term "C3-C6 cycloalkyl" shall be understood to mean a saturated monovalent monocyclic, cyclic, spirocyclic or bridged ring having 3, 4, 5 or 6 carbon atoms, specific examples of which include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The term "C5-C9 cycloalkyl" shall be understood to mean a saturated monovalent monocyclic, cyclic, spirocyclic or bridged ring having 3, 4, 5, 6, 7 or 8 carbon atoms. The term "alkyl" shall be understood to mean a saturated monovalent monocyclic, cyclic, spirocyclic or bridged ring having 5, 6, 7, 8 or 9 carbon atoms. The term "C5-C7 cycloalkyl" shall be understood to mean a saturated monovalent monocyclic, cyclic, spirocyclic or bridged ring having 5, 6 or 7 carbon atoms. Specific examples of the cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl and the like. The term "C3-C 10 The term "cycloalkyl" may include "C3-C8 cycloalkyl", "C3-C6 cycloalkyl", "C5-C9 cycloalkyl" or "C5-C7 cycloalkyl", the term "C3-C8 cycloalkyl" may include "C3-C6 cycloalkyl" or "C5-C7 cycloalkyl", the term "C5-C9 cycloalkyl" may include "C5-C7 cycloalkyl".

[0274] The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and exists in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered ring. Specific examples of the cycloalkenyl group include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, or cycloheptadienyl. The term "C5-C 10 The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and exists in the form of a monocyclic, fused ring, bridged ring or spirocyclic ring, and has 5, 6, 7, 8, 9 or 10 carbon atoms. The term "C5-C9 cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and exists in the form of a monocyclic, fused ring, bridged ring or spirocyclic ring, and has 5, 6, 7, 8 or 9 carbon atoms. The term "C5-C7 cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and exists in the form of a monocyclic, fused ring, bridged ring or spirocyclic ring, and has 5, 6 or 7 carbon atoms. The term "C3-C6 cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and exists in the form of a monocyclic, fused ring, bridged ring or spirocyclic ring, and has 3, 4, 5 or 6 carbon atoms. The term "C5-C 10 The term "cycloalkenyl" may include "C5-C9 cycloalkenyl" or "C5-C7 cycloalkenyl", and the term "C5-C9 cycloalkenyl" may include "C5-C7 cycloalkenyl".

[0275] The term "heterocyclyl" or "heterocycle" refers to a fully saturated or partially saturated (heteroaromatic as a whole that is not aromatic) monovalent monocyclic, fused, spirocyclic or bridged ring group containing 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups (i.e., heteroatom-containing atomic groups) in the ring atoms, wherein the "heteroatoms or heteroatomic groups" include but are not limited to nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P), boron atom (B), -S(=O)2-, -S(=O)- and optionally substituted -NH-, -S(=O)(=NH)-, -C(=O)NH-, -C(=NH)-, -S(=O)2NH-, -S(=O)NH- or -NHC(=O)NH-, etc., which generally contain 3 to 20 ring atoms. The term "5-14 membered heterocyclyl" refers to a heterocyclyl group having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, and wherein the ring atoms contain 1 to 5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms. "5-14 membered heterocyclyl" may include "6-14 membered heterocyclyl", "6-11 membered heterocyclyl", "6-10 membered heterocyclyl", "6-8 membered heterocyclyl", "5-10 membered heterocyclyl", "5-9 membered heterocyclyl", "5-8 membered heterocyclyl" or "5-7 membered heterocyclyl". The term "5-10 membered heterocyclyl" may include "5-9 membered heterocyclyl", "5-8 membered heterocyclyl", "5-7 membered heterocyclyl", "6-10 membered heterocyclyl" or "6-8 membered heterocyclyl". The term "4-10 membered heterocyclyl" refers to a heterocyclyl having 4, 5, 6, 7, 8, 9 or 10 ring atoms, and the ring atoms thereof contain 1-5 heteroatoms or heteroatom groups independently selected from the above-mentioned. "4-10 membered heterocyclyl" includes "4-7 membered heterocyclyl", wherein specific examples of 4-membered heterocyclyl include but are not limited to azetidinyl or oxetanyl; specific examples of 5-membered heterocyclyl include but are not limited to tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of 6-membered heterocyclyl include but are not limited to The heterocyclic group is limited to tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl, or 4H-[1,3,4]thiadiazinyl; specific examples of 7-membered heterocyclic groups include, but are not limited to, diazepanyl. The heterocyclic group may also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl. Optionally, the heterocyclic group may be a benzo-fused ring group of the above 4-7 membered heterocyclic groups, specific examples of which include, but are not limited to, dihydroisoquinolinyl.The “4-10 membered heterocyclyl” may include the ranges of “5-10 membered heterocyclyl”, “5-9 membered heterocyclyl”, “5-8 membered heterocyclyl”, “5-7 membered heterocyclyl”, “5-6 membered heterocyclyl”, “6-10 membered heterocyclyl”, “6-8 membered heterocyclyl”, “4-8 membered heterocyclyl”, “4-7 membered heterocyclyl”, “4-6 membered heterocyclyl”, “4-10 membered heterocycloalkyl”, “5-10 membered heterocycloalkyl”, “4-7 membered heterocycloalkyl”, “5-6 membered heterocycloalkyl”, “6-8 membered heterocycloalkyl”, and the like; and the “4-7 membered heterocyclyl” may further include the ranges of “4-6 membered heterocyclyl”, “5-7 membered heterocyclyl”, “5-6 membered heterocyclyl”, “4-7 membered heterocyclyl”, “4-6 membered heterocycloalkyl”, “5-7 membered heterocycloalkyl”, “5-6 membered heterocycloalkyl”, and the like. Although some bicyclic heterocyclic groups in the present disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclic group as a whole is still non-aromatic.

[0276] The term "heterocycloalkyl" refers to a fully saturated monovalent cyclic group in the form of a monocyclic, fused, bridged or spirocyclic ring, wherein the ring atoms of the ring contain 1-5 heteroatoms or heteroatom groups (i.e., heteroatom-containing atomic groups). The "heteroatoms or heteroatom groups" include, but are not limited to, nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P), boron atom (B), -S(=O)2-, -S(=O)- and optionally substituted -NH-, -S(=O)(=NH)-, -C(=O)NH-, -C(=NH)-, -S(=O)2NH-, -S(=O)NH- or -NHC(=O)NH-, which usually contain 3 to 20 ring atoms. The term "3-10 membered heterocycloalkyl" refers to a heterocycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1 to 5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms. “3-10 membered heterocycloalkyl” includes “3-8 membered heterocycloalkyl”, wherein specific examples of 4 membered heterocycloalkyl include but are not limited to azetidinyl, oxetanyl or thietanyl; specific examples of 5 membered heterocycloalkyl include but are not limited to tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl or tetrahydropyrazolyl; specific examples of 6 membered heterocycloalkyl include but are not limited to piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl or 1,4-dithianyl; specific examples of 7 membered heterocycloalkyl include but are not limited to azepanyl, oxetanyl or thiepanyl.

[0277] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. The aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. The term "C6-C 20 "Aryl" is understood to be a monovalent aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms. In particular, it is a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 or a ring having 13 carbon atoms ("C 13 aryl) such as fluorenyl; or a ring having 14 carbon atoms ("C 14 The term "C6-C 10 "Aryl" is understood to be a monovalent aromatic, all-carbon monocyclic or bicyclic group having 6, 7, 8, 9 or 10 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indenyl; or a ring having 10 carbon atoms ("C 10 "aryl"), for example naphthyl.

[0278] The term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic or fused polycyclic ring system having aromatic properties, which contains at least one, preferably 1, 2, 3 or 4, ring atoms selected from N, O, S, and the remaining ring atoms are carbon, and is a 5-14 membered aromatic ring radical. The heteroaryl group is preferably a 5-10 membered, more preferably a 5- or 6-membered heteroaryl group. The term "5- to 10-membered heteroaryl" is understood to include monovalent monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and containing 1, 2, 3, 4 or 5, preferably 1, 2 or 3, heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl or isoquinolyl, and the like; or acinyl, indolizinyl, purinyl, and the like, and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl, and the like. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms, and containing 1, 2 or 3, preferably 1 or 2, heteroatoms independently selected from N, O and S. The term "6 membered heteroaryl" refers to an aromatic ring system having 6 ring atoms, and containing 1, 2 or 3, preferably 1 or 2, heteroatoms independently selected from N, O and S. The term "5-10 membered heteroaryl" may include "5-6 membered heteroaryl" or "6 membered heteroaryl", and the term "5-6 membered heteroaryl" may include "6 membered heteroaryl".

[0279] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0280] The term "hydroxy" refers to an -OH group.

[0281] The term "cyano" refers to a -CN group.

[0282] The term "amino" refers to a -NH2 group.

[0283] The term "nitro" refers to a -NO2 group.

[0284] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their own knowledge and this disclosure.

[0285] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0286] The term "pharmaceutically acceptable salt" or "pharmaceutically usable salt" refers to salts of pharmaceutically acceptable acids or bases, including salts formed between a compound and an inorganic acid or organic acid, and salts formed between a compound and an inorganic base or an organic base.

[0287] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure, or their stereoisomers, or pharmaceutically acceptable salts, and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

[0288] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0289] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0290] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0291] Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically-labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent.

[0292] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

[0293] Typical routes of administration of the compounds of the present disclosure, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0294] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, and the like.

[0295] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.

[0296] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, or flavoring agents.

[0297] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0298] The dosage of the compound or composition used in the treatment methods of the present disclosure will generally vary with the severity of the disease, the weight of the patient and the relative efficacy of the compound, but as a general guide, a suitable daily dosage of the compound of Formula (I), Formula (I)-1, Formula (I)-2 or (II) described herein is 0.01 mg / kg to 1000 mg / kg.

[0299] The compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present disclosure.

[0300] The chemical reactions of the embodiments of the present disclosure are carried out in a suitable solvent that is compatible with the chemical transformations of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments. DETAILED DESCRIPTION

[0301] The present disclosure is described in detail below by way of specific embodiments, but this does not imply any adverse limitations on the present disclosure. Various specific embodiments of the present disclosure have been described herein in detail, and it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

[0302] All reagents used in this disclosure were commercially available and used without further purification.

[0303] Unless otherwise specified, the ratios expressed for mixed solvents are volume ratios. Unless otherwise specified, % refers to wt%.

[0304] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The units of NMR shifts are 10 -6 (ppm). The solvents for NMR determination are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 " refers to the half-maximal inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved. "EC 50 " refers to the half-maximal effective concentration of a drug or prodrug, that is, the concentration of the drug or prodrug required to achieve 50% of the effect.

[0305] The eluent mentioned below can be a mixed eluent formed by two or more solvents, and the ratio thereof is the volume ratio of each solvent.

[0306] Abbreviations:

[0307] DCE: dichloroethane; TEA: triethylamine; DCM: dichloromethane; DMF: N,N-dimethylformamide; THF: tetrahydrofuran; DPPA: diphenylphosphoryl azide; MeOH: methanol; NIS: N-iodosuccinimide; NCS: N-chlorosuccinimide; NBS: N-bromosuccinimide; MeCN: acetonitrile; Xphos Pd G3: methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II); Boc: tert-butoxycarbonyl; DIEA: N,N-diisopropylethylamine; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; dioxane: 1,4-dioxane; t-BuOK: potassium tert-butoxide; t-BuONa: sodium tert-butoxide; Pd(OAc)2: palladium acetate; dppf: 1,1'-bis(diphenylphosphino)ferrocene; MeI: methyl iodide; EtOH: ethanol; Pd-PE PPSI-Ipent-Cl: (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-κN)palladium; Pd(dppf)Cl2: 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride; FA: formic acid; NaBH(OAc)3: sodium acetate borohydride; NaOAc: sodium acetate; AcOH: acetic acid; DMSO: dimethyl sulfoxide; PPA: polyphosphoric acid; AIBN: azobisisobutyronitrile; t-BuONO: tert-butyl nitrite; LDA: lithium diisopropylamide; RuPhos Pd G3: methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium(II); Py: pyridine; DMSO: dimethyl sulfoxide; water: water; 2-MeTHF: 2-methyltetrahydrofuran; cataCXium A-Pd-G3: [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate; m-CPBA: m-chloroperbenzoic acid; NH2Boc: tert-butyl carbamate; SFC: supercritical fluid chromatography; KOAc: potassium acetate; B2Pin2: pinacol borate; MeONa: sodium methoxide; MW: microwave; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; Xantphos: 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene; toluene: toluene.

[0308] Example 1: Synthesis of 2-amino-8-chloro-3-(4-(piperazin-1-yl)phenyl)-9H-benzo[e]pyrazolo[5,1-b][1,3]oxazin-9-one hydrochloride (Compound 1)

[0309] Step 1: Synthesis of methyl 1-(2-chloro-6-fluorobenzoyl)-5-hydroxy-1H-pyrazole-3-carboxylate (1c)

[0310] 2-Chloro-6-fluorobenzoic acid (1a, 12 g, 68.75 mmol) was dissolved in dichloroethane (120 mL), and thionyl chloride (81.79 g, 687.46 mmol, 49.93 mL) was added. The reaction mixture was stirred at 80°C for 16 hours. Thin-layer chromatography (petroleum ether:tetrahydrofuran = 3:1) indicated the disappearance of the starting material. The reaction mixture was concentrated under reduced pressure to obtain 2-chloro-6-fluorobenzoyl chloride, which was used directly in the next step. Methyl 5-hydroxy-1H-pyrazole-3-carboxylate (1b, 9.57 g, 67.36 mmol) was dissolved in N,N-dimethylformamide (200 mL), and triethylamine (20.45 g, 202.07 mmol, 28.18 mL) was added. A solution of 2-chloro-6-fluorobenzoyl chloride (13 g, 67.36 mmol) in dichloroethane (30 mL) was then added dropwise at 0°C. The reaction solution was stirred at 25 ° C for 16 hours. LCMS showed that the reaction was complete. The reaction solution was diluted with water (500 mL) and ethyl acetate (500 mL). The aqueous phase was extracted with ethyl acetate (500 mL * 3), and the organic phase was washed with saturated brine (300 mL * 2). The collected organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 100 / 17) to give the title compound (18 g).

[0311] MS m / z(ESI):298.7[M+H] + .

[0312] Step 2: Synthesis of 2-chloro-6-((3-(methoxycarbonyl)-1H-pyrazol-5-yl)oxy)benzoic acid (1d)

[0313] Intermediate 1c (10 g, 33.48 mmol) was dissolved in N,N-dimethylformamide (200 mL), and cesium carbonate (27.27 g, 83.71 mmol) was added. The reaction mixture was stirred at 60°C for 5 hours. LCMS indicated the reaction was complete. The reaction mixture was diluted with water (500 mL), and then dilute hydrochloric acid (1.5 M) was added to adjust the pH to 5-6. The aqueous phase was extracted with ethyl acetate (300 mL x 3), and the organic phase was washed with saturated brine (300 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 100 / 30, containing 0.1% acetic acid) to afford the title compound (3.89 g).

[0314] MS m / z(ESI):297.0[M+H] + .

[0315] Step 3: Synthesis of 5-(2-carboxy-3-chlorophenoxy)-1H-pyrazole-3-carboxylic acid (1e)

[0316] Intermediate 1d (3.89 g, 13.11 mmol) was dissolved in tetrahydrofuran (30 mL) and water (30 mL), and potassium hydroxide (2.21 g, 39.34 mmol) was added. The reaction solution was stirred at 25°C for 16 hours. LCMS showed that the reaction was complete. The reaction solution was extracted with ethyl acetate (30 mL), and dilute hydrochloric acid (1.5 M) was added to the aqueous phase to adjust the pH to 5-6. The aqueous phase was collected and purified by reverse phase column chromatography (120 g silica, water / acetonitrile = 100 / 45) to give the title compound (1.9 g).

[0317] MS m / z(ESI):283.1[M+H] + .

[0318] Step 4: Synthesis of 8-chloro-9-oxo-9H-benzo[e]pyrazolo[5,1-b][1,3]oxazine-2-carboxylic acid (1f)

[0319] Intermediate 1e (1.9 g, 6.72 mmol) was dissolved in dichloroethane (20 mL) and thionyl chloride (8.00 g, 67.22 mmol, 4.88 mL) was added. The reaction mixture was stirred at 80 ° C for 3 hours. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure, quenched by adding water (4 mL), and concentrated again under reduced pressure to give the title compound (1.72 g), which was used directly in the next step.

[0320] MS m / z(ESI):264.7[M+H] + .

[0321] Step 5: Synthesis of 2-amino-8-chloro-9H-benzo[e]pyrazolo[5,1-b][1,3]oxazin-9-one (1 g)

[0322] Intermediate 1f (1.78 g, 6.73 mmol) was dissolved in N,N-dimethylformamide (30 mL). Triethylamine (1.02 g, 10.09 mmol, 1.41 mL) and diphenylphosphoryl azide (2.78 g, 10.09 mmol) were added, and the reaction mixture was stirred at 25°C for 16 hours. Water (121.21 mg, 6.73 mmol, 20 mL) was added. The reaction mixture was stirred at 100°C for 2 hours. LCMS confirmed the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica, dichloromethane / tetrahydrofuran = 100 / 10) to afford the title compound (470 mg).

[0323] MS m / z(ESI):235.8[M+H] + .

[0324] Step 6: Synthesis of 2-amino-8-chloro-3-iodo-9H-benzo[e]pyrazolo[5,1-b][1,3]oxazin-9-one (1h)

[0325] Intermediate 1g (200 mg, 848.80 μmol) was dissolved in acetonitrile (5 mL), and N-iodosuccinimide (229.16 mg, 1.02 mmol) was added. The reaction solution was stirred at 50°C for 0.5 hours, and then at 80°C for 0.5 hours. LCMS confirmed the reaction was complete. The reaction solution was diluted with tetrahydrofuran (20 mL) and dichloromethane (20 mL) until all the solids dissolved. The product was then purified by column chromatography (silica, dichloromethane / tetrahydrofuran = 100 / 3) to give the title compound (245 mg).

[0326] MS m / z(ESI):361.9[M+H] + .

[0327] Step 7: Synthesis of tert-butyl 4-(4-(2-amino-8-chloro-9-oxo-9H-benzo[e]pyrazolo[5,1-b][1,3]oxazin-3-yl)phenyl)piperazine-1-carboxylate (1j)

[0328] Intermediate 1h (100 mg, 276.61 μmol) and 4-(4-tert-butyloxycarbonylpiperazinyl)phenylboronic acid xanaxol ester (1i, 107.41 mg, 276.61 μmol) were dissolved in tetrahydrofuran (8 mL) and water (2 mL). Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (23.41 mg, 27.66 μmol) and potassium phosphate (176.14 mg, 829.82 μmol) were added under a nitrogen atmosphere. The reaction solution was stirred at 50°C for 2 hours. LCMS detection showed that the reaction was complete. The reaction solution was diluted with water (10 mL) and ethyl acetate (10 mL), the aqueous phase was extracted with ethyl acetate (10 mL*2), the organic phase was washed with saturated brine (10 mL*2), the collected organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 100 / 30, containing 0.1% ammonia water) to give the title compound (57 mg).

[0329] MS m / z(ESI):496.1[M+H] + .

[0330] Step 8: Synthesis of 2-amino-8-chloro-3-(4-(piperazin-1-yl)phenyl)-9H-benzo[e]pyrazolo[5,1-b][1,3]oxazin-9-one hydrochloride (Compound 1)

[0331] Intermediate 1j (4.4 mg, 8.87 μmol) was dissolved in dichloromethane (0.5 mL), and dioxane hydrochloride (2 M, 0.5 mL) was added. The reaction mixture was stirred at 25°C for 1 hour. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (0.5 mL) was added. The mixture was stirred at room temperature for 10 minutes, then filtered, and the filter cake was dried to give the title compound (0.95 mg).

[0332] MS m / z(ESI):396.1[M+H] + ;

[0333] 1 H NMR(400MHz,DMSO-d6)δ=8.93(br s,2H),7.78-7.68(m,1H),7.55-7.46(m,4H),7.15-7.07(m,2H),5.90(s,2H),3.42-3.39(m,4H),3.28-3.21(m,4H).

[0334] Example 2: Synthesis of 2-amino-8-chloro-3-(4-(piperazin-1-yl)phenyl)pyrazolo[5,1-b]quinazolin-9(4H)-one hydrochloride (Compound 2)

[0335] Step 1: Synthesis of tert-butyl 2-(2-chloro-6-fluorobenzoyl)hydrazinecarboxylate (2a)

[0336] Intermediate 1a (1.39 g, 7.94 mmol) was dissolved in dichloromethane (20 mL), and N,N-diisopropylethylamine (1.47 g, 11.35 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.43 g, 9.08 mmol) were added, followed by tert-butyl carbazate (1 g, 7.57 mmol). The reaction solution was stirred at 25°C for 12 hours. LCMS showed that the reaction was complete. The reaction solution was washed with water (20 mL) and then concentrated to dryness under reduced pressure. The concentrate was purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 0-35%) to give the title compound (890 mg).

[0337] MS m / z(ESI):311.0[M+Na] + .

[0338] Step 2: Synthesis of 2-chloro-6-fluorobenzoylhydrazide hydrochloride (2b)

[0339] Intermediate 2a (490 mg, 1.70 mmol) was dissolved in dichloromethane (3 mL) and dioxane hydrochloride (4 M, 4.24 mL) was added. The reaction mixture was allowed to react at 25°C for 2 hours. LCMS confirmed the reaction was complete. The reaction mixture was concentrated to dryness under reduced pressure to obtain the title compound (450 mg).

[0340] MS m / z(ESI):189.1[M+H] + .

[0341] Step 3: Synthesis of tert-butyl 4-(4-(dicyanomethyl)phenyl)piperazine-1-carboxylate (2d)

[0342] Tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate (2c, 1 g, 2.93 mmol) and malononitrile (212.95 mg, 3.22 mmol) were dissolved in dioxane (10 mL). Potassium tert-butoxide (822.08 mg, 7.33 mmol) was added under nitrogen. The reaction mixture was stirred at 80°C for 30 minutes. 1,1'-bis(diphenylphosphino)ferrocene (324.93 mg, 586.10 μmol) and palladium acetate (65.79 mg, 293.05 μmol) in dioxane (4 mL) were added. The reaction mixture was stirred at 80°C for 11.5 hours. LCMS confirmed the reaction was complete. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 0-20%) to give the title compound (200 mg).

[0343] 1 H NMR (400MHz, DMSO-d6) δ = 7.37 (d, J = 8.4Hz, 2H), 7.06 (d, J = 8.6Hz, 2H), 6.31 (s, 1H), 3.52-3.43 (m, 8H), 1.42 (s, 9H).

[0344] Step 4: Synthesis of tert-butyl 4-(4-(3,5-diamino-1-(2-chloro-6-fluorobenzoyl)-1H-pyrazol-4-yl)phenyl)piperazine-1-carboxylate (2e)

[0345] Intermediate 2d (170 mg, 520.85 μmol) and intermediate 2b (128.94 mg, 572.93 μmol) were dissolved in dioxane (3 mL). Triethylamine (263.52 mg, 2.60 mmol) was added under nitrogen, and the reaction mixture was allowed to react at 120°C for 12 hours. LCMS confirmed the reaction was complete. The reaction mixture was extracted with ethyl acetate (5 mL x 3) and water (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The title compound (50 mg) was then purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 0-30%).

[0346] MS m / z(ESI):515.3[M+H] + .

[0347] Step 5: Synthesis of tert-butyl 4-(4-(2-amino-8-chloro-9-oxo-4,9-dihydropyrazolo[5,1-b]quinazolin-3-yl)phenyl)piperazine-1-carboxylate (2f)

[0348] Intermediate 2e (50 mg, 97.09 μmol) was dissolved in N,N-dimethylformamide (2 mL), and sodium hydride (11.65 mg, 291.27 μmol, 60% content) was added. The reaction solution was reacted at 25°C for 2 hours. The reaction was complete as determined by LCMS. The reaction solution was quenched with water (1 mL), then extracted with dichloromethane (10 mL*3) and water (3 mL). The organic phase was concentrated under reduced pressure, and the concentrate was purified by thin-layer chromatography (silica, petroleum ether / tetrahydrofuran = 1:2) to obtain the title compound (20 mg).

[0349] MS m / z(ESI):495.3[M+H] + .

[0350] Step 6: Synthesis of 2-amino-8-chloro-3-(4-(piperazin-1-yl)phenyl)pyrazolo[5,1-b]quinazolin-9(4H)-one hydrochloride (Compound 2)

[0351] Intermediate 2f (20 mg, 40.41 μmol) was dissolved in dichloromethane (2 mL), and dioxane hydrochloride (2 M, 202.03 μL) was added. The reaction mixture was incubated at 25°C for 2 hours. LCMS confirmed the reaction was complete. The reaction mixture was concentrated to dryness under reduced pressure, washed with ethyl acetate (5 mL), and dried to afford the title compound (14 mg).

[0352] MS m / z(ESI):395.3[M+H] + ;

[0353] 1 H NMR(400MHz,DMSO-d6)δ=11.88(br s,1H),9.31(s,2H),7.62-7.57(m,1H),7.55-7.50(m,1H),7.36(d,J=8.6Hz,2H),7 .27(d,J=7.5Hz,1H),7.14(d,J=8.8Hz,2H),3.49-3.40(m,4H),3.29-3.20(m,4H).

[0354] Example 3: Synthesis of 2-amino-8-chloro-3-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[5,1-b]quinazolin-9(4H)-one (Compound 3)

[0355] Step 1: Synthesis of 2-(6-chloropyridin-3-yl)-3,3-bis(methylthio)acrylonitrile (3b)

[0356] 2-(6-chloropyridin-3-yl)acetonitrile (3a, 200 mg, 1.31 mmol) was dissolved in N, N-dimethylformamide (4 mL), and carbon disulfide (119.76 mg, 1.57 mmol) and sodium hydride (94.38 mg, 2.36 mmol, 60% purity) were slowly added dropwise in an ice-water bath at 0°C. The reaction solution was stirred at 25°C for 4 hours. Iodomethane (558.15 mg, 3.93 mmol) was then added, and the reaction solution was stirred at 25°C for 1 hour. LCMS showed that the reaction was complete. The reaction solution was quenched by adding water (5 mL), and then diluted with water (15 mL) and ethyl acetate (15 mL). The aqueous phase was extracted with ethyl acetate (15 mL*3), and the organic phase was washed twice with saturated brine (15 mL*2). The collected organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (silica, petroleum ether / ethyl acetate = 100 / 12) to obtain the title compound (260 mg).

[0357] MS m / z(ESI):257.0[M+H] + .

[0358] Step 2: Synthesis of methyl 2-chloro-6-((2-(6-chloropyridin-3-yl)-2-cyano-1-(methylthio)vinyl)amino)benzoate (3d)

[0359] Intermediate 3b (210 mg, 817.84 μmol) and methyl 2-amino-6-chlorobenzoate (3c, 182.16 mg, 981.41 μmol) were dissolved in N,N-dimethylformamide (6 mL). Cesium carbonate (532.94 mg, 1.64 mmol) was added, and the reaction mixture was stirred at 50°C for 16 hours. LCMS indicated the reaction was complete. The reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL). The aqueous phase was extracted with ethyl acetate (15 mL x 3), and the organic phase was washed with brine (15 mL x 2). The collected organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica, petroleum ether / ethyl acetate = 100 / 30) to afford the title compound (160 mg).

[0360] MS m / z(ESI):394.1[M+H] + .

[0361] Step 3: Synthesis of 2-amino-8-chloro-3-(6-chloropyridin-3-yl)pyrazolo[5,1-b]quinazolin-9(4H)-one (3e)

[0362] Intermediate 3d (160 mg, 405.81 μmol) was dissolved in ethanol (6 mL), and hydrazine hydrate (0.36 g, 5.75 mmol, 80% purity) was added. The reaction mixture was stirred at 60°C for 16 hours. LCMS indicated the reaction was complete. The reaction mixture was filtered, and the filter cake was washed with petroleum ether (10 mL x 2) and then dried to yield the title compound (135 mg).

[0363] MS m / z(ESI):346.1[M+H] + .

[0364] Step 4: Synthesis of 2-amino-8-chloro-3-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[5,1-b]quinazolin-9(4H)-one (Compound 3)

[0365] Intermediate 3e (100 mg, 288.87 μmol) and anhydrous piperazine (497.65 mg, 5.78 mmol) were dissolved in N,N-dimethylformamide (7.5 mL), and cesium carbonate (282.36 mg, 866.62 μmol) was added. The reaction solution was microwaved at 160°C for 10 hours. The reaction solution was filtered, and the filtrate was purified by high performance liquid chromatography (ACSSH-CD C18, 5 μm silica, diameter, 150 mm length; using decreasingly polar mixtures of water (containing 0.225% formic acid) and acetonitrile (acetonitrile ratio 5%-25%) as eluent) to give the title compound (10.42 mg) (5.2 mg).

[0366] MS m / z(ESI):396.2[M+H] + ;

[0367] 1 H NMR (400MHz, DMSO-d6) δ = 8.31 (s, 1H), 8.27 (s, 1H), 7.71 (d, J = 7.3Hz, 1H), 7.55-7.43 (m, 1H), 7.42-7.30 (m,1H),7.12(d,J=7.3Hz,1H),6.96(d,J=8.8Hz,1H),5.49(s,2H),3.71-3.70(m,4H),3.14-2.96(m,4H).

[0368] Example 4: Synthesis of 3-(6-(4-((4-(4-(2-amino-8-chloro-9-oxo-9H-benzo[e]pyrazolo[5,1-b][1,3]oxazin-3)-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 4)

[0369] Step 1: Synthesis of 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (4b)

[0370] 3-(6-Bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (4a, 500 mg, 1.55 mmol) and 4-(dimethoxymethyl)piperidine (369.56 mg, 2.32 mmol) were dissolved in dioxane (10 mL). (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-κN)palladium (66.58 mg, 77.37 μmol) and cesium carbonate (1.01 g, 3.09 mmol) were added at 25°C. The reaction mixture was stirred at 100°C under nitrogen for 2 hours. LCMS indicated the reaction was complete. The reaction mixture was filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, tetrahydrofuran:petroleum ether=1:2) to give the title compound (539 mg).

[0371] MS m / z(ESI):402.2[M+H] + .

[0372] Step 2: Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-4-carbaldehyde (4c)

[0373] Intermediate 4b (100 mg, 249.1 μmol) was dissolved in formic acid (1 mL), and the reaction mixture was stirred at 60°C for 2 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to give the title compound (88 mg).

[0374] MS m / z(ESI):356.3[M+H] + .

[0375] Step 3: Synthesis of 3-(6-(4-((4-(4-(2-amino-8-chloro-9-oxo-9H-benzo[e]pyrazolo[5,1-b][1,3]oxazin-3)-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 4)

[0376] Compound 1 (62 mg, 144.00 μmol) and intermediate 4c (56.29 mg, 158.40 μmol) were dissolved in N,N-dimethylformamide (2 mL). Sodium acetate (35.44 mg, 431.99 μmol), acetic acid (25.94 mg, 431.99 μmol), and sodium acetate borohydride (91.56 mg, 431.99 μmol) were added. The reaction mixture was stirred at 25°C for 1 hour. LCMS indicated the reaction was complete. The reaction mixture was diluted with dimethyl sulfoxide (1 mL), filtered, and the filtrate was purified by high-performance liquid chromatography (Phenomenex Gemini NX column, 5 μm silica, 30 mm diameter, 150 mm length; using decreasingly polar mixtures of water (containing 0.05% ammonia) and acetonitrile (acetonitrile ratio 28%-68%) as eluent) to afford the title compound (27.8 mg).

[0377] MS m / z(ESI):735.2[M+H] + ;

[0378] 1 H NMR (400MHz, DMSO-d6)δ=10.97(s,1H),7.78-7.67(m,1H),7.58-7.36(m,5H),7.30-7.21(m,1H),7.16(s,1 H),7.05(d,J=8.8Hz,2H),5.93-5.79(m,2H),5.09(dd,J=4.9,13.3Hz,1H),4.39-4.27(m,1H),4.24-4.13(m ,1H),3.83-3.69(m,2H),3.24-3.15(m,4H),2.97-2.84(m,1H),2.80-2.68(m,2H),2.54(s,4H),2.48-2.30 (m,2H),2.23(d,J=6.9Hz,2H),2.04-1.93(m,1H),1.90-1.79(m,2H),1.78-1.67(m,1H),1.32-1.19(m,2H).

[0379] Example 5: Synthesis of 3-(5-(4-((4-(4-(2-amino-8-chloro-9-oxo-4,9-dihydropyrazolo[5,1-b]quinazolin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 5)

[0380] Compound 2 (10 mg, 23.18 μmol) and 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-4-carbaldehyde (5a, 9.47 mg, 23.18 μmol) were dissolved in dimethyl sulfoxide (0.5 mL). Acetic acid (4.18 mg, 69.55 μmol), sodium acetate (5.71 mg, 69.55 μmol), and sodium acetate borohydride (14.74 mg, 69.55 μmol) were added. The reaction mixture was incubated at 25°C for 1 hour. LCMS confirmed the reaction was complete, and the reaction mixture was quenched by adding water (0.1 mL) and concentrated to dryness under reduced pressure. Purification by high performance liquid chromatography (Phenomenex Gemini NX, 5 μm silica, 40 mm diameter, 150 mm length; using decreasingly polar mixtures of water (containing 0.05% ammonia) and acetonitrile (acetonitrile ratio 21%-61%) as eluent) gave the title compound (6.8 mg).

[0381] MS m / z(ESI):734.4[M+H] + ;

[0382] 1 H NMR (400MHz, DMSO-d6) δ = 11.50 (br s, 1H), 10.94 (s, 1H), 7.59-7.44 (m, 3H), 7.31 (d, J = 8.2Hz, 2H), 7.17 (d, J = 7.1Hz, 1H), 7.12-7.01 (m, 4H), 5.44 (br s,2H),5.04(dd,J=4.8,13.3Hz,1H),4.38-4.27(m,1H),4.26-4.14(m,1H),3.89(d,J=13.0Hz,2H),3.20(s,4H),2.93-2.78( m,3H),2.70-2.60(m,5H),2.40-2.30(m,1H),2.23(d,J=6.7Hz,2H),2.00-1.90(m,1H),1.85-1.70(m,3H),1.30-1.10(m,2H).

[0383] Example 6: Synthesis of 3-(5-(4-((4-(5-(2-amino-8-chloro-9-oxo-4,9-dihydropyrazolo[5,1-b]quinazolin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 6)

[0384] Compound 3 (8.96 mg, 22.64 μmol) and intermediate 5a (16.09 mg, 45.27 μmol) were dissolved in dimethyl sulfoxide (1 mL). Sodium acetate (5.57 mg, 67.91 μmol) was added, and the reaction mixture was stirred at 25°C for 10 minutes. Acetic acid (4.08 mg, 67.91 μmol) and sodium acetate borohydride (14.39 mg, 67.91 μmol) were then added. The reaction mixture was stirred at 25°C for 1 hour. LCMS indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was purified by HPLC (Boston Prime C18 column, 5 μm silica, 30 mm diameter, 150 mm length; using decreasingly polar mixtures of water (containing 0.225% formic acid) and acetonitrile (acetonitrile ratio 4%-44%) as eluent) to obtain the title compound (2.51 mg).

[0385] MS m / z(ESI):735.3[M+H] + ;

[0386] 1 H NMR (400MHz, DMSO-d6) δ = 11.58 (s, 1H), 10.94 (s, 1H), 8.18 (d, J = 2.4Hz, 1H), 7.58 (dd, J = 2.4, 8.6Hz, 1H), 7.55-7.47 (m, 2 H),7.43(d,J=7.7Hz,1H),7.18(d,J=7.0Hz,1H),7.09-7.01(m,2H),6.94(d,J=8.8Hz,1H),5.52(s,2H),5.04(dd,J=5.2, 13.3Hz,1H),4.41-4.26(m,1H),4.25-4.07(m,1H),3.89(d,J=12.5Hz,2H),3.53-3.45(m,6H),2.96-2.75(m,3H),2.63-2 .51(m,2H),2.46-2.28(m,2H),2.22(d,J=6.6Hz,2H),2.02-1.90(m,1H),1.82(d,J=10.3Hz,3H),1.21(d,J=11.7Hz,2H).

[0387] Example 7: Synthesis of 2-amino-9-chloro-4-(4-(piperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one (Compound 7)

[0388] Step 1: Synthesis of 4-bromo-5-chloropyridin-2-amine (7b)

[0389] 2-Amino-4-bromopyridine (7a, 2 g, 11.56 mmol) was dissolved in N,N-dimethylformamide (20 mL), and N-chlorosuccinimide (1.70 g, 12.72 mmol) was added. The reaction mixture was reacted at 25°C for 4 hours, diluted with water (50 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. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 3 / 1) to obtain the title compound (2.4 g).

[0390] 1 H NMR (400MHz, DMSO-d6) δ = 8.00 (s, 1H), 6.81 (s, 1H), 6.36 (s, 2H).

[0391] Step 2: Synthesis of 4-bromo-5-chloro-2-nitropyridine (7c)

[0392] Intermediate 7b (1.8 g, 8.68 mmol) was dissolved in concentrated sulfuric acid (20 mL), and hydrogen peroxide (30% (w / w) aqueous solution, 9.84 g, 86.77 mmol) was added at 0°C. The reaction mixture was reacted at 25°C for 12 hours, diluted with water (100 mL), and filtered to obtain the title compound (900 mg).

[0393] 1 H NMR (400MHz, DMSO-d6) δ = 8.88 (s, 1H), 8.77 (s, 1H).

[0394] Step 3: Synthesis of methyl 2-((4-bromo-6-nitropyridin-3-yl)oxy)-6-chlorobenzoate (7e)

[0395] Intermediate 7c (850 mg, 3.58 mmol) and methyl 2-chloro-6-hydroxybenzoate (7d, 534.38 mg, 2.86 mmol) were dissolved in N,N-dimethylformamide (10 mL), and cesium carbonate (2.33 g, 7.16 mmol) was added. The reaction mixture was reacted at 50°C under nitrogen for 4 hours. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (10 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, and the filtrate was concentrated and purified by column chromatography (silica, petroleum ether / ethyl acetate = 3 / 1) to obtain the title compound (670 mg).

[0396] 1 H NMR (400MHz, DMSO-d6) δ = 8.87 (s, 1H), 7.75-7.69 (m, 1H), 7.68-7.63 (m, 2H), 7.53-7.49 (m, 1H), 3.79 (s, 3H).

[0397] Step 4: Synthesis of methyl 2-((6-amino-4-bromopyridin-3-yl)oxy)-6-chlorobenzoate (7f)

[0398] Intermediate 7e (670 mg, 1.73 mmol) was dissolved in ethanol (10 mL) and water (2 mL), and iron powder (965.40 mg, 17.29 mmol) and ammonium chloride (924.72 mg, 17.29 mmol) were added. The reaction mixture was reacted at 80°C for 2 hours, cooled to room temperature, filtered, and the filtrate was concentrated and purified by preparative liquid chromatography (Boston Prime C18: 5 μm silica, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.225% formic acid) and acetonitrile (acetonitrile ratio 17%-57%) as the eluent) to obtain the title compound (44 mg).

[0399] MS m / z(ESI):356.6,358.6[M+H] + .

[0400] Step 5: Synthesis of 2-((6-amino-4-bromopyridin-3-yl)oxy)-6-chlorobenzoic acid (7 g)

[0401] Intermediate 7f (30 mg, 83.90 μmol) was dissolved in methanol (0.5 mL) and water (0.5 mL), and potassium hydroxide (47.07 mg, 838.96 μmol) was added. The reaction mixture was reacted at 80°C for 12 hours. The pH of the reaction mixture was adjusted to pH 6-7 with hydrochloric acid (1.5 M) and extracted with ethyl acetate (5 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound (30 mg).

[0402] MS m / z(ESI):342.6,344.6[M+H] + .

[0403] Step 6: Synthesis of 2-amino-4-bromo-9-chloro-10H-chromeno[3,2-b]pyridin-10-one (7h)

[0404] The intermediate 7 g (30 mg, 87.32 μmol) was dissolved in polyphosphoric acid (1 mL), and the reaction solution was reacted at 120° C. for 2 hours. The reaction solution was cooled to room temperature, diluted with water (1 mL), and the pH was adjusted to pH 8-9 with solid sodium carbonate. The title compound (30 mg) was obtained by filtration.

[0405] MS m / z(ESI):324.6,326.6[M+H] + .

[0406] Step 7: Synthesis of tert-butyl 4-(4-(2-amino-9-chloro-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)piperazine-1-carboxylate (7i)

[0407] Intermediate 7h (23.2 mg, 71.27 μmol) and intermediate 1i (24.91 mg, 64.14 μmol) were dissolved in dioxane (1 mL) and water (0.2 mL). 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride (5.21 mg, 7.13 μmol) and potassium carbonate (19.70 mg, 142.53 μmol) were added. The reaction mixture was reacted at 80°C under nitrogen for 2 hours. The reaction mixture was cooled to room temperature, concentrated, diluted with water (1 mL), stirred at room temperature for 10 minutes, and filtered. The filter cake was dispersed in ethyl acetate (1 mL), stirred at room temperature for 30 minutes, and filtered to obtain the title compound (19 mg).

[0408] MS m / z(ESI):507.0[M+H] + .

[0409] Step 8: Synthesis of 2-amino-9-chloro-4-(4-(piperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one (Compound 7)

[0410] Intermediate 7i (19 mg, 37.48 μmol) was dissolved in dichloromethane (0.5 mL), and dioxane hydrochloride (2 M, 187.38 μL) was added. The reaction mixture was reacted at 25°C for 2 hours, concentrated, and purified by preparative liquid chromatography (Phenomenex Gemini NX: 5 μm silica, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.05% ammonia) and acetonitrile (acetonitrile ratio 27%-67%) as the eluent) to obtain the title compound (1.1 mg).

[0411] MS m / z(ESI):407.0[M+H] + ;

[0412] 1 H NMR (400MHz, DMSO-d6) δ=7.73-7.67(m,1H),7.61(d,J=8.8Hz,2H),7.46(dd,J=4.5,8.1Hz, 2H),7.09(d,J=8.9Hz,2H),6.96(s,1H),6.47(s,2H),3.22-3.18(m,4H),2.90-2.84(m,4H).

[0413] Example 8: Synthesis of 2-amino-9-chloro-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-10H-chromeno[3,2-b]pyridin-10-one (Compound 8)

[0414] Step 1: Synthesis of tert-butyl 4-(4-(5-chloro-2-nitropyridin-4-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (8b)

[0415] Intermediate 7c (1.5 g, 6.32 mmol) was dissolved in dioxane (40 mL) and water (10 mL), and tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (8a, 2.38 g, 6.32 mmol), potassium carbonate (2.62 g, 18.95 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (462.26 mg, 631.74 μmol) were added. The reaction solution was stirred at 80°C for 2 hours. The reaction solution was cooled to room temperature, water (30 mL) was added, and the mixture was extracted twice with ethyl acetate (50 mL). Anhydrous sodium sulfate was added to dry the organic phase, filtered, and the filtrate was concentrated to dryness under reduced pressure. The title compound (800 mg) was obtained by column chromatography (silica, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1).

[0416] MS m / z(ESI):352.0[M+H-56] + .

[0417] Step 2: Synthesis of tert-butyl 4-(4-(5-(3-chloro-2-(methoxycarbonyl)phenoxy)-2-nitropyridin-4-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (8c)

[0418] Intermediate 8b (800 mg, 1.96 mmol) was dissolved in N,N-dimethylformamide (10 mL), and methyl 2-chloro-6-hydroxybenzoate (7d, 366 mg, 1.96 mmol) and cesium carbonate (1.92 g, 5.88 mmol) were added. The reaction solution was stirred at 80°C for 2 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The title compound (520 mg) was purified by column chromatography (silica, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to obtain the title compound.

[0419] MS m / z(ESI):558.1[M+H] + .

[0420] Step 3: Synthesis of tert-butyl 4-(4-(2-amino-5-(3-chloro-2-(methoxycarbonyl)phenoxy)pyridin-4-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (8d)

[0421] Intermediate 8c (520 mg, 931.93 μmol) was dissolved in ethanol (4 mL) and water (4 mL), and ammonium chloride (747.75 mg, 13.98 mmol) and iron powder (780.65 mg, 13.98 mmol) were added. The reaction was stirred at 80°C for 2 hours. The reaction solution was cooled to room temperature, filtered through celite, and concentrated under reduced pressure to remove ethanol. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL*2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to dryness to give the title compound (420 mg).

[0422] MS m / z(ESI):528.2[M+H] + .

[0423] Step 4: Synthesis of 2-((6-amino-4-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)oxy)-6-chlorobenzoic acid (8e)

[0424] Intermediate 8d (420 mg, 795.46 μmol) was dissolved in methanol (4 mL) and water (4 mL), and potassium hydroxide (89.26 mg, 1.59 mmol) was added. The reaction mixture was stirred at 80°C for 10 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove methanol. Dilute hydrochloric acid (1.5 M) was added to adjust the pH to 4. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL*2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain the title compound (350 mg).

[0425] MS m / z(ESI):514.2[M+H] + .

[0426] Step 5: Synthesis of 2-amino-9-chloro-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-10H-chromeno[3,2-b]pyridin-10-one (Compound 8)

[0427] Intermediate 8e (200 mg, 389.13 μmol) was dissolved in polyphosphoric acid (0.8 mL). The reaction mixture was stirred at 120°C for 1 hour. The reaction mixture was cooled to room temperature and added dropwise to water (5 mL). The pH was adjusted to 9 with 15% aqueous sodium hydroxide solution, and the mixture was extracted with dichloromethane:methanol (10:1) (5 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The title compound (3.8 mg) was purified by HPLC (Phenomenex luna C18 column, 10 μm silica, 25 mm diameter, 150 mm length; eluent: a mixture of water (0.225% formic acid) and acetonitrile (8%-38% acetonitrile).

[0428] MS m / z(ESI):396.1[M+H] + ;

[0429] 1 H NMR (400MHz, DMSO-d6) δ=8.57(s,1H),8.33(s,1H),7.89(d,J=8.4Hz,1H),7.76(t,J=8.1Hz,1H),7.48(d,J=7.6 Hz,1H),7.20(s,1H),6.39(s,2H),4.61-4.40(m,1H),3.23-3.19(m,2H),2.85-2.74(m,2H),2.11-1.97(m,4H).

[0430] Example 9: Synthesis of 2-amino-9-chloro-4-(6-(piperazin-1-yl)pyridin-3-yl)-10H-chromeno[3,2-b]pyridin-10-one (Compound 9)

[0431] Step 1: Synthesis of tert-butyl 4-(5'-chloro-2'-nitro-[3,4'-bipyridyl]-6-yl)piperazine-1-carboxylate (9b)

[0432] Intermediate 7c (1.5 g, 6.32 mmol) was dissolved in dioxane (32 mL) and water (8 mL), and tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (9a, 2.46 g, 6.32 mmol), potassium carbonate (2.62 g, 18.95 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (462.26 mg, 631.74 μmol) were added. The reaction solution was stirred at 80°C for 2 hours. The reaction solution was cooled to room temperature, water (40 mL) was added, and the mixture was extracted with ethyl acetate (40 mL*2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give the title compound (2 g).

[0433] 1 H NMR (400MHz, DMSO-d6) δ = 8.82 (s, 1H), 8.43 (d, J = 2.4Hz, 1H), 8.36 (s, 1H), 7.90 (dd, J = 2. 5,9.0Hz,1H),7.01(d,J=9.1Hz,1H),3.66-3.62(m,4H),3.47-3.43(m,4H),1.43(s,9H).

[0434] Step 2: Synthesis of tert-butyl 4-(5'-(3-chloro-2-(methoxycarbonyl)phenoxy)-2'-nitro-[3,4'-bipyridyl]-6-yl)piperazine-1-carboxylate (9c)

[0435] Intermediate 9b (1 g, 2.38 mmol) was dissolved in N,N-dimethylformamide (25 mL), and intermediate 7d (444.41 mg, 2.38 mmol) and cesium carbonate (2.33 g, 7.15 mmol) were added. The reaction was stirred at 80°C for 16 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to obtain the title compound (900 mg).

[0436] MS m / z(ESI):570.2[M+H] + .

[0437] Step 3: Synthesis of tert-butyl 4-(2'-amino-5'-(3-chloro-2-(methoxycarbonyl)phenoxy)-[3,4'-bipyridyl]-6-yl)piperazine-1-carboxylate (9d)

[0438] Intermediate 9c (900 mg, 1.58 mmol) was dissolved in ethanol (10 mL) and water (10 mL). Ammonium chloride (1.27 g, 23.68 mmol) and iron powder (1.32 g, 23.68 mmol) were added, and the reaction was stirred at 80°C for 1 hour. The reaction solution was cooled to room temperature, filtered through celite, and concentrated under reduced pressure to remove ethanol. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL*2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to give the title compound (709 mg).

[0439] MS m / z(ESI):540.3[M+H] + .

[0440] Step 4: Synthesis of 2-((6'-amino-6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-[3,4'-bipyridyl]-3'-yl)oxy)-6-chlorobenzoic acid (9e)

[0441] Intermediate 9d (609 mg, 1.13 mmol) was dissolved in methanol (6 mL) and water (6 mL), and potassium hydroxide (189.82 mg, 3.38 mmol) was added. The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove methanol. Dilute hydrochloric acid (1.5 M) was added to adjust the pH to 4. Water (15 mL) was added to precipitate a solid, which was filtered and dried to obtain the title compound (380 mg).

[0442] MS m / z(ESI):526.1[M+H] + .

[0443] Step 5: Synthesis of 2-amino-9-chloro-4-(6-(piperazin-1-yl)pyridin-3-yl)-10H-chromeno[3,2-b]pyridin-10-one (Compound 9)

[0444] Compound 9e (50 mg, 95.06 μmol) was dissolved in polyphosphoric acid (1 mL). The reaction mixture was stirred at 120°C for 8 hours. The reaction mixture was cooled to room temperature and added dropwise to water (5 mL). The pH was adjusted to 9 with 15% aqueous sodium hydroxide solution. The product precipitated from the water (5 mL). The mixture was filtered, the filter cake dried, and purified by high-performance liquid chromatography (Phenomenex luna C18 column, 10 μm silica, 25 mm diameter, 150 mm length; eluent: a mixture of water (0.225% formic acid) and acetonitrile (acetonitrile ratio 0%-30%)) to afford the title compound (1.3 mg).

[0445] MS m / z(ESI):408.1[M+H] + ;

[0446] 1 H NMR (400MHz, DMSO-d6) δ = 8.48 (d, J = 2.4Hz, 1H), 7.94 (dd, J = 2.5, 8.9Hz, 1H), 7.73-7.66 (m, 1H) ,7.47(t,J=8.6Hz,2H),7.01-6.97(m,2H),6.52(s,2H),3.59-3.55(m,4H),2.89-2.85(m,4H).

[0447] Example 10: Synthesis of 2-amino-9-chloro-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)-10H-chromeno[3,2-b]pyridin-10-one (Compound 10)

[0448] Step 1: Synthesis of tert-butyl 6-(5-chloro-2-nitropyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (10b)

[0449] Intermediate 7c (650 mg, 2.74 mmol) and tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (10a, 983.51 mg, 2.74 mmol) were dissolved in 1,4-dioxane (16 mL) and water (4 mL), and potassium carbonate (1.14 g, 8.21 mmol) was added. After nitrogen replacement three times, 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (200.32 mg, 273.76 μmol) was added. The reaction solution was stirred at 80°C under a nitrogen atmosphere for 2 hours. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (60 mL*3). The mixture was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 9 / 1) to give the title compound (570 mg).

[0450] MS m / z(ESI):390.1[M+H] + .

[0451] Step 2: Synthesis of tert-butyl 6-(5-(3-chloro-2-(methoxycarbonyl)phenoxy)-2-nitropyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (10c)

[0452] Intermediate 10b (480 mg, 1.23 mmol) and intermediate 7d (229.75 mg, 1.23 mmol) were dissolved in N,N-dimethylformamide (7 mL), and cesium carbonate (802.36 mg, 2.46 mmol) was added. The reaction solution was stirred at 80°C for 2 hours. Water (10 mL) was added to the reaction solution, and the solution was extracted with ethyl acetate (30 mL*3). The organic phase was washed with saturated brine (30 mL*3), concentrated to dryness under reduced pressure, and purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 5 / 1) to obtain the title compound (460 mg).

[0453] MS m / z(ESI):540.1[M+H] + .

[0454] Step 3: Synthesis of tert-butyl 6-(2-amino-5-(3-chloro-2-(methoxycarbonyl)phenoxy)pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (10d)

[0455] Intermediate 10c (460 mg, 851.91 μmol) was dissolved in ethanol (4 mL) and water (1 mL), and ammonium chloride (227.84 mg, 4.26 mmol) and iron powder (190.30 mg, 3.41 mmol) were added. The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to remove the ethanol. Water (5 mL) was added and the mixture was extracted with ethyl acetate (15 mL*3). The organic phase was washed with water (15 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the title compound (430 mg).

[0456] MS m / z(ESI):510.1[M+H] + .

[0457] Step 4: Synthesis of 2-((6-amino-4-(2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)oxy)-6-chlorobenzoic acid (10e)

[0458] Intermediate 10d (445 mg, 872.58 μmol) was dissolved in methanol (3 mL) and water (3 mL), and potassium hydroxide (195.83 mg, 3.49 mmol) was added. The reaction mixture was reacted at 80°C for 24 hours. The reaction mixture was concentrated under reduced pressure to remove the methanol. Water (10 mL) was added to the reaction mixture, and the pH was adjusted to 2-3 with dilute hydrochloric acid. A solid precipitated, which was filtered and the filter cake dried to obtain the title compound (400 mg).

[0459] MS m / z(ESI):496.1[M+H] + .

[0460] Step 5: Synthesis of 2-amino-9-chloro-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)-10H-chromeno[3,2-b]pyridin-10-one (Compound 10)

[0461] Intermediate 10e (400 mg, 806.53 μmol) was dissolved in concentrated sulfuric acid (4 mL). The reaction mixture was reacted at 100°C for 1 hour. The reaction mixture was poured into ice water (10 mL) and adjusted to pH 12 with 15% aqueous sodium hydroxide solution. A solid precipitated, which was filtered and the filter cake dried to give the title compound (258 mg).

[0462] MS m / z(ESI):378.0[M+H] + ;

[0463] 1 H NMR (400MHz, DMSO-d6) δ = 7.72-7.65 (m, 1H), 7.48-7.39 (m, 4H), 7.21 (d, J = 7.9Hz, 1H),7.00-6.96(m,1H),6.54(s,2H),3.95(s,2H),3.06-2.99(m,2H),2.81(s,2H).

[0464] Example 11: Synthesis of 3-(6-(4-((4-(4-(2-amino-9-chloro-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 11)

[0465] Compound 7 (9.17 mg, 22.56 μmol) and intermediate 4c (6.41 mg, 18.05 μmol) were dissolved in N,N-dimethylformamide (0.5 mL). Sodium acetate borohydride (14.34 mg, 67.67 μmol), sodium acetate (5.55 mg, 67.67 μmol), and acetic acid (4.06 mg, 67.67 μmol) were added. The reaction mixture was reacted at 25°C for 2 hours, filtered, and the filtrate was purified by preparative liquid chromatography (Phenomenex Gemini NX: 5 μm silica, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.05% ammonia) and acetonitrile (acetonitrile ratio 27%-67%) as the eluent) to obtain the title compound (1.6 mg).

[0466] MS m / z(ESI):746.4[M+H] + ;

[0467] 1 H NMR (400MHz, DMSO-d6) δ = 10.98 (s, 1H), 7.73-7.67 (m, 1H), 7.62 (d, J = 8.6Hz, 2H), 7.48-7.41 (m, 3H), 7.27 (dd, J =2.3,8.5Hz,1H),7.17(d,J=2.2Hz,1H),7.11(d,J=9.0Hz,2H),6.97(s,1H),6.48(s,2H),5.10(dd,J=5.3,12.8 Hz,1H),4.37-4.31(m,1H),4.24-4.17(m,1H),3.78(d,J=10.3Hz,2H),2.79-2.71(m,2H),2.31-2.21(m,2H),2. 04-1.95(m,1H),1.88-1.81(m,2H),1.60-1.45(m,4H),1.40-1.15(m,4H),1.01-0.98(m,2H),0.88-0.84(m,4H).

[0468] Example 12: Synthesis of 3-(6-(4-((4-(4-(2-amino-9-chloro-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 12)

[0469] Compound 8 (32 mg, 80.84 μmol) and intermediate 4c (28.73 mg, 80.84 μmol) were dissolved in dimethyl sulfoxide (2 mL), and sodium acetate borohydride (51.40 mg, 242.52 μmol), anhydrous sodium acetate (19.89 mg, 242.52 μmol), and acetic acid (4.85 mg, 80.84 μmol) were added. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (Phenomenex luna C18 column, 5 μm silica, 25 mm diameter, 150 mm length; using a mixture of water (containing 0.225% formic acid) and acetonitrile (acetonitrile ratio 3%-35%) as the eluent) to obtain the title compound (9.2 mg).

[0470] MS m / z(ESI):735.2[M+H] + ;

[0471] 1H NMR (400MHz, DMSO-d6) δ=10.99(s,1H),8.60(s,1H),8.21(s,1H),7.94-7.90(m,1H),7.76(t,J=8.1Hz,1H),7.47(d,J=7 .6Hz,1H),7.42(d,J=8.4Hz,1H),7.26(dd,J=2.1,8.4Hz,1H),7.20(s,1H),7.17(d,J=1.8Hz,1H),6.44(s,2H),5.16-5. 02(m,1H),4.41-4.16(m,3H),3.79-3.76(m,2H),3.02-2.99(m,2H),2.95-2.85(m,1H),2.77-2.68(m,2H),2.61-2.59(m ,1H),2.45-2.22(m,1H),2.25-2.23(m,2H),2.14-1.95(m,7H),1.85-1.82(m,2H),1.73-1.69(m,1H),1.25-1.21(m,2H).

[0472] Example 13: Synthesis of 3-(6-(4-((4-(5-(2-amino-9-chloro-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 13)

[0473] Compound 9 (100 mg, 245.19 μmol) and intermediate 4c (130.70 mg, 367.78 μmol) were dissolved in dimethyl sulfoxide (2 mL), and sodium acetate borohydride (155.90 mg, 735.56 μmol), anhydrous sodium acetate (60.34 mg, 735.56 μmol), and acetic acid (14.72 mg, 245.19 μmol) were added. The reaction mixture was stirred at 25°C for 2 hours, then concentrated to dryness under reduced pressure and purified by high-performance liquid chromatography (Phenomenex luna C18 column, 5 μm silica, 25 mm diameter, 150 mm length; using a mixture of water (containing 0.225% formic acid) and acetonitrile (acetonitrile ratio 6%-36%) as the eluent) to obtain the title compound (9.2 mg).

[0474] MS m / z(ESI):747.2[M+H] + ;

[0475] 1H NMR (400MHz, DMSO-d6) δ = 11.04 (s, 1H), 8.54 (d, J = 2.1Hz, 1H), 8.00 (dd, J = 2.3, 8.9Hz, 1H), 7.80- 7.72(m,1H),7.57-7.46(m,3H),7.25-7.19(m,1H),7.10-7.05(m,1H),7.05-7.02(m,1H),6.56(br s,2H),5.16(dd,J=5.0,13.3Hz,1H),4.43-4.36(m,1H),4.31-4.22(m, 1H),3.84-3.82(m,2H),3.69-3.59(m,5H),3.05-2.91(m,2H),2.80-2.7 7(m,2H),2.72-2.60(m,2H),2.44-2.38(m,2H),2.31-2.29(m,2H),2.11 -2.01(m,1H),1.91-1.89(m,2H),1.87-1.79(m,2H),1.40-1.26(m,2H).

[0476] Example 14: Synthesis of 3-(6-(4-((6-(2-amino-9-chloro-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-4-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 14)

[0477] Step 1: Synthesis of methyl 5-bromo-3-methoxy-2-methylbenzoate (14b)

[0478] Methyl 5-bromo-3-hydroxy-2-methylbenzoate (14a, 1.4 g, 5.71 mmol) was dissolved in anhydrous N,N-dimethylformamide (60 mL), and cesium carbonate (7.45 g, 22.85 mmol) and iodomethane (3.24 g, 22.85 mmol) were added. The reaction mixture was stirred at 25°C for 12 hours, extracted with ethyl acetate (150 mL) and water (100 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Purification by thin-layer chromatography (silica, petroleum ether:tetrahydrofuran = 3:1) afforded the title compound (1.2 g).

[0479] 1 H NMR (400MHz, DMSO-d6) δ = 7.44 (d, J = 1.8Hz, 1H), 7.34 (d, J = 1.8Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 2.25 (s, 3H).

[0480] Step 2: Synthesis of methyl 5-bromo-2-(bromomethyl)-3-methoxybenzoate (14c)

[0481] Intermediate 14b (1.1 g, 4.25 mmol) was dissolved in dichloroethane (20 mL), and N-bromosuccinimide (755.64 mg, 4.25 mmol) and azobisisobutyronitrile (69.71 mg, 424.55 μmol) were added. The reaction mixture was stirred at 80°C for 1 hour. The reaction mixture was cooled to room temperature and extracted with dichloromethane (150 mL) and water (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The title compound (1.33 g) was obtained by thin-layer chromatography (silica, petroleum ether:tetrahydrofuran = 10:1).

[0482] 1 H NMR (400MHz, DMSO-d6) δ = 7.57 (d, J = 2.0Hz, 1H), 7.53 (d, J = 2.0Hz, 1H), 4.89 (s, 2H), 3.94 (s, 3H), 3.87 (s, 3H).

[0483] Step 3: Synthesis of 3-(6-bromo-4-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (14e)

[0484] Intermediate 14c (810 mg, 2.40 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (14d, 394.44 mg, 2.40 mmol) were dissolved in anhydrous N,N-dimethylformamide (8 mL), and N,N-diisopropylethylamine (1.55 g, 11.98 mmol) was added. The reaction mixture was stirred at 80°C for 6 hours. The reaction mixture was cooled to room temperature, water (10 mL) was added, and the mixture was filtered. The filter cake was dried to obtain the title compound (520 mg).

[0485] 1 H NMR (400MHz, DMSO-d6) δ = 10.99 (s, 1H), 7.47-7.35 (m, 2H), 5.09 (dd, J = 5.1, 13.2Hz, 1H), 4.44-4.30 (m, 1H), 4.24-4.14(m,1H),3.92(s,3H),2.92-2.85(m,1H),2.63-2.54(m,1H),2.45-2.35(m,1H),2.06-1.92(m,1H).

[0486] Step 4: Synthesis of 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-4-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (14f)

[0487] Intermediate 14e (300 mg, 849.46 μmol) and 4-(dimethoxymethyl)piperidine (162.31 mg, 1.02 mmol) were dissolved in anhydrous dioxane (6 mL). (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-κN)palladium (73.10 mg, 84.95 μmol) and cesium carbonate (553.54 mg, 1.70 mmol) were added. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 12 hours. LCMS showed that the reaction was complete. The reaction mixture was concentrated to dryness under reduced pressure, slurried with water (10 mL), filtered, and the filter cake was dried to give the title compound (110 mg).

[0488] MS m / z(ESI):432.1[M+H] + .

[0489] Step 5: Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-3-oxoisoindolin-5-yl)piperidine-4-carbaldehyde (14 g)

[0490] Intermediate 14f (100 mg, 231.76 μmol) was dissolved in formic acid (1 mL), and the reaction mixture was stirred at 60° C. for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure to obtain the title compound (89 mg).

[0491] MS m / z(ESI):386.1[M+H] + .

[0492] Step 6: Synthesis of 3-(6-(4-((6-(2-amino-9-chloro-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-4-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 14)

[0493] Compound 10 (70 mg, 185.27 μmol) and intermediate 14g (71.41 mg, 185.27 μmol) were dissolved in dimethyl sulfoxide (2 mL), and sodium acetate (45.60 mg, 555.82 μmol), acetic acid (33.38 mg, 555.82 μmol), and sodium acetate borohydride (58.90 mg, 277.91 μmol) were added. The reaction solution was stirred at 25°C for 2 hours, and the reaction was quenched by adding 2 drops of water. The product was purified by high performance liquid chromatography (Phenomenex C18 column, 10 μm silica, 40 mm diameter, 150 mm length; using a mixture of water (0.225% formic acid) and acetonitrile (acetonitrile ratio 5%-35%) as the eluent) to obtain the title compound (53.1 mg).

[0494] MS m / z(ESI):747.2[M+H] + ;

[0495] 1 H NMR (400MHz, DMSO-d6) δ = 10.96 (s, 1H), 7.71-7.64 (m, 1H), 7.49-7.43 (m, 4H), 7.26 (d, J = 7.9Hz, 1H), 6.99 (s, 1H),6.79(d,J=11.3Hz,2H),6.55(s,2H),5.10-5.04(m,1H),4.26(d,J=16.8Hz,1H),4.11(d,J=16.6Hz,1H),3 .87(s,3H),3.80(d,J=12.0Hz,2H),3.66(s,2H),2.95(s,2H),2.92-2.85(m,1H),2.82-2.75(m,2H),2.75-2.7 1(m,2H),2.65-2.53(m,1H),2.44-2.35(m,3H),2.01-1.94(m,1H),1.87(d,J=10.6Hz,3H),1.36-1.22(m,2H).

[0496] Example 15: Synthesis of 3-(6-(4-((5-(2-amino-9-chloro-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)isoindolin-2-yl)methyl)piperidin-1-yl)-4-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 15)

[0497] Step 1: Synthesis of tert-butyl 5-(5-chloro-2-nitropyridin-4-yl)isoindoline-2-carboxylate (15b)

[0498] Intermediate 7c (1 g, 4.21 mmol) and tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate (15a, 1.45 g, 4.21 mmol) were dissolved in 1,4-dioxane (40 mL) and water (10 mL), and potassium carbonate (1.16 g, 8.42 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (308.17 mg, 421.16 μmol) were added. The reaction solution was stirred at 80°C under a nitrogen atmosphere for 2 hours. Water (30 mL) was added to the reaction solution and extracted with dichloromethane (90 mL*3). The organic phase was washed three times with water (90 mL*3) and then dried over anhydrous sodium sulfate. After filtration, it was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 6 / 1) to give the title compound (1.13 g). 1 H NMR (400MHz, DMSO-d6) δ8.87(s,1H),8.31(d,J=1.4Hz,1H),7.58(d,J=2.3Hz,1H),7.53(s,2H),4.67(d,J=9.4Hz,4H),1.47(s,9H).

[0499] Step 2: Synthesis of tert-butyl 5-(5-(3-chloro-2-(methoxycarbonyl)phenoxy)-2-nitropyridin-4-yl)isoindoline-2-carboxylate (15c)

[0500] Intermediate 15b (1.1 g, 2.93 mmol) and intermediate 7d (546.16 mg, 2.93 mmol) were dissolved in N,N-dimethylformamide (22 mL), and cesium carbonate (1.91 g, 5.85 mmol) was added. The reaction mixture was stirred at 80°C for 2 hours. Water (100 mL) was added and the mixture was extracted with dichloromethane (150 mL x 3). The organic phase was washed with water (150 mL x 3) and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 3 / 1) to obtain the title compound (1.2 g).

[0501] MS m / z(ESI):526.0[M+H] + .

[0502] Step 3: Synthesis of tert-butyl 5-(2-amino-5-(3-chloro-2-(methoxycarbonyl)phenoxy)pyridin-4-yl)isoindoline-2-carboxylate (15d)

[0503] Intermediate 15c (1.2 g, 2.28 mmol) was dissolved in ethanol (12 mL) and water (3 mL). Iron powder (382.26 mg, 6.84 mmol) and ammonium chloride (610.24 mg, 11.41 mmol) were added to the reaction solution. The reaction solution was stirred at 80°C for 1 hour. The reaction solution was filtered and concentrated under reduced pressure to remove the ethanol. Water (10 mL) was added and extracted with dichloromethane (30 mL*3). The organic phase was washed with water (30 mL*3) and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure to dryness, the title compound (1.02 g) was obtained.

[0504] MS m / z(ESI):496.1[M+H] + .

[0505] Step 4: Synthesis of 2-((6-amino-4-(2-(tert-butoxycarbonyl)isoindolin-5-yl)pyridin-3-yl)oxy)-6-chlorobenzoic acid (15e)

[0506] Intermediate 15d (1.02 g, 2.06 mmol) was dissolved in methanol (6 mL), tetrahydrofuran (3 mL), and water (3 mL), and potassium hydroxide (230.78 mg, 4.11 mmol) was added. The reaction mixture was stirred at 80°C for 20 hours. The reaction mixture was concentrated under reduced pressure to remove the methanol. Water (5 mL) was added and the pH was adjusted to 3-4 with dilute hydrochloric acid (1 M). The mixture was extracted with dichloromethane (60 mL*3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to dryness to obtain the title compound (1.27 g).

[0507] MS m / z(ESI):482.1[M+H] + .

[0508] Step 5: Synthesis of 2-amino-9-chloro-4-(isoindolin-5-yl)-10H-chromeno[3,2-b]pyridin-10-one (15f)

[0509] Intermediate 15e (1.27 g, 2.64 mmol) was dissolved in sulfuric acid (6 mL). The reaction mixture was stirred at 100°C for 1 hour, cooled to room temperature, poured into ice water, and adjusted to pH 8-9 with 15% aqueous sodium hydroxide. The reaction mixture was filtered and the filter cake was dried to obtain the title compound (881 mg).

[0510] MS m / z(ESI):364.0[M+H] + .

[0511] Step 6: Synthesis of 3-(6-(4-((5-(2-amino-9-chloro-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)isoindolin-2-yl)methyl)piperidin-1-yl)-4-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0512] Intermediate 15f (60 mg, 164.93 μmol) and Intermediate 14g (63.57 mg, 164.93 μmol) were dissolved in dimethyl sulfoxide (1 mL). Sodium acetate (40.59 mg, 494.78 μmol), acetic acid (9.90 mg, 164.93 μmol), and sodium acetate borohydride (53.62 mg, 247.39 μmol) were added. The reaction was stirred at 25°C for 0.5 h, and then quenched by adding two drops of water. The product was purified by HPLC (Phenomenex luna C18 column, 10 μm silica, 25 mm diameter, 150 mm length; eluent: a mixture of water (0.225% formic acid) and acetonitrile (8%-38% acetonitrile)) to afford the title compound (17.6 mg).

[0513] MS m / z(ESI):733.3[M+H] + ;

[0514] 1 H NMR(400MHz, DMSO-d6)δ10.95(s,1H),7.68(t,J=8.1Hz,1H),7.58(s,1H),7.55-7.50(m,1H),7.49-7.38(m, 3H),6.98(s,1H),6.84-6.75(m,2H),6.60-6.51(m,2H),5.06(dd,J=5.1,13.3Hz,1H),4.30-4.22(m,1H),4. 14-4.07(m,1H),4.05-3.95(m,4H),3.87(s,3H),3.81(d,J=12.0Hz,2H),2.94-2.86(m,1H),2.78(t,J=11.4 Hz,2H),2.68-2.61(m,4H),2.00-1.95(m,1H),1.91(d,J=10.6Hz,2H),1.80-1.71(m,1H),1.39-1.27(m,2H).

[0515] Example 16: Synthesis of 9-chloro-4-(4-(piperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one hydrochloride (Compound 16)

[0516] Step 1: Synthesis of 3-(3-chloro-2-(methoxycarbonyl)phenoxy)-4-nitropyridine 1-oxide (16b)

[0517] Intermediate 7d (6.20 g, 33.21 mmol) was dissolved in N,N-dimethylformamide (30 mL). Sodium hydride (1.39 g, 34.79 mmol, 60% content) was added at 0°C, and the reaction mixture was stirred at 0°C for 0.5 hours. A solution of 3-fluoro-4-nitropyridine-N-oxide (16a, 5 g, 31.63 mmol) in N,N-dimethylformamide (30 mL) was added at 0°C, and the reaction mixture was stirred at 0°C for 0.5 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 1) to afford the title compound (9.78 g).

[0518] MS m / z(ESI):325.1[M+H] + .

[0519] Step 2: Synthesis of methyl 2-((4-aminopyridin-3-yl)oxy)-6-chlorobenzoate (16c)

[0520] Intermediate 16b (4.01 g, 12.35 mmol) was dissolved in acetic acid (80 mL). Iron powder (2.07 g, 37.05 mmol) was added at 25°C, and the reaction mixture was stirred at 100°C for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure to remove the acetic acid. The pH was adjusted to 10 with aqueous sodium hydroxide at 0°C, diluted with ethyl acetate (200 mL), and the precipitate was filtered to remove. The mixture was then extracted with ethyl acetate (300 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to provide the title compound (2.89 g).

[0521] MS m / z(ESI):279.0[M+H] + .

[0522] Step 3: Synthesis of methyl 2-((4-bromopyridin-3-yl)oxy)-6-chlorobenzoate (16d)

[0523] Intermediate 16c (400 mg, 1.44 mmol) was dissolved in acetonitrile (8 mL). Cuprous bromide (247.07 mg, 1.72 mmol) and tert-butyl nitrite (740.03 mg, 7.18 mmol) were added at 0°C. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 4 / 1) to afford the title compound (357 mg).

[0524] MS m / z(ESI):341.9,343.9[M+H] + .

[0525] Step 4: Synthesis of tert-butyl 4-(4-(3-(3-chloro-2-(methoxycarbonyl)phenoxy)pyridin-4-yl)phenyl)piperazine-1-carboxylate (16e)

[0526] Intermediate 16d (100 mg, 291.91 μmol) and intermediate 1i (113.35 mg, 291.91 μmol) were dissolved in dioxane (2 mL) and water (0.4 mL). 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride (21.36 mg, 29.19 μmol) and potassium carbonate (80.69 mg, 583.82 μmol) were added. The reaction mixture was stirred at 80°C under nitrogen for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 4 / 1) to afford the title compound (137 mg).

[0527] MS m / z(ESI):524.2[M+H] + .

[0528] Step 5: Synthesis of tert-butyl 4-(4-(9-chloro-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)piperazine-1-carboxylate (16f)

[0529] Intermediate 16e (107 mg, 204.20 μmol) was dissolved in tetrahydrofuran (3.31 mL). A solution of lithium diisopropylamide in tetrahydrofuran (2 M, 420 μL) was added dropwise at 0°C under a nitrogen atmosphere. The reaction was stirred at 0°C for 0.5 h. The reaction was quenched with saturated aqueous ammonium chloride (0.5 mL) and concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 2 / 1) to afford the title compound (82 mg).

[0530] MS m / z(ESI):492.1[M+H] + .

[0531] Step 6: Synthesis of 9-chloro-4-(4-(piperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one hydrochloride (Compound 16)

[0532] Intermediate 16f (82 mg, 166.68 μmol) was dissolved in methanol (0.5 mL), and dioxane hydrochloride (2 M, 833.39 μL) was added dropwise at 25°C. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure, slurried with petroleum ether:ethyl acetate = 3:1 (10 mL), and filtered to afford the title compound (61 mg).

[0533] MS m / z(ESI):392.2[M+H] + ;

[0534] 1 H NMR (400MHz, DMSO-d6) δ = 9.34 (br s,2H),8.76(d,J=4.6Hz,1H),7.91(d,J=4.6Hz,1H),7.83-7.78(m,3H),7.55( d,J=8.1Hz,2H),7.21(d,J=8.9Hz,2H),3.59-3.55(m,4H),3.33-9.20(m,4H).

[0535] Example 17: Synthesis of (S)-9-chloro-4-(4-(3-methylpiperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one (Compound 17)

[0536] Step 1: Synthesis of (S)-tert-butyl 4-(4-(3-(3-chloro-2-(methoxycarbonyl)phenoxy)pyridin-4-yl)phenyl)-2-methylpiperazine-1-carboxylate (17b)

[0537] Intermediate 16d (100 mg, 291.91 μmol) and tert-butyl (S)-2-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (17a, 117.45 mg, 291.91 μmol) were dissolved in 1,4-dioxane (2 mL) and water (0.5 mL). Potassium carbonate (80.69 mg, 583.82 μmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (21.36 mg, 29.19 μmol) were added. The reaction mixture was stirred at 80°C under a nitrogen atmosphere for 2 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with water (30 mL x 3). The organic phase was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 2 / 1) to give the title compound (109 mg).

[0538] MS m / z(ESI):538.2[M+H] + .

[0539] Step 2: Synthesis of (S)-tert-butyl 4-(4-(9-chloro-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)-2-methylpiperazine-1-carboxylate (17c)

[0540] Intermediate 17b (100 mg, 185.86 μmol) was dissolved in tetrahydrofuran (2 mL), and a solution of lithium diisopropylamide in tetrahydrofuran (2 M, 371.72 μL) was slowly added at -45°C. The reaction mixture was stirred at -45°C under a nitrogen atmosphere for 0.5 hours. Saturated aqueous ammonium chloride (5 mL) was added to the reaction mixture at 0°C to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was concentrated to dryness under reduced pressure to obtain the title compound (60 mg).

[0541] MS m / z(ESI):506.2[M+H] + .

[0542] Step 3: Synthesis of (S)-9-chloro-4-(4-(3-methylpiperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one (Compound 17)

[0543] Intermediate 17c (55 mg, 108.70 μmol) was dissolved in methanol (0.5 mL), and a 2M dioxane hydrochloride solution (543.49 μL) was added. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure and purified by HPLC (Phenomenex Gemini NX column, 5 μm silica, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.05% ammonia) and acetonitrile (acetonitrile ratio 22%-62%) as the eluent) to obtain the title compound (11 mg).

[0544] MS m / z(ESI):406.1[M+H] + ;

[0545] 1 H NMR (400MHz, DMSO-d6) δ8.71(d,J=4.6Hz,1H),7.85(d,J=4.6Hz,1H),7.82-7.71(m,3H),7.54(t,J=7.6Hz,2H),7.11(d,J=8.9 Hz,2H),3.71-3.69(m,2H),3.00-2.98(m,1H),2.85-2.74(m,2H),2.69-2.68(m,1H),2.36-2.27(m,1H),1.05(d,J=6.3Hz,3H).

[0546] Example 18: Synthesis of 9-amino-4-(4-(piperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one hydrochloride (Compound 18)

[0547] Step 1: Synthesis of tert-butyl 4-(4-(9-((tert-butoxycarbonyl)amino)-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)piperazine-1-carboxylate (18a)

[0548] Intermediate 16f (150 mg, 304.90 μmol) and tert-butyl carbamate (39.29 mg, 335.39 μmol) were dissolved in dioxane (5 mL). Cesium carbonate (198.68 mg, 609.80 μmol) and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (25.53 mg, 30.49 μmol) were added. The reaction mixture was stirred at 100°C under nitrogen for 8 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was concentrated under reduced pressure and the concentrate was purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 2 / 1) to afford the title compound (106 mg).

[0549] MS m / z(ESI):573.3[M+H] + .

[0550] Step 2: Synthesis of 9-amino-4-(4-(piperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one hydrochloride (Compound 18)

[0551] Intermediate 18a (100 mg, 174.63 μmol) was dissolved in methanol (126.81 μL). Dioxane hydrochloride (2 M, 833.39 μL) was added dropwise at 25°C, and the reaction mixture was stirred at 25°C for 4 hours. Additional dioxane hydrochloride (2 M, 873.13 μL) was added to the reaction system, and the reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the product was slurried with ethyl acetate to obtain the title compound (55 mg).

[0552] MS m / z(ESI):373.2[M+H] + ;

[0553] 1 H NMR(400MHz,DMSO-d6)δ=9.38(br s,2H),8.69(d,J=4.9Hz,1H),7.91(d,J=4.9Hz,1H),7.80(d,J=8.9Hz,2H),7.45(t,J=8.3Hz,1H),7.2 0(d,J=8.8Hz,2H),6.64(d,J=8.3Hz,1H),6.49(d,J=7.9Hz,1H),3.61-3.55(m,4H),3.30-3.20(m,4H).

[0554] Example 19: Synthesis of 9-chloro-2-ethylamino-4-(4-(piperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one (Compound 19)

[0555] Step 1: Synthesis of tert-butyl 4-(4-(5-chloro-2-nitropyridin-4-yl)phenyl)piperazine-1-carboxylate (19a)

[0556] Intermediate 1i (200 mg, 515.06 μmol) and intermediate 7c (122.29 mg, 515.06 μmol) were dissolved in water (1 mL) and dioxane (4 mL). Potassium carbonate (213.55 mg, 1.55 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (37.69 mg, 51.51 μmol) were added. The reaction mixture was stirred at 80°C under a nitrogen atmosphere for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was concentrated under reduced pressure and the concentrate was purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 20 / 1) to yield the title compound (88 mg).

[0557] 1 H NMR (400MHz, DMSO-d6) δ8.80(s,1H),8.27(s,1H),7.57(d,J=8.80Hz,2H),7.12(d,J=8.93Hz,2H),3.44-3.52(m,4H),3.25-3.31(m,4H),1.44(s,9H).

[0558] Step 2: Synthesis of tert-butyl 4-(4-(5-(3-chloro-2-(methoxycarbonyl)phenoxy)-2-nitropyridin-4-yl)phenyl)piperazine-1-carboxylate (19b)

[0559] Intermediate 19a (310 mg, 740.08 μmol) was dissolved in N,N-dimethylformamide (3 mL), and intermediate 7d (186.59 mg, 1.00 mmol) and cesium carbonate (482.21 mg, 1.48 mmol) were added. The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 7 / 1) to provide the title compound (275 mg).

[0560] MS m / z(ESI):591.0[M+Na] + .

[0561] Step 3: Synthesis of tert-butyl 4-(4-(2-amino-5-(3-chloro-2-(methoxycarbonyl)phenoxy)pyridin-4-yl)phenyl)piperazine-1-carboxylate (19c)

[0562] Intermediate 19b (350 mg, 615.11 μmol) and ammonium chloride (263.17 mg, 4.92 mmol) were dissolved in ethanol (3 mL) and water (0.6 mL). Iron powder (343.54 mg, 6.15 mmol) was added, and the reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to remove ethanol. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was concentrated under reduced pressure to provide the title compound (357 mg).

[0563] MS m / z(ESI):539.1[M+H] + .

[0564] Step 4: Synthesis of tert-butyl 4-(4-(5-(3-chloro-2-(methoxycarbonyl)phenoxy)-2-ethylaminopyridin-4-yl)phenyl)piperazine-1-carboxylate (19d)

[0565] Intermediate 19c (200 mg, 371.04 μmol) and aqueous acetaldehyde (5 M, 111.31 μL) were dissolved in anhydrous methanol (3 mL). Acetic acid (66.84 mg, 1.11 mmol) was added. The reaction mixture was stirred at 25°C for 2 hours. Sodium cyanoborohydride (69.95 mg, 1.11 mmol) was added, and the reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated to dryness under reduced pressure and extracted with ethyl acetate (5 mL x 3) and water (5 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:tetrahydrofuran = 1:1) to afford the title compound (70 mg).

[0566] MS m / z(ESI):567.2[M+H] + .

[0567] Step 5: Synthesis of 2-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-6-(ethylamino)pyridin-3-yl)oxy)-6-chlorobenzoic acid (19e)

[0568] Intermediate 19d (70 mg, 123.44 μmol) was dissolved in water (0.5 mL) and methanol (0.5 mL). Potassium hydroxide (34.63 mg, 617.20 μmol) was added, and the reaction mixture was allowed to react at 80°C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove methanol, and the pH was adjusted to 5-7 with 1.5 M aqueous hydrochloric acid. A solid precipitated, which was filtered and dried to provide the title compound (50 mg).

[0569] MS m / z(ESI):552.8[M+H] + .

[0570] Step 6: Synthesis of 9-chloro-2-(ethylamino)-4-(4-(piperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one (Compound 19)

[0571] Intermediate 19e (80 mg, 144.65 μmol) was dissolved in sulfuric acid (0.5 mL), and the reaction mixture was reacted at 100°C for 0.5 h. The reaction mixture was added dropwise to ice water (5 mL) to quench the reaction mixture. The pH was adjusted to 8 with aqueous potassium hydroxide solution, and a solid precipitated. The solid was filtered and dried to obtain the title compound (50 mg).

[0572] MS m / z(ESI):435.1[M+H] + ;

[0573] 1 H NMR (400MHz, DMSO-d6) δ=7.71-7.65(m,1H),7.60(d,J=8.8Hz,2H),7.45(d,J=8.3Hz,2H),7.10(d,J=8.9Hz,2H),6 .98(t,J=5.3Hz,1H),6.94(s,1H),3.41-3.38(m,2H),3.25-3.22(m,4H),2.95-2.92(m,4H),1.20(t,J=7.1Hz,3H).

[0574] Example 20: Synthesis of (S)-9-chloro-2-(methylamino)-4-(4-(3-methylpiperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one (Compound 20)

[0575] Step 1: Synthesis of (S)-tert-butyl 4-(4-(5-chloro-2-nitropyridin-4-yl)phenyl)-2-methylpiperazine-1-carboxylate (20a)

[0576] Intermediate 17a (2 g, 4.97 mmol) and intermediate 7c (1.18 g, 4.97 mmol) were dissolved in 1,4-dioxane (40 mL) and water (10 mL). Potassium carbonate (1.37 g, 9.94 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (363.73 mg, 497.10 μmol) were added. The reaction mixture was stirred at 80°C under a nitrogen atmosphere for 2 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with water (150 mL x 3). The organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 4 / 1) to yield the title compound (1.53 g).

[0577] MS m / z(ESI):433.1[M+H] + .

[0578] Step 2: Synthesis of (S)-tert-butyl 4-(4-(5-(3-chloro-2-(methoxycarbonyl)phenoxy)-2-nitropyridin-4-yl)phenyl)-2-methylpiperazine-1-carboxylate (20b)

[0579] Intermediate 20a (502.17 mg, 1.16 mmol) and Intermediate 7d (237.07 mg, 1.27 mmol) were dissolved in N,N-dimethylformamide (8 mL), and cesium carbonate (752.65 mg, 2.31 mmol) was added. The reaction mixture was stirred at 80°C for 16 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined. The organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 7 / 1) to obtain the title compound (430 mg).

[0580] MS m / z(ESI):583.2[M+H] + .

[0581] Step 3: Synthesis of (S)-tert-butyl 4-(4-(2-amino-5-(3-chloro-2-(methoxycarbonyl)phenoxy)pyridin-4-yl)phenyl)-2-methylpiperazine-1-carboxylate (20c)

[0582] Intermediate 20b (430 mg, 737.53 μmol) was dissolved in ethanol (4 mL) and water (1 mL), and ammonium chloride (197.25 mg, 3.69 mmol) and iron powder (123.57 mg, 2.21 mmol) were added. The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was filtered, and the filter cake was rinsed with an appropriate amount of tetrahydrofuran. The filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the title compound (400 mg).

[0583] MS m / z(ESI):553.2[M+H] + .

[0584] Step 4: Synthesis of (S)-tert-butyl 4-(4-(5-(3-chloro-2-(methoxycarbonyl)phenoxy)-2-(methylamino)pyridin-4-yl)phenyl)-2-methylpiperazine-1-carboxylate (20d)

[0585] Intermediate 20c (340 mg, 614.78 μmol) and methylboronic acid (29.44 mg, 491.82 μmol) were dissolved in dioxane (4.01 mL) at 25°C, and pyridine (291.77 mg, 3.69 mmol) and copper acetate (245.57 mg, 1.23 mmol) were added. The reaction solution was reacted at 100°C under an oxygen atmosphere for 12 hours. The reaction solution was extracted with water (20 mL) and ethyl acetate (20 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 2 / 1) to give the title compound (85 mg).

[0586] MS m / z(ESI):567.3[M+H] + .

[0587] Step 5: Synthesis of (S)-2-((4-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)phenyl)-6-(methylamino)pyridin-3-yl)oxy)-6-chlorobenzoic acid (20e)

[0588] Intermediate 20d (85 mg, 149.89 μmol) was dissolved in methanol (1 mL), tetrahydrofuran (0.5 mL), and water (0.5 mL), and potassium hydroxide (70 mg, 1.25 mmol) was added. The reaction mixture was stirred at 80°C for 4 hours. The reaction mixture was concentrated under reduced pressure to remove methanol and tetrahydrofuran, and 2M dilute hydrochloric acid was added to adjust the pH to 4-5. After filtration, the filter cake was rinsed with water (10 mL) and dried under vacuum to obtain the title compound (80 mg).

[0589] MS m / z(ESI):553.3[M+H] + .

[0590] Step 6: Synthesis of (S)-9-chloro-2-(methylamino)-4-(4-(3-methylpiperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one (Compound 20)

[0591] Intermediate 20e (20 mg, 36.16 μmol) was dissolved in concentrated sulfuric acid (0.5 mL). The reaction mixture was stirred at 100°C for 16 minutes. The reaction mixture was added to ice water (2 mL) at 0°C and the pH was adjusted to 8-9 with potassium hydroxide solution. The reaction mixture was stirred at 0°C for 10 minutes. A solid precipitated, which was filtered, dried, and purified by HPLC (Boston Prime C18, 5 μm silica, 30 mm diameter, 150 mm length; eluent: a mixture of water (containing 0.225% formic acid) and acetonitrile (13%-33% acetonitrile)) to afford the title compound (1.5 mg).

[0592] MS m / z(ESI):435.1[M+H] + ;

[0593] 1 H NMR (400MHz, DMSO-d6)δ=7.73-7.65(m,1H),7.64-7.57(m,2H),7.49-7.41(m,2H),7.14-7.06(m, 2H),7.01-6.92(m,2H),3.75-3.68(m,2H),3.09-3.02(m,1H),2.93-2. 83(m,5H),2.77-2.68(m,1H),2.44-2.35(m,1H),1.10(d,J=6.0Hz,3H).

[0594] Example 21: Synthesis of 2-amino-9-hydroxy-4-(4-(piperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one (Compound 21)

[0595] Step 1: Synthesis of 2-amino-9-methoxy-4-(4-(piperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one (21a)

[0596] Compound 7 (65 mg, 159.76 μmol) was dissolved in methanol (1 mL), and a methanolic sodium methoxide solution (86.30 mg, 479.28 μmol, 30% content) was added. The reaction mixture was stirred in a microwave at 120°C for 1.5 hours. The residue after concentration was stirred in water (1 mL) for 0.5 hours, filtered, and the filter cake was dried under vacuum to obtain the title compound (65 mg).

[0597] MS m / z(ESI):403.3[M+H] + .

[0598] Step 2: Synthesis of 2-amino-9-hydroxy-4-(4-(piperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one (Compound 21)

[0599] Intermediate 21a (65 mg, 161.51 μmol) was dissolved in dichloromethane (1 mL), and boron tribromide (121.39 mg, 484.54 μmol, 46.69 μL) was added at 0°C under a nitrogen atmosphere. The reaction mixture was reacted at 25°C for 2 hours. The reaction mixture was quenched by adding ice water dropwise, and then the reaction mixture was concentrated. The residue was purified by high-performance liquid chromatography (Phenomenex Gemini NX, 5 μm silica, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.225% formic acid) and acetonitrile (acetonitrile ratio 0%-40%) as eluent) to obtain the title compound (14 mg).

[0600] MS m / z(ESI):389.3[M+H] + ;

[0601] 1 H NMR (400MHz, DMSO-d6) δ = 7.72-7.55 (m, 3H), 7.10 (d, J = 8.9Hz, 2H), 7.01 (s, 1H), 6.92 (d, J=8.6Hz,1H),6.77(d,J=7.9Hz,1H),6.56(s,2H),3.26-3.23(m,4H),2.98-2.90(m,4H).

[0602] Example 22: Synthesis of 3-(6-(4-((4-(4-(9-chloro-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-4-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 22)

[0603] Compound 16 (54.65 mg, 127.60 μmol) and intermediate 14g (55.00 mg, 142.70 μmol) were dissolved in N,N-dimethylformamide (3 mL). Sodium acetate (31.40 mg, 382.80 μmol), acetic acid (22.99 mg, 382.80 μmol), and sodium acetate borohydride (81.13 mg, 382.80 μmol) were added at 25°C, and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with water (0.5 mL), diluted with N,N-dimethylformamide (2 mL), filtered, and the filtrate was purified by high-performance liquid chromatography (Boston Prime C18, 5 μm silica, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.225% formic acid) and acetonitrile (acetonitrile ratio 23%-43%) as the eluent) to obtain the title compound (25 mg).

[0604] MS m / z(ESI):761.2[M+H] + ;

[0605] 1 H NMR (400MHz, DMSO-d6) δ=10.96(s,1H),8.73(d,J=4.6Hz,1H),7.86(d,J=4.5Hz,1H),7.82-7.73(m,3H),7.54(t,J=7 .4Hz,2H),7.19-7.08(m,2H),6.82-6.75(m,2H),5.07(dd,J=5.1,13.3Hz,1H),4.29-4.23(m,1H),4.14-4.08(m,1H) ,3.87(s,3H),3.80(d,J=12.3Hz,2H),3.35-3.33(m,4H),2.97-2.85(m,1H),2.76(t,J=11.3Hz,2H),2.61(s,1H),2. 55-2.52(m,4H),2.46-2.32(m,1H),2.25(d,J=7.0Hz,2H),2.03-1.93(m,1H),1.89-1.71(m,3H),1.33-1.19(m,2H).

[0606] Example 23: Synthesis of 3-(6-(4-((4-(4-(9-chloro-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 23)

[0607] Compound 16 (54.65 mg, 127.60 μmol) and intermediate 4c (45.35 mg, 127.61 μmol) were dissolved in N,N-dimethylformamide (5 mL), and sodium acetate borohydride (108.17 mg, 510.40 μmol), sodium acetate (41.87 mg, 510.40 μmol), and acetic acid (7.66 mg, 127.60 μmol) were added. The reaction mixture was reacted at 25°C for 2 hours. The reaction mixture was concentrated and purified by high-performance liquid chromatography (Phenomenex Gemini NX, 5 μm silica, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.225% formic acid) and acetonitrile (acetonitrile ratio 11%-51%) as the eluent) to obtain the title compound (11 mg).

[0608] MS m / z(ESI):731.4[M+H] + ;

[0609] 1 H NMR (400MHz, DMSO-d6) δ = 10.97 (s, 1H), 8.73 (d, J = 4.5Hz, 1H), 7.90-7.84 (m, 1H), 7.82-7.71 (m, 3H), 7.60-7.4 9(m,2H),7.42(d,J=8.4Hz,1H),7.26(dd,J=2.0,8.4Hz,1H),7.20-7.07(m,3H),5.10(dd,J=4.9,13.2Hz,1H),4 .41-4.16(m,2H),3.77(d,J=12.0Hz,2H),3.42-3.36(m,4H),2.99-2.86(m,1H),2.74(t,J=11.6Hz,2H),2.61-2 .53(m,4H),2.43-2.32(m,1H),2.25(d,J=6.6Hz,2H),2.05-1.95(m,1H),1.90-1.70(m,3H),1.34-1.19(m,3H).

[0610] Example 24: Synthesis of 3-(6-(4-(((S)-4-(4-(9-chloro-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)-2-methylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 24)

[0611] Compound 17 (11 mg, 27.10 μmol) and intermediate 4c (14.45 mg, 40.65 μmol) were dissolved in N,N-dimethylformamide (1.2 mL). Sodium acetate (6.67 mg, 81.31 μmol), acetic acid (1.63 mg, 27.10 μmol), and sodium acetate borohydride (6.89 mg, 32.52 μmol) were added. The reaction mixture was stirred at 25°C for 0.5 h. Two drops of water were added to the reaction mixture, and the title compound (7.1 mg) was purified by high-performance liquid chromatography (Phenomenex Gemini NX column, 5 μm silica, 30 mm diameter, 150 mm length; eluent: a mixture of water (0.05% ammonia) and acetonitrile (acetonitrile ratio 36%-76%)).

[0612] MS m / z(ESI):745.2[M+H] + ;

[0613] 1 H NMR (400MHz, DMSO-d6) δ=10.97(s,1H),8.72(d,J=4.6Hz,1H),7.85(d,J=4.6Hz,1H),7.82-7.71(m,3H),7.54(t,J=7.5H z,2H),7.41(d,J=8.4Hz,1H),7.26(dd,J=2.0,8.1Hz,1H),7.19-7.10(m,3H),5.10(dd,J=5.3,13.4Hz,1H),4.37-4.29( m,1H),4.24-4.16(m,1H),3.83-3.73(m,2H),3.64-3.59(m,2H),3.04-2.94(m,2H),2.93-2.85(m,1H),2.81-2.66(m,3H ),2.64-2.55(m,3H),2.41-2.25(m,2H),2.07-1.90(m,3H),1.79-1.72(m,2H),1.31-1.17(m,2H),1.09(d,J=6.2Hz,3H).

[0614] Example 25: Synthesis of 3-(6-(4-((4-(4-(2-amino-9-chloro-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-4-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 25)

[0615] Compound 7 (23 mg, 56.53 μmol) and intermediate 14g (21.79 mg, 56.53 μmol) were dissolved in N,N-dimethylformamide (1 mL). Sodium acetate (23.19 mg, 282.65 μmol) was added and shaken until clear. Acetic acid (3.39 mg, 56.53 μmol) and sodium acetate borohydride (35.94 mg, 169.59 μmol) were then added. The reaction mixture was allowed to react at 25°C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by preparative liquid chromatography (YMC-Actus Triart C18 column, 5 μm silica, 40 mm diameter, 150 mm length; using a mixture of water (containing 0.08% ammonium bicarbonate solution) and acetonitrile (acetonitrile ratio 31%-71%) as the eluent) to obtain the title compound (11.9 mg).

[0616] MS m / z(ESI):776.4[M+H] + ;

[0617] 1 H NMR (400MHz, DMSO-d6) δ=10.97(s,1H),7.73-7.66(m,1H),7.63-7.61(m,2H),7.48-7.44(m,2H),7.11(d,J=9.0Hz,2H ),6.97(s,1H),6.79(d,J=11.4Hz,2H),6.48(s,2H),5.13-5.00(m,1H),4.27-4.25(m,1H),4.15-4.05(m,1H),3.87(s ,3H),3.82-3.79(m,2H),3.31-3.25(m,4H),2.92-2.90(m,1H),2.77-2.75(m,2H),2.61-2.59(m,1H),2.56-2.54(m,4 H),2.42-2.39(m,1H),2.26-2.24(m,2H),2.03-1.93(m,1H),1.86-1.84(m,2H),1.78-1.76(m,1H),1.28-1.26(m,2H).

[0618] Example 26: Synthesis of 3-(6-(4-((4-(4-(9-amino-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-4-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 26)

[0619] Compound 18 (52.7 mg, 128.89 μmol) and intermediate 14g (54.06 mg, 140.26 μmol) were dissolved in N,N-dimethylformamide (1.5 mL). Sodium acetate (31.72 mg, 386.66 μmol), acetic acid (23.22 mg, 386.66 μmol) and sodium acetate borohydride (81.95 mg, 386.66 μmol) were added at 25°C, and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was quenched with water (0.5 mL), diluted with N,N-dimethylformamide (2 mL), and filtered. The filtrate was purified by HPLC (Boston Prime C18, 5 μm silica, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.225% formic acid) and acetonitrile (acetonitrile ratio 18%-38%) as eluent) to give the title compound (36.4 mg).

[0620] MS m / z(ESI):742.4[M+H] + ;

[0621] 1 H NMR (400MHz, DMSO-d6) δ = 10.97 (s, 1H), 8.65 (d, J = 4.5Hz, 1H), 7.95-7.81 (m, 1H), 7.78 (d, J = 4.6Hz, 1H), 7.71 (d, J = 8.6Hz, 2H), 7.42 ( t,J=8.2Hz,1H),7.12(d,J=8.9Hz,2H),6.79(d,J=11.5Hz,2H),6.59(d,J=8.0Hz,1H),6.47(d,J=8.1Hz,1H),5.07(dd,J=4.9,13.1Hz, 1H),4.30-4.22(m,1H),4.14-4.07(m,1H),3.87(s,3H),3.81-3.79(m,2H),3.31-3.29(m,4H),2.96-2.86(m,1H),2.77-2.74(m,2H), 2.62-2.59(m,1H),2.54-2.52(m,4H),2.42-2.39(m,1H),2.26-2.24(m,2H),2.03-1.93(m,1H),1.90-1.71(m,3H),1.33-1.22(m,2H).

[0622] Example 27: Synthesis of 3-(6-(4-((4-(4-(9-chloro-2-methylamino-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-4-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 27)

[0623] Step 1: Synthesis of tert-butyl 4-(4-(5-(3-chloro-2-(methoxycarbonyl)phenoxy)-2-(methylamino)pyridin-4-yl)phenyl)piperazine-1-carboxylate (27a)

[0624] Intermediate 19c (240 mg, 445.25 μmol) and methylboronic acid (23.99 mg, 400.73 μmol) were dissolved in dioxane (5 mL). Pyridine (105.99 mg, 1.34 mmol, 107.95 μL) and copper acetate (161.75 mg, 890.50 μmol) were added at 25°C, and the reaction mixture was allowed to react at 100°C for 12 hours. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (8 mL x 3). The organic phase was washed with water (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, petroleum ether / ethyl acetate = 1:1) to provide the title compound (123 mg).

[0625] MS m / z(ESI):553.2[M+H] + .

[0626] Step 2: Synthesis of 2-((4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)phenyl)-6-(methylamino)pyridin-3-yl)oxy)-6-chlorobenzoic acid (27b)

[0627] Intermediate 27a (123 mg, 222.40 μmol) was dissolved in water (5 mL) and methanol (5 mL), and potassium hydroxide (62.39 mg, 1.11 mmol) was added. The reaction mixture was reacted at 80°C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove methanol, and the pH was adjusted to 5-7 with 1.5 M aqueous hydrochloric acid. A solid precipitated, which was filtered and dried to obtain the title compound (68 mg).

[0628] MS m / z(ESI):539.2[M+H] + .

[0629] Step 3: Synthesis of 9-chloro-2-methylamino-4-(4-(piperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one (27c)

[0630] Intermediate 27b (58 mg, 107.60 μmol) was dissolved in concentrated sulfuric acid (1 mL), and the reaction mixture was reacted at 100°C for 2 hours. The reaction mixture was added dropwise to ice water (5 mL) to quench the reaction mixture. The pH was adjusted to 8 with aqueous potassium hydroxide solution. A solid precipitated, which was filtered and the filter cake dried to obtain the title compound (61 mg).

[0631] MS m / z(ESI):421.1[M+H] + .

[0632] Step 4: Synthesis of 3-(6-(4-((4-(4-(9-chloro-2-methylamino-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-4-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 27)

[0633] Intermediate 27c (61 mg, 144.93 μmol) and Intermediate 14g (55.86 mg, 144.93 μmol) were dissolved in N,N-dimethylformamide (2 mL). Sodium acetate (59.44 mg, 724.65 μmol) was added and shaken until clear. Acetic acid (8.70 mg, 144.93 μmol) and sodium acetate borohydride (92.15 mg, 434.79 μmol) were then added. The reaction mixture was allowed to react at 25°C for 2 hours. The reaction mixture was filtered, and the filtrate was purified by preparative liquid chromatography (YMC-Actus Triart C18 column, 5 μm silica, 40 mm diameter, 150 mm length; using a mixture of water (containing 0.08% ammonia) and acetonitrile (acetonitrile ratio 34% to 74%) as the eluent) to obtain the title compound (5.7 mg).

[0634] MS m / z(ESI):790.4[M+H] + ;

[0635] 1H NMR (400MHz, DMSO-d6) δ = 10.97 (s, 1H), 7.72-7.67 (m, 1H), 7.62 (d, J = 8.8Hz, 2H), 7.46 (dd, J = 2.0, 8.1Hz, 2H), 7.11 (d, J = 8.8Hz, 2H),7.01-6.97(m,1H),6.95(s,1H),6.78(d,J=11.2Hz,2H),5.15-5.00(m,1H),4.26(d,J=16.7Hz,1H),4.11(d,J=16.7Hz,1H), 3.87(s,3H),3.80(d,J=13.2Hz,2H),3.30(d,J=5.5Hz,4H),2.91(d,J=4.8Hz,4H),2.82-2.70(m,2H),2.63-2.59(m,1H),2.54(s ,4H),2.46-2.35(m,1H),2.25(d,J=7.0Hz,2H),2.01-1.95(m,1H),1.84(d,J=13.0Hz,2H),1.79-1.70(m,1H),1.30-1.21(m,2H).

[0636] Example 28: Synthesis of 3-(6-(4-((4-(4-(9-chloro-2-ethylamino-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-4-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 28)

[0637] Compound 19 (36 mg, 82.77 μmol) and intermediate 14g (47.85 mg, 124.16 μmol) were dissolved in N,N-dimethylformamide (1 mL). Sodium acetate (20.37 mg, 248.32 μmol) was added and shaken until clear. Acetic acid (14.91 mg, 248.32 μmol) and sodium acetate borohydride (52.63 mg, 248.32 μmol) were then added. The reaction mixture was allowed to react at 25°C for 1 hour. The reaction mixture was filtered, and the filtrate was purified by HPLC (Boston Prime C18 column, 5 μm silica, 30 mm diameter, 150 mm length; eluent: a mixture of water (containing 0.05% ammonia) and acetonitrile (acetonitrile ratio 53%-73%)) to obtain the title compound (18.3 mg).

[0638] MS m / z(ESI):804.1[M+H] + ;

[0639] 1H NMR (400MHz, DMSO-d6) δ = 10.96 (s, 1H), 7.71-7.65 (m, 1H), 7.60 (d, J = 8.8Hz, 2H), 7.44 (dd, J = 1.4, 8. 2Hz,2H),7.10(d,J=8.8Hz,2H),7.00-6.91(m,2H),6.77(d,J=10.5Hz,2H),5.06(dd,J=4.9,13.3Hz, 1H),4.26(d,J=16.9Hz,1H),4.10(d,J=16.8Hz,1H),3.86(s,3H),3.79(d, J=12.1Hz,2H),3.34-3.32(m,2H),3.28(s,4H),2.93-2.84(m,1H),2.77-2 .73(m,2H),2.64-2.51(m,5H),2.41-2.39(m,1H),2.29-2.18(m,2H),2.01 -1.92(m,1H),1.88-1.69(m,3H),1.37-1.23(m,2H),1.19(t,J=7.2Hz,3H).

[0640] Example 29: Synthesis of 3-(6-(4-((4-(4-(9-chloro-10-oxo-2-propylamino-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-4-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 29)

[0641] Step 1: Synthesis of tert-butyl 4-(4-(5-(3-chloro-2-(methoxycarbonyl)phenoxy)-2-propylaminopyridin-4-yl)phenyl)piperazine-1-carboxylate (29a)

[0642] Intermediate 19c (200 mg, 371.04 μmol) and propionaldehyde (32.33 mg, 556.56 μmol) were dissolved in anhydrous methanol (3 mL), and acetic acid (66.66 mg, 1.11 mmol) was added. The reaction mixture was stirred at 25°C for 3 hours. Sodium cyanoborohydride (69.95 mg, 1.11 mmol) was added, and the reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:tetrahydrofuran = 4:1) to afford the title compound (120 mg).

[0643] MS m / z(ESI):581.3[M+H] + .

[0644] Step 2: Synthesis of 2-((4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)phenyl)-6-propylaminopyridin-3-yl)oxy)-6-chlorobenzoic acid (29b)

[0645] Intermediate 29a (120 mg, 206.50 μmol) was dissolved in water (0.5 mL) and methanol (0.5 mL). Potassium hydroxide (57.93 mg, 1.03 mmol) was added, and the reaction mixture was allowed to react at 80°C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove methanol, and the pH was adjusted to 5-7 with 1.5 M aqueous hydrochloric acid. A solid precipitated, which was filtered and dried to provide the title compound (75 mg).

[0646] MS m / z(ESI):567.3[M+H] + .

[0647] Step 3: Synthesis of 9-chloro-4-(4-(piperazin-1-yl)phenyl)-2-propylamino-10H-chromeno[3,2-b]pyridin-10-one (29c)

[0648] Intermediate 29b (55 mg, 96.99 μmol) was dissolved in sulfuric acid (0.25 mL), and the reaction mixture was reacted at 100°C for 0.5 h. The reaction mixture was added dropwise to ice water (10 mL) to quench the reaction mixture. The pH was adjusted to 10 with 2 M aqueous potassium hydroxide solution. A solid precipitated, which was filtered and the filter cake was dried to obtain the title compound (40 mg).

[0649] MS m / z(ESI):449.1[M+H] + .

[0650] Step 4: Synthesis of 3-(6-(4-((4-(4-(9-chloro-10-oxo-2-propylamino-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-4-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 29)

[0651] Intermediate 29c (35 mg, 77.96 μmol) and Intermediate 14g (33.05 mg, 85.76 μmol) were dissolved in N,N-dimethylformamide (1 mL). Sodium acetate (19.19 mg, 233.94 μmol) was added and shaken until clear. Acetic acid (14.04 mg, 233.80 μmol) and sodium acetate borohydride (49.57 mg, 233.88 μmol) were then added. The reaction mixture was allowed to react at 25°C for 2 hours. The reaction mixture was filtered, and the filtrate was purified by HPLC (Boston Prime C18 column, 5 μm silica, 30 mm diameter, 150 mm length; eluent: a mixture of water (containing 0.05% ammonia) and acetonitrile (55%-75% acetonitrile)) to afford the title compound (11.3 mg).

[0652] MS m / z(ESI):818.4[M+H] + ;

[0653] 1 H NMR (400MHz, DMSO-d6) δ=10.96(s,1H),7.71-7.66(m,1H),7.61(d,J=8.8Hz,2H),7.45(dd,J=2.1,8.2H z,2H),7.11(d,J=8.9Hz,2H),7.01-6.96(m,2H),6.78(d,J=10.3Hz,2H),5.07(dd,J=4.8,13.3Hz,1H),4 .26(d,J=16.9Hz,1H),4.11(d,J=16.8Hz,1H),3.87(s,3H),3.81-3.79(m,2H),3.36-3.32(m,2H),3.32- 3.25(m,4H),2.96-2.85(m,1H),2.77-2.75(m,2H),2.62-2.59(m,1H),2.56-2.52(m,4H),2.42-2.39(m, 1H),2.27-2.24(m,2H),2.01-1.94(m,1H),1.89-1.72(m,3H),1.65-1.58(m,2H),1.33-1.22(m,2H),0.97(t,J=7.4Hz,3H).

[0654] Example 30: Synthesis of 3-(6-(4-(((S)-4-(4-(9-chloro-2-methylamino-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)-2-methylpiperazin-1-yl)methyl)piperidin-1-yl)-4-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 30)

[0655] Compound 20 (34 mg, 78.18 μmol) and intermediate 14g (42.18 mg, 109.45 μmol) were dissolved in N,N-dimethylformamide (1 mL). Sodium acetate (19.24 mg, 234.53 μmol), sodium acetate borohydride (49.71 mg, 234.53 μmol), and acetic acid (14.08 mg, 234.53 μmol) were added. The reaction mixture was allowed to react at 25°C for 1 hour. The reaction mixture was filtered, and the filtrate was purified by high-performance liquid chromatography (Boston Prime C18, 5 μm silica, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.225% formic acid) and acetonitrile (acetonitrile ratio 20%-40%) as the eluent) to obtain the title compound (15.9 mg).

[0656] MS m / z(ESI):804.5[M+H] + ;

[0657] 1 H NMR (400MHz, DMSO-d6) δ = 10.96 (s, 1H), 7.73-7.66 (m, 1H), 7.65-7.58 (m, 2H), 7.50-7.42 (m, 2H), 7.14-7.07 (m, 2H), 7.01-6.93 ( m,2H),6.83-6.79(m,1H),6.78-6.75(m,1H),5.13-5.02(m,1H),4.35-4.04(m,2H),3.89-3.84(m,3H),3.83-3.75(m,2H),3.65-3 .54(m,2H),3.02-2.95(m,2H),2.93-2.88(m,3H),2.83-2.77(m,1H),2.77-2.70(m,1H),2.70-2.64(m,1H),2.63-2.58(m,1H),2. 54(s,3H),2.45-2.38(m,1H),2.36-2.24(m,2H),2.09-1.86(m,3H),1.82-1.66(m,2H),1.29-1.22(m,1H),1.09(d,J=6.1Hz,3H).

[0658] Example 31: Synthesis of 3-(6-(4-((4-(4-(2-amino-9-hydroxy-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-4-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 31)

[0659] Compound 21 (8.7 mg, 22.40 μmol) and intermediate 14g (12.95 mg, 33.60 μmol) were dissolved in dimethyl sulfoxide (1 mL), and sodium acetate borohydride (18.99 mg, 89.59 μmol), sodium acetate (7.35 mg, 89.59 μmol), and acetic acid (1.35 mg, 22.40 μmol) were added. The reaction solution was reacted at 25°C for 2 hours, quenched by the addition of water (0.2 mL), and purified by preparative liquid chromatography (Phenomenex Gemini NX, 5 μm silica, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.225% formic acid) and acetonitrile (acetonitrile ratio 7%-47%) as the eluent) to obtain the title compound (6.8 mg).

[0660] MS m / z(ESI):758.3[M+H] + ;

[0661] 1 H NMR (400MHz, DMSO-d6) δ = 12.98 (s, 1H), 10.95 (s, 1H), 7.70-7.56 (m, 3H), 7.11 ( d,J=8.9Hz,2H),7.02(s,1H),6.92(d,J=8.6Hz,1H),6.82-6.71(m,3H),6.56(br s,2H),5.07(dd,J=5.1,13.3Hz,1H),4.32-4.02(m,2H),3.87(s,3H),3.79(d,J=13.4Hz,2H),3.32-3.28(m,4H),2.95-2.86(m,1H),2.81-2 .70(m,2H),2.54(s,4H),2.45-2.32(m,2H),2.27-2.23(m,2H),2.00- 1.94(m,1H),1.85-1.83(m,2H),1.79-1.70(m,1H),1.29-1.23(m,2H).

[0662] Example 32: Synthesis of (S)-9-chloro-3-ethyl-4-(6-(3-methylpiperazin-1-yl)pyridin-3-yl)-10H-chromeno[3,2-b]pyridin-10-one hydrochloride (Compound 32)

[0663] Step 1: Synthesis of 3-fluoro-5-vinylpyridin-4-amine (32b)

[0664] 3-Bromo-5-fluoropyridin-4-amine (32a, 1 g, 5.24 mmol) and potassium vinyl trifluoroborate (841.56 mg, 6.28 mmol) were dissolved in dioxane (15 mL) and water (5 mL). Cesium carbonate (3.41 g, 10.47 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (383.09 mg, 523.56 μmol) were added. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with water (40 mL x 3). The organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 2 / 1) to obtain the title compound (491 mg).

[0665] MS m / z(ESI):139.0[M+H] + .

[0666] Step 2: Synthesis of 3-ethyl-5-fluoropyridin-4-amine (32c)

[0667] Intermediate 32b (491 mg, 3.55 mmol) was dissolved in methanol (5 mL), and wet palladium on carbon (431.69 mg, 10% loading) was added. The reaction mixture was stirred at 25°C under a hydrogen atmosphere (15 psi) for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the title compound (466 mg).

[0668] 1 H NMR (400MHz, Methanol-d4) δ = 7.90 (d, J = 3.3Hz, 1H), 7.80-7.76 (m, 1H), 2.57 (q, J = 7.6Hz, 2H), 1.22 (t, J = 7.5Hz, 3H).

[0669] Step 3: Synthesis of 3-ethyl-5-fluoro-4-nitropyridine (32d)

[0670] Intermediate 32c (500 mg, 3.57 mmol) was dissolved in concentrated sulfuric acid (6 mL), and aqueous hydrogen peroxide (2.43 g, 21.40 mmol, 30% content) was slowly added dropwise at 0°C. The reaction mixture was stirred at 60°C for 16 hours. The reaction mixture was added to ice water (30 mL) and extracted with ethyl acetate (180 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 10 / 1) to afford the title compound (261 mg).

[0671] 1H NMR (400MHz, DMSO-d6) δ = 8.87 (s, 1H), 8.72 (s, 1H), 2.73 (q, J = 7.5Hz, 2H), 1.27-1.15 (m, 3H).

[0672] Step 4: Synthesis of methyl 2-chloro-6-((5-ethyl-4-nitropyridin-3-yl)oxy)benzoate (32e)

[0673] Intermediate 32d (261 mg, 1.53 mmol) was dissolved in N,N-dimethylformamide (6 mL), and cesium carbonate (1.25 g, 3.84 mmol) and Intermediate 7d (257.61 mg, 1.38 mmol) were added. The reaction mixture was stirred at 25°C for 2 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with water (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 2 / 1) to obtain the title compound (370 mg).

[0674] MS m / z(ESI):337.0[M+H] + .

[0675] Step 5: Synthesis of methyl 2-((4-amino-5-ethylpyridin-3-yl)oxy)-6-chlorobenzoate (32f)

[0676] Intermediate 32e (340 mg, 1.01 mmol) was dissolved in ethanol (2 mL) and water (0.5 mL). Iron powder (451.10 mg, 8.08 mmol) and ammonium chloride (540.11 mg, 10.10 mmol) were added. The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was filtered, and the filtrate was diluted with dichloromethane (50 mL) and washed with water (15 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the title compound (266 mg).

[0677] MS m / z(ESI):307.1[M+H] + .

[0678] Step 6: Synthesis of methyl 2-chloro-6-((5-ethyl-4-iodopyridin-3-yl)oxy)benzoate (32 g)

[0679] Intermediate 32f (233 mg, 759.59 μmol) was dissolved in acetonitrile (4 mL). t-Butyl nitrite (548.30 mg, 5.32 mmol, 632.41 μL) and cuprous iodide (173.60 mg, 911.51 μmol) were added at 0°C under nitrogen. The reaction mixture was stirred at 25°C for 16 hours. Water (15 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with water (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 3 / 1) to afford the title compound (176 mg).

[0680] MS m / z(ESI):417.9[M+H] + .

[0681] Step 7: Synthesis of (S)-tert-butyl 4-(3'-(3-chloro-2-(methoxycarbonyl)phenoxy)-5'-ethyl-[3,4'-bipyridyl]-6-yl)-2-methylpiperazine-1-carboxylate (32h)

[0682] Intermediate 32g (140 mg, 335.23 μmol) and Intermediate 41c (129.20 mg, 402.27 μmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL). Potassium carbonate (92.66 mg, 670.46 μmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (24.53 mg, 33.52 μmol) were added. The reaction mixture was stirred at 80°C for 2 hours. Water (15 mL) was added and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phase was washed with water (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 4 / 1) to afford the title compound (116 mg).

[0683] MS m / z(ESI):567.3[M+H] + .

[0684] Step 8: Synthesis of (S)-tert-butyl 4-(5-(9-chloro-3-ethyl-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)pyridin-2-yl)-2-methylpiperazine-1-carboxylate (32i)

[0685] Intermediate 32h (153.02 mg, 269.83 μmol) was dissolved in 2-methyltetrahydrofuran (2 mL). Under nitrogen, a solution of lithium diisopropylamine (2 M, 222.19 μL) was slowly added dropwise at -78°C. The reaction mixture was stirred at -78°C for 20 minutes. Saturated ammonium chloride solution (5 mL) was added to the reaction mixture at -78°C to quench the reaction. Water (4 mL) was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the title compound (123 mg).

[0686] MS m / z(ESI):535.3[M+H] + .

[0687] Step 9: Synthesis of (S)-9-chloro-3-ethyl-4-(6-(3-methylpiperazin-1-yl)pyridin-3-yl)-10H-chromeno[3,2-b]pyridin-10-one hydrochloride (Compound 32)

[0688] Intermediate 32i (105 mg, 196.25 μmol) was dissolved in anhydrous dichloromethane (2 mL), and dioxane hydrochloride solution (2 M, 1.96 mL) was added. The reaction mixture was stirred at 25°C for 2 hours and concentrated to dryness under reduced pressure to obtain the title compound (90 mg).

[0689] MS m / z(ESI):435.1[M+H] + ;

[0690] 1 H NMR (400MHz, DMSO-d6) δ=9.94-9.67(m,2H),8.79(s,1H),8.28(d,J=2.2Hz,1H),7.97(dd,J=2.2,9.0Hz,1H),7.73(t,J=4.8Hz,1H),7 .53-7.48(m,1H),7.41-7.33(m,2H),4.61-4.44(m,2H),3.55-3.05(m,5H),2.77-2.60(m,2H),1.41-1.31(m,3H),1.17-1.06(m,3H).

[0691] Example 33: Synthesis of (S)-9-chloro-3-isopropyl-4-(6-(3-methylpiperazin-1-yl)pyridin-3-yl)-10H-chromeno[3,2-b]pyridin-10-one (Compound 33)

[0692] Step 1: Synthesis of 3-fluoro-5-(prop-1-en-2-yl)pyridin-4-amine (33b)

[0693] 3-Bromo-5-fluoropyridin-4-amine (33a, 3 g, 15.71 mmol) and potassium isopropenyltrifluoroborate (3.49 g, 23.56 mmol) were dissolved in dioxane (60 mL) and water (12 mL). 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride (1.15 g, 1.57 mmol) and cesium carbonate (10.24 g, 31.41 mmol) were added. The reaction mixture was stirred at 100°C under nitrogen for 16 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, tetrahydrofuran / petroleum ether = 0 / 1 to 1 / 3) to obtain the title compound (2.22 g).

[0694] MS m / z(ESI):153.0[M+H] + .

[0695] Step 2: Synthesis of 3-fluoro-5-isopropylpyridin-4-amine (33c)

[0696] Intermediate 33b (2.22 g, 14.59 mmol) was dissolved in methanol (40 mL). Wet palladium on carbon (1.77 g, 10% loading) was added at 25°C. The reaction mixture was stirred under a hydrogen atmosphere (15 psi) at 25°C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the title compound (2.03 g).

[0697] MS m / z(ESI):155.3[M+H] + .

[0698] Step 3: Synthesis of 3-fluoro-5-isopropyl-4-nitropyridine (33d)

[0699] Intermediate 33c (2.03 g, 13.17 mmol) was dissolved in concentrated sulfuric acid (20 mL). Hydrogen peroxide (14.93 g, 131.66 mmol, 30% content) was added dropwise at 0°C. The reaction solution was stirred at 60°C for 16 hours. The reaction solution was diluted with water (200 mL) at 0°C, the pH was adjusted to 7 with sodium hydroxide, and extracted with ethyl acetate (200 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, tetrahydrofuran / petroleum ether = 0 / 1 to 1 / 2) to provide the title compound (710 mg).

[0700] MS m / z(ESI):185.2[M+H] + .

[0701] Step 4: Synthesis of methyl 2-chloro-6-((5-isopropyl-4-nitropyridin-3-yl)oxy)benzoate (33e)

[0702] Intermediate 33d (650 mg, 3.53 mmol) was dissolved in N,N-dimethylformamide (12 mL). Cesium carbonate (2.30 g, 7.06 mmol) and Intermediate 7d (757.34 mg, 4.06 mmol) were added at 25°C. The reaction mixture was stirred at 25°C for 24 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 x 3 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, tetrahydrofuran / petroleum ether = 0 / 1 to 1 / 4) to obtain the title compound (1.22 g).

[0703] MS m / z(ESI):351.2[M+H] + .

[0704] Step 5: Synthesis of methyl 2-((4-amino-5-isopropylpyridin-3-yl)oxy)-6-chlorobenzoate (33f)

[0705] Intermediate 33e (1.22 g, 3.48 mmol) and ammonium chloride (1.49 g, 27.83 mmol) were dissolved in ethanol (10 mL) and water (2 mL). Iron powder (1.55 g, 27.83 mmol) was added at 25°C, and the reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove ethanol, diluted with water (100 mL), and extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (980 mg).

[0706] MS m / z(ESI):321.2[M+H] + .

[0707] Step 6: Synthesis of methyl 2-chloro-6-((4-iodo-5-isopropylpyridin-3-yl)oxy)benzoate (33 g)

[0708] Intermediate 33f (220 mg, 685.85 μmol) was dissolved in acetonitrile (3 mL). Cuprous iodide (156.74 mg, 823.02 μmol) and tert-butyl nitrite (353.62 mg, 3.43 mmol, 407.87 μL) were added at 0°C. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, tetrahydrofuran / petroleum ether = 0 / 1 to 1 / 4) to obtain the title compound (190 mg).

[0709] MS m / z(ESI):432.0[M+H] + .

[0710] Step 7: Synthesis of (S)-tert-butyl 4-(3'-(3-chloro-2-(methoxycarbonyl)phenoxy)-5'-isopropyl-[3,4'-bipyridyl]-6-yl)-2-methylpiperazine-1-carboxylate (33h)

[0711] Intermediate 33g (147 mg, 340.55 μmol) and Intermediate 41c (131.25 mg, 408.66 μmol) were dissolved in dioxane (2 mL) and water (0.4 mL). 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride (24.92 mg, 34.06 μmol) and potassium carbonate (94.13 mg, 681.10 μmol) were added. The reaction mixture was stirred at 90°C under nitrogen for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, tetrahydrofuran / petroleum ether = 0 / 1 to 1 / 5) to obtain the title compound (277 mg).

[0712] MS m / z(ESI):581.4[M+H] + .

[0713] Step 8: Synthesis of (S)-tert-butyl 4-(5-(9-chloro-3-isopropyl-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)pyridin-2-yl)-2-methylpiperazine-1-carboxylate (33i)

[0714] Intermediate 33h (160 mg, 275.34 μmol) was dissolved in tetrahydrofuran (2 mL), and lithium diisopropylamide (2 M, 413.01 μL) was added dropwise at 0°C. The reaction solution was stirred at -78°C for 0.5 hours. The reaction solution was quenched with aqueous ammonium chloride (0.2 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (151 mg).

[0715] MS m / z(ESI):549.3[M+H] + .

[0716] Step 9: Synthesis of (S)-9-chloro-3-isopropyl-4-(6-(3-methylpiperazin-1-yl)pyridin-3-yl)-10H-chromeno[3,2-b]pyridin-10-one (Compound 33)

[0717] Intermediate 33i (150 mg, 273.19 μmol) was dissolved in dichloromethane (1 mL), and dioxane hydrochloride (2 M, 1.37 mL) was added dropwise at 25°C. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by HPLC (Boston Prime C18, 5 μm silica, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.05% ammonia and ammonium bicarbonate) and acetonitrile (40%-60% acetonitrile) as the eluent) to afford the title compound (20 mg).

[0718] MS m / z(ESI):449.3[M+H] + ;

[0719] 1 H NMR (400MHz, DMSO-d6) δ=8.89(s,1H),8.15(s,1H),7.74-7.60(m,2H),7.49(d,J=7.9Hz,1H),7.34(d,J=8.4Hz,1H),7.01(d,J=8.6 Hz,1H),4.30-4.17(m,2H),3.07-2.95(m,2H),2.87-2.66(m,3H),2.47-2.40(m,1H),1.27(d,J=3.5Hz,6H),1.07(d,J=6.2Hz,3H).

[0720] Example 34: Synthesis of (S)-9-chloro-3-cyclopropyl-4-(6-(3-methylpiperazin-1-yl)pyridin-3-yl)-10H-chromeno[3,2-b]pyridin-10-one (Compound 34)

[0721] Step 1: Synthesis of methyl 2-((4-amino-5-bromopyridin-3-yl)oxy)-6-chlorobenzoate (34a)

[0722] Intermediate 16c (4 g, 14.35 mmol) was dissolved in acetonitrile (70 mL), and N-bromosuccinimide (3.07 g, 17.22 mmol) was added. The reaction mixture was stirred at 25°C for 12 hours, concentrated to dryness under reduced pressure, and purified by column chromatography (silica, petroleum ether:tetrahydrofuran = 3:1) to obtain the title compound (4.72 g).

[0723] MS m / z(ESI):356.9,358.9[M+H] + .

[0724] Step 2: Synthesis of methyl 2-((4-amino-5-cyclopropylpyridin-3-yl)oxy)-6-chlorobenzoate (34b)

[0725] Intermediate 34a (4.72 g, 13.20 mmol) and cyclopropylboronic acid (4.54 g, 52.80 mmol) were dissolved in anhydrous dioxane (125 mL) and water (25 mL). [n-Butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (961.29 mg, 1.32 mmol) and cesium carbonate (12.90 g, 39.60 mmol) were added. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 3 hours. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was concentrated under reduced pressure and the concentrate was purified by column chromatography (silica, dichloromethane:tetrahydrofuran = 10:1) to afford the title compound (3.54 g).

[0726] MS m / z(ESI):319.0[M+H] + .

[0727] Step 3: Synthesis of methyl 2-((4-bromo-5-cyclopropylpyridin-3-yl)oxy)-6-chlorobenzoate (34c)

[0728] Intermediate 34b (3.54 g, 11.11 mmol) and cuprous bromide (1.75 g, 12.22 mmol) were dissolved in acetonitrile (70 mL). Tert-butyl nitrite (2.29 g, 22.21 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. Ethyl acetate (600 mL) and water (500 mL) were added for extraction. The organic phase was concentrated under reduced pressure, and the concentrate was purified by column chromatography (silica, petroleum ether:tetrahydrofuran = 2:1) to afford the title compound (2.68 g).

[0729] MS m / z(ESI):382.0,384.0[M+H] + .

[0730] Step 4: Synthesis of (S)-tert-butyl 4-(3'-(3-chloro-2-(methoxycarbonyl)phenoxy)-5'-cyclopropyl-[3,4'-bipyridyl]-6-yl)-2-methylpiperazine-1-carboxylate (34d)

[0731] Intermediate 34c (200 mg, 522.69 μmol) and intermediate 41c (179.41 mg, 558.61 μmol) were dissolved in anhydrous dioxane (4 mL) and water (1 mL). Potassium carbonate (128.67 mg, 931.02 μmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (34.06 mg, 46.55 μmol) were added. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 2 hours. The reaction mixture was concentrated to dryness and purified by column chromatography (silica, petroleum ether:tetrahydrofuran = 2:1) to afford the title compound (180 mg).

[0732] MS m / z(ESI):579.2[M+H] + .

[0733] Step 5: Synthesis of (S)-tert-butyl 4-(5-(9-chloro-3-cyclopropyl-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)pyridin-2-yl)-2-methylpiperazine-1-carboxylate (34e)

[0734] Intermediate 34d (170 mg, 293.57 μmol) was dissolved in tetrahydrofuran (3 mL), and lithium diisopropylamine solution (2 M, 0.44 mL) was slowly added at -78°C. The reaction mixture was stirred at -78°C under a nitrogen atmosphere for 1 hour. Saturated ammonium chloride solution (2 mL) was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was concentrated to dryness under reduced pressure to obtain the title compound (170 mg).

[0735] MS m / z(ESI):547.2[M+H] + .

[0736] Step 6: Synthesis of (S)-9-chloro-3-cyclopropyl-4-(6-(3-methylpiperazin-1-yl)pyridin-3-yl)-10H-chromeno[3,2-b]pyridin-10-one (Compound 34)

[0737] Intermediate 34e (170 mg, 310.76 μmol) was dissolved in methanol (2 mL), and dioxane hydrochloride (2 M, 3.11 mL) was added. The reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by HPLC (Phenomenex Gemini NX column, 5 μm silica, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.225% formic acid) and acetonitrile (acetonitrile ratio 12%-52%) as eluent) to afford the title compound (30 mg).

[0738] MS m / z(ESI):447.1[M+H] +;

[0739] 1 H NMR (400MHz, DMSO-d6) δ = 8.36 (s, 1H), 8.29 (d, J = 2.0Hz, 1H), 7.76 (dd, J = 2.1, 8.8Hz,1H),7.70(t,J=8.2Hz,1H),7.48(d,J=7.8Hz,1H),7.36(d,J=8.4Hz,1H ),7.12-6.99(m,1H),4.40-4.18(m,2H),3.10-3.02(m,1H),2.93-2.74(m,3H) ,2.59-2.53(m,1H),1.96-1.85(m,1H),1.16-1.08(m,3H),1.08-0.96(m,4H).

[0740] Example 35: Synthesis of 9-chloro-3-methyl-4-(4-(piperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one hydrochloride (Compound 35)

[0741] Step 1: Synthesis of 3-bromo-5-fluoropyridin-4-amine (33a)

[0742] 3-Fluoropyridin-4-amine (35a, 1 g, 8.92 mmol) was dissolved in acetonitrile (20 mL), and a solution of N-bromosuccinimide (1.67 g, 9.37 mmol) in acetonitrile (10 mL) was added. The reaction mixture was stirred at 25°C for 4 hours. The reaction mixture was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 1 / 1) to give the title compound (1.43 g).

[0743] 1 H NMR (400MHz, DMSO-d6) δ8.14 (s, 1H), 8.12 (d, J = 2.6Hz, 1H), 6.45 (s, 2H).

[0744] Step 2: Synthesis of 3-bromo-5-fluoro-4-nitropyridine (35b)

[0745] Intermediate 33a (1.2 g, 6.28 mmol) was dissolved in concentrated sulfuric acid (12 mL), and hydrogen peroxide (4.16 g, 36.69 mmol, 30% purity) was slowly added dropwise at 0°C. The reaction mixture was stirred at 60°C for 16 hours. The reaction mixture was added to ice water (30 mL), and a sufficient amount of saturated sodium sulfite solution was added. The pH was adjusted to 8-9 with sodium hydroxide solution after monitoring with potassium iodide paper moistened with starch until the solution did not turn blue. The mixture was extracted with ethyl acetate (180 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated to dryness under reduced pressure, and purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 13 / 1) to afford the title compound (898 mg).

[0746] 1 H NMR(400MHz,DMSO-d6)δ9.06(s,1H),9.00(s,1H).

[0747] Step 3: Synthesis of 3-fluoro-5-methyl-4-nitropyridine (35c)

[0748] Intermediate 35b (898 mg, 4.06 mmol) and methylboronic acid (291.90 mg, 4.88 mmol) were dissolved in 1,4-dioxane (12 mL) and water (3 mL). Cesium carbonate (2.65 g, 8.13 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (297.34 mg, 406.36 μmol) were added. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (40 mL x 3). The organic phases were combined and washed with water (30 mL x 3). The organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 10 / 1) to yield the title compound (396 mg).

[0749] MS m / z(ESI):157.1[M+H] + .

[0750] Step 4: Synthesis of 3-fluoro-5-methyl-4-nitropyridine 1-oxide (35d)

[0751] Intermediate 35c (396 mg, 2.54 mmol) was dissolved in dichloromethane (8 mL), and m-chloroperbenzoic acid (617.97 mg, 3.04 mmol, 85% purity) was added at 0°C. The reaction mixture was stirred at 25°C for 16 hours. Saturated aqueous sodium sulfite solution (10 mL) was added to the reaction mixture, followed by water (10 mL) and extraction with dichloromethane (20 mL x 3). The organic phases were combined. The organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 2 / 1) to give the title compound (265 mg).

[0752] MS m / z(ESI):173.1[M+H] + .

[0753] Step 5: Synthesis of 3-(3-chloro-2-(methoxycarbonyl)phenoxy)-5-methyl-4-nitropyridine 1-oxide (35e)

[0754] Intermediate 7d (210 mg, 1.13 mmol) was dissolved in N,N-dimethylformamide (5 mL), and cesium carbonate (733.39 mg, 2.25 mmol) and intermediate 35d (193.71 mg, 1.13 mmol) were added. The reaction mixture was stirred at 50°C for 2 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 water (60 mL*3), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 3 / 2) to obtain the title compound (420 mg).

[0755] MS m / z(ESI):339.0[M+H] + ;

[0756] 1 H NMR (400MHz, DMSO-d6) δ8.32(d,J=0.7Hz,1H),8.05(d,J=1.3Hz,1H),7.63-7.55( m,1H),7.54-7.47(m,1H),7.38(dd,J=0.7,8.2Hz,1H),3.83(s,3H),2.31(s,3H).

[0757] Step 6: Synthesis of methyl 2-((4-amino-5-methylpyridin-3-yl)oxy)-6-chlorobenzoate (35f)

[0758] Intermediate 35e (420 mg, 1.24 mmol) was dissolved in acetic acid (4 mL), and iron powder (207.75 mg, 3.72 mmol) was added at 0°C. The reaction mixture was stirred at 100°C for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure to remove most of the acetic acid. Sodium hydroxide solution was added to adjust the pH to 9-10, filtered, and the filtrate was extracted with ethyl acetate (30 mL*3). The organic phases were combined and washed with water (20 mL*). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the title compound (343 mg).

[0759] MS m / z(ESI):293.1[M+H] + .

[0760] Step 7: Synthesis of methyl 2-((4-bromo-5-methylpyridin-3-yl)oxy)-6-chlorobenzoate (35 g)

[0761] Intermediate 35f (320 mg, 1.09 mmol) was dissolved in acetonitrile (6 mL). Tert-butyl nitrite (450.92 mg, 4.37 mmol) and cuprous bromide (235.23 mg, 1.64 mmol) were added at 0°C under nitrogen. The reaction mixture was stirred at 25°C for 16 hours. Water (30 mL) was added to the reaction mixture and extracted with ethyl acetate (30 mL*3). The organic phases were combined, washed with water (20 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Purification by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 4 / 1) gave the title compound (270 mg).

[0762] 1 H NMR (400MHz, DMSO-d6) δ8.40(s,1H),8.17(s,1H),7.50-7.43(m,1H),7.40-7.35(m,1H),6.84(dd,J=0.6,8.4Hz,1H),3.85(s,3H),2.40(s,3H).

[0763] Step 8: Synthesis of tert-butyl 4-(4-(3-(3-chloro-2-(methoxycarbonyl)phenoxy)-5-methylpyridin-4-yl)phenyl)piperazine-1-carboxylate (35h) Intermediate 35g (250 mg, 701.07 μmol) and intermediate 1i (272.23 mg, 701.07 μmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL), and potassium carbonate (193.78 mg, 1.40 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (51.30 mg, 70.11 μmol) were added. The reaction solution was stirred at 80°C for 2 hours. Water (20 mL) was added to the reaction solution and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with water (20 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Purification by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 4 / 1) gave the title compound (297 mg).

[0764] MS m / z(ESI):538.3[M+H] + .

[0765] Step 9: Synthesis of tert-butyl 4-(4-(9-chloro-3-methyl-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)piperazine-1-carboxylate (35i)

[0766] Intermediate 35h (297 mg, 552.01 μmol) was dissolved in tetrahydrofuran (6 mL), and lithium diisopropylamine solution (2 M, 1.10 mL) was slowly added dropwise at -78°C under nitrogen. The reaction mixture was stirred at -78°C for 0.5 hours. Saturated ammonium chloride solution (5 mL) was added to the reaction mixture at -78°C to quench the reaction. Water (20 mL) was added to the reaction mixture at room temperature, and the mixture 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 to dryness under reduced pressure. Purification by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 1 / 1) afforded the title compound (165 mg).

[0767] MS m / z(ESI):506.3[M+H] + .

[0768] Step 10: Synthesis of 9-chloro-3-methyl-4-(4-(piperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one hydrochloride (Compound 35): Intermediate 35i (165 mg, 326.09 μmol) was dissolved in methanol (2 mL), and a 2M solution of dioxane hydrochloride (1.63 mL) was added. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure and purified by HPLC (C18 column, 30 mm diameter, 150 mm length; eluent: a mixture of water (containing 0.05% HCl) and acetonitrile (11%-51%)) to afford the title compound (30 mg).

[0769] MS m / z(ESI):406.1[M+H] + ;

[0770] 1 H NMR(400MHz,DMSO-d6)δ9.17(br s,2H),8.75-8.69(m,1H),7.74-7.67(m,1H),7.50(d,J=7.2Hz,1H),7.45-7.38(m,2H),7 .31(d,J=8.2Hz,1H),7.21-7.15(m,2H),3.52(d,J=4.8Hz,4H),3.27(s,4H),2.33(s,3H).

[0771] Example 36: Synthesis of (S)-9-chloro-3-methyl-4-(4-(3-methylpiperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one hydrochloride (Compound 36)

[0772] Step 1: Synthesis of (S)-tert-butyl 4-(4-(3-(3-chloro-2-(methoxycarbonyl)phenoxy)-5-methylpyridin-4-yl)phenyl)-2-methylpiperazine-1-carboxylate (36a)

[0773] Intermediate 35g (289.83 mg, 812.76 μmol) and Intermediate 17a (327 mg, 812.76 μmol) were dissolved in anhydrous dioxane (6 mL) and water (1.5 mL). Potassium carbonate (224.66 mg, 1.63 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (59.47 mg, 81.28 μmol) were added. The reaction mixture was stirred at 80°C for 2 hours. Water (10 mL) was added and the mixture was extracted with ethyl acetate (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by thin-layer chromatography (silica, petroleum ether:tetrahydrofuran = 2:1) to afford the title compound (403 mg).

[0774] MS m / z(ESI):552.1[M+H] + .

[0775] Step 2: Synthesis of (S)-tert-butyl 4-(4-(9-chloro-3-methyl-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)-2-methylpiperazine-1-carboxylate (36b)

[0776] Intermediate 36a (150 mg, 271.71 μmol) was dissolved in tetrahydrofuran (2 mL). Lithium diisopropylamide (1 M, 543.42 μL) was added dropwise at -78°C under a nitrogen atmosphere. The reaction mixture was stirred at -78°C for 1 hour. The reaction mixture was quenched with aqueous ammonium chloride (1 mL) at -78°C and extracted with water (1 mL) and ethyl acetate (5 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound (130 mg).

[0777] MS m / z(ESI):520.3[M+H] + .

[0778] Step 3: Synthesis of (S)-9-chloro-3-methyl-4-(4-(3-methylpiperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one hydrochloride (Compound 36)

[0779] Intermediate 36b (30 mg, 57.69 μmol) was dissolved in anhydrous methanol (0.5 mL), and dioxane hydrochloride (2 M, 576.90 μL) was added. The reaction was stirred at 25°C for 1 hour. The reaction solution was concentrated to dryness under reduced pressure and purified by HPLC (C18, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.05% hydrochloric acid) and acetonitrile (acetonitrile ratio 10%-50%) as eluent) to provide the title compound (3.8 mg).

[0780] MS m / z(ESI):420.1[M+H] + ;

[0781] 1 H NMR (400MHz, DMSO-d6) δ = 9.47 (br s, 1H), 9.26 (br s,1H),8.72(s,1H),7.72(t,J=8.4Hz,1H),7.50(dd,J=0.9,7.9Hz,1H),7.42(d,J=8.8Hz,2H),7.34-7.28(m,1H),7.23-7.15 (m,2H),4.00-3.88(m,2H),3.42-3.39(m,2H),3.15(d,J=8.1Hz,2H),2.97-2.86(m,1H),2.34(s,3H),1.35(d,J=6.6Hz,3H).

[0782] Example 37: Synthesis of 9-chloro-3-ethyl-4-(4-(piperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one hydrochloride (Compound 37)

[0783] Step 1: Synthesis of tert-butyl 4-(4-(3-(3-chloro-2-(methoxycarbonyl)phenoxy)-5-ethylpyridin-4-yl)phenyl)piperazine-1-carboxylate (37a)

[0784] Intermediate 32g (225.37 mg, 539.63 μmol) and intermediate 1i (230.50 mg, 593.59 μmol) were dissolved in anhydrous dioxane (4 mL) and water (1 mL). Potassium carbonate (149.16 mg, 1.08 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (39.48 mg, 53.96 μmol) were added. The reaction mixture was stirred at 80°C for 2 hours. Water (8 mL) was added and the mixture was extracted with ethyl acetate (13 mL x 3). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by thin-layer chromatography (silica, petroleum ether:tetrahydrofuran = 1:1) to afford the title compound (230 mg).

[0785] MS m / z(ESI):552.3[M+H] + .

[0786] Step 2: Synthesis of tert-butyl 4-(4-(9-chloro-3-ethyl-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)piperazine-1-carboxylate (37b)

[0787] Intermediate 37a (230 mg, 416.62 μmol) was dissolved in tetrahydrofuran (4 mL). Under nitrogen, a solution of lithium diisopropylamine (2 M, 520.78 μL) was slowly added dropwise at -78°C. The reaction mixture was stirred at -78°C for 1 hour. Saturated ammonium chloride solution (5 mL) was added to the reaction mixture at -78°C to quench the reaction. Water (4 mL) was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate (8 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to provide the title compound (223 mg).

[0788] MS m / z(ESI):520.2[M+H] + .

[0789] Step 3: Synthesis of 9-chloro-3-ethyl-4-(4-(piperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one hydrochloride (Compound 37)

[0790] Intermediate 37b (100 mg, 192.30 μmol) was dissolved in anhydrous methanol (1.5 mL), and a 2M dioxane hydrochloride solution (1.92 mL) was added. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure and purified by HPLC (ACSSH-CL C18 column, 30 mm diameter, 150 mm length; using a mixture of water (0.05% hydrochloric acid) and acetonitrile (acetonitrile ratio 5%-45%) as the eluent) to afford the title compound (20 mg).

[0791] MS m / z(ESI):420.2[M+H] + ;

[0792] 1 H NMR(400MHz,DMSO-d6)δ=9.09(br s,2H),8.79-8.74(m,1H),7.73-7.67(m,1H),7.50(d,J=7.9Hz,1H),7.37(d,J=8.6Hz,2H),7.28(d,J=8.6 Hz,1H),7.18(d,J=8.4Hz,2H),3.54-3.49(m,4H),3.28(s,4H),2.71-2.64(m,2H),1.10(t,J=7.6Hz,3H).

[0793] Example 38: Synthesis of (S)-9-amino-3-ethyl-4-(4-(3-methylpiperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one hydrochloride (Compound 38)

[0794] Step 1: Synthesis of (S)-tert-butyl 4-(4-(3-(3-chloro-2-(methoxycarbonyl)phenoxy)-5-ethylpyridin-4-yl)phenyl)-2-methylpiperazine-1-carboxylate (38a)

[0795] Intermediate 32g (344.81 mg, 825.63 μmol) and Intermediate 17a (597.92 mg, 1.49 mmol) were dissolved in anhydrous dioxane (4 mL) and water (1 mL). Potassium carbonate (228.21 mg, 1.65 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (60.41 mg, 82.56 μmol) were added. The reaction mixture was stirred at 80°C for 2 hours. Water (8 mL) was added and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by thin-layer chromatography (silica, petroleum ether:tetrahydrofuran = 1:1) to afford the title compound (280 mg).

[0796] MS m / z(ESI):566.2[M+H] + .

[0797] Step 2: Synthesis of (S)-tert-butyl 4-(4-(9-chloro-3-ethyl-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)-2-methylpiperazine-1-carboxylate (38b)

[0798] Intermediate 38a (270 mg, 476.96 μmol) was dissolved in tetrahydrofuran (3.5 mL). Under nitrogen, a solution of lithium diisopropylamine (2 M, 596.20 μL) was slowly added dropwise at -78°C. The reaction mixture was stirred at -78°C for 1 hour. Saturated ammonium chloride solution (5 mL) was added to the reaction mixture at -78°C to quench the reaction. Water (8 mL) was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate (8 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to provide the title compound (230 mg).

[0799] MS m / z(ESI):534.3[M+H] + .

[0800] Step 3: Synthesis of (S)-tert-butyl 4-(4-(9-(tert-butoxycarbonyl)amino)-3-ethyl-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)-2-methylpiperazine-1-carboxylate (38c)

[0801] Intermediate 38b (210 mg, 393.23 μmol) and tert-butyl carbamate (69.10 mg, 589.84 μmol) were dissolved in anhydrous dioxane (3.5 mL). Methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (32.89 mg, 39.32 μmol) and cesium carbonate (256.24 mg, 786.45 μmol) were added. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. The reaction solution was cooled to room temperature, water (13 mL) was added, and the mixture was extracted with ethyl acetate (13 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica, dichloromethane / tetrahydrofuran = 1 / 0 to 1 / 1) to give the title compound (145 mg).

[0802] MS m / z(ESI):615.5[M+H] + .

[0803] Step 4: Synthesis of (S)-9-amino-3-ethyl-4-(4-(3-methylpiperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one hydrochloride (Compound 38)

[0804] Intermediate 38c (55 mg, 89.47 μmol) was dissolved in anhydrous methanol (1 mL), and a dioxane hydrochloride solution (2 M, 894.70 μL) was added. The reaction mixture was stirred at 50°C for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure to obtain the title compound (45 mg).

[0805] MS m / z(ESI):415.2[M+H] + .

[0806] 1 H NMR (400MHz, DMSO-d6) δ = 9.63-9.52 (m, 1H), 9.45-9.29 (m, 1H), 8.70 (s, 1H), 7 .39-7.31(m,3H),7.18(d,J=8.8Hz,2H),6.57(d,J=8.2Hz,1H),6.22(d,J=7.8H z,1H),3.95-3.91(m,1H),3.42-3.39(m,3H),3.18-3.09(m,2H),2.92(J=10.8 ,12.8Hz,1H),2.67-2.64(m,2H),1.35(d,J=6.8Hz,3H),1.08(t,J=7.5Hz,3H).

[0807] Example 39: Synthesis of Compound 39

[0808] Step 1: Synthesis of intermediates 39a and 39b

[0809] Intermediate 14f (1 g) was subjected to chiral separation (DAICEL CHIRALPAK AD column, 10 μm silica, 30 mm diameter, 250 mm length; using a mixture of isopropanol (containing 0.1% ammonia) and CO2 (50%-50%) as eluent) to give intermediate 39a (384 mg, first peak) and intermediate 39b (360 mg, second peak).

[0810] The two title products were then further analyzed separately by the following chiral HPLC analysis conditions.

[0811] Intermediate 39a:

[0812] The chiral HPLC peak time was 1.754 minutes;

[0813] MS m / z(ESI):432.2[M+H] + .

[0814] Intermediate 39b:

[0815] The chiral HPLC peak time was 1.934 minutes;

[0816] MS m / z(ESI):432.2[M+H] + .

[0817] Step 2: Synthesis of intermediate 39c

[0818] Intermediate 39a (200.00 mg, 463.51 μmol) was dissolved in anhydrous formic acid (1 mL), and the reaction mixture was stirred at 60° C. for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure to obtain the title compound (180 mg).

[0819] MS m / z(ESI):386.1[M+H] + .

[0820] Step 3: Synthesis of compound 39

[0821] Compound 16 (38.26 mg, 89.32 μmol) and intermediate 39c (29.17 mg, 75.68 μmol) were dissolved in N,N-dimethylformamide (1 mL). Sodium acetate (21.98 mg, 267.96 μmol), acetic acid (16.09 mg, 267.96 μmol) and sodium acetate borohydride (56.79 mg, 267.96 μmol) were added at 25°C, and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was quenched with water (0.5 mL), diluted with N,N-dimethylformamide (2 mL), and filtered. The filtrate was purified by high performance liquid chromatography (Phenomenex Gemini NX, 5 μm silica, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.225% formic acid) and acetonitrile (acetonitrile ratio 13%-53%) as eluent) to give the title compound (18.8 mg).

[0822] MS m / z(ESI):761.4[M+H] + ;

[0823] 1 H NMR (400MHz, DMSO-d6) δ = 10.94 (s, 1H), 8.73 (d, J = 4.4Hz, 1H), 7.85 (d, J = 4.3Hz, 1H), 7.82-7.7 3(m,3H),7.54(t,J=7.7Hz,2H),7.14(d,J=8.7Hz,2H),6.78(d,J=9.5Hz,2H),5.07(dd,J=5.0, 13.1Hz,1H),4.30-4.23(m,1H),4.15-4.08(m,1H),3.87(s,3H),3.80-3.78(m,2H),3.32-3.30(m,4H),2.97-2.85(m,1H),2.78-2.76(m,2 H),2.65-2.61(m,1H),2.60-2.55(m,4H),2.47-2.36(m,1H),2.26-2.15(m,2H),2.04-1.93(m,1H),1.89-1.71(m,3H),1.34-1.21(m,2H).

[0824] Example 40: Synthesis of Compound 40

[0825] Step 1: Synthesis of intermediate 40a

[0826] Intermediate 39b (200.00 mg, 463.51 μmol) was dissolved in anhydrous formic acid (1 mL), and the reaction mixture was stirred at 60° C. for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure to obtain the title compound (170 mg).

[0827] MS m / z(ESI):386.1[M+H] + .

[0828] Step 2: Synthesis of compound 40

[0829] Compound 16 (38.26 mg, 89.32 μmol) and intermediate 40a (29.17 mg, 75.68 μmol) were dissolved in N,N-dimethylformamide (1 mL). Sodium acetate (21.98 mg, 267.96 μmol), acetic acid (16.09 mg, 267.96 μmol), and sodium acetate borohydride (56.79 mg, 267.96 μmol) were added at 25°C, and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with water (0.5 mL), diluted with N,N-dimethylformamide (2 mL), filtered, and the filtrate was purified by HPLC (Boston Prime C18, 5 μm silica, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.225% formic acid) and acetonitrile (acetonitrile ratio 23%-43%) as the eluent) to obtain the title compound (16.4 mg).

[0830] MS m / z(ESI):761.4[M+H] + ;

[0831] 1H NMR (400MHz, DMSO-d6) δ=10.94(s,1H),8.73(d,J=4.5Hz,1H),7.85(d,J=4.4Hz,1H),7.82-7.72(m,3H),7.54(t,J=7 .5Hz,2H),7.14(d,J=8.6Hz,2H),6.78(d,J=8.9Hz,2H),5.07(dd,J=4.8,13.1Hz,1H),4.30-4.23(m,1H),4.15-4.08 (m,1H),3.87(s,3H),3.80-3.78(m,2H),3.33-3.32(m,4H),2.96-2.86(m,1H),2.79-2.76(m,2H),2.65-2.61(m,1H) ,2.60-2.55(m,4H),2.42-2.39(m,1H),2.27-2.25(m,2H),2.03-1.94(m,1H),1.90-1.73(m,3H),1.33-1.21(m,2H).

[0832] Example 41: Synthesis of Compound 41

[0833] Step 1: Synthesis of (S)-tert-butyl 4-(5-bromopyridin-2-yl)-2-methylpiperazine-1-carboxylate (41b)

[0834] Dissolve 2-fluoro-5-bromopyridine (41a, 5 g, 28.41 mmol) and tert-butyl (S)-2-methylpiperazine-1-carboxylate (6.83 g, 34.09 mmol) in N,N-dimethylformamide (100 mL). Add N,N-diisopropylethylamine (11.02 g, 85.23 mmol, 14.85 mL). The reaction mixture is stirred at 120°C for 3 hours. Add water (100 mL) and extract with ethyl acetate (100 mL x 3). The organic layer is dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:tetrahydrofuran = 5:1) to afford the title compound (1.6 g).

[0835] MS m / z(ESI):356.1,358.1[M+H] + .

[0836] Step 2: Synthesis of (S)-(6-(4-(tert-Butoxycarbonyl)-3-methylpiperazin-1-yl)pyridin-3-yl)boronic acid (Intermediate 41c)

[0837] Intermediate 41b (1.6 g, 4.49 mmol) and pinacol diboron (1.71 g, 6.74 mmol) were dissolved in anhydrous dioxane (40 mL). Potassium acetate (881.52 mg, 8.98 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (328.62 mg, 449.11 μmol) were added. The mixture was reacted at 100°C under nitrogen for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure and extracted with ethyl acetate (40 mL x 3) and water (40 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain the title compound (1.3 g).

[0838] MS m / z(ESI):322.1[M+H] + .

[0839] Step 3: Synthesis of (S)-tert-butyl 4-(3'-(3-chloro-2-(methoxycarbonyl)phenoxy)-5'-methyl-[3,4'-bipyridyl]-6-yl)-2-methylpiperazine-1-carboxylate (41d)

[0840] Intermediate 41c (216.16 mg, 673.03 μmol) and Intermediate 35g (200 mg, 560.85 μmol) were dissolved in anhydrous dioxane (4 mL) and water (1 mL). Potassium carbonate (155.03 mg, 1.12 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (41.04 mg, 56.09 μmol) were added. The reaction mixture was stirred at 100°C under nitrogen for 3 hours. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The title compound (290 mg) was purified by column chromatography (silica, petroleum ether:tetrahydrofuran = 2:1) to obtain the title compound.

[0841] MS m / z(ESI):553.3[M+H] + .

[0842] Step 4: Synthesis of (S)-tert-butyl 4-(5-(9-chloro-3-methyl-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)pyridin-2-yl)-2-methylpiperazine-1-carboxylate (41e)

[0843] Intermediate 41d (120 mg, 216.98 μmol) was dissolved in tetrahydrofuran (1.5 mL). Lithium diisopropylamide (2 M, 216.98 μL) was added dropwise at -78°C under a nitrogen atmosphere. The reaction mixture was stirred at -78°C for 1 hour. The reaction mixture was quenched with aqueous ammonium chloride (1 mL) at -78°C and extracted with water (2 mL) and ethyl acetate (2 mL x 3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the title compound (90 mg).

[0844] MS m / z(ESI):521.1[M+H] + .

[0845] Step 5: Synthesis of (S)-9-chloro-3-methyl-4-(6-(3-methylpiperazin-1-yl)pyridin-3-yl)-10H-chromeno[3,2-b]pyridin-10-one hydrochloride (41f)

[0846] Intermediate 41e (100 mg, 191.94 μmol) was dissolved in anhydrous methanol (1 mL), and dioxane hydrochloride (2 M, 1.92 mL) was added. The reaction mixture was stirred at 25° C. for 2 hours and concentrated to dryness under reduced pressure to obtain the title compound (40 mg).

[0847] MS m / z(ESI):421.1[M+H] + .

[0848] Step 6: Synthesis of compound 41

[0849] Intermediate 41f (16.30 mg, 35.64 μmol) and intermediate 39c (15.11 mg, 39.20 μmol) were dissolved in N,N-dimethylformamide (0.5 mL). Sodium acetate (8.77 mg, 106.92 μmol), acetic acid (6.42 mg, 106.92 μmol), and sodium acetate borohydride (22.66 mg, 106.92 μmol) were added at 25°C, and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with water (0.5 mL), diluted with N,N-dimethylformamide (2 mL), filtered, and the filtrate was purified by HPLC (C18, 5 μm silica, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.05% hydrochloric acid) and acetonitrile (acetonitrile ratio 13%-43%) as eluent) to afford the title compound (5.0 mg).

[0850] MS m / z(ESI):790.3[M+H] + ;

[0851] 1H NMR(400MHz, DMSO-d6)δ=11.38-11.19(m,1H),11.01(s,1H),8.75(s,1H),8.38-8.31(m,1H),8.00-7.93(m,1H),7 .80-7.58(m,3H),7.52(d,J=0.9,7.8Hz,1H),7.40-7.31(m,2H),5.11(dd,J=5.1,13.3Hz,1H),4.58(t,J=12.1Hz, 2H),4.40(d,J=17.6Hz,1H),4.24(d,J=17.6Hz,2H),3.94(s,3H),3.58-3.38(m,6H),3.36-2.84(m,5H),2.60(d,J =16.3Hz,1H),2.44(m,J=4.3,13.0Hz,2H),2.39(s,3H),2.35-2.28(m,1H),2.10-1.84(m,4H),1.57-1.37(m,3H).

[0852] Example 42: Synthesis of Compound 42

[0853] Compound 32 (43.35 mg, 91.97 μmol) and intermediate 39c (42.54 mg, 110.37 μmol) were dissolved in anhydrous N,N-dimethylformamide (1 mL). Sodium acetate borohydride (58.48 mg, 275.91 μmol), sodium acetate (22.63 mg, 275.91 μmol), and acetic acid (16.57 mg, 275.91 μmol, 15.80 μL) were added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure. The title compound (6.8 mg) was purified by high-performance liquid chromatography (ACSSH-CP C18, 40 mm diameter, 150 mm length; using a mixture of water (containing 0.05% ammonia) and acetonitrile (acetonitrile ratio 32%-72%) as the eluent).

[0854] MS m / z(ESI):804.6[M+H] + ;

[0855] 1H NMR (400MHz, DMSO-d6) δ=10.93(s,1H),8.78(s,1H),8.20(s,1H),7.76-7.67(m,2H),7.52-7.47(m,1H),7.35(d,J=8.6H z,1H),7.07-7.01(m,1H),6.78(d,J=13.9Hz,2H),5.11-5.02(m,1H),4.29-4.22(m,1H),4.14-4.07(m,1H),4.04(d,J=1 0.8Hz,2H),3.90-3.84(m,3H),3.80(d,J=10.3Hz,2H),3.04-2.84(m,4H),2.83-2.65(m,5H),2.58(d,J=12.8Hz,3H),2. 29-2.20(m,1H),2.09-1.89(m,3H),1.82-1.68(m,2H),1.35-1.18(m,2H),1.13(t,J=7.6Hz,3H),1.08(d,J=6.0Hz,3H).

[0856] Example 43: Synthesis of Compound 43

[0857] Compound 33 (40 mg, 89.10 μmol) and intermediate 39c (37.43 mg, 97.12 μmol) were dissolved in N,N-dimethylformamide (1 mL). Sodium acetate (21.93 mg, 267.29 μmol), acetic acid (16.05 mg, 267.29 μmol), and sodium acetate borohydride (56.65 mg, 267.29 μmol) were added at 25°C, and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with water (0.5 mL), filtered, and the filtrate was purified by HPLC (Boston Prime C18, 5 μm silica, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.05% ammonia and ammonium bicarbonate) and acetonitrile (acetonitrile ratio 34%-74%) as eluent) to obtain the title compound (6.4 mg).

[0858] MS m / z(ESI):818.5[M+H] + ;

[0859] 1H NMR (400MHz, DMSO-d6) δ=10.97(s,1H),8.89(s,1H),8.16(d,J=2.2Hz,1H),7.76-7.63(m,2H),7.50(d,J=7.7Hz,1H),7.34(d,J= 8.6Hz,1H),7.04(d,J=9.0Hz,1H),6.78(d,J=13.9Hz,2H),5.08(dd,J=5.1,13.2Hz,1H),4.26(d,J=16.7Hz,1H),4.11(d,J=16.7H z,1H),4.04(d,J=10.8Hz,2H),3.87(s,3H),3.82-3.79(m,2H),3.26-3.18(m,1H),3.06-2.87(m,4H),2.82-2.71(m,2H),2.59-2. 57(m,2H),2.45-2.38(m,2H),2.30-2.20(m,1H),2.09-1.90(m,3H),1.81-1.68(m,2H),1.31-1.25(m,8H),1.09(d,J=6.2Hz,3H).

[0860] Example 44: Synthesis of Compound 44

[0861] Compound 34 (45.22 mg, 101.19 μmol) and intermediate 39c (30 mg, 77.84 μmol) were dissolved in anhydrous N,N-dimethylformamide (1 mL). Acetic acid (9.35 mg, 155.68 μmol), sodium acetate (12.77 mg, 155.68 μmol), and sodium acetate borohydride (32.99 mg, 155.68 μmol) were added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was filtered and purified by high-performance liquid chromatography (C18, 5 μm silica, 40 mm diameter, 150 mm length; using a mixture of water (containing 0.05% ammonia) and acetonitrile (acetonitrile ratio 33%-73%) as the eluent) to obtain the title compound (5.8 mg).

[0862] MS m / z(ESI):816.3[M+H] + ;

[0863] 1H NMR (400MHz, DMSO-d6) δ=10.96(s,1H),8.36(s,1H),8.28(d,J=2.4Hz,1H),7.76(dd,J=2.4,8.9Hz,1H),7.73-7.67(m,1H),7.48(d,J= 7.3Hz,1H),7.38-7.34(m,1H),7.04(d,J=8.9Hz,1H),6.81-6.73(m,2H),5.11-5.02(m,1H),4.25(d,J=16.8Hz,1H),4.10(d,J=16.9Hz ,1H),4.07-3.97(m,2H),3.86(s,3H),3.83-3.74(m,2H),3.23-3.16(m,1H),2.98-2.84(m,3H),2.83-2.70(m,2H),2.62-2.55(m,2H), 2.47-2.37(m,2H),2.28-2.17(m,1H),2.06-1.89(m,4H),1.79-1.68(m,2H),1.31-1.18(m,2H),1.11-1.07(m,3H),1.07-0.97(m,4H).

[0864] Example 45: Synthesis of Compound 45

[0865] Step 1: Synthesis of methyl 2-((4-amino-5-chloropyridin-3-yl)oxy)-6-chlorobenzoate (45a)

[0866] Intermediate 16c (500 mg, 1.79 mmol) was dissolved in acetonitrile (10 mL), and N-chlorosuccinimide (359.36 mg, 2.69 mmol) was added. The reaction mixture was stirred at 25°C for 16 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phases were combined and washed with water (60 mL*3), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 3 / 1) to obtain the title compound (540 mg).

[0867] MS m / z(ESI):313.0[M+H] + .

[0868] Step 2: Synthesis of methyl 2-chloro-6-((5-chloro-4-iodopyridin-3-yl)oxy)benzoate (45b)

[0869] To a solution of cuprous iodide (535.22 mg, 2.81 mmol) in acetonitrile (4.5 mL) was added tert-butyl nitrite (434.69 mg, 4.22 mmol) dropwise at 0°C, and the reaction was stirred at 0°C for 15 minutes. A solution of intermediate 45a (440 mg, 1.41 mmol) in acetonitrile (4.5 mL) was added dropwise to the reaction at 0°C. The reaction was stirred at 50°C for 1 hour. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (60 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 5 / 1) to afford the title compound (320 mg).

[0870] MS m / z(ESI):424.0[M+H] + .

[0871] Step 3: Synthesis of tert-butyl 4-(4-(3-chloro-5-(3-chloro-2-(methoxycarbonyl)phenoxy)pyridin-4-yl)phenyl)piperazine-1-carboxylate (45c) Intermediate 45b (387 mg, 912.70 μmol) and intermediate 1i (283.53 mg, 730.16 μmol) were dissolved in 1,4-dioxane (8 mL) and water (2 mL), and potassium carbonate (252.28 mg, 1.83 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (66.78 mg, 91.27 μmol) were added. The reaction mixture was stirred at 80°C under nitrogen for 2 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (60 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The mixture was purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 0% to 8%) to give the title compound (338 mg).

[0872] MS m / z(ESI):558.1[M+H] + .

[0873] Step 4: Synthesis of tert-butyl 4-(4-(3,9-dichloro-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)piperazine-1-carboxylate (45d)

[0874] Intermediate 45c (328 mg, 587.34 μmol) was dissolved in tetrahydrofuran (3 mL), and lithium diisopropylamine solution (2 M, 1.17 mL) was added dropwise at -78°C under a nitrogen atmosphere. The reaction mixture was stirred at -78°C for 1 hour. Saturated aqueous ammonium chloride (1.5 mL) was added to the reaction mixture at -78°C to quench the reaction. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined and concentrated to dryness under reduced pressure to obtain the title compound (314 mg).

[0875] MS m / z(ESI):526.1[M+H] + .

[0876] Step 5: Synthesis of tert-butyl 4-(4-(9-chloro-3-methoxy-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)piperazine-1-carboxylate (45e)

[0877] Intermediate 45d (110 mg, 208.96 μmol) was dissolved in methanol (5.5 mL), and a methanol solution of sodium methoxide (112.89 mg, 626.89 μmol, 30% content) was added. The reaction solution was microwaved at 80°C for 40 minutes. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 3 / 2) to give the title compound (75 mg).

[0878] MS m / z(ESI):522.2[M+H] + .

[0879] Step 6: Synthesis of 9-chloro-3-methoxy-4-(4-(piperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one hydrochloride (45f)

[0880] Intermediate 45e (75 mg, 143.68 μmol) was dissolved in methanol (1 mL), and a dioxane hydrochloride solution (2 M, 718.40 μL) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure to obtain the title compound (60 mg).

[0881] MS m / z(ESI):422.2[M+H] + .

[0882] Step 7: Synthesis of compound 45

[0883] Intermediate 45f (38.02 mg, 82.96 μmol) and intermediate 39c (35.17 mg, 91.26 μmol) were dissolved in N,N-dimethylformamide (1 mL). Sodium acetate (34.03 mg, 414.81 μmol), acetic acid (14.95 mg, 248.89 μmol), and sodium acetate borohydride (26.37 mg, 124.44 μmol) were added. The reaction was stirred at 25°C for 0.5 h. Two drops of water were added to quench the reaction and the product was purified by HPLC (C18 column, silica, 30 mm diameter, 150 mm length; eluent: a mixture of water (containing 0.05% hydrochloric acid) and acetonitrile (acetonitrile ratio 14%-54%)) to afford the title compound (29.5 mg).

[0884] MS m / z(ESI):791.2[M+H] + ;

[0885] 1 H NMR (400MHz, DMSO-d6) δ = 10.99 (s, 1H), 10.40 (br s,1H),8.76(s,1H),7.74-7.67(m,1H),7.49(d,J=8.9Hz,3H),7.34(dd,J=0.9,8.5Hz,1H),7.24-6.93(m,4H),5.08( dd,J=5.0,13.4Hz,1H),4.31(d,J=17.1Hz,1H),4.15(d,J=17.1Hz,1H),4.04(s,3H),3.97(d,J=12.6Hz,2H),3.92-3 .87(m,3H),3.81(d,J=13.0Hz,2H),3.67(d,J=11.3Hz,2H),3.37-3.33(m,2H),3.22-3.15(m,4H),3.08-3.00(m,1H) ,2.95-2.87(m,1H),2.63-2.55(m,2H),2.45-2.40(m,1H),2.23-2.13(m,1H),2.06-1.93(m,3H),1.65-1.45(m,2H).

[0886] Example 46: Synthesis of 3-(6-(4-((4-(4-(9-chloro-3-methyl-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-4-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (Compound 46)

[0887] Compound 35 (54.54 mg, 123.19 μmol) and intermediate 14g (47.48 mg, 123.19 μmol) were dissolved in N,N-dimethylformamide (1 mL), and sodium acetate (50.53 mg, 615.95 μmol), acetic acid (7.40 mg, 123.19 μmol), and sodium acetate borohydride (52.22 mg, 246.38 μmol) were added. The reaction mixture was stirred at 25°C for 0.5 h. Water (2 drops) was added to quench the reaction and the product was purified by HPLC (Boston Green ODS column, 5 μm silica, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.05% hydrochloric acid) and acetonitrile (acetonitrile ratio 20%-40%) as the eluent) to obtain the title compound (29.2 mg).

[0888] MS m / z(ESI):775.2[M+H] + ;

[0889] 1 H NMR (400MHz, DMSO-d6) δ11.45(s,1H),10.98(s,1H),8.75(s,1H),7.86(s,1H),7.72(s,1H),7.76-7.67(m,1H),7. 50(d,J=7.8Hz,1H),7.44(d,J=8.6Hz,2H),7.35(d,J=8.6Hz,1H),7.22(d,J=8.8Hz,2H),5.12(d,J=8.2Hz,1H),4. 42(d,J=17.7Hz,1H),4.27(d,J=17.7Hz,1H),4.00(d,J=12.3Hz,2H),3.95(s,3H),3.68(s,5H),3.60-3.49(m,4H) ,3.25(s,4H),2.97-2.84(m,1H),2.60(d,J=16.9Hz,1H),2.47-2.43(m,1H),2.38-2.25(m,5H),2.12-1.95(m,3H).

[0890] Example 47: Synthesis of Compound 47

[0891] Compound 35 (21.8 mg, 49.28 μmol) and intermediate 39c (18.99 mg, 49.28 μmol) were dissolved in N,N-dimethylformamide (1 mL). Sodium acetate (20.21 mg, 246.38 μmol), acetic acid (2.96 mg, 49.28 μmol), and sodium acetate borohydride (15.67 mg, 73.91 μmol) were added. The reaction was stirred at 25°C for 0.5 h. Water (2 drops) was added to quench the reaction and the product was purified by HPLC (C18 column, 30 mm diameter, 150 mm length; eluent: a mixture of water (containing 0.05% hydrochloric acid) and acetonitrile (15%-55% acetonitrile)) to afford the title compound (9.4 mg).

[0892] MS m / z(ESI):775.1[M+H] + ;

[0893] 1 H NMR(400MHz,DMSO-d6)δ=11.12(br s,1H),11.00(s,1H),8.73(s,1H),7.74-7.68(m,1H),7.67-7.47(m,3H),7.44(d,J=8.6Hz,2H),7.36-7.31( m,1H),7.21(d,J=8.8Hz,2H),5.11(dd,J=4.9,13.2Hz,1H),4.39(d,J=17.5Hz,1H),4.23(d,J=17.6Hz,1H),4 .00-3.98(m,4H),3.93(s,3H),3.73-3.68(m,4H),3.48-3.46(m,2H),3.24-3.23(m,4H),2.96-2.86(m,1H), 2.60-2.59(m,2H),2.45-2.43(m,1H),2.34(s,3H),2.24-2.15(m,2H),2.04-1.95(m,1H),1.94-1.77(m,2H).

[0894] Example 48: Synthesis of Compound 48

[0895] Compound 35 (54.49 mg, 123.19 μmol) and intermediate 40a (47.48 mg, 123.19 μmol) were dissolved in N,N-dimethylformamide (1 mL). Sodium acetate (50.53 mg, 615.95 μmol), acetic acid (7.40 mg, 123.19 μmol), and sodium acetate borohydride (52.22 mg, 246.38 μmol) were added. The reaction was stirred at 25°C for 0.5 h. Water (2 drops) was added to quench the reaction. The title compound (29.2 mg) was obtained by HPLC (Phenomenex Gemini NX column, 5 μm silica, 30 mm diameter, 150 mm length; eluent: a mixture of water (containing 0.05% ammonia) and acetonitrile (33%-73% acetonitrile).

[0896] MS m / z(ESI):775.3[M+H] + ;

[0897] 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),8.71(s,1H),7.74-7.68(m,1H),7.50(dd,J=0.9,7.9Hz,1H),7.40-7.31(m, 3H),7.12(d,J=8.8Hz,2H),6.83-6.75(m,2H),5.08(dd,J=5.1,13.2Hz,1H),4.26(d,J=16.7Hz,1H),4.15-4.07(m ,1H),3.87(s,3H),3.81(d,J=12.5Hz,2H),3.33-3.26(m,4H),2.98-2.86(m,1H),2.77-2.75(m,2H),2.64-2.53(m ,5H),2.46-2.38(m,1H),2.34(s,3H),2.28-2.25(m,2H),2.03-1.93(m,1H),1.90-1.71(m,3H),1.34-1.21(m,2H).

[0898] Example 49: Synthesis of Compound 49

[0899] Compound 36 (54.34 mg, 119.08 μmol) and intermediate 39c (36.71 mg, 95.26 μmol) were dissolved in N,N-dimethylformamide (1 mL). Sodium acetate (29.30 mg, 357.23 μmol), acetic acid (21.45 mg, 357.23 μmol), and sodium acetate borohydride (75.71 mg, 357.23 μmol) were added at 25°C, and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with water (0.5 mL), diluted with N,N-dimethylformamide (2 mL), filtered, and the filtrate was purified by HPLC (Phenomenex Gemini NX column, 30 mm diameter, 150 mm length; eluent: a mixture of water (containing 0.05% hydrochloric acid) and acetonitrile (acetonitrile ratio 18%-58%)) to afford the title compound (17.0 mg).

[0900] MS m / z(ESI):789.4[M+H] + ;

[0901] 1 H NMR (400MHz, DMSO-d6) δ=10.97(s,1H),10.48-10.05(m,1H),8.72(s,1H),7.74-7.67(m,1H),7.50(d,J=7.6Hz,1H),7.46-7.39(m,2H ),7.34-7.27(m,2H),7.21(d,J=8.6Hz,2H),7.05-7.01(m,1H),5.07(dd,J=5.0,12.9Hz,1H),4.32-4.27(m,1H),4.13(d,J=16.8Hz,1 H),4.06-3.97(m,2H),3.89(s,3H),3.85-3.82(m,2H),3.25-3.20(m,2H),3.03-2.97(m,2H),2.92-2.84(m,2H),2.61-2.59(m,2H),2 .55(d,J=2.6Hz,2H),2.45-2.38(m,2H),2.34(s,3H),2.24-2.12(m,3H),2.03-1.93(m,2H),1.87-1.79(m,1H),1.47(d,J=6.3Hz,3H).

[0902] Example 50: Synthesis of Compound 50

[0903] Compound 18 (164.69 mg, 402.77 μmol) and intermediate 39c (169.20 mg, 439.02 μmol) were dissolved in N,N-dimethylformamide (3 mL). Sodium acetate (99.12 mg, 1.21 mmol), acetic acid (72.56 mg, 1.21 mmol), and sodium acetate borohydride (256.09 mg, 1.21 mmol) were added at 25°C, and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with water (0.5 mL), diluted with N,N-dimethylformamide (2 mL), filtered, and the filtrate was purified by HPLC (Xtimate C18, 5 μm silica, 40 mm diameter, 150 mm length; using a mixture of water (containing 0.225% formic acid) and acetonitrile (8%-48% acetonitrile) as the eluent) to afford the title compound (157.5 mg).

[0904] MS m / z(ESI):742.3[M+H] + ;

[0905] 1 H NMR (400MHz, DMSO-d6) δ = 10.95 (s, 1H), 8.65 (d, J = 4.5Hz, 1H), 7.92-7.66 (m, 5H), 7.42 (t, J = 8.2Hz, 1H), 7.12 (d, J = 8.9 Hz,2H),6.78(d,J=9.2Hz,2H),6.60(d,J=8.2Hz,1H),6.47(d,J=8.1Hz,1H),5.07(dd,J=5.0,13.2Hz,1H),4.30-4.22(m ,1H),4.15-4.08(m,1H),3.87(s,3H),3.79(d,J=12.2Hz,2H),3.31-3.30(m,4H),2.96-2.86(m,1H),2.76(t,J=11.8Hz, 2H),2.63-2.53(m,5H),2.44-2.36(m,1H),2.25-2.20(m,2H),2.02-1.93(m,1H),1.89-1.72(m,3H),1.33-1.19(m,2H).

[0906] Example 51: Synthesis of Compound 51

[0907] Compound 18 (219.58 mg, 537.03 μmol) and intermediate 40a (225.61 mg, 585.36 μmol) were dissolved in N,N-dimethylformamide (5.5 mL). Sodium acetate (132.16 mg, 1.61 mmol), acetic acid (96.75 mg, 1.61 mmol), and sodium acetate borohydride (341.45 mg, 1.61 mmol) were added at 25°C, and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with water (0.5 mL), diluted with N,N-dimethylformamide (2 mL), filtered, and the filtrate was purified by HPLC (Boston Prime C18, 5 μm silica, 40 mm diameter, 150 mm length; using a mixture of water (containing 0.225% formic acid) and acetonitrile (7%-47% acetonitrile) as the eluent) to obtain the title compound (256 mg).

[0908] MS m / z(ESI):742.5[M+H] + ;

[0909] 1 H NMR (400MHz, DMSO-d6) δ = 10.95 (s, 1H), 8.65 (d, J = 4.6Hz, 1H), 7.92-7.68 (m, 5H), 7.42 (t, J = 8.1Hz, 1H), 7.12 (d, J = 8.9Hz, 2H), 6.82- 6.75(m,2H),6.59(d,J=7.7Hz,1H),6.47(d,J=8.7Hz,1H),5.07(dd,J=5.0,13.4Hz,1H),4.27(d,J=16.9Hz,1H),4.11(d,J=16.6Hz,1H ),3.87(s,3H),3.80(d,J=12.0Hz,2H),3.31-3.30(m,4H),2.95-2.86(m,1H),2.77(t,J=11.1Hz,2H),2.61(d,J=2.1Hz,1H),2.57-2. 54(m,4H),2.46-2.39(m,1H),2.26(d,J=6.8Hz,2H),2.02-1.94(m,1H),1.85(d,J=12.8Hz,2H),1.81-1.72(m,1H),1.33-1.23(m,2H).

[0910] Example 52: Synthesis of Compound 52

[0911] Step 1: Synthesis of tert-butyl 4-(4-(9-(tert-butoxycarbonyl)amino)-3-methoxy-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)piperazine-1-carboxylate (52a)

[0912] Intermediate 45e (30 mg, 57.47 μmol) and tert-butyl carbamate (8.08 mg, 68.97 μmol) were dissolved in dioxane (1 mL). Methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (4.81 mg, 5.75 μmol) and cesium carbonate (56.18 mg, 172.42 μmol) were added under a nitrogen atmosphere. The reaction mixture was stirred at 100°C for 2 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (silica, petroleum ether:tetrahydrofuran = 1 / 1) to afford the title compound (10 mg).

[0913] MS m / z(ESI):603.3[M+H] + .

[0914] Step 2: Synthesis of 9-amino-3-methoxy-4-(4-(piperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one hydrochloride (52b)

[0915] Intermediate 52a (10 mg, 16.59 μmol) was dissolved in methanol (1 mL) and dioxane hydrochloride (2 M, 1 mL) was added. The reaction mixture was stirred at 25°C for 16 hours. The temperature was then raised to 40°C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (9 mg).

[0916] MS m / z(ESI):403.1[M+H] + .

[0917] Step 3: Synthesis of compound 52

[0918] Intermediate 52b (8.73 mg, 19.88 μmol) and intermediate 39c (7.66 mg, 19.88 μmol) were dissolved in N,N-dimethylformamide (1 mL). Sodium acetate (4.89 mg, 59.64 μmol), acetic acid (3.59 mg, 59.64 μmol), and sodium acetate borohydride (12.64 mg, 59.64 μmol) were added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with dimethyl sulfoxide (0.5 mL), filtered, and the filtrate was purified by HPLC (Boston Prime C18 column, 5 μm silica, 30 mm diameter, 150 mm length; eluent: a mixture of water (containing 0.08% ammonium bicarbonate) and acetonitrile (30%-60% acetonitrile)) to afford the title compound (1 mg).

[0919] MS m / z(ESI):772.3[M+H] + ;

[0920] 1 H NMR(400MHz,DMSO-d6)δ=11.00(br s,1H),8.64(s,1H),7.43-7.28(m,3H),7.10(d,J=8.8Hz,2H),6.83-6.72(m,2H),6.58-6.48(m,1H ),6.27(d,J=8.8Hz,1H),5.13(m,1H),4.31-4.20(m,1H),4.15-4.05(m,1H),4.00(s,3H),3.89(s, 3H),3.83-3.73(m,2H),3.02-2.82(m,2H),2.81-2.70(m,2H),2.61-2.53(m,5H),2.44-2.35(m,4H ),2.27-2.20(m,2H),2.02-1.91(m,1H),1.91-1.88(m,2H),1.80-1.69(m,1H),1.33-1.20(m,2H).

[0921] Example 53: Synthesis of Compound 53

[0922] Step 1: Synthesis of (S)-tert-butyl 4-(4-(9-(tert-butoxycarbonyl)amino)-3-methyl-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)-2-methylpiperazine-1-carboxylate (53a)

[0923] Intermediate 36b (227 mg, 436.52 μmol) and tert-butyl carbamate (61.36 mg, 523.83 μmol) were dissolved in anhydrous dioxane (4 mL). Cesium carbonate (284.46 mg, 873.05 μmol) and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (36.51 mg, 43.65 μmol) were added. The reaction mixture was stirred at 100°C under nitrogen for 2 hours. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The title compound (124 mg) was purified by column chromatography (silica, petroleum ether:tetrahydrofuran = 2:1) to afford the title compound.

[0924] MS m / z(ESI):601.2[M+H] + .

[0925] Step 2: Synthesis of (S)-9-amino-3-methyl-4-(4-(3-methylpiperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one hydrochloride (53b)

[0926] Intermediate 53a (94 mg, 156.48 μmol) was dissolved in anhydrous methanol (1 mL), and dioxane hydrochloride (2 M, 1.6 mL) was added. The reaction mixture was stirred at 25° C. for 1 hour and concentrated to dryness under reduced pressure to obtain the title compound (60 mg).

[0927] MS m / z(ESI):401.2[M+H] + .

[0928] Step 3: Synthesis of compound 53

[0929] Intermediate 53b (32.73 mg, 74.91 μmol) and intermediate 39c (28.87 mg, 74.91 μmol) were dissolved in N,N-dimethylformamide (1 mL). Sodium acetate (18.43 mg, 224.73 μmol), acetic acid (13.50 mg, 224.73 μmol), and sodium acetate borohydride (47.63 mg, 224.73 μmol) were added at 25°C, and the reaction was stirred at 25°C for 1 hour. The reaction was quenched with water (0.5 mL), diluted with N,N-dimethylformamide (2 mL), filtered, and the filtrate was purified by HPLC (Boston Prime C18 column, 30 mm diameter, 150 mm length; eluent: water (containing 0.05% hydrochloric acid) and acetonitrile (13%-5% acetonitrile)) to afford the title compound (32.8 mg).

[0930] MS m / z(ESI):770.3[M+H] + ;

[0931] 1 H NMR (400MHz, DMSO-d6) δ = 10.98 (s, 1H), 10.89-10.60 (m, 1H), 8.67 (s, 1H), 7.47-7.10 (m, 7H), 6.57 (d, J = 8.3Hz, 1H), 6.29-6.21(d,J=5.2Hz,1H),5.09(dd,J=5.0,13.1Hz,1H),4.35(d,J=17.4Hz,1H),4.18(d,J=17.6Hz,1H),3.95-4.0 4(m,5H),3.91(s,3H),3.78(d,J=11.6Hz,5H),3.51-3.39(m,3H),3.33-3.17(m,3H),3.07-2.98(m,1H),2.97-2.85( m,1H),2.68-2.55(m,1H),2.32(s,3H),2.22-2.10(m,1H),2.03-1.87(m,2H),1.81-1.57(m,2H),1.53-1.40(m,3H).

[0932] Example 54: Synthesis of Compound 54

[0933] Compound 37 (54.34 mg, 119.08 μmol) and intermediate 39c (55.07 mg, 142.89 μmol) were dissolved in anhydrous N,N-dimethylformamide (1 mL). Acetic acid (21.45 mg, 357.23 μmol, 20.45 μL), sodium acetate (29.30 mg, 357.23 μmol), and sodium acetate borohydride (75.71 mg, 357.23 μmol) were added. The reaction mixture was stirred at 25°C for 2 hours. Tetrahydrofuran (5 mL) was added to the reaction mixture, filtered, and concentrated to dryness. The residue was purified by high-performance liquid chromatography (ACSSH-CL C18 column, 5 μm silica, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.05% hydrochloric acid) and acetonitrile (acetonitrile ratio 10%-50%) as the eluent) to obtain the title compound (23.6 mg).

[0934] MS m / z(ESI):789.3[M+H] + ;

[0935] 1H NMR (400MHz, DMSO-d6) δ = 11.02 (s, 1H), 10.89-10.88 (m, 1H), 8.77 (s, 1H), 7.73-7.67 (m, 1H), 7.49 (d, J = 7.1Hz, 3H), 7. 39(d,J=8.6Hz,2H),7.31(d,J=0.8Hz,1H),7.22(d,J=8.8Hz,2H),5.16-5.07(m,1H),4.45-4.33(m,2H),4.22(d,J=17. 5Hz,2H),4.01-3.98(m,4H),3.93(s,3H),3.24-3.21(m,5H),2.97-2.85(m,2H),2.69-2.67(m,3H),2.61-2.59(m,2H), 2.45-2.43(m,1H),2.35-2.32(m,1H),2.24-2.13(m,2H),2.05-1.95(m,1H),1.89-1.75(m,2H),1.10(t,J=7.5Hz,3H).

[0936] Example 55: Synthesis of 3-(6-(4-((1-(4-(9-chloro-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-4-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 55)

[0937] Step 1: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-3-oxoisoindolin-5-yl)piperazine-1-carboxylate (55a)

[0938] Intermediate 14e (100 mg, 283.15 μmol) and tert-butyl piperazine-1-carboxylate (63.28 mg, 339.78 μmol) were dissolved in dioxane (2 mL). (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-κN)palladium (24.37 mg, 28.32 μmol) and cesium carbonate (276.77 mg, 849.46 μmol) were added. The reaction mixture was stirred at 80°C under a nitrogen atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure and diluted with water (3 mL). A solid precipitated, which was filtered and dried to give the title compound (91 mg).

[0939] MS m / z(ESI):481.0[M+Na] + .

[0940] Step 2: Synthesis of 3-(4-methoxy-1-oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (55b)

[0941] Intermediate 55a (75 mg, 163.57 μmol) was dissolved in dichloromethane (1 mL), and dioxane hydrochloride (2 M, 817.87 μL) was added. The reaction mixture was reacted at 25° C. for 2 hours and concentrated under reduced pressure to give the title compound (60 mg).

[0942] MS m / z(ESI):359.1[M+H] + .

[0943] Step 3: Synthesis of 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (55d)

[0944] 1-Bromo-4-iodobenzene (55c, 1 g, 3.53 mmol) and 4-(dimethoxymethyl)piperidine (562.83 mg, 3.53 mmol) were dissolved in toluene (10 mL). Sodium tert-butoxide (679.40 mg, 7.07 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (204.53 mg, 353.48 μmol), and tris(dibenzylideneacetone)dipalladium (161.84 mg, 176.74 μmol) were added. The reaction mixture was stirred at 80°C under a nitrogen atmosphere for 2 hours. Water (30 mL) was added to the reaction solution and extracted with ethyl acetate (90 mL*3). The organic phases were combined and washed with water (90 mL*3). The organic phase was dried over anhydrous sodium sulfate and filtered, concentrated to dryness under reduced pressure, and purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 0% to 6%) to give the title compound (728 mg).

[0945] MS m / z(ESI):314.0,316.0[M+H] + .

[0946] Step 4: Synthesis of 4-(dimethoxymethyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (55e)

[0947] Intermediate 55d (728 mg, 2.32 mmol) and pinacol diboronate (706.01 mg, 2.78 mmol) were dissolved in 1,4-dioxane (12 mL). Potassium acetate (454.77 mg, 4.63 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (169.53 mg, 231.69 μmol) were added. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 2 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (90 mL x 3). The combined organic phases were washed with water (90 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 1 / 0 to 19 / 1) to afford the title compound (496 mg).

[0948] MS m / z(ESI):362.2[M+H] + .

[0949] Step 5: Synthesis of methyl 2-chloro-6-((4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)pyridin-3-yl)oxy)benzoate (55f)

[0950] Intermediate 55e (350 mg, 968.77 μmol) and Intermediate 16d (331.87 mg, 968.77 μmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL). Potassium carbonate (267.78 mg, 1.94 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (70.89 mg, 96.88 μmol) were added. The reaction mixture was reacted at 80°C under a nitrogen atmosphere for 2 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with water (30 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 2 / 1) to provide the title compound (413 mg).

[0951] MS m / z(ESI):497.1[M+H] + .

[0952] Step 6: Synthesis of 9-chloro-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one (55 g)

[0953] Intermediate 55f (200 mg, 402.43 μmol) was dissolved in tetrahydrofuran (5 mL), and lithium diisopropylamine solution (2 M, 804.86 μL) was slowly added dropwise at -78°C. The reaction mixture was allowed to react at -78°C for 1 hour. Saturated aqueous ammonium chloride solution (5 mL) was added dropwise to the reaction mixture at -78°C to quench the reaction. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (60 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the title compound (243 mg).

[0954] MS m / z(ESI):465.2[M+H] + .

[0955] Step 7: Synthesis of 1-(4-(9-chloro-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)piperidine-4-carbaldehyde (55h)

[0956] The intermediate 55 g (140 mg, 301.11 μmol) was dissolved in formic acid (2 mL). The reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure to obtain the title compound (181 mg).

[0957] MS m / z(ESI):419.1[M+H] + .

[0958] Step 8: Synthesis of 3-(6-(4-((1-(4-(9-chloro-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-4-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 55)

[0959] Intermediate 55h (60 mg, 143.24 μmol) and intermediate 55b (45.25 mg, 114.59 μmol) were dissolved in N,N-dimethylformamide (1 mL). Sodium acetate (117.51 ​​mg, 1.43 mmol), acetic acid (8.60 mg, 143.24 μmol), and sodium acetate borohydride (45.54 mg, 214.86 μmol) were added. The reaction mixture was stirred at 25°C for 0.5 h. The reaction mixture was filtered and purified by HPLC (Phenomenex Gemini NX column, 5 μm silica, 30 mm diameter, 150 mm length; eluent: a mixture of water (0.225% formic acid) and acetonitrile (acetonitrile ratio 14%-54%)) to afford the title compound (29.5 mg).

[0960] MS m / z(ESI):761.3[M+H] + ;

[0961] 1 H NMR (400MHz, DMSO-d6) δ11.94(s,1H),8.71(d,J=4.8Hz,1H),7.84(d,J=4.6Hz,1H),7.81-7.70(m,3 H),7.57-7.50(m,2H),7.17-7.07(m,2H),6.81(s,1H),6.78-6.74(m,1H),5.06(dd,J=5.0,13.1Hz,1 H),4.30-4.23(m,1H),4.11(d,J=16.8Hz,1H),3.97-3.82(m,6H),2.97-2.76(m,4H),2.62-2.52(m, 6H),2.46-2.34(m,2H),2.28-2.20(m,2H),1.98-1.96(m,1H),1.91-1.74(m,3H),1.33-1.17(m,2H).

[0962] Example 56: Synthesis of Compound 56

[0963] Compound 38 (27.2 mg, 60.31 μmol) and intermediate 39c (23.25 mg, 60.33 μmol) were dissolved in anhydrous N,N-dimethylformamide (1 mL). Acetic acid (10.87 mg, 180.94 μmol, 10.36 μL), sodium acetate (14.84 mg, 180.94 μmol), and sodium acetate borohydride (38.35 mg, 180.94 μmol) were added. The reaction mixture was stirred at 25°C for 2 hours. Dimethyl sulfoxide (0.5 mL) was added, the mixture was filtered, and concentrated to dryness. The title compound (15.4 mg) was purified by high-performance liquid chromatography (ACSSH-CL C18 column, 30 mm diameter, 150 mm length; eluent: a mixture of water (containing 0.05% hydrochloric acid) and acetonitrile (acetonitrile ratio 15%-55%)).

[0964] MS m / z(ESI):784.4[M+H] + ;

[0965] 1H NMR (400MHz, DMSO-d6) δ = 11.05 (s, 1H), 10.96-10.91 (m, 1H), 8.75-8.68 (m, 1H), 7.65-7.43 (m, 2H), 7.40-7.31 (m, 3H), 7.27-7.13 (m,2H),6.57(d,J=8.0Hz,1H),6.28-6.19(m,1H),5.10(J=5.0,13.1Hz,1H),4.38(d,J=17.5Hz,1H),4.22(d,J=17.4Hz,1H),4.03- 4.01(m,2H),3.93(s,3H),3.50-3.41(m,6H),3.06-3.04(m,1H),2.98-2.83(m,2H),2.68-2.66(m,3H),2.55-2.53(m,1H),2.46-2 .19(m,4H),2.06-1.94(m,2H),1.92-1.72(m,2H),1.52-1.49(m,2H),1.45-1.43(m,1H),1.28-1.20(m,1H),1.09(t,J=7.4Hz,3H).

[0966] Example 57: Synthesis of 9-chloro-4-(3-fluoro-4-(piperazin-1-yl)phenyl)-3-methyl-10H-chromeno[3,2-b]pyridin-10-one hydrochloride (Compound 57)

[0967] Step 1: Synthesis of tert-butyl 4-(4-bromo-2-fluorophenyl)piperazine-1-carboxylate (57b)

[0968] 1-Bromo-3-fluoro-4-iodobenzene (57a, 3 g, 9.97 mmol) and tert-butyl piperazine-1-carboxylate (1.86 g, 9.97 mmol) were dissolved in dioxane (60 mL). Sodium tert-butoxide (1.92 g, 19.94 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (576.90 mg, 997.03 μmol) and tris(dibenzylideneacetone)dipalladium (912.99 mg, 997.03 μmol) were added at 25°C. The reaction solution was stirred at 80°C under nitrogen protection for 2 hours. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (100 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, petroleum ether:tetrahydrofuran = 1:0 to 30:1) to give the title compound (2.09 g).

[0969] MS m / z(ESI):359.0,361.0[M+H] + .

[0970] Step 2: Synthesis of tert-butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (57c)

[0971] Intermediate 57b (2.04 g, 5.68 mmol) and pinacol diboron (2.16 g, 8.52 mmol) were dissolved in dioxane (40 mL). 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride (415.52 mg, 567.88 μmol) and potassium acetate (1.11 g, 11.36 mmol) were added at 25°C. The reaction mixture was stirred at 100°C under nitrogen for 2 hours. The reaction mixture was diluted with water (60 mL) and extracted with dichloromethane (60 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, petroleum ether:tetrahydrofuran = 1:0 to 50:1) to provide the title compound (2.09 g).

[0972] MS m / z(ESI):407.2[M+H] + .

[0973] Step 3: Synthesis of tert-butyl 4-(4-(3-(3-chloro-2-(methoxycarbonyl)phenoxy)-5-methylpyridin-4-yl)-2-fluorophenyl)piperazine-1-carboxylate (57d)

[0974] Intermediate 57c (353 mg, 868.82 μmol) and Intermediate 35g (265 mg, 743.13 μmol) were dissolved in dioxane (4 mL) and water (0.8 mL). 1,1'-Bis(diphenylphosphino)ferrocenepalladium dichloride (63.57 mg, 86.88 μmol) and potassium carbonate (240.48 mg, 1.74 mmol) were added at 25°C. The reaction mixture was stirred at 80°C under nitrogen for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, petroleum ether:tetrahydrofuran = 1:0 to 4:1) to provide the title compound (318 mg).

[0975] MS m / z(ESI):556.3[M+H] + .

[0976] Step 4: Synthesis of tert-butyl 4-(4-(9-chloro-3-methyl-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)-2-fluorophenyl)piperazine-1-carboxylate (57e)

[0977] Intermediate 57d (318 mg, 571.92 μmol) was dissolved in tetrahydrofuran (2 mL), and lithium diisopropylamide (2 M, 1.14 mL) was added at -78°C. The reaction was stirred at -78°C for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride (1.5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, dichloromethane:tetrahydrofuran = 1:0 to 30:1) to provide the title compound (169 mg).

[0978] MS m / z(ESI):524.2[M+H] + .

[0979] Step 5: Synthesis of 9-chloro-4-(3-fluoro-4-(piperazin-1-yl)phenyl)-3-methyl-10H-chromeno[3,2-b]pyridin-10-one hydrochloride (Compound 57)

[0980] Intermediate 57e (159 mg, 303.45 μmol) was dissolved in dichloromethane (1 mL), and dioxane hydrochloride (2 M, 1.52 mL) was added at 25° C. The reaction mixture was stirred at 25° C. for 16 hours and concentrated under reduced pressure to give the title compound (153 mg).

[0981] MS m / z(ESI):424.1[M+H] + ;

[0982] 1 H NMR(400MHz,DMSO-d6)δ=9.01(br s,2H),8.75(s,1H),7.75-7.69(m,1H),7.52(d,J=7.7Hz,1H),7.46-7.44(m ,1H),7.36-7.28(m,3H),3.40-3.36(m,4H),3.32-3.29(m,4H),2.34(s,3H).

[0983] Example 58: Synthesis of (S)-9-chloro-4-(3-chloro-4-(3-methylpiperazin-1-yl)phenyl)-3-methyl-10H-chromeno[3,2-b]pyridin-10-one hydrochloride (Compound 58)

[0984] Step 1: Synthesis of tert-butyl (S)-4-(4-bromo-2-chlorophenyl)-2-methylpiperazine-1-carboxylate (58b)

[0985] 4-Bromo-2-chloro-1-iodobenzene (58a, 1 g, 3.15 mmol) and tert-butyl (S)-2-methylpiperazine-1-carboxylate (504.88 mg, 2.52 mmol) were dissolved in toluene (10 mL). Sodium tert-butoxide (605.66 mg, 6.30 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (182.33 mg, 315.11 μmol), and tris(dibenzylideneacetone)dipalladium (144.28 mg, 157.56 μmol) were added. The reaction mixture was stirred at 120°C under nitrogen for 16 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (90 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. Purification by column chromatography (silica, petroleum ether:ethyl acetate = 1:0 to 20:1) gave the title compound (388 mg).

[0986] MS m / z(ESI):389.2,391.2[M+H] + .

[0987] Step 2: Synthesis of (S)-tert-butyl 4-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methylpiperazine-1-carboxylate (58c)

[0988] Intermediate 58b (386.35 mg, 995.60 μmol) and pinacol diboron (202.26 mg, 796.48 μmol) were dissolved in 1,4-dioxane (4 mL). Potassium acetate (195.42 mg, 1.99 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (72.85 mg, 99.56 μmol) were added. The reaction mixture was stirred at 100°C under nitrogen for 3 hours. Water (10 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 3). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Purification by column chromatography (silica, petroleum ether:ethyl acetate = 1:0 to 20:1) afforded the title compound (252 mg).

[0989] MS m / z(ESI):437.1[M+H] + .

[0990] Step 3: Synthesis of (S)-tert-butyl 4-(2-chloro-4-(3-(3-chloro-2-(methoxycarbonyl)phenoxy)-5-methylpyridin-4-yl)phenyl)-2-methylpiperazine-1-carboxylate (58d)

[0991] Intermediate 35g (170 mg, 476.73 μmol) and Intermediate 58c (249.87 mg, 572.07 μmol) were dissolved in 1,4-dioxane (6 mL) and water (1.5 mL). Potassium carbonate (131.77 mg, 953.45 μmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (34.88 mg, 47.67 μmol) were added. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 2 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Purification by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 4 / 1) afforded the title compound (207 mg).

[0992] MS m / z(ESI):586.1[M+H] + .

[0993] Step 4: Synthesis of (S)-tert-butyl 4-(2-chloro-4-(9-chloro-3-methyl-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)-2-methylpiperazine-1-carboxylate (58e)

[0994] Intermediate 58d (207 mg, 352.94 μmol) was dissolved in 2-methyltetrahydrofuran (2 mL). Lithium diisopropylamide solution (2 M, 705.88 μL) was slowly added at -78°C under a nitrogen atmosphere. The reaction mixture was stirred at -78°C for 1 hour. Saturated aqueous ammonium chloride (2 mL) was added to the reaction mixture at -78°C, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain the title compound (188 mg).

[0995] MS m / z(ESI):554.2[M+H] + .

[0996] Step 5: Synthesis of (S)-9-chloro-4-(3-chloro-4-(3-methylpiperazin-1-yl)phenyl)-3-methyl-10H-chromeno[3,2-b]pyridin-10-one hydrochloride (Compound 58)

[0997] Intermediate 58e (30 mg, 54.11 μmol) was dissolved in methanol (1 mL), and a 2M solution of dioxane hydrochloride (270.53 μL) was added. The reaction mixture was stirred at 25°C for 2 hours. The residue after concentration was purified by HPLC (Boston Prime C18 column, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.05% hydrochloric acid) and acetonitrile (acetonitrile ratio 10%-50%) as the eluent) to afford the title compound (6.7 mg).

[0998] MS m / z(ESI):454.1[M+H] + ;

[0999] 1 H NMR(400MHz, DMSO-d6)δ=9.86-9.34(m,2H),8.90-8.67(m,1H),7.77-7.63(m,2 H),7.49(d,J=6.9Hz,2H),7.41(t,J=8.4Hz,1H),7.35-7.28(m,1H),4.05-4.00 (m,1H),3.52-3.50(m,1H),3.18(d,J=3.6Hz,1H),3.05(dd,J=4.8,7.3Hz,1H), 2.36-2.29(m,3H),2.06-1.96(m,3H),1.35(d,J=6.3Hz,1H),1.20-1.16(m,2H).

[1000] Example 59: Synthesis of 9-chloro-4-(3-methoxy-4-(piperazin-1-yl)phenyl)-3-methyl-10H-chromeno[3,2-b]pyridin-10-one hydrochloride (Compound 59)

[1001] Step 1: Synthesis of tert-butyl 4-(4-bromo-2-methoxyphenyl)piperazine-1-carboxylate (59b)

[1002] 4-Bromo-1-iodo-2-methoxybenzene (59a, 2 g, 6.39 mmol) and tert-butyl piperazine-1-carboxylate (1.07 g, 5.75 mmol) were dissolved in toluene (50 mL). Tris(dibenzylideneacetone)dipalladium (292.62 mg, 319.56 μmol), sodium tert-butoxide (1.84 g, 19.17 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (369.81 mg, 639.12 μmol) were added. The reaction mixture was incubated at 60°C under a nitrogen atmosphere for 3 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 5:1) to afford the title compound (2.11 g).

[1003] MS m / z(ESI):371.0,373.1[M+H] + .

[1004] Step 2: Synthesis of tert-butyl 4-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (59c)

[1005] Intermediate 59b (2.1 g, 5.66 mmol) was dissolved in dioxane (60 mL), and pinacol diboron (2.15 g, 8.48 mmol), potassium acetate (1.11 g, 11.31 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (413.88 mg, 565.63 μmol) were added. The reaction mixture was incubated at 100°C under a nitrogen atmosphere for 4 hours. The reaction mixture was quenched with water (60 mL) and extracted with ethyl acetate (60 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 5:1) to afford the title compound (1.99 g).

[1006] MS m / z(ESI):419.7[M+H] + .

[1007] Step 3: Synthesis of tert-butyl 4-(4-(3-(3-chloro-2-(methoxycarbonyl)phenoxy)-5-methylpyridin-4-yl)-2-methoxyphenyl)piperazine-1-carboxylate (59d)

[1008] Intermediate 59c (285.07 mg, 681.44 μmol) and Intermediate 35g (270 mg, 757.15 μmol) were dissolved in dioxane (4 mL) and water (1 mL). Potassium carbonate (313.94 mg, 2.27 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (55.40 mg, 75.72 μmol) were added. The reaction mixture was incubated at 80°C under a nitrogen atmosphere for 2 hours. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 2:1) to afford the title compound (313 mg).

[1009] MS m / z(ESI):568.7[M+H] + .

[1010] Step 4: Synthesis of tert-butyl 4-(4-(9-chloro-3-methyl-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)-2-methoxyphenyl)piperazine-1-carboxylate (59e)

[1011] Intermediate 59d (113 mg, 198.92 μmol) was dissolved in 2-methyltetrahydrofuran (1 mL). Lithium diisopropylamide (2 M, 400 μL) was slowly added dropwise at -78°C under a nitrogen atmosphere. The reaction mixture was allowed to react at -78°C under a nitrogen atmosphere for 0.5 h. The reaction mixture was quenched by the addition of saturated ammonium chloride solution (2 mL) at -78°C and concentrated under reduced pressure to remove tetrahydrofuran. The mixture was extracted with ethyl acetate (1 mL x 3). The organic phase was washed with water (3 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to dryness to obtain the title compound (100 mg).

[1012] MS m / z(ESI):536.2[M+H] + .

[1013] Step 5: Synthesis of 9-chloro-4-(3-methoxy-4-(piperazin-1-yl)phenyl)-3-methyl-10H-chromeno[3,2-b]pyridin-10-one hydrochloride (Compound 59)

[1014] Intermediate 59e (25 mg, 46.64 μmol) was dissolved in dichloromethane (0.5 mL), and dioxane hydrochloride (2 M, 467 μL) was added. The reaction mixture was incubated at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (Boston Prime C18 column, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.05% hydrochloric acid) and acetonitrile (acetonitrile ratio 5% to 45%) as the eluent) to provide the title compound (2.2 mg).

[1015] MS m / z(ESI):436.0[M+H] + ;

[1016] 1 H NMR(400MHz,DMSO-d6)δ=9.31(br s,2H),8.81(s,1H),7.82-7.70(m,1H),7.47-7.45(m,1H),7.41-7.38(m,1H),7.20-7.1 4(m,2H),7.11-7.05(m,1H),3.81(s,3H),3.34(m,4H),3.29-3.23(m,4H),2.39(s,3H).

[1017] Example 60: Synthesis of (S)-2-amino-9-fluoro-4-(4-(3-methylpiperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one (Compound 60)

[1018] Step 1: Synthesis of (S)-tert-butyl 4-(4-(5-(3-fluoro-2-(methoxycarbonyl)phenoxy)-2-nitropyridin-4-yl)phenyl)-2-methylpiperazine-1-carboxylate (60b)

[1019] Intermediate 20a (1.15 g, 2.66 mmol) and methyl 2-fluoro-6-hydroxybenzoate (60a, 677.96 mg, 3.98 mmol) were dissolved in N,N-dimethylformamide (15 mL), and potassium carbonate (1.1 g, 7.97 mmol) was added. The reaction mixture was stirred at 90°C for 16 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined. The organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 1 / 0 to 7 / 1) to obtain the title compound (1.3 g).

[1020] MS m / z(ESI):567.3[M+H] + .

[1021] Step 2: Synthesis of (S)-tert-butyl 4-(4-(2-amino-5-(3-fluoro-2-(methoxycarbonyl)phenoxy)pyridin-4-yl)phenyl)-2-methylpiperazine-1-carboxylate (60c)

[1022] Intermediate 60b (1.3 g, 2.29 mmol) was dissolved in ethanol (50 mL) and water (10 mL), and ammonium chloride (1.23 g, 22.94 mmol) and iron powder (1.28 g, 22.94 mmol) were added. The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was filtered, and the filter cake was rinsed with an appropriate amount of tetrahydrofuran. The filtrate was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain the title compound (1.12 g).

[1023] MS m / z(ESI):537.4[M+H] + .

[1024] Step 3: Synthesis of (S)-2-((6-amino-4-(4-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)phenyl)pyridin-3-yl)oxy)-6-fluorobenzoic acid (60d)

[1025] Intermediate 60c (1.12 g, 2.09 mmol) was dissolved in ethanol (15 mL) and water (3 mL), and potassium hydroxide (585.53 mg, 10.44 mmol) was added. The reaction mixture was stirred at 80°C for 5 hours. The reaction mixture was concentrated under reduced pressure to remove ethanol, and 2 M dilute hydrochloric acid was added to adjust the pH to 4-5. After filtration, the filter cake was rinsed with water (10 mL) and dried to obtain the title compound (1 g).

[1026] MS m / z(ESI):523.3[M+H] + .

[1027] Step 4: Synthesis of (S)-2-amino-9-fluoro-4-(4-(3-methylpiperazin-1-yl)phenyl)-10H-chromeno[3,2-b]pyridin-10-one (Compound 60)

[1028] Intermediate 60d (1 g, 1.91 mmol) was dissolved in concentrated sulfuric acid (10 mL). The reaction mixture was stirred at 100°C for 30 minutes. The reaction mixture was added to ice water (100 mL) at 0°C and the pH was adjusted to 8-9 with aqueous potassium hydroxide solution (10%). The reaction mixture was stirred at 0°C for 10 minutes, filtered, and the filter cake was dried to give the title compound (600 mg).

[1029] MS m / z(ESI):405.4[M+H] + ;

[1030] 1H NMR (400MHz, DMSO-d6) δ=7.75(dd,J=13.9,7.9Hz,1H),7.60(d,J=8.4Hz,2H),7.31(d,J=8.5Hz,1H),7.23–7.15(m,1H),7.09(d,J=8.5Hz,2H),6.96(s ,1H),6.50(s,2H),3.69(t,J=10.3Hz,2H),3.01(d,J=11.0Hz,1H),2.82(s, 2H), 2.67(t,J=10.5Hz,1H), 2.32(t,J=10.7Hz,1H), 1.07(d,J=6.1Hz,3H).

[1031] Example 61: Synthesis of Compound 61

[1032] Compound 57 (43.44 mg, 94.37 μmol) and intermediate 39c (39.64 mg, 102.86 μmol) were dissolved in N,N-dimethylformamide (1 mL). Sodium acetate (15.48 mg, 188.74 μmol), acetic acid (17 mg, 283.11 μmol), and sodium acetate borohydride (60 mg, 283.11 μmol) were added at 25°C, and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with water (0.2 mL), diluted with N,N-dimethylformamide (1 mL), filtered, and the filtrate was purified by HPLC (Boston Prime C18, 5 μm silica, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.05% hydrochloric acid) and acetonitrile (acetonitrile ratio 15%-55%) as the eluent) to afford the title compound (32.5 mg).

[1033] MS m / z(ESI):793.3[M+H] + ;

[1034] 1H NMR (400MHz, DMSO-d6) δ = 10.99 (br s, 1H), 10.81 (br s,1H),8.74(s,1H),7.79-7.66(m,1H),7.54-7.42(m,2H),7.39-7.16(m,5H),5.15-5.02 (m,1H),4.35(d,J=16.3Hz,1H),4.19(d,J=16.8Hz,1H),3.92(s,3H),3.78-3.75(m,2H), 3.68-3.62-(m,6H),3.33-3.17(m,6H),2.97-2.86(m,1H),2.64-2.57(m,1H),2.45-2.40 (m,J=2.4Hz,1H),2.34(s,3H),2.29-2.19(m,1H),2.14-1.93(m,3H),1.77-1.54(m,2H).

[1035] Example 62: Synthesis of Compound 62

[1036]

[1037] Compound 58 (54.01 mg, 110.05 μmol) and intermediate 39c (33.93 mg, 88.04 μmol) were dissolved in N,N-dimethylformamide (1 mL). Sodium acetate (45.14 mg, 550.24 μmol), acetic acid (6.61 mg, 110.05 μmol), and sodium acetate borohydride (34.99 mg, 165.07 μmol) were added. The reaction was stirred at 25°C for 0.5 h. Water (0.2 mL) was added to quench the reaction. The reaction was purified by HPLC (Boston Prime C18 column, 30 mm diameter, 150 mm length; eluent: a mixture of water (0.05% hydrochloric acid) and acetonitrile (17%-57% acetonitrile)) to afford the title compound (24.4 mg).

[1038] MS m / z(ESI):823.5[M+H] + ;

[1039] 1H NMR (400MHz, DMSO-d6) δ11.01(s,1H),10.64-10.29(m,1H),8.74(s,1H),7.76-7.62(m,2H),7.51(d,J=7.6Hz, 2H),7.41(d,J=7.9Hz,1H),7.31(d,J=8.6Hz,1H),7.00(s,2H),5.08(dd,J=4.3,12.9Hz,1H),4.36-4.25(m,1H) ,4.19-4.09(m,1H),3.89(s,3H),3.87-3.75(m,3H),3.58(d,J=1.0Hz,1H),3.32(s,2H),3.15-2.85(m,5H),2. 64-2.53(m,2H),2.43(d,J=13.8Hz,2H),2.32(s,3H),2.24-1.95(m,4H),1.91-1.80(m,1H),1.63-1.41(m,5H).

[1040] Example 63: Synthesis of Compound 63

[1041] Compound 59 (54.18 mg, 114.7 μmol) and intermediate 39c (35.37 mg, 91.76 μmol) were dissolved in N,N-dimethylformamide (1 mL). Sodium acetate (28.23 mg, 344.11 μmol), acetic acid (20.66 mg, 344.11 μmol) and sodium acetate borohydride (72.93 mg, 344.11 μmol) were added at 25°C, and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was quenched with water (0.5 mL), diluted with N,N-dimethylformamide (2 mL), and filtered. The filtrate was purified by high performance liquid chromatography (Boston Prime C18, 5 μm silica, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.08% ammonia and ammonium bicarbonate) and acetonitrile (acetonitrile ratio 38%-68%) as eluent) to give the title compound (14.2 mg).

[1042] MS m / z(ESI):805.3[M+H] + ;

[1043] 1H NMR (400MHz, DMSO-d6) δ=10.96(s,1H),8.72(s,1H),7.74-7.66(m,1H),7.49(d,J=7.5Hz,1H),7.36(d,J=8.6 Hz,1H),7.11(m,1H),7.07-6.98(m,2H),6.82-6.71(m,2H),5.15-4.96(m,1H),4.31-4.20(m,1H),4.10(m,1H) ,3.87(s,3H),3.82(s,3H),3.78(m,2H),3.20-3.03(m,4H),2.90(m,1H),2.81-2.69(m,2H),2.56(m,4H),2.47 -2.39(m,2H),2.39-2.33(m,3H),2.29-2.19(m,2H),2.02-1.91(m,1H),1.89-1.71(m,3H),1.34-1.18(m,2H).

[1044] Example 64: Synthesis of Compound 64

[1045] Compound 60 (30 mg, 74.18 μmol) and intermediate 39c (34.31 mg, 89.01 μmol) were dissolved in DMSO (1 mL). Sodium acetate (30.42 mg, 370.89 μmol), acetic acid (13.36 mg, 222.53 μmol), and sodium acetate borohydride (47.16 mg, 222.53 μmol) were added at 25°C. The reaction was stirred at 25°C for 1 hour. The reaction was quenched with water (0.5 mL), diluted with DMSO (2 mL), filtered, and the filtrate was purified by HPLC (Boston Prime C18 column, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.05% hydrochloric acid) and acetonitrile (acetonitrile ratio 15%-55%) as eluent) to obtain the title compound (20 mg).

[1046] MS m / z(ESI):774.7[M+H] + ;

[1047] 1H NMR(400MHz, DMSO-d6)δ=11.25–11.05(m,1H),11.00(s,1H),7.98–7.91(m,1H),7.85–7.75(m,2H),7.58–7.51( m,2H),7.44–7.37(m,3H),7.33–7.24(m,2H),5.10(dd,J=13.1,4.9Hz,1H),4.37(d,J=17.5Hz,1H),4.20(d,J=1 7.4Hz,1H),4.14–4.05(m,2H),3.92(s,3H),3.68–3.53(m,3H),3.52–3.17(m,8H),3.04–2.85(m,2H),2.60(d,J =17.1Hz,1H),2.47–2.34(m,2H),2.05–1.91(m,2H),1.78(s,2H),1.52(d,J=4.9Hz,2H),1.41(d,J=6.4Hz,1H).

[1048] Example 65: Synthesis of Compound 65

[1049] Step 1: Synthesis of intermediates 65a and 65b

[1050] Intermediate 55a (1 g) was subjected to chiral separation (DAICEL CHIRALPAK AD column, 10 μm silica, 30 mm diameter, 250 mm length; using a mixture of isopropanol (containing 0.1% ammonia) and CO2 (55%-55%) as eluent) to give intermediate 65a (385 mg, first peak) and intermediate 65b (390 mg, second peak).

[1051] The two title products were then further analyzed separately by the following chiral HPLC analysis conditions.

[1052] Intermediate 65a:

[1053] The chiral HPLC peak time was 2.094 minutes;

[1054] MS m / z(ESI):459.1[M+H] + .

[1055] Intermediate 65b:

[1056] The chiral HPLC peak time was 2.959 minutes;

[1057] MS m / z(ESI):459.1[M+H] + .

[1058] Step 2: Synthesis of intermediate 65c

[1059] Intermediate 65a (300 mg, 654.7 μmol) was dissolved in anhydrous dichloromethane (3 mL), and dioxane hydrochloride (2 M, 4 mL) was added. The reaction mixture was stirred at 25° C. for 2 hours and concentrated to dryness under reduced pressure to obtain the title compound (230 mg).

[1060] MS m / z(ESI):359.3[M+H] + .

[1061] Step 3: Synthesis of methyl 2-chloro-6-((4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-5-methylpyridin-3-yl)oxy)benzoate (65d)

[1062] Intermediate 55e (120 mg, 332.15 μmol) and Intermediate 35g (118.44 mg, 332.15 μmol) were dissolved in dioxane (5 mL) and water (1 mL). Potassium carbonate (91.81 mg, 664.30 μmol) and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (24.31 mg, 33.22 μmol) were added. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 2 hours. The reaction mixture was concentrated to dryness and purified by column chromatography (silica, petroleum ether:tetrahydrofuran = 2:1) to afford the title compound (140 mg).

[1063] MS m / z(ESI):511.1[M+H] + .

[1064] Step 4: Synthesis of 9-chloro-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-methyl-10H-chromeno[3,2-b]pyridin-10-one (65e)

[1065] Intermediate 65d (130 mg, 254.4 μmol) was dissolved in 2-methyltetrahydrofuran (2 mL), and lithium diisopropylamide solution (2 M, 510 μL) was slowly added at -78°C. The reaction mixture was stirred at -78°C under a nitrogen atmosphere for 2 hours. Saturated ammonium chloride solution (2 mL) was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was concentrated to dryness under reduced pressure to provide the title compound (140 mg).

[1066] MS m / z(ESI):479.1[M+H] + .

[1067] Step 5: Synthesis of 1-(4-(9-chloro-3-methyl-10-oxo-10H-chromeno[3,2-b]pyridin-4-yl)phenyl)piperidine-4-carbaldehyde (65f)

[1068] Intermediate 65e (140 mg, 292.30 μmol) was dissolved in formic acid (1 mL). The reaction mixture was stirred at 60°C for 1 hour and concentrated to dryness under reduced pressure to obtain the title compound (120 mg).

[1069] MS m / z(ESI):433.0[M+H] + .

[1070] Step 6: Synthesis of compound 65

[1071] Intermediate 65f (60 mg, 138.60 μmol) and intermediate 65c (65.67 mg, 166.32 μmol) were dissolved in N,N-dimethylformamide (1 mL). Acetic acid (24.97 mg, 415.80 μmol), sodium acetate (22.74 mg, 277.20 μmol), and sodium acetate borohydride (58.75 mg, 277.20 μmol) were added. The reaction was stirred at 25°C for 1 hour. The reaction was quenched with 0.5 mL of water and filtered. The filtrate was purified by HPLC (Boston Prime C18 column, 5 μm silica, 30 mm diameter, 150 mm length; eluent: a mixture of water (containing 0.05% ammonia) and acetonitrile (50%-70% acetonitrile)) to afford the title compound (7.4 mg).

[1072] MS m / z(ESI):775.2[M+H] + ;

[1073] 1H NMR(400MHz,DMSO-d6)δ=10.96(br s,1H),8.68(s,1H),7.74-7.65(m,1H),7.48(d,J=7.9Hz,1H),7.36-7.30(m,3H),7.12-7.06(m,2H ),6.83-6.74(m,2H),5.10-5.02(m,1H),4.30-4.22(m,1H),4.14-4.07(m,1H),3.86(s,3H),3.25-3 .21(m,4H),2.94-2.84(m,2H),2.83-2.75(m,2H),2.60-2.54(m,4H),2.44-2.37(m,2H),2.33(s,3 H),2.28-2.23(m,2H),2.04-1.92(m,2H),1.91-1.82(m,2H),1.82-1.75(m,1H),1.33-1.19(m,2H).

[1074] Example 66: Synthesis of Compound 66

[1075] Step 1: Synthesis of intermediate 66a

[1076] Intermediate 65b (300 mg, 654.7 μmol) was dissolved in anhydrous dichloromethane (3 mL), and dioxane hydrochloride (2 M, 4 mL) was added. The reaction mixture was stirred at 25° C. for 2 hours and concentrated to dryness under reduced pressure to obtain the title compound (225 mg).

[1077] MS m / z(ESI):359.3[M+H] + .

[1078] Step 2: Synthesis of compound 66

[1079] Intermediate 65f (60 mg, 138.60 μmol) and intermediate 66a (65.67 mg, 166.32 μmol) were dissolved in N,N-dimethylformamide (1 mL). Acetic acid (24.97 mg, 415.80 μmol), sodium acetate (22.74 mg, 277.20 μmol), and sodium acetate borohydride (58.75 mg, 277.20 μmol) were added. The reaction was stirred at 25°C for 1 hour. The reaction was quenched with 0.5 mL of water and filtered. The filtrate was purified by HPLC (Boston Prime C18 column, 5 μm silica, 30 mm diameter, 150 mm length; eluent: a mixture of water (containing 0.05% ammonia) and acetonitrile (50%-70% acetonitrile)) to afford the title compound (9.5 mg).

[1080] MS m / z(ESI):775.3[M+H] + ;

[1081] 1 H NMR(400MHz,DMSO-d6)δ=10.96(br s,1H),8.67(s,1H),7.74-7.64(m,1H),7.47(d,J=7.5Hz,1H),7.36-7.28(m,3H),7.13-7.05( m,2H),6.83-6.69(m,2H),5.11-5.00(m,1H),4.31-4.22(m,1H),4.16-4.05(m,1H),3.86(s,3H ),3.26-3.17(m,4H),2.92-2.84(m,1H),2.83-2.73(m,2H),2.64-2.52(m,5H),2.47-2.35(m, 2H),2.33(s,3H),2.28-2.20(m,2H),2.07-1.92(m,2H),1.91-1.72(m,3H),1.32-1.17(m,2H).

[1082] Biological activity and related properties test examples

[1083] Test Example 1: TR-FRET Binding Assay

[1084] The assay was performed using the BRM TR-FRET Assay Kit (BPS Bioscience, cat#40342). 3X BRD TR-FRET Assay buffer was diluted to 1X, and BRM (1:1000), Bromodomain Ligand 2 (1:40), Tb-labeled donor (1:100), and Dye-labeled acceptor (1:100) were diluted accordingly. PFI-3 (Selleck, CAS No. 1819363-80-8) served as a positive control, DMSO as a negative control, and a BRM-free control as a blank control. Test compounds were prepared in DMSO to a 10 mM stock solution. A 3-fold serial dilution of each stock solution was performed using DMSO over nine concentration points. 2 μL of the stock solution was transferred to 198 μL of ddH2O and diluted again 100-fold. Transfer 2 μL of the diluted test compound solution and 3 μL of the diluted BRM solution to a 96-well white plate (Cisbio, cat# 66PL96025) and incubate at room temperature for 10 minutes. Subsequently, 5 μL of diluted Bromodomain Ligand 2, 5 μL of Tb-labeled donor, and 5 μL of Dye-labeled acceptor solution were added to each well. The final concentrations of the compounds were 10,000, 3,333.33, 1,111.11, 370.37, 123.46, 41.15, 13.72, 4.57, and 1.52 nM, respectively. The cells were shaken for 30 seconds and briefly centrifuged at 1,000 rpm. After incubation at room temperature for 30 minutes, the cells were analyzed using an Envision multi-function microplate reader (PerkinElmer). The TR-FRET ratio (655 nm / 622 nm) was analyzed using GraphPad software. The concentration-effect curves were fitted with a nonlinear four-parameter curve, and the EC values ​​of the compounds were calculated. 50 , the calculation method is as follows:

[1085] Among them: FRET Sample : FRET value of each well in the compound addition group;

[1086] FRET Blank : FRET value of blank control group;

[1087] FRET DMSO : FRET value of negative control group;

[1088] The binding activity of the compounds of the present disclosure to BRM was tested according to the above test method (EC 50), some of the results are summarized in Table 1.

[1089] Table 1

[1090] Test Example 2: Detecting the BRM and BRG1 protein degradation activity of compounds using HiBiT detection technology

[1091] 1. Cell line construction:

[1092] HiBiT detection technology was used to detect the effect of compounds on the degradation of BRM and BRG1 proteins. The HiBiT tag was inserted after the start codon or before the stop codon of BRM and BRG1 proteins. When the compound degraded BRM or BRG1 protein, the degradation of BRM and BRG1 protein could be quantified by detecting the expression level of the HiBiT tag. According to the insertion site of HiBiT, sgRNA and donor DNA of BRM and BRG1 were designed; Cas9 transfection reagent (TrueCut TM Cas9 Protein v2, A36498, Invitrogen; Lipofectamine TM CRISPRMAX TM Cas9 transfection reagent, CMAX00003, Invitrogen; Opti-MEM TM I Reduced Serum Medium, 31985070, Thermofisher), the required amounts of various reagents, sgRNA, and donor DNA were calculated according to the amount of transfection reagent required for a 6-well plate in the instruction manual, and transfection was performed on SW1573 cells according to the Cas9 transfection protocol. After 24 hours, the culture medium was replaced with normal culture medium; culture was continued until 3 days after transfection, and each group of cells was expanded, and the expression level of the HiBiT tag in the pool was detected using the Nano Glo HiBiT Lytic Detection System (N3050, Promega); the cell pool with high HiBiT tag expression was seeded in a 96-well plate as a monoclonal clone, and the expression level of the HiBiT tag in the monoclonal clone was detected using the Nano Glo HiBiT Lytic Detection System (N3050, Promega); if the fluorescence value of the HiBiT tag amplified from the monoclonal cells is high at this time, it indicates that this group of cells may have successfully linked to the HiBiT tag. These monoclonal cells were amplified and sequenced to confirm that the HiBiT sequence was successfully connected and homozygous, and then used for subsequent degradation experiments.

[1093] 2. Cell Seeding and Compound Administration:

[1094] SW1573 HiBiT knock-in cells constructed using the above method were digested and dispersed from the cell culture flask, resuspended in culture medium (DMEM medium (Thermo Fisher, Catalog No. 11995073) containing 10% FBS (Thermo Fisher, Catalog No. 10099141C) and 1% Penicillin-Streptomycin Solution (Thermo Fisher, Catalog No. 15140-122)), and the cell concentration was adjusted (SW1573 HiBiT knock-in cells, 9000 cells / well) and seeded in 384-well plates and cultured overnight at 37°C, 5% CO2. The test compound was prepared into a 10 mM stock solution in DMSO, and a small amount was diluted to 1 mM in DMSO for later use. Prepare 1 mM compound solution and DMSO, use Echo 650 Series Acoustic Liquid Handlers (Beckman, model Echo 650) to perform a 10-point 3-fold serial dilution of the 1 mM test compound solution (compounds 5 and 6), and transfer 30 nL of the compound to a 384-well cell culture plate containing culture medium and dilute 1000-fold to obtain final compound concentrations of 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15 and 0.05 nM, respectively. Alternatively, a 10 mM solution of the test compound (compounds 14, 15, 22-31, 39-46, 49-53, and 55) was serially diluted 3-fold over 10 concentration points. 30 nL of the compound was transferred to a 384-well cell culture plate containing culture medium and diluted 1000-fold to obtain final compound concentrations of 10,000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52, and 0.51 nM, respectively. The 384-well cell culture plate containing the compound was incubated at 37°C, 5% CO2 for 16-18 hours.

[1095] 3. Protein degradation detection:

[1096] 15 μL of reaction solution (Nano Glo HiBiT Lytic Detection System (N3050, Promega) configured according to the protocol) was added to each well of a 384-well plate, incubated at room temperature for 10 min, and scanned and analyzed using an Envision multi-function microplate reader (purchased from PerkinElmer).

[1097] 4. Degradation of DC 50 calculate

[1098] EXCEL XLfit5.4.0 was used to calculate the protein degradation rate at each concentration. Each concentration point had 2 replicates to generate a protein degradation curve and calculate DC. 50 and D max .

[1099] Protein degradation rate (%) = (High control - corresponding well reading) / (High control - Low control) * 100%

[1100] High control = 0.1% DMSO, defined as 0% degradation

[1101] Low control = PBS (no cells), defined as 100% degradation

[1102] The degradation curve is generated by the degradation rate of 10 concentration points, and the degradation DC is calculated 50 and D max The results are shown in Table 2.

[1103] Table 2

[1104] The activity of the compounds of the present disclosure in degrading BRG1 of SW1573 cells is weaker than the activity in degrading BRM of SW1573 cells, and they can selectively degrade BRM of SW1573 cells.

[1105] Test Example 3: Using In-Cell Western blotting to detect the degradation activity of compounds on BRM and BRG1 proteins in Hela cells

[1106] Experimental method: HeLa cells (purchased from ATCC) were digested and blown off from the cell culture flask, resuspended in culture medium (DMEM medium (Thermo Fisher, Catalog No. 11995073) containing 10% FBS (Thermo Fisher, Catalog No. 10099141C) and 1% Penicillin-Streptomycin Solution (Thermo Fisher, Catalog No. 15140-122)), and the cell concentration was adjusted (HeLa: 5000 cells / well) and seeded in 384-well plates and cultured overnight at 37°C, 5% CO2. The test compound was prepared into a 10 mM stock solution in DMSO and the cells were handled using Echo 650 Series Acoustic Liquid Handlers (Beckman, Model Echo 650) A 10 mM solution of the test compound was serially diluted 3-fold over 10 concentration points. 30 nL of the compound was transferred to a 384-well cell culture plate containing culture medium and diluted 1000-fold to obtain final compound concentrations of 10,000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52, and 0.51 nM, respectively. The 384-well plate containing the compound was incubated at 37°C, 5% CO2 for 16-18 hours.

[1107] Add 50 μL of pre-cooled PBS (purchased from Hyclone, product number SH30256.01) to each well of a 384-well plate for washing; discard the solution, add 50 μL of 4% paraformaldehyde fixative (purchased from Biosharp, product number BL539A), and incubate at room temperature for 20 minutes; discard the fixative, add 50 μL of 0.1% Triton X-100 (purchased from SIGMA, product number 93443-100ML) PBS solution, and incubate at room temperature for 30 minutes; discard the solution, add 50 μL of Li-Cor blocking solution. Buffer blocking solution (purchased from Li-Cor, product number 927-70001), incubate at room temperature for 1 hour; discard the blocking solution, add 50 μL primary antibody (rabbit anti-BRM / BRG1 (1:500; BRM antibody purchased from CST, product number 11966S; BRG1 antibody purchased from CST, product number 49360S); mouse anti-α-Tubulin (1:2000, purchased from SIGMA, product number T6074-200UL)), and incubate at 4°C overnight.

[1108] Discard the primary antibody, add 50 μL PBS to wash 4 times; discard the solution, add 50 μL secondary antibody (Anti-rabbit IgG (H+L) (DyLight TM680Conjugate) (purchased from CST, product number 5366S); Anti-mouse IgG (H+L) (DyLight TM 800 4X PEG Conjugate (purchased from CST, Cat. No. 5257S) (1:5000) was incubated at room temperature in the dark for 1-1.5 hours. The secondary antibody was discarded, and the membrane was washed four times with 50 μL PBS and discarded. Scanning was performed using a Sapphire Dual-Mode Multispectral Laser Imaging System (purchased from Azure Biosystems).

[1109] Calculation of degradation DC 50 :

[1110] Azure spot software was used to analyze images obtained from a Sapphire dual-mode multispectral laser imaging system. The images were opened, the red (680 channel) and green (800 channel) layers separated, and each well was framed with a box of the appropriate aperture. Fluorescence readings were calculated for each well. Wells dosed with 30 μM CABA1 (MedChemExpress, Cat. No. HY-128359) were set as negative controls to correct for background values ​​across the entire scan. The processed images and data were then saved and transferred to a computer for analysis.

[1111] The red (680 channel, target protein, including BRM and BRG1) fluorescence reading was divided by the green (800 channel, internal reference α-Tubulin (1:2000, purchased from SIGMA, catalog number T6074-200UL)) fluorescence reading for normalization, and then the protein degradation rate of each concentration was calculated separately, with 2 replicates for each concentration point. The protein degradation curve was generated and DC was calculated based on the protein degradation rate of the test compound at 10 concentration points using EXCEL XLfit5.4.0. 50 and D max .

[1112] Target protein degradation rate (%) = 100% - 100% * Normalized reading of the corresponding well / Normalized High control reading

[1113] Normalized reading = target protein / internal reference α-Tubulin

[1114] High control = 0.1% DMSO, defined as 0% degradation

[1115] Negative control = 30μM CBI1 dosing well, defined as 100% degradation

[1116] The degradation activity of the compounds of the present disclosure on Hela cell BRM and BRG1 was...

Claims

1. A compound represented by formula (I)-1 or formula (I)-2 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, represents a single or double bond; X is selected from -NR 4 (CH2) r -、-O(CH2) r -or-S(CH2) r -; Z is selected from C1-C3 alkylene, C2-C3 alkenylene, C2-C3 alkynylene, O, OCHR q , S, SCHR q NR q NR q CHR q ', C(O) or C(O)NR q The C1-C3 alkylene, C2-C3 alkenylene or C2-C3 alkynylene is optionally substituted by one or more R 6a replace; Ring A is a benzene ring or a 5-6 membered heteroaromatic ring; R q , R q ' is independently selected from H, deuterium, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group is optionally replaced by one or more R 7a replace; R 1 Selected from deuterium, OH, halogen, CN, COOH, NO2, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl or 4-8 membered heterocyclic group, the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl or 4-8 membered heterocyclic group is optionally substituted by one or more R 1a replace; R 2 is selected from deuterium, halogen, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -C(O)R a 、-C(O)OR a 、-C(O)NHR a OR-P(O)(OR b )2, wherein the OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl is optionally replaced by one or more R 2a Replacement, R a and R b Each of the above-mentioned C1-C6 alkyl, NH2, C3-C6 cycloalkyl or 4-8 membered heterocyclic group is independently selected from H, C1-C6 alkyl, NH2, C3-C6 cycloalkyl or 4-8 membered heterocyclic group, wherein the C1-C6 alkyl, NH2, C3-C6 cycloalkyl or 4-8 membered heterocyclic group is optionally replaced by one or more R 2a replace; R 3 Selected from C3-C6 cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group, the C3-C6 cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group is optionally substituted by one or more R 3a replace; Or, when t is 1 or 2, R 3 With an R 2 and their respective atoms together form a 5-10 membered heteroaromatic ring or a 5-14 membered heterocyclic ring, wherein the 5-10 membered heteroaromatic ring or the 5-14 membered heterocyclic ring is optionally substituted by one or more R 3b replace; R 4 is selected from hydrogen, C1-C6 alkyl, C(O)(C1-C6 alkyl), C3-C6 cycloalkyl, C(O)(C3-C6 cycloalkyl), C6-C 10 Aryl, C(O)-(C6-C 10 aryl), 5-10 membered heteroaryl, C(O)-(5-10 membered heteroaryl), 4-8 membered heterocyclyl or C(O)-4-8 membered heterocyclyl, the C1-C6 alkyl, C(O)(C1-C6 alkyl), C3-C6 cycloalkyl, C(O)(C3-C6 cycloalkyl), C6-C 10 Aryl, C(O)-(C6-C 10 aryl), 5-10 membered heteroaryl, C(O)-(5-10 membered heteroaryl), 4-8 membered heterocyclyl or C(O)-4-8 membered heterocyclyl, optionally substituted with one or more R 4a replace; R 1a , R 2a , R 3a , R 3b , R 4a , R 6a , R 7a are independently selected from deuterium, OH, CN, halogen, =O, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclyl, C6-C 10 aryl or 5-10 membered heteroaryl, the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more R c replace; R c is selected from halogen, OH, NH2, =O, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl or 4-8 membered heterocyclyl; r, t are independently selected from 0, 1 or 2; f is selected from 0 or 1; n is selected from 0, 1, 2, 3 or 4.

2. The compound of formula (I)-1 or formula (I)-2 according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, wherein: Ring A is a benzene ring or a 6-membered heteroaromatic ring, or, Ring A is a benzene ring.

3. The compound according to claim 1 or 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: r is selected from 0 or 1; or, r is 0, that is, X is selected from NR 4 , O or S.

4. The compound according to any one of claims 1 to 3, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: X is selected from NR 4 , O or S, R 4 is selected from hydrogen or optionally substituted by one or more R 4a Substituted with the following groups: C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl or 4-8 membered heterocyclyl; or, X is selected from NR 4 , O or S, R 4 is selected from hydrogen or optionally substituted by one or more R 4a Substituted C1-C6 alkyl; or, X is selected from NR 4 , O or S, R 4 is selected from hydrogen or C1-C6 alkyl; or, X is selected from NH, NCH3, O or S; or, X is selected from NH, O or S; or, X is selected from NH or O; or, X is selected from O.

5. The compound according to any one of claims 1 to 4, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: Z is selected from O, OCHR q , S, SCHR q NR q NR q CHR q ', C(O) or C(O)NR q ; Alternatively, Z is selected from O or NR q ; Or, Z is selected from O.

6. The compound according to any one of claims 1 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 4a is selected from deuterium, OH, halogen, =O, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group is optionally replaced by R c Replace; or, R 4a Selected from deuterium, OH, halogen, =O, NH2, C1-C6 alkyl, C1-C6 alkyl-O-, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

7. The compound according to any one of claims 1 to 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R q , R q ' is independently selected from H, deuterium or C1-C6 alkyl, the C1-C6 alkyl is optionally replaced by one or more R 7a Replace; or, R q , R q ' is independently selected from H or deuterium.

8. The compound according to any one of claims 1 to 7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: f is 0.

9. The compound according to any one of claims 1 to 8, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from deuterium, OH, halogen, CN, COOH, NO2, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group is optionally replaced by one or more R 1a Replace; or, R 1 is selected from deuterium, OH, halogen, NH2 or C1-C6 alkyl, wherein the OH, NH2 or C1-C6 alkyl is optionally replaced by one or more R 1a Replace; or, R 1 is selected from deuterium, OH, halogen, NH2, C1-C6 alkyl, C1-C6 alkyl-O-, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2; or, R 1 is selected from OH, NH2 or halogen such as F, Cl, Br; or, R 1 Selected from halogens such as F, Cl, Br.

10. The compound according to any one of claims 1 to 9, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: n is selected from 0, 1 or 2; or, n is selected from 0 or 1; Alternatively, n is selected from 1.

11. The compound according to any one of claims 1 to 10, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 Selected from deuterium, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, -C(O)R a OR-P(O)(OR b )2, wherein the OH, NH2, C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by one or more R 2a Replacement, R a and R b independently selected from H or optionally one or more R 2a Substituted C1-C6 alkyl, R 3 Selected from one or more R 3a Substituted with the following groups: C3-C6 cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group, or when t is 1 or 2, R 3 With an R 2 and the atoms to which they are attached together form a 3b substituted 5-6 membered heteroaromatic ring or 5-14 membered heterocyclic ring; or, R 2 Selected from deuterium, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, -C(O)R a OR-P(O)(OR b )2, the NH2, C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by one or more R 2a Replacement, R a and R b independently selected from H or optionally one or more R 2a Substituted C1-C6 alkyl, R 3 Selected from one or more R 3a Substituted with the following groups: C3-C6 cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group, or when t is 1 or 2, R 3 With an R 2 and the atoms to which they are attached together form a 3b Substituted 5-6 membered heteroaromatic ring or 5-14 membered heterocyclic ring.

12. The compound according to any one of claims 1 to 11, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 Selected from deuterium, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, -C(O)R a OR-P(O)(OR b )2, wherein the OH, NH2, C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by one or more R 2a Replacement, R a and R b independently selected from H or optionally one or more R 2a Substituted C1-C6 alkyl, R 3 Selected from one or more R 3a Substituted with the following groups: C3-C6 cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl; or, R 2 Selected from deuterium, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, -C(O)R a OR-P(O)(OR b )2, the NH2, C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by one or more R 2a Replacement, R a and R b independently selected from H or optionally one or more R 2a Substituted C1-C6 alkyl, R 3 Selected from one or more R 3a Substituted with the following groups: C3-C6 cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl; or, R 2 is selected from deuterium, OH, NH2, C1-C6 alkyl or C3-C6 cycloalkyl, wherein the OH, NH2, C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by one or more R 2a Replacement, R 3 Selected from one or more R 3a Substituted with the following groups: C6-C 10 aryl or 5-10 membered heteroaryl; or, R 2 is selected from deuterium, OH, NH2 or C1-C6 alkyl, wherein the OH, NH2 or C1-C6 alkyl is optionally replaced by one or more R 2a Replacement, R 3 Selected from one or more R 3a Substituted with the following groups: C6-C 10 aryl or 5-10 membered heteroaryl; or, R 2 is selected from deuterium, NH2, C1-C6 alkyl, wherein the C1-C6 alkyl is optionally replaced by one or more R 2a Replacement, R 3 Selected from one or more R 3a Substituted with the following groups: C6-C 10 Aryl or 5-10 membered heteroaryl.

13. The compound according to any one of claims 1 to 11, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: t is 1 or 2, R 3 With an R 2 and the atoms to which they are attached together form a 3b substituted 5-6 membered heteroaromatic ring or 5-14 membered heterocyclic ring; or, t is 1 or 2, R 3 With an R 2 and the atoms to which they are attached together form a 3b substituted 5-6 membered heteroaromatic ring or 5-10 membered heterocyclic ring; or, t is 1 or 2, R 3 With an R 2 and the atoms to which they are attached together form a 3b substituted 5-10 membered heterocyclic ring; or, t is 1, R 3 With R 2 and the atoms to which they are attached together form a 3b Substituted 5-10 membered heterocyclic ring.

14. The compound or stereoisomer thereof or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein the compound of formula (I)-1 or formula (I)-2 or stereoisomer thereof or pharmaceutically acceptable salt thereof is selected from the following compounds or stereoisomers thereof or pharmaceutically acceptable salts thereof:

15. The compound represented by formula (II) or its stereoisomer or its pharmaceutically acceptable salt, TL-Linker-DIM (II) in, TL is the residue formed after the compound of formula (I)-1 according to claim 1 loses one hydrogen atom, that is, The ring A, R 1 , R 2 , R 3 , X, Z, n, t and f are as defined in claim 1; or, TL is a residue formed after the compound of formula (I)-2 according to claim 1 loses one hydrogen atom, that is, The ring A, R 1 , R 2 , R 3 , X, Z, n, t and f are as defined in claim 1; The DIM is a ligand compound capable of binding to E3 ubiquitin ligase; The Linker is a connecting group that covalently binds a TL and a DIM.

16. The compound of formula (II) according to claim 15, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The DIM is selected from CRBN ligands, ie, the binding portion that binds to cereblon type E3 ubiquitin ligase, or VHL ligands, ie, the binding portion that binds to Von Hippel-Lindau type E3 ubiquitin ligase; or, the DIM is selected from CRBN ligands.

17. The compound of formula (II) according to claim 15 or 16, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: TL by R 3 Connected to Linker, and TL is The ring A, R 1 , R 2 , R 3 , X, Z, n, t and f are as defined in claim 15; or, TL is The R 1 , R 2 , R 3 , x, n and t are as defined in claim 15.

18. The compound of formula (II) according to claim 15 or 16, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: TL by R 3 Connected to Linker, and TL is The ring A, R 1 , R 2 , R 3 , X, Z, n, t and f are as defined in claim 15; or, TL is The R 1 , R 2 , R 3 , x, n and t are as defined in claim 15.

19. The compound of formula (II) according to any one of claims 15 to 18, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The TL is 20. The compound of formula (II) according to any one of claims 15 to 19, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The Linker is selected from: -L A -、-L B -、-R 1L -、-R 2L -、-Q 1 -、-Q 2 -、 Where: -L A -、-L B - independently selected from a bond, -O-, -S-, -NR 3’ -、-CR 4’ R 5’ -、-CR 4’ R 5’ -NR 3’ -、-CR 4’ R 5’ -O-, -C(O)-, -CR 4’ R 5’ -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -C(O)O- or -C(O)NR 6’ -; R 1L and R 2L are independently selected from a bond, -C(O)-, alkylene, heteroalkylene, alkenylene and alkynylene, wherein the alkylene, heteroalkylene, alkenylene and alkynylene are optionally substituted with a group selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =O, cycloalkyl, heterocyclyl, aryl, heteroaryl; Q 1 , Q 2 , Q 3 and Q 4 Each of the cycloalkyl, heterocyclyl, aryl, heteroaryl or cycloalkenyl groups is independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =O, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 3’ is selected from the group consisting of H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R 4’ and R 5’ Each is independently selected from H, halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =O, cycloalkyl, heterocyclyl, aryl or heteroaryl; R 6’ is selected from H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

21. The compound of formula (II) according to any one of claims 15 to 20, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The DIM is selected from the structure shown in formula (DIM-1) or (DIM-2): in: Selected from Y is a bond, or Y is selected from Y A , O, NH, NR E 、C(O)O、C(O)NR E '、NR E 'C(O),Y A -NH, Y A -NR E , Y A -C(O),Y A -C(O)O、Y A -OC(O),Y A -C(O)NR E ' or Y A -NR E 'C(O), wherein said Y A is selected from C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene; X' is selected from C(O) or C(R A )2;X A -X B Selected from C(R A )=NorC(R A )2-C(R A )2; Every R A independently selected from H or C1-C3 alkyl, the C1-C3 alkyl being optionally substituted by C6-C 10 Aryl or 5-10 membered heteroaryl substituted; Every R A 'Independently selected from C1-C3 alkyl; Every R B are independently selected from H or C1-C3 alkyl, or two R B Together with the atoms to which it is attached, it forms C(O), C3-C6 cycloalkyl, C3-C6 cycloalkenyl or 4-6 membered heterocyclyl; R C Selected from H, halogen or C1-C3 alkyl; Every R D Independently selected from halogen, NO2, NH2, OH, COOH, C1-C6 alkyl or C1-C6 alkoxy; Every R E independently selected from C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C(O)-C1-C6 alkyl, C(O)-C2-C6 alkenyl, C(O)-C3-C8 cycloalkyl or C(O)-3-8 membered heterocycloalkyl, wherein R E Optionally substituted by a group selected from: halogen, N(R a )2. NHC(O)R a 、NHC(O)OR a , OR b , C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 The aryl or 5-10 membered heteroaryl is optionally further substituted by a group selected from the group consisting of halogen, NH2, CN, NO2, OH, COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; R E ' is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted by a group selected from the following: halogen, N(R a )2. NHC(O)R a 、NHC(O)OR a , OR b , C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 The aryl or 5-10 membered heteroaryl is optionally further substituted by a group selected from the group consisting of halogen, NH2, CN, NO2, OH, COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; Every R a Independently selected from H or C1-C6 alkyl; R b Selected from H or p-toluenesulfonyl; t' is selected from 0 or 1; m is selected from 0, 1, 2 or 3; p is selected from 0, 1 or 2.

22. The compound of formula (II) according to any one of claims 15 to 20, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The DIM is selected from the structure shown in formula (DIM-11): in: X C is selected from a bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R'-, -P(O)(OR')-, -P(O)(NR'2)-, -C(O)-, -C(S)- or X D is selected from C, N or Si; X E is selected from a bond, -C(R')2-, -NR'-, -O-, -S- or -Si(R')2-; R F Does not exist, or R F is selected from H, deuterium, halogen, CN, -OR', -SR', -S(O)R', -S(O)2R', -N(R')2, -P(O)(OR')2, -P(O)(N(R')2)OR', -P(O)(N(R')2)2, -Si(OH)2R', -Si(OH)(R')2, -Si(R')3 or C1-C4 alkyl; Each R G is independently selected from H, deuterium, R H , halogen, CN, -NO2, -OR’, -SR’, -N(R’)2, -Si(R’)3, -S(O)2R’, -S(O)2N(R’)2, -S(O)R’, -C(O)R’, -C(O)OR’, -C(O)N(R’)2, -C(O)N(R’)OR’, -C(R’)2N(R’)C(O)R’, -C(R’)2N(R’)C(O)N(R’)2, -OC(O)R’, -OC(O)N(R’)2, -OP(O)(R’)2, -OP(O)(OR’)2, -OP(O)(OR’)N(R’)2, -OP(O)(N(R’)2)2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)N(R’)2, -N(R’)S(O)2R’, -N(R’)P(O)(R’)2, -N(R’)P(O)(OR’)2, -N(R’)P(O)(OR’)N(R’)2 or -N(R’)P(O)(N(R’)2)2; Every R H Independently selected from C1-C6 alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl; Ring E, Ring F, and Ring G are independently selected from phenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl, 5-7 membered heterocyclyl, or 5-6 membered heteroaryl, wherein ring E, ring F and ring G are each optionally further substituted with =O; L 1 is selected from a bond, a C1-C3 alkylene, a C2-C3 alkenylene or a C2-C3 alkynylene, wherein any one or two methylene groups in the C1-C3 alkylene, C2-C3 alkenylene or C2-C3 alkynylene are optionally replaced by -O-, -C(O)-, -C(S)-, -C(R')2-, -CH(R')-, -C(F)2-, -N(R')-, -S- or -S(O)2-; Each R' is independently selected from H, C1-C6 alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, or two R' and the atoms to which they are attached together form a 4-7 membered heterocyclyl or 5-6 membered heteroaryl; q is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

23. A compound of formula (II) according to any one of claims 15 to 20, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The DIM is selected from the structure shown in formula (DIM-12): Wherein: Ring H is selected from C5-C9 cycloalkyl, C5-C9 cycloalkenyl or 5-9 membered heterocyclyl, wherein the C5-C9 cycloalkyl, C5-C9 cycloalkenyl or 5-9 membered heterocyclyl is optionally substituted by =O; k is selected from 0, 1, 2, 3 or 4; X C , X D , X E , R F , R G , L 1 and Ring E is as defined in claim 22.

24. A compound of formula (II) according to any one of claims 15 to 20, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The DIM is selected from the structure shown in formula (DIM-13): Among them, the X C , X D , X E , R F , R G , L 1 , ring E and k are as defined in claim 23.

25. The compound of formula (II) according to any one of claims 15 to 24, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound has a structure selected from one of the following:

26. A pharmaceutical composition comprising a compound of formula (I)-1 or (I)-2 according to any one of claims 1 to 14, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a compound of formula (II) according to any one of claims 15 to 25, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

27. Use of a compound of formula (I)-1 or formula (1)-2 as described in any one of claims 1-14, or its stereoisomer or its pharmaceutically acceptable salt, or a compound of formula (II) as described in any one of claims 15-25, or its stereoisomer or its pharmaceutically acceptable salt, or a pharmaceutical composition as described in claim 26 in the preparation of a medicament for preventing or treating a BRM-mediated disease, wherein the BRM-mediated disease is preferably a tumor.

28. A compound of formula (I)-1 or formula (I)-2 or its stereoisomer or its pharmaceutically acceptable salt as described in any one of claims 1-14, or a compound of formula (II) or its stereoisomer or its pharmaceutically acceptable salt as described in any one of claims 15-25, or a pharmaceutical composition as described in claim 26 for preventing or treating a BRM-mediated disease, wherein the BRM-mediated disease is preferably a tumor.

29. Use of a compound of formula (I)-1 or formula (I)-2 as described in any one of claims 1-14, or its stereoisomer, or its pharmaceutically acceptable salt, or a compound of formula (II) as described in any one of claims 15-25, or its stereoisomer, or its pharmaceutically acceptable salt, or a pharmaceutical composition as described in claim 26 in preventing or treating a BRM-mediated disease, wherein the BRM-mediated disease is preferably a tumor.

30. A method for treating a disease mediated by BRM, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I)-1 or (I)-2 as described in any one of claims 1 to 14, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a compound of formula (II) as described in any one of claims 15 to 25, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 26, wherein the BRM-mediated disease is preferably a tumor, and optionally wherein, The individual is a mammal, preferably a human.