Heteroaryl-substituted bicyclic compounds and their applications

Abstract

A series of heteroaryl-substituted bicyclic compounds and their applications are disclosed, specifically the compounds shown in formula (P), their stereoisomers and pharmaceutically acceptable salts.

Description

[0001] This invention claims the following priority:

[0002] CN202210457171.1, application date: April 27, 2022;

[0003] CN202210632218.3, application date: June 6, 2022;

[0004] CN202210818491.5, application date: July 11, 2022;

[0005] CN202210983311.9, application date: August 16, 2022;

[0006] CN202211177697.0, application date: September 26, 2022;

[0007] CN202211429833.0, application date: November 4, 2022;

[0008] CN202211618983.6, application date: December 15, 2022. Technical Field

[0009] This invention relates to a series of heteroaryl-substituted bicyclic compounds and their applications, particularly to compounds of formula (P), their stereoisomers, and pharmaceutically acceptable salts thereof. Background Art

[0010] Hematopoietic progenitor kinase 1 (HPK1) is an immunosuppressive regulatory kinase, a member of the mammalian serine / threonine kinase superfamily (SLK), belonging to the microtubule-associated protein family, and is expressed in a restricted manner in hematopoietic stem cells. HPK1 is a negative signaling regulator of the T cell receptor (TCR). Upon TCR activation, cytoplasmic HPK1 is recruited to the vicinity of the cell membrane. Activated HPK1 phosphorylates the adaptor protein SLP76, thereby activating SLP76 as a docking site for the negative regulatory protein 14-3-3π, ultimately leading to instability of the TCR signaling complex and downregulating TCR signaling.

[0011] HPK1 can inhibit the proliferation, invasion, and metastasis of lung cancer cells; HPK1 deficiency also plays an important role in the pathogenesis of pancreatic ductal carcinoma, indicating that HPK1 kinase has an extremely important role in disease treatment. Therefore, the discovery of small molecule inhibitors of HPK1 kinase is an urgent need in current drug development. Our aim is to develop highly active HPK1 inhibitors for tumor treatment. Summary of the Invention

[0012] This invention provides compounds of formula (P), their stereoisomers, or pharmaceutically acceptable salts thereof.

[0013]

[0014] in,

[0015] X is selected from O and S;

[0016] Y is selected from C(R8)2 and C(R8)=C(R8);

[0017] T is selected from CH and N;

[0018] T1 is selected from CH and N;

[0019] T2 and T3 are independently selected from CH, CF and N, respectively;

[0020] T4 is selected from CR6 and N;

[0021] R2 is selected from 5-membered 6-membered heteroaryl groups, wherein the 5-membered 6-membered heteroaryl group is optionally surrounded by 1, 2, or 3 R groups. a replace;

[0022] R3 and R4, along with the carbon atoms bonded to them, constitute...

[0023] E and E1 are independently selected from -C(R7)2-, -O-, and -N(R5)-, respectively;

[0024] n and m are independently selected from 0 and 1, respectively;

[0025] R5 is selected from H and C. 1-3 Alkyl, the C 1-3 Alkyl groups may be optionally substituted with 1, 2, or 3 Rs;

[0026] R6 is selected from H, halogens, and -C. 1-3 Alkyl-C 1-3 Alkylamino;

[0027] R7 is selected from H, F, Cl, Br, I, OH, NH2, C 1-3 Alkyl and C 1-3 Alkoxy;

[0028] R8 is selected from H and D;

[0029] Each R a Selected independently from D, halogen, and C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3The alkoxy groups can be independently and optionally substituted by 1, 2 or 3 R groups;

[0030] Each R b Each element is independently selected from H, D, OH, halogens, and C. 1-3 Alkyl, the C 1-3 The alkyl group may be optionally replaced by one, two, or three halogens;

[0031] Or, 2 Rs b The carbon atoms that are connected to them form C=O or cyclopropyl groups;

[0032] Each R is independently selected from halogens and D.

[0033] In some embodiments of the present invention, the above-mentioned compound, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from:

[0034]

[0035] in,

[0036] X, T, T1, T2, T3, T4, R2, R3, R4 and R8 are as defined in this invention.

[0037] In some embodiments of the present invention, the above-mentioned R... a The variables are independently selected from D, F, CH3 and CD3, respectively, and other variables are as defined in this invention.

[0038] In some embodiments of the present invention, the above-mentioned R... a The variables are independently selected from D, F and CH3, respectively, and other variables are as defined in this invention.

[0039] In some embodiments of the present invention, the above-mentioned R... b The halogens are independently selected from H, D, F, Cl, Br, I, OH, CH3, CH2CH3 and CH2CH2CH3, wherein CH3, CH2CH3 and CH2CH2CH3 are optionally substituted by 1, 2 or 3 halogens, and other variables are as defined in this invention.

[0040] In some embodiments of the present invention, the above-mentioned R... b The halogens are independently selected from H, D, CH3, CH2CH3 and CH2CH2CH3, respectively, wherein CH3, CH2CH3 and CH2CH2CH3 are optionally replaced by 1, 2 or 3 halogens, and other variables are as defined in this invention.

[0041] In some embodiments of the present invention, the above-mentioned R... b The variables are independently selected from H, D, F, OH, CH3 and CF3, respectively, and other variables are as defined in this invention.

[0042] In some embodiments of the present invention, the above-mentioned R... b The variables are independently selected from H, D, CH3 and CF3, respectively, and other variables are as defined in this invention.

[0043] In some embodiments of the present invention, R2 is selected from pyrrolopyridyl and imidazopyridyl, wherein the pyrrolopyridyl and imidazopyridyl are optionally surrounded by 1, 2 or 3 R2 groups. a Replace, R a Other variables are as defined in this invention.

[0044] In some embodiments of the present invention, R2 is selected from... Other variables are as defined in this invention.

[0045] In some embodiments of the present invention, R2 is selected from... Other variables are as defined in this invention.

[0046] In some embodiments of the present invention, R6 is selected from H, F and -CH2-N(CH3)2, and other variables are as defined in the present invention.

[0047] In some embodiments of the present invention, R6 is selected from H and F, and other variables are as defined in the present invention.

[0048] In some embodiments of the present invention, R5 is selected from H, CH3, CD3, CH2CH3 and CH(CH3)2, and other variables are as defined in the present invention.

[0049] In some embodiments of the present invention, R7 is selected from H, F, Cl, Br, I, OH, NH2, CH3, CH2CH3 and CH2CH2CH3, and other variables are as defined in the present invention.

[0050] In some embodiments of the present invention, R7 is selected from H, F, OH, CH3 and OCH3, and other variables are as defined in the present invention.

[0051] In some embodiments of the present invention, R7 is selected from F, OH, CH3 and OCH3, and other variables are as defined in the present invention.

[0052] In some embodiments of the present invention, R7 is selected from F, OH and CH3, and other variables are as defined in the present invention.

[0053] In some embodiments of the present invention, T2 is selected from N, CF and CH, and other variables are as defined in the present invention.

[0054] In some embodiments of the present invention, T3 is selected from CH and N, and other variables are as defined in the present invention.

[0055] In some embodiments of the present invention, T4 is selected from CH and N, and other variables are as defined in the present invention.

[0056] In some embodiments of the present invention, E and E1 are independently selected from -CH2-, -CHF-, -CF2-, -CH(OH)-, -CH(CH3)-, -O-, -NH-, -N(CH3)-, -N(CD3)-, -N(CH2CH3)-, And -CH(OCH3)-, other variables are as defined in this invention.

[0057] In some embodiments of the present invention, E and E1 are independently selected from -CH2-, -CHF-, -CF2-, -CH(OH)-, -CH(CH3)-, -O-, -NH-, -N(CH3)-, -N(CD3)-, -N(CH2CH3)- and Other variables are as defined in this invention.

[0058] In some embodiments of the present invention, the above-mentioned E is selected from -CH2-, -CHF-, -CF2-, -CH(OH)-, -CH(CH3)-, -O-, -NH-, -N(CH3)-, -N(CD3)-, -N(CH2CH3)- and Other variables are as defined in this invention.

[0059] In some embodiments of the present invention, the above-mentioned E1 is selected from -CH2-, -CHF-, -CF2-, -CH(OH)-, -CH(CH3)-, -O-, -NH-, -N(CH3)-, -N(CD3)-, -N(CH2CH3)- and Other variables are as defined in this invention.

[0060] In some embodiments of the present invention, E and E1 are independently selected from -CH2-, -CF2-, -CH(OH)-, -CH(CH3)-, -O-, -NH-, -N(CH3)-, -N(CH2CH3)- and Other variables are as defined in this invention.

[0061] In some embodiments of the present invention, E and E1 are independently selected from -CH2-, -C(OH)-, -C(CH3)-, -O-, NH, -N(CH3)- and -N(CH2CH3)-, and other variables are as defined in the present invention.

[0062] In some embodiments of the present invention, the carbon atoms attached to R3 and R4 constitute...

[0063] Other variables are as defined in this invention.

[0064] In some embodiments of the present invention, the carbon atoms attached to R3 and R4 constitute...

[0065]

[0066] Each R b Other variables are as defined in this invention.

[0067] In some embodiments of the present invention, the carbon atoms attached to R3 and R4 constitute...

[0068]

[0069] Other variables are as defined in this invention. This invention also provides compounds of formula (XII), their stereoisomers, or pharmaceutically acceptable salts thereof.

[0070]

[0071] in,

[0072] X is selected from O and S;

[0073] T1 is selected from CH and N;

[0074] T2 and T3 are independently selected from CH, CF and N, respectively;

[0075] T4 is selected from CR6 and N;

[0076] R2 is selected from 5-membered 6-membered heteroaryl groups, wherein the 5-membered 6-membered heteroaryl group is optionally surrounded by 1, 2, or 3 R groups. a replace;

[0077] When T is CH or N, R3 and R4, together with the carbon atoms bonded to them, constitute...

[0078] Alternatively, when T is CF or N, R3 is selected from... R4 is selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino and -CH2-C 1-3 Alkylamino;

[0079] E and E1 are independently selected from -C(R7)2-, -O-, and -N(R5)-, respectively;

[0080] n and m are independently selected from 0 and 1, respectively;

[0081] R5 is selected from H and C. 1-3 Alkyl, the C 1-3 Alkyl groups may be optionally substituted with 1, 2, or 3 Rs;

[0082] R6 is selected from H, halogens, and -C. 1-3 Alkyl-C 1-3 Alkylamino;

[0083] R7 is selected from H, F, Cl, Br, I, OH, NH2, C 1-3 Alkyl and C 1-3 Alkoxy;

[0084] R8 is selected from H and D;

[0085] Each R a Selected independently from D, halogen, and C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy groups can be independently and optionally substituted by 1, 2 or 3 R groups;

[0086] Each R b Each element is independently selected from H, D, OH, halogens, and C. 1-3 Alkyl, the C 1-3 The alkyl group may be optionally replaced by one, two, or three halogens;

[0087] Or, 2 Rs b The carbon atoms that are connected to them form C=O or cyclopropyl groups;

[0088] Each R is independently selected from halogens and D.

[0089] The present invention also provides compounds of formula (XIII), their stereoisomers, or pharmaceutically acceptable salts thereof.

[0090]

[0091] in,

[0092] X is selected from O and S;

[0093] T1 is selected from CH and N;

[0094] T2 and T3 are independently selected from CH, CF and N, respectively;

[0095] T4 is selected from CR6 and N;

[0096] R2 is selected from 5-membered 6-membered heteroaryl groups, wherein the 5-membered 6-membered heteroaryl group is optionally surrounded by 1, 2, or 3 R groups. a replace;

[0097] When T is CH or N, R3 and R4, together with the carbon atoms bonded to them, constitute...

[0098] Alternatively, when T is CF or N, R3 is selected from... R4 is selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino and -CH2-C 1-3 Alkylamino;

[0099] E and E1 are independently selected from -C(R7)2-, -O-, and -N(R5)-, respectively;

[0100] n and m are independently selected from 0 and 1, respectively;

[0101] R5 is selected from H and C. 1-3 Alkyl, the C 1-3 Alkyl groups may be optionally substituted with 1, 2, or 3 Rs;

[0102] R6 is selected from H, halogens, and -C. 1-3 Alkyl-C 1-3 Alkylamino;

[0103] R7 is selected from H, F, Cl, Br, I, OH, NH2, C 1-3 Alkyl and C 1-3 Alkoxy;

[0104] R8 is selected from H and D;

[0105] Each R a Selected independently from D, halogen, and C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy groups can be independently and optionally substituted by 1, 2 or 3 R groups;

[0106] Each R b Each element is independently selected from H, D, OH, halogens, and C. 1-3 Alkyl, the C 1-3 The alkyl group may be optionally replaced by one, two, or three halogens;

[0107] Or, 2 Rs b The carbon atoms that are connected to them form C=O or cyclopropyl groups;

[0108] Each R is independently selected from halogens and D.

[0109] The present invention also provides compounds of formula (XII), their stereoisomers, or pharmaceutically acceptable salts thereof.

[0110]

[0111] in,

[0112] X is selected from O and S;

[0113] T is selected from CH, CF, and N;

[0114] T1 is selected from CH and N;

[0115] T2 and T3 are independently selected from CH, CF and N, respectively;

[0116] T4 is selected from CR6 and N;

[0117] R2 is selected from 5-membered 6-membered heteroaryl groups, wherein the 5-membered 6-membered heteroaryl group is optionally surrounded by 1, 2, or 3 R groups. a replace;

[0118] When T is CH or N, R3 and R4, together with the carbon atoms bonded to them, constitute...

[0119] Alternatively, when T is CF or N, R3 is selected from... R4 is selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino and -CH2-C 1-3 Alkylamino;

[0120] E and E1 are independently selected from -C(R7)2-, -O-, and -N(R5)-, respectively;

[0121] n and m are independently selected from 0 and 1, respectively;

[0122] R5 is selected from H and C. 1-3 Alkyl, the C 1-3 Alkyl groups may be optionally substituted with 1, 2, or 3 Rs;

[0123] R6 is selected from H, halogens, and -C. 1-3 Alkyl-C 1-3 Alkylamino;

[0124] R7 is selected from H, F, Cl, Br, I, OH, NH2, and C. 1-3 alkyl;

[0125] R8 is selected from H and D;

[0126] Each R a Selected independently from D, halogen, and C 1-3 Alkyl and C 1-3Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy groups can be independently and optionally substituted by 1, 2 or 3 R groups;

[0127] Each R b Each element is independently selected from H, D, OH, halogens, and C. 1-3 Alkyl, the C 1-3 The alkyl group may be optionally replaced by one, two, or three halogens;

[0128] Or, 2 Rs b The carbon atoms that are connected to them form C=O or cyclopropyl groups;

[0129] R is selected from halogens and D.

[0130] The present invention also provides compounds of formula (V), their stereoisomers, or pharmaceutically acceptable salts thereof.

[0131]

[0132] in,

[0133] X is selected from O and S;

[0134] T is selected from CH, CF, and N;

[0135] T1 is selected from CH and N;

[0136] R2 is selected from 5-membered 6-membered heteroaryl groups, wherein the 5-membered 6-membered heteroaryl group is optionally surrounded by 1, 2, or 3 R groups. a replace;

[0137] When T is CH or N, R3 and R4, together with the carbon atoms bonded to them, constitute...

[0138] Alternatively, when T is CF or N, R3 is selected from... R4 is selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino and -CH2-C 1-3 Alkylamino;

[0139] E and E1 are independently selected from -C(R7)2-, -O-, and -N(R5)-, respectively;

[0140] n and m are independently selected from 0 and 1, respectively;

[0141] R5 is selected from H and C. 1-3 alkyl;

[0142] R6 is selected from H and -C. 1-3 Alkyl-C 1-3 Alkylamino;

[0143] R7 is selected from H, F, Cl, Br, I, OH, NH2, and C. 1-3 alkyl;

[0144] Each R a Selected independently from D, halogen, and C 1-3 Alkyl and C 1-3 Alkoxy;

[0145] Each R b Selected independently from H, D and C respectively 1-3 Alkyl, the C 1-3 The alkyl group may be optionally replaced by one, two, or three halogens;

[0146] Or, 2 Rs b They form C=O or cyclopropyl groups with the carbon atoms they share.

[0147] The present invention also provides compounds of formula (V), their stereoisomers, or pharmaceutically acceptable salts thereof.

[0148]

[0149] in,

[0150] X is selected from O and S;

[0151] T is selected from CH, CF, and N;

[0152] T1 is selected from CH and N;

[0153] R2 is selected from 5-membered 6-membered heteroaryl groups, wherein the 5-membered 6-membered heteroaryl group is optionally surrounded by 1, 2, or 3 R groups. a replace;

[0154] When T is CH or N, R3 and R4, together with the carbon atoms bonded to them, constitute...

[0155] Alternatively, when T is CF or N, R3 is selected from... R4 is selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino and -CH2-C 1-3 Alkylamino;

[0156] E and E1 are independently selected from -C(R7)2-, -O-, and -N(R5)-, respectively;

[0157] n and m are independently selected from 0 and 1, respectively;

[0158] R5 is selected from H and C. 1-3 alkyl;

[0159] R6 is selected from H and -C. 1-3Alkyl-C 1-3 Alkylamino;

[0160] R7 is selected from H, F, Cl, Br, I, OH, NH2, and C. 1-3 alkyl;

[0161] Each R a Selected independently from D, halogen, and C 1-3 Alkyl and C 1-3 Alkoxy;

[0162] Each R b Selected independently from H, D and C respectively 1-3 alkyl;

[0163] Or, 2 Rs b They form C=O with the carbon atoms they share.

[0164] The present invention also provides compounds of formula (V), their stereoisomers, or pharmaceutically acceptable salts thereof.

[0165]

[0166] in,

[0167] X is selected from O and S;

[0168] T is selected from CH, CF, and N;

[0169] T1 is selected from CH and N;

[0170] R2 is selected from 5-membered 6-membered heteroaryl groups, wherein the 5-membered 6-membered heteroaryl group is optionally surrounded by 1, 2, or 3 R groups. a replace;

[0171] When T is CH or N, R3 and R4, together with the carbon atoms bonded to them, constitute...

[0172] When T is CF or N, R3 is selected from R4 is selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino and -CH2-C 1-3 Alkylamino;

[0173] E and E1 are independently selected from -C(R7)2-, -O-, and -N(R5)-, respectively;

[0174] n and m are independently selected from 0 and 1, respectively;

[0175] R5 is selected from H and C. 1-3 alkyl;

[0176] R6 is selected from H and -C. 1-3Alkyl-C 1-3 Alkylamino;

[0177] R7 is selected from H, F, Cl, Br, I, OH, NH2, and C. 1-3 alkyl;

[0178] Each R a Selected independently from D, halogen, and C 1-3 Alkyl and C 1-3 Alkoxy;

[0179] Each R b Selected independently from H, D and C respectively 1-3 alkyl;

[0180] Or, 2 Rs b They form C=O with the carbon atoms they share.

[0181] The present invention also provides compounds of formula (V), their stereoisomers, or pharmaceutically acceptable salts thereof.

[0182]

[0183] in,

[0184] X is selected from O and S;

[0185] T is selected from CH, CF, and N;

[0186] T1 is selected from CH and N;

[0187] R2 is selected from 5-membered 6-membered heteroaryl groups, wherein the 5-membered 6-membered heteroaryl group is optionally surrounded by 1, 2, or 3 R groups. a replace;

[0188] When T is CH or N, R3 and R4, together with the carbon atoms bonded to them, constitute...

[0189] When T is CF or N, R3 is selected from R4 is selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino and -CH2-C 1-3 Alkylamino;

[0190] E and E1 are independently selected from -O- and -N(R5)-, respectively;

[0191] n and m are independently selected from 0 and 1, respectively;

[0192] R5 is selected from H and C. 1-3 alkyl;

[0193] R6 is selected from H and -C. 1-3 Alkyl-C1-3 Alkylamino;

[0194] Each R a Selected independently from D, halogen, and C 1-3 Alkyl and C 1-3 Alkoxy;

[0195] Each R b They are selected independently from H and D respectively;

[0196] Or, 2 Rs b They form C=O with the carbon atoms they share.

[0197] In some embodiments of the present invention, the above-mentioned R... a The variables are independently selected from D, F, CH3 and CD3, respectively, and other variables are as defined in this invention.

[0198] In some embodiments of the present invention, the above-mentioned R... b The variables are independently selected from H, D, F, OH, CH3 and CF3, respectively, and other variables are as defined in this invention.

[0199] In some embodiments of the present invention, R2 is selected from pyrrolopyridyl and imidazopyridyl, wherein the pyrrolopyridyl and imidazopyridyl are optionally surrounded by 1, 2 or 3 R2 groups. a Replace, R a Other variables are as defined in this invention.

[0200] In some embodiments of the present invention, R2 is selected from pyrrolopyridyl and imidazopyridyl, wherein the pyrrolopyridyl and imidazopyridyl are optionally surrounded by 1, 2 or 3 R2 groups. a Replacement, other variables as defined in this invention.

[0201] In some embodiments of the present invention, R2 is selected from... Other variables are as defined in this invention.

[0202] In some embodiments of the present invention, R6 is selected from H, F and -CH2-N(CH3)2, and other variables are as defined in the present invention.

[0203] In some embodiments of the present invention, R6 is selected from H and -CH2-N(CH3)2, and other variables are as defined in the present invention.

[0204] In some embodiments of the present invention, R5 is selected from H, CH3, CD3, CH2CH3 and CH(CH3)2, and other variables are as defined in the present invention.

[0205] In some embodiments of the present invention, R7 is selected from H, F, OH, CH3 and OCH3, and other variables are as defined in the present invention.

[0206] In some embodiments of the present invention, T2 is selected from N, CF and CH, and other variables are as defined in the present invention.

[0207] In some embodiments of the present invention, T3 is selected from CH and N, and other variables are as defined in the present invention.

[0208] In some embodiments of the present invention, T4 is selected from CH and N, and other variables are as defined in the present invention.

[0209] In some embodiments of the present invention, E and E1 are independently selected from -CH2-, -CHF-, -CF2-, -CH(OH)-, -CH(CH3)-, -O-, -NH-, -N(CH3)-, -N(CD3)-, -N(CH2CH3)-, And -CH(OCH3)-, other variables are as defined in this invention.

[0210] In some embodiments of the present invention, E and E1 are independently selected from -O-, -N(CH3)- and -N(CH2CH3)-, respectively, and other variables are as defined in the present invention.

[0211] In some embodiments of the present invention, when T is CH or N, R3 and R4, together with the carbon atoms attached to them, constitute... Other variables are as defined in this invention.

[0212] In some embodiments of the present invention, when T is CH or N, R3 and R4, together with the carbon atoms attached to them, constitute... Other variables are as defined in this invention.

[0213] In some embodiments of the present invention, when T is CH or N, R3 and R4, together with the carbon atoms attached to them, constitute... Each R b Each element is independently selected from H, D, OH, halogens, and C. 1-3 Alkyl, the C 1-3 Alkyl groups may be optionally substituted with one, two, or three halogens, and other variables are as defined in this invention.

[0214] In some embodiments of the present invention, the carbon atoms attached to R3 and R4 constitute... Each R b Each element is independently selected from H, D, OH, halogens, and C.1-3 Alkyl, the C 1-3 Alkyl groups may be optionally substituted with one, two, or three halogens, and other variables are as defined in this invention.

[0215] In some embodiments of the present invention, when T is CH or N, R3 and R4, together with the carbon atoms attached to them, constitute... Other variables are as defined in this invention.

[0216] In some embodiments of the present invention, when T is CH or N, R3 and R4, together with the carbon atoms attached to them, constitute... Alternatively, when T is CH or N, R3 and R4, along with the carbon atoms bonded to them, constitute... Other variables are as defined in this invention.

[0217] In some embodiments of the present invention, when T is CH or N, R3 and R4, together with the carbon atoms attached to them, constitute... Other variables are as defined in this invention.

[0218] In some embodiments of the present invention, when T is CH or N, R3 and R4, together with the carbon atoms attached to them, constitute... Other variables are as defined in this invention.

[0219] In some embodiments of the present invention, when T is CH or N, R3 and R4, together with the carbon atoms attached to them, constitute... Other variables are as defined in this invention.

[0220] In some embodiments of the present invention, when T is CH or N, R3 and R4, together with the carbon atoms attached to them, constitute... Alternatively, when T is CH or N, R3 and R4, along with the carbon atoms bonded to them, constitute... Other variables are as defined in this invention.

[0221] In some embodiments of the present invention, when T is CF or N, R3 is selected from... R4 is selected from -CH2-N(CH3)2, and other variables are as defined in this invention.

[0222] The present invention also includes some solutions derived from arbitrary combinations of the above variables.

[0223] In some embodiments of the present invention, the above-mentioned compound, its stereoisomers, or pharmaceutically acceptable salts thereof are selected from,

[0224]

[0225] Wherein, E, T1, R2 and R4 are as defined in this invention.

[0226] In some embodiments of the present invention, the above-mentioned compound, its stereoisomers, or pharmaceutically acceptable salts thereof are selected from,

[0227]

[0228] Among them, E, E1, T, T1, R2, R b m and n are as defined in this invention.

[0229] In some embodiments of the present invention, the above-mentioned compound, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from:

[0230]

[0231] Wherein, E, E1, T, T1, R2, and m are as defined in this invention.

[0232] E2 is selected from N and CH.

[0233] In some embodiments of the present invention, the above-mentioned compound, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from:

[0234]

[0235] Wherein, E, E1, T, T1, R2 and m are as defined in this invention.

[0236] The present invention also provides compounds of the following formula, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249] In some embodiments of the present invention, the above-mentioned compound, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from:

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282] The present invention also provides the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating solid tumors.

[0283] The present invention also provides the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating various types of tumors.

[0284] The present invention also provides the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating HPK1-related diseases.

[0285] The present invention also provides the following synthesis method:

[0286] Method 1:

[0287]

[0288] Method 2:

[0289] Method 3:

[0290] Method 4:

[0291]

[0292] Method 5:

[0293] Method 6:

[0294] Technical Effects

[0295] The compounds of this invention exhibit excellent HPK1 kinase inhibitory activity, weak inhibition of its subtype GLK (MAP4K3), and excellent HPK1 selectivity. These compounds significantly increase IL-2 levels in Jurkat cells and exhibit excellent inhibitory activity against SLP76 phosphorylation in Jurkat cells. The compounds demonstrate good stability on human liver microsomes and good in vivo metabolic stability, excellent oral absorption drug exposure, and good oral bioavailability. In cell membrane permeability studies, the compounds of this invention exhibit excellent membrane permeability.

[0296] Definition and Description

[0297] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0298] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0299] The term "pharmaceutically acceptable salt" refers to the salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, with a specific substituent. When the compounds of this invention contain relatively acidic functional groups, a base addition salt can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. When the compounds of this invention contain relatively basic functional groups, an acid addition salt can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Certain specific compounds of this invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0300] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0301] Unless otherwise stated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereo isomers, enantiomers, optical isomers, diastereomers and tautomers.

[0302] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0303] Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0304] Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" arise because the single bonds of double bonds or cyclic carbon atoms cannot rotate freely.

[0305] Unless otherwise stated, the term "diastereomer" refers to a stereoisomer of a molecule having two or more chiral centers and being in a non-mirror relationship with each other.

[0306] Unless otherwise stated, "(+)" indicates right-handed rotation, "(-)" indicates left-handed rotation, and "(±)" indicates racemic rotation.

[0307] Unless otherwise specified, use wedge-shaped solid line keys. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key The relative configuration of the center of a solid is indicated by a wavy line. Indicates wedge-shaped solid line key or wedge-shaped dashed key Or use wavy lines Indicates a straight solid line key Or straight dashed key

[0308] Unless otherwise stated, the terms "tautomer" or "tautomer form" refer to isomers with different functional groups in dynamic equilibrium at room temperature, capable of rapidly interconverting into each other. Tautomers can be chemically equilibrated if possible (e.g., in solution). For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions involving the rearrangement of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between the tautomers pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0309] Unless otherwise stated, the terms "rich in one isomer," "isomer enrichment," "rich in one enantiomer," or "enantiomer enrichment" mean that the content of one isomer or enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0310] Unless otherwise stated, the terms "isomer excess" or "enantiomer excess" refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomer excess (ee value) is 80%.

[0311] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated, and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0312] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14 C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0313] The terms “optional” or “optionally” refer to events or conditions that may occur but are not required to occur as described below, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0314] The term "substituted" refers to the substitution of one or more hydrogen atoms on a particular atom by a substituent. Substituents can include deuterium and hydrogen variants, provided the valence state of the particular atom is normal and the resulting compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.

[0315] The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents may be arbitrary on the basis of chemical feasibility.

[0316] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0317] When the number of a linking group is 0, such as -(CRR)0-, it indicates that the linking group is a single bond.

[0318] When the number of a substituent is 0, it means that the substituent does not exist. For example, -A-(R)0 means that the structure is actually -A.

[0319] When a substituent is vacant, it means that the substituent does not exist. For example, if X is vacant in AX, it means that the structure is actually A.

[0320] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0321] When a substituent can be cross-bonded to two or more atoms on a ring, this substituent can bond with any atom on that ring, for example, structural units. This indicates that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene. When the listed substituents do not specify which atom they are attached to the substituted group, such substituents can be bonded to any of their atoms. For example, a pyridyl group as a substituent can be attached to the substituted group through any carbon atom on the pyridine ring.

[0322] When the listed linking groups do not specify their linking direction, the linking direction is arbitrary, for example, The linker group L is -MW-. In this case, -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form a ring. Alternatively, rings A and B can be connected in the opposite direction to the left-to-right reading order to form a ring. The combination of linking groups, substituents, and / or their variants is permitted only if such a combination produces a stable compound.

[0323] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of that group can be connected to other groups by chemical bonds. When the chemical bond connection is non-directional and the connectable site contains H atoms, the number of H atoms at that site will decrease accordingly with the number of chemical bonds connected, resulting in a group with a corresponding valence. The chemical bonds connecting the site to other groups can be straight solid line bonds. Straight dashed key or wavy line For example, a straight solid line bond in -OCH3 indicates that the oxygen atom in that group is connected to other groups; The straight dashed bond in the diagram indicates that the group is connected to other groups through both ends of the nitrogen atom in the group; The wavy lines in the text indicate that the phenyl group is connected to other groups through the carbon atoms at positions 1 and 2 of the phenyl group. This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... Even if H atoms are drawn on -N- in these four connection methods, Still includes In this type of linkage, when a chemical bond is attached, the number of hydrogen atoms at that site is reduced by one, resulting in a monovalent piperidinyl group.

[0324] Unless otherwise specified, the number of atoms in a ring is usually defined as the elemental number of the ring. For example, a “5-7 elemental ring” refers to a “ring” with 5-7 atoms arranged around it.

[0325] Unless otherwise specified, D in this invention represents deuterium ( 2 H).

[0326] Unless otherwise specified, the term “halogen” or “halogen” itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.

[0327] Unless otherwise specified, the term "C" 1-3 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0328] Unless otherwise specified, the term "C" 1-3 "Alkoxy" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 、C 2-3 C3 and C2 alkoxy groups, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.

[0329] Unless otherwise specified, the term "C" 1-3 "Alkylamino" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule via a nitrogen atom. The C 1-3 Alkylamino groups include C 1-2 C3 and C2 alkylamino groups, etc. C 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, etc.

[0330] Unless otherwise specified, the term "5-membered and 6-membered heteroaryl" refers to a bicyclic group with a conjugated π-electron system consisting of 5 ring atoms and 6 ring atoms, sharing two ring atoms. One, two, three, or four of these ring atoms are heteroatoms independently selected from O, S, and N, while the remainder are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p (where p is 1 or 2). The 5-6 heteroaryl group can be attached to the rest of the molecule via a heteroatom or a carbon atom. Examples of the 5-6 heteroaryl group include, but are not limited to, pyrrolopyridinyl and imidazopyridinyl.

[0331] The structures of the compounds of this invention can be confirmed by conventional methods well known to those skilled in the art. If this invention relates to the absolute configuration of a compound, that absolute configuration can be confirmed by conventional techniques in the art. For example, single-crystal X-ray diffraction (SXRD) is used, where the cultured single crystal is used to collect diffraction intensity data using a Bruker D8 venture diffractometer with CuKα radiation as the light source. The scanning method is as follows: After scanning and collecting relevant data, the crystal structure can be further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0332] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0333] The solvent used in this invention is commercially available.

[0334] This invention uses the following abbreviations: DCM represents dichloromethane, EA represents ethyl acetate, PE represents petroleum ether, THF represents tetrahydrofuran, DMF represents N,N-dimethylformamide, MeOH represents methanol, AcOH represents acetic acid, MTBE represents methyl tert-butyl ether, TFA represents trifluoroacetic acid, TEA represents triethylamine, DIEA represents N,N-diisopropylethylamine, Pd(OAc)2 represents palladium(II) acetate, Pd(PPh3)4 represents tetrakis(triphenylphosphine)palladium, Pd(dppf)Cl2.CH2Cl2 represents bis(diphenylphosphine)ferrocene dichloropalladium(II) dichloromethane complex, Pd(dppf)Cl2 represents bis(diphenylphosphine)ferrocene dichloropalladium(II), Pd2(dba)3 represents tridibenzylacetone dipalladium, BINAP represents 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, XPhos Pd G2 represents chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II), RuPhos Pd G2 represents chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II), Xantphos Pd G4 represents (4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II)methanesulfonic acid, Ruphos represents 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl, Xphos represents 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, Xantphos represents 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene, Dys-Martin oxidant represents (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzioyl-3(1H)-one, Boc2O represents di-tert-butyl dicarbonate, BocNH2 represents tert-butyloxycarbonylamine, s-BuLi represents sec-butyllithium, NaBH(OAc)3 represents sodium triacetoxyborohydride, HOBt represents 1-hydroxyl 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, Cs2CO3-cesium carbonate, BH3.THF-borane tetrahydrofuran solution, TfOH-trifluoromethanesulfonic acid, ZnBr2-zinc bromide, Raney-Ni-Ni, DAST-diethylaminosulfuric acid, NaH-sodium hydride, CD3I-deuterated iodomethane, KOAc-potassium acetate, MeI-iodomethane, TBSCl-tert-butyldimethylchlorosilane, (PMB)2NH-di(p-methoxybenzyl)amino, Boc-tert-butoxycarbonyl, PMB-p-methoxybenzyl, DMB-2,4-dimethoxybenzyl, Select-F-1-chloromethyl-4-fluoro-1,4-azabenzotriazole Bicyclic [2.2.2]octanebis(tetrafluoroborate), prep-HPLC represents high performance liquid chromatography for preparation and separation.

[0335] Compounds are named according to conventional naming principles in the field or using Software naming conventions are used; commercially available compounds use supplier catalog names. Attached Figure Description

[0336] Figure 1 Predicted binding mode of compound A to HPK1;

[0337] Figure 2 Predicted binding mode of compound B to HPK1;

[0338] Figure 3 Prediction of the binding mode between compound C and HPK1;

[0339] Figure 4 Predicted binding mode of compound D to HPK1;

[0340] Figure 5 Predicted binding mode of compound E to HPK1;

[0341] Figure 6 Predicted binding mode of compound F to HPK1;

[0342] Figure 7 Prediction of the binding mode of compound G to HPK1;

[0343] Figure 8 Prediction of the binding mode between compound H and HPK1;

[0344] Figure 9 Prediction of the binding mode of compound I with HPK1;

[0345] Figure 10 Predicted binding mode of compound J to HPK1;

[0346] Figure 11 Prediction of the binding mode between compound K and HPK1;

[0347] Figure 12 Prediction of the binding mode of compound L to HPK1;

[0348] Figure 13 Predicted binding mode of compound M to HPK1. Detailed Implementation

[0349] The present invention will be described in detail below with reference to examples, but this does not imply any adverse limitation on the invention. The compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention. 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 invention without departing from the spirit and scope of the invention.

[0350] Calculation Example 1

[0351]

[0352]

[0353] The molecular covalent docking process is achieved by using Maestro ( The process was performed using Glide[1] and the default options in version 2017-2). The cocrystal structure of HPK1 (PDB ID code: 7KAC) was selected as the docking template. To prepare the protein, hydrogen atoms were added using the protein preparation wizard module of Maestro[2] and the OPLS3 force field was used. For the preparation of the ligand, a 3D structure was generated and energy minimization was performed using LigPrep[3]. The ligand centroid was generated using the ligand centroid in the 7KAC crystal structure. Docking grids were then constructed. The ligands were removed, and example compounds were placed during molecular docking. The interaction types between the protein receptor and ligands were analyzed, and reasonable docking conformations were selected and saved based on the calculated docking score and glide gscore.

[0354] [1]Glide, LLC, New York, NY, 2017.

[0355] [2] Maestro, LLC, New York, NY, 2017.

[0356] [3]LigPrep, LLC, New York, NY, 2017.

[0357] Conclusion: The compound of this invention binds well to the HPK1 protein.

[0358] Example 1

[0359]

[0360]

[0361] Step 1: Synthesis of compound BB-1-2

[0362] Under nitrogen protection, compound BB-1-1 (3 g, 14.71 mmol, 1 eq) was dissolved in DMF (30 mL), and morpholine (2.56 g, 29.41 mmol, 2.59 mL, 2 eq) and potassium carbonate (4.06 g, 29.41 mmol, 2 eq) were added. The mixture was reacted at 100 °C for 1 hour. After cooling, water (100 mL) and ethyl acetate (100 mL) were added for extraction. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 50%) to obtain compound BB-1-2. MS m / z: 271.0, 273.0 [M+1] + ; 1 HNMR (400MHz, DMSO-d6) δ9.84(s,1H),7.80-7.69(m,1H),7.65-7.56(m,1H),3.86-3.68(m,4H),3.21-3.07(m,4H).

[0363] Step 2: Synthesis of compound BB-1

[0364] Under nitrogen protection, compound BB-1-2 (2.7 g, 9.96 mmol, 1 eq) was dissolved in DCM (30 mL), and dimethylamine aqueous solution (1.35 g, 11.95 mmol, 1.51 mL, 40% purity, 1.2 eq), glacial acetic acid (598.06 mg, 9.96 mmol, 569.58 μL, 1 eq), and NaBH(OAc)3 (4.22 g, 19.92 mmol, 2 eq) were added. The reaction was carried out at 20 °C for 1 hour. Water (50 mL) was added, and the pH was adjusted to 10 with sodium hydroxide aqueous solution (6 M). The mixture was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 50% to methanol / ethyl acetate = 0% to 16%) to obtain compound BB-1. MS m / z: 300.1, 302.1 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ7.54-7.42(m,2H),3.79-3.68(m,4H),3.45(s,2H),3.04-2.92(m,4H),2.23(s,6H).

[0365] Step 3: Synthesis of compound BB-2-2

[0366] Under nitrogen protection, compound BB-2-1 (5 g, 36.73 mmol, 1 eq) was dissolved in DCM (50 mL), and N-bromosuccinimide (7.19 g, 40.40 mmol, 1.1 eq) was added. The reaction mixture was stirred at 20 °C for 2 hours. The reaction solution was poured into a saturated sodium thiosulfate solution (50 mL), the DCM was concentrated, and the mixture was homogenized for 1 hour. The mixture was filtered, the filter cake was washed with water (20 mL), and the filter cake was dried to obtain compound BB-2-2. MS m / z: 215.0 [M+1] + ; 1 HNMR (400MHz, CDCl3) δ8.11-8.08(m,1H),7.59(s,1H),7.29-7.27(m,1H),6.86-6.82(m,1H).

[0367] Step 4: Synthesis of compound BB-2

[0368] Under nitrogen protection, compounds BB-2-2 (1.7 g, 7.91 mmol, 1 eq) and BB-2-3 (4.41 g, 23.72 mmol, 4.84 mL, 3 eq) were dissolved in tetrahydrofuran (35 mL). A tetrahydrofuran solution of isopropyl magnesium chloride (1.37 M, 11.54 mL, 2 eq) was added dropwise at 0 °C, and the reaction was stirred at 0 °C for 2 hours. The reaction mixture was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give compound BB-2. MS m / z: 180.9 [M+1-82] + .

[0369] Step 5: Synthesis of compounds 1-3

[0370] Under nitrogen protection, compound 1-1 (5 g, 21.73 mmol, 1 eq) was dissolved in dioxane (50 mL), followed by 1-2 (8.28 g, 32.60 mmol, 1.5 eq), Pd(dppf)Cl2 (1.59 g, 2.17 mmol, 0.1 eq), and potassium acetate (4.27 g, 43.47 mmol, 2 eq). The reaction was carried out at 90 °C for 1 hour. After cooling, the reaction was quenched with water (100 mL), and extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 5%–16%) to obtain compound 1-3. MS m / z: 278.1 [M+1] + .

[0371] Step 6: Synthesis of compounds 1-5

[0372] Under nitrogen protection, compounds 1-3 (500 mg, 1.80 mmol, 1 eq) were dissolved in dioxane (5 mL) and water (1 mL). BB-4 (472.75 mg, 1.80 mmol, 1 eq), Pd(dppf)Cl2 (132.02 mg, 180.43 μmol, 0.1 eq), and potassium carbonate (498.72 mg, 3.61 mmol, 2 eq) were added, and the reaction was carried out at 90 °C for 2 hours. After cooling, the reaction was quenched with water (5 mL), extracted with ethyl acetate (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 50%) to obtain compounds 1-5. MS m / z: 286.1 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ8.47-8.30(m,1H),7.87(s,1H),7.69(s,1H),7.52-7.38(m,2H),7.04-6.87(m,4H),3.81(s,3H).

[0373] Step 7: Synthesis of compounds 1-6

[0374] Under nitrogen protection, compounds 1-5 (370 mg, 1.30 mmol, 1 eq) were dissolved in dioxane (10 mL), followed by BB-1 (389.35 mg, 1.30 mmol, 1 eq), cesium carbonate (845.18 mg, 2.59 mmol, 2 eq), Xantphos (225.14 mg, 389.10 μmol, 0.3 eq), and Pd2(dba)3 (237.54 mg, 259.40 μmol, 0.2 eq). The reaction was carried out at 110 °C for 12 hours. After cooling, the reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / methanol = 10%–50%) to obtain compounds 1-6. MS m / z: 505.2 [M+1] + .

[0375] Step 8: Synthesis of Compound 1

[0376] Under nitrogen protection, ammonium chloride (212.03 mg, 3.96 mmol, 10 eq) was added to a tetrahydrofuran solution of bis(trimethylsilylaminolithium) (1 M, 3.96 mL, 10 eq), followed by the addition of compounds 1-6 dissolved in tetrahydrofuran (2 mL) (200 mg, 396.39 μmol, 1 eq). The reaction was carried out at 20 °C for 1 hour. The reaction was quenched with methanol (5 mL), and the reaction solution was concentrated to obtain the crude product. Compound 1 was purified by prep-HPLC (column: Phenomenex C1875*30 mm*3 μm; flowability: [water (NH4HCO3)-acetonitrile]; acetonitrile %: 15%-55%, 8 min). MS m / z: 490.3 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ11.11(s,1H),8.87-8.73(m,1H),8.71-8.56(m,1H),8.28(s,1H),7.97(s,1H),7.74(s,1H),7.71-7.61( m,2H),7.58-7.46(m,2H),7.04-6.94(m,1H),6.91-6.82(m,1H),3.79-3.71(m,4H),3.53(s,2H),3.01-2.91(m,4H),2.29(s,6H).

[0377] Example 2

[0378]

[0379]

[0380] Step 1: Synthesis of compound BB-3-3

[0381] Under nitrogen protection, compounds BB-3-1 (4.7 g, 28.29 mmol, 1 eq) and BB-3-2 (2.71 g, 31.12 mmol, 2.74 mL, 1.1 eq) were dissolved in DMF (50 mL), and the reaction was stirred at 20 °C for 6 minutes. The reaction solution was poured into water (500 mL), stirred for 10 minutes, filtered, and the filter cake was washed with ethanol (30 mL). The filter cake was then dried to give compound BB-3-3. MS m / z: 234.2 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ8.46 (d, J = 2.8 Hz, 1H), 8.32-8.29 (m, 1H), 7.00 (d, J = 2.0 Hz, 1H), 3.93-3.91 (m, 4H), 3.51-3.49 (m, 4H).

[0382] Step 2: Synthesis of compound BB-3-4

[0383] Raney nickel (2 g, 34.08 mmol, 3.97 eq) was added to a dry argon-protected hydrogenation flask. Tetrahydrofuran (20 mL) was slowly added along the flask wall, followed by ammonia (7.28 g, 51.93 mmol, 8.00 mL, 25% purity, 6.06 eq). Then BB-3-3 (2 g, 8.58 mmol, 1 eq) was added. The reaction was purged with hydrogen three times and stirred at 30 °C and a hydrogen pressure of 15 Psi for 3 hours. The reaction solution was filtered, and the filter cake was washed with methanol (50 mL). The filtrate was concentrated to give compound BB-3-4. MS m / z: 208.3 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ6.99 (d, J = 8.4 Hz, 1H), 6.65 (d, J = 2.8 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 3.82 (s, 6H), 3.58 (s, 2H), 2.85-2.83 (m, 4H), 1.58 (m, 2H).

[0384] Step 3: Synthesis of compound BB-3

[0385] Under nitrogen protection, compound BB-3-4 (0.5 g, 2.41 mmol, 1 eq), formaldehyde aqueous solution (391.52 mg, 4.82 mmol, 359.19 μL, 37% purity, 2 eq) were added to methanol (20 mL), followed by zinc chloride (164.39 mg, 1.21 mmol, 56.49 μL, 0.5 eq) and sodium cyanoborohydride (151.59 mg, 2.41 mmol, 1 eq). The reaction mixture was reacted at 25 °C for 12 hours. The reaction solution was added to water (30 mL), extracted with dichloromethane:methanol (10:1, 30 mL × 4), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound BB-3. MS m / z: 236.1 [M+1] + .

[0386] Step 4: Synthesis of Compound 2-2

[0387] Under nitrogen protection, a tetrahydrofuran solution of n-butyllithium (2.5M, 44.32mL, 2.62eq) was added to 120mL of tetrahydrofuran at -78°C. 2,2,6,6-Tetramethylpiperidine (17.92g, 126.88mmol, 21.54mL, 3eq) was added dropwise. The mixture was heated to 0°C and stirred for 1 hour. After cooling to -78°C, 10g (42.29mmol, 1eq) of 2-1 dissolved in 80mL of tetrahydrofuran was added dropwise. After stirring for 1.5 hours, DMF (11.87g, 162.46mmol, 12.50mL, 3.84eq) was added. The mixture was heated to 20°C and stirred for 4 hours. The reaction solution was quenched in hydrochloric acid aqueous solution (50 mL, 1 M). The aqueous phase was extracted with ethyl acetate (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether = 10%–33%) to give compound 2-2. MS m / z: 263.9 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ8.92 (s, 1H), 8.55 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 5.2 Hz, 1H).

[0388] Step 5: Synthesis of compounds 2-4

[0389] Under nitrogen protection, compounds 2-2 (2 g, 7.56 mmol, 1 eq) and 2-3 (1.09 g, 7.94 mmol, 1.03 mL, 1.05 eq) were dissolved in DCM (50 mL), and glacial acetic acid (45.41 mg, 756.26 μmol, 43.25 μL, 0.1 eq) was added. The mixture was stirred at 20 °C for 1 hour, and NaBH(OAc)3 (3.21 g, 15.13 mmol, 2 eq) was added. The mixture was stirred for another 15 hours. The reaction mixture was poured into a saturated sodium bicarbonate solution (100 mL), concentrated with dichloromethane, homogenized in aqueous phase for 30 minutes, filtered, and the filter cake was homogenized in anhydrous ethanol (30 mL) for 30 minutes, filtered, concentrated, and dried to obtain compound 2-4. MS m / z: 367.0 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ8.72(s,1H),7.27(d,J=8.8Hz,2H),6.92(d,J=8.4Hz,2H),4.65(s,2H),4.34(s,2H),3.73(s,3H).

[0390] Step 6: Synthesis of compounds 2-5

[0391] Under nitrogen protection, compounds 2-4 (500 mg, 1.36 mmol, 1 eq) and BB-2 (2 g, 2.29 mmol, 30% purity, 1.68 eq) were dissolved in dioxane (30 mL) and water (5 mL). Potassium phosphate (866.11 mg, 4.08 mmol, 3 eq) and Pd(dppf)Cl2 (99.52 mg, 136.01 μmol, 0.1 eq) were added, and the reaction was stirred at 50 °C for 12 hours. The reaction solution was concentrated, and ethyl acetate (50 mL) and water (20 mL) were added. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (10 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 10%–100%) to give compound 2-5. MS m / z: 423.1 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ8.65(s,1H),8.04(d,J=5.2Hz,1H),7.67(s,1H),7.35(d,J=9.2Hz ,1H),7.24(d,J=8.8Hz,2H),6.86-6.80(m,3H),4.72(s,2H),4.22(s,2H),3.78(s,3H).

[0392] Step 7: Synthesis of compounds 2-6

[0393] Under nitrogen protection, compounds 2-5 (150 mg, 354.75 μmol, 1 eq) and BB-3 (83.48 mg, 354.75 μmol, 1 eq) were dissolved in DCM (10 mL), and RuPhos Pd G2 (27.55 mg, 35.47 μmol, 0.1 eq), Ruphos (16.55 mg, 35.47 μmol, 0.1 eq), and cesium carbonate (346.75 mg, 1.06 mmol, 3 eq) were added. The mixture was stirred at 110 °C for 1 hour. The reaction solution was filtered, and the filtrate was concentrated to obtain a crude product, which was purified by column chromatography (dichloromethane / methanol 0%–16%) to give compound 2-6. MS m / z: 622.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ9.20(s,1H),8.48-8.43(m,2H),7.75(m,1H),7.65(s,1H),7.51(s,1H),7.26-7.24(m,2H),7.16(s,1 H),6.96-6.95(m,1H),6.89-6.85(m,2H),4.62(s,2H),4.38(s,2H),3.75-3.69(m,9H),2.88-2.86(m,4H),2.28-2.24(m,6H).

[0394] Step 8: Synthesis of Compound 2

[0395] Compounds 2-6 (130 mg, 209.10 μmol, 1 eq) were dissolved in trifluoroacetic acid (10 mL), and the reaction was carried out under microwave stirring at 130 °C for 16 hours. The reaction solution was concentrated and purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH4HCO3)-acetonitrile]; acetonitrile %: 10%-40%, 8 min) to obtain compound 2. MS m / z: 502.1 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ9.22(s,1H),8.91(s,1H),8.51-8.48(m,2H),7.87-7.86(m,1H),7.80(s,1H),7.61-7.60(m,1H),7.54-7.51(m ,1H),7.14-7.12(m,1H),6.97-6.96(m,1H),4.40(s,2H),3.74-3.72(m,4H),3.48-3.43(m,2H),2.88-2.86(m,4H),2.22-2.18(m,6H).

[0396] Example 3

[0397]

[0398] Step 1: Synthesis of compound BB-4

[0399] Under nitrogen protection, compound BB-2-1 (4.26 g, 31.29 mmol, 1 eq) was dissolved in anhydrous N,N-dimethylformamide (40 mL) at 20 °C, and N-iodosuccinimide (7.74 g, 34.42 mmol, 1.1 eq) was added. The mixture was heated to 50 °C and reacted for 1 hour. The reaction was quenched with saturated sodium thiosulfate solution (40 mL), extracted with ethyl acetate (40 mL × 3), and the organic phases were combined. The organic phases were washed successively with water (100 mL × 2) and saturated brine (50 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give compound BB-4. MS m / z: 263.0 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ8.40-8.37(m,1H),7.69(s,1H),7.55-7.52(m,1H),7.11-7.07(m,1H).

[0400] Step 2: Synthesis of compound BB-5-2

[0401] Under nitrogen protection, compound BB-5-1 (2.5 g, 15.67 mmol, 1 eq) was dissolved in N,N-dimethylformamide (25 mL) at 20 °C, followed by the addition of morpholine (2.73 g, 31.34 mmol, 2.76 mL, 2 eq) and potassium carbonate (6.50 g, 47.01 mmol, 3 eq). The mixture was heated to 100 °C and reacted for 2 hours. The reaction was quenched with water (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Compound BB-5-2 was purified by column chromatography (ethyl acetate / petroleum ether = 0%–20%). MS m / z: 227.0 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ9.87(s,1H),7.72-7.70(m,1H),7.66-7.64(m,1H),3.77-3.75(m,4H),3.13-3.11(m,4H).

[0402] Step 3: Synthesis of compound BB-5

[0403] Under nitrogen protection, compound BB-5-2 (1 g, 4.41 mmol, 1 eq) was dissolved in methanol (20 mL) at 0 °C. Dimethylamine aqueous solution (1.49 g, 13.24 mmol, 1.68 mL, 40% purity, 3 eq) and glacial acetic acid (105.98 mg, 1.76 mmol, 100.93 μL, 0.4 eq) were added, and the reaction was carried out at 0 °C for 0.5 hours. Sodium cyanoborohydride (1.11 g, 17.65 mmol, 4 eq) was then added, and the reaction was carried out at 0 °C for 1.5 hours. The reaction was quenched with water (20 mL), the solvent was concentrated under reduced pressure, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The purified compound BB-5 was obtained by column chromatography (ethyl acetate / petroleum ether = 0%–100%). MS m / z: 256.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ7.57(d,J=8.4Hz,1H),7.38(d,J=8.4Hz,1H),3.76-3.73(m,4H),3.45(s,2H),3.03-2.97(m,4H),2.22(s,6H).

[0404] Step 4: Synthesis of compound 3-2

[0405] Under nitrogen protection, compound 3-1 (300 mg, 1.61 mmol, 1 eq) was dissolved in dioxane (15 mL) and water (3 mL). Compound BB-2 (4.6 g, 2.28 mmol, 13% purity, 1.42 eq), potassium phosphate (1.02 g, 4.82 mmol, 3 eq), and XPhos Pd G2 (126.50 mg, 160.78 μmol, 0.1 eq) were added, and the reaction was carried out at 100 °C for 2 hours. After cooling, the reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The organic phase was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. Compound 3-2 was purified by column chromatography (ethyl acetate / petroleum ether = 0%–100%). MS m / z: 287.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ10.24-10.15(m,1H),8.25(s,1H),7.97(d,J=8.8Hz,1H),7. 53-7.52(m,1H),7.42(d,J=2.4Hz,1H),7.22-7.17(m,1H),6.88(s,2H),3.92(s,3H).

[0406] Step 5: Synthesis of Compound 3-3

[0407] Under nitrogen protection, compound 3-2 (50 mg, 174.67 μmol, 1 eq) was dissolved in dioxane (2 mL), and compound BB-5 (53.60 mg, 209.60 μmol, 1.2 eq), cesium carbonate (113.82 mg, 349.33 μmol, 2 eq), BINAP (13.05 mg, 20.96 μmol, 0.12 eq), and palladium acetate (3.92 mg, 17.47 μmol, 0.1 eq) were added. The reaction was carried out at 120 °C for 2 hours. After cooling, the reaction was quenched with water (10 mL), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The organic phase was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The purified compound 3-3 was obtained by separation by thin-layer chromatography (ethyl acetate / methanol / triethylamine = 80:20:0.5%). MS m / z: 506.3 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ10.22-10.18(m,1H),9.24-9.13(m,1H),8.41(s,1H),8.20(d,J=9.2Hz,1H),7.63-7.59(m ,2H),7.27-7.24(m,1H),7.23-7.05(m,1H),4.01(s,3H),3.75-3.69(m,9H),2.95-2.93(m,4H),2.40-2.38(m,4H).

[0408] Step 6: Synthesis of Compound 3

[0409] Under nitrogen protection, a tetrahydrofuran solution (1M, 427.26 μL, 8 eq) of lithium bis(trimethylsilyl)aminoacetonitrile was added to a mixture of compound 3-3 (27 mg, 53.41 μmol, 1 eq) and ammonium chloride (17.14 mg, 320.45 μmol, 6 eq), and the reaction was carried out at 20 °C for 1 h. The reaction was quenched with methanol (2 mL), and the solvent was concentrated under reduced pressure to obtain the crude product. Compound 3 was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH4HCO3)-acetonitrile]; acetonitrile %: 15%-45%, 8 min). MS m / z: 491.2 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ11.56(s,1H),9.59-9.56(m,1H),9.36(d,J=8.8Hz,1H),8.29(s,1H),8.22-8.20(m,1H),8.08(d,J=10.0Hz,1H),8.0 1-7.99(m,1H),7.63-7.49(m,2H),7.19-7.06(m,1H),6.90(d,J=8.4Hz ,1H),3.76-3.73(m,4H),3.54(s,2H),2.96-2.94(m,4H),2.30(s,6H).

[0410] Example 4

[0411]

[0412]

[0413] Step 1: Synthesis of compound BB-6-2

[0414] Under nitrogen protection, compound BB-6-1 (0.5 g, 2.42 mmol, 1 eq) was dissolved in tetrahydrofuran (5 mL), cooled to -78 °C, and a solution of diisopropylaminolithium tetrahydrofuran (2 M, 1.45 mL, 1.2 eq) was added. The reaction was continued at -78 °C for 1 hour, followed by the introduction of carbon dioxide (1.07 g, 24.22 mmol, 10 eq), and the temperature was raised to 25 °C for 1 hour. Similarly, under nitrogen protection, compound BB-6-1 (8 g, 38.75 mmol, 1 eq) was dissolved in tetrahydrofuran (80 mL), cooled to -78 °C, and a solution of diisopropylaminolithium tetrahydrofuran (2 M, 23.25 mL, 1.2 eq) was added. The reaction was continued at -78 °C for 1 hour, followed by the introduction of carbon dioxide (17.05 g, 387.47 mmol, 10 eq), and the temperature was raised to 25 °C for 1 hour. The reactions were combined, quenched with saturated sodium bicarbonate (50 mL), extracted with ethyl acetate (50 mL × 2), and the organic phase was discarded. The aqueous phase was adjusted to pH 4 with hydrochloric acid (3 M, approximately 50 mL), extracted with dichloromethane:methanol (10:1, 100 mL × 5), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound BB-6-2. MS m / z: 250.1, 252.1 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ8.47 (s, 1H), 2.30 (s, 3H).

[0415] Step 2: Synthesis of compound BB-6-3

[0416] Under nitrogen protection, compound BB-6-2 (2.7 g, 10.78 mmol, 1 eq) was dissolved in DMF (27 mL), and potassium carbonate (4.47 g, 32.34 mmol, 3 eq) and methyl iodoform (3.06 g, 21.56 mmol, 1.34 mL, 2 eq) were added. The reaction was carried out at 25 °C for 2 hours. Water (30 mL) and ethyl acetate (50 mL × 2) were added for extraction. The organic phases were combined, washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 5%–10%) to obtain compound BB-6-3. MS m / z: 266.0, 263.9 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ8.59(s,1H),3.97(s,3H),2.31(s,3H).

[0417] Step 3: Synthesis of compound BB-6-4

[0418] Under nitrogen protection, compound BB-6-3 (0.97 g, 3.67 mmol, 1 eq) was dissolved in 1,2-dichloroethane (10 mL), and azobisisobutyronitrile (60.22 mg, 366.72 μmol, 0.1 eq) and N-bromosuccinimide (1.31 g, 7.33 mmol, 2 eq) were added. The reaction mixture was reacted at 85 °C for 2 hours. After cooling, the reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (ethyl acetate / petroleum ether = 5%) to obtain compound BB-6-4. MS m / z: 345.8, 343.8 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ8.76 (s, 1H), 4.60 (s, 2H), 4.00 (s, 3H).

[0419] Step 4: Synthesis of compound BB-6-5

[0420] Under nitrogen protection, compound BB-6-4 (0.6 g, 1.75 mmol, 1 eq) was dissolved in methanol (6 mL), and a methanol solution of ammonia (7 M, 6.00 mL, 24.04 eq) was added. The reaction was carried out at 25 °C for 1 hour. The mixture was filtered, the filter cake was washed with methanol (5 mL), and dried to give compound BB-6-5. MS m / z: 246.9, 248.9 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ9.36(s,1H),8.73(s,1H),4.47(s,2H).

[0421] Step 5: Synthesis of compound BB-6

[0422] Under nitrogen protection, compound BB-6-5 (0.7 g, 2.83 mmol, 1 eq) was dissolved in dioxane (7 mL), and di-tert-butyl dicarbonate (925.99 mg, 4.24 mmol, 974.72 μL, 1.5 eq) and 4-dimethylaminopyridine (69.11 mg, 565.71 μmol, 0.2 eq) were added. The reaction mixture was reacted at 25 °C for 1 hour. The reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (ethyl acetate / petroleum ether = 0%–5%) to obtain compound BB-6. MS m / z: 346.9, 348.9 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ8.75(s,1H),4.74(s,2H),1.54(s,9H).

[0423] Step 6: Synthesis of compound BB-7

[0424] Under nitrogen protection, compound BB-7-1 (2.6 g, 13.61 mmol, 1 eq) was dissolved in tetrahydrofuran (55 mL). After cooling to 0 °C, a tetrahydrofuran solution of sodium bis(trimethylsilyl)amino (1 M, 27.23 mL, 2 eq) was added. After stirring for 0.5 hours, di-tert-butyl dicarbonate (7.43 g, 34.03 mmol, 7.82 mL, 2.5 eq) was added, and the reaction was carried out at 25 °C for 2 hours. The reaction solution was slowly added to a saturated ammonium chloride aqueous solution (100 mL), extracted with ethyl acetate (100 mL × 3), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0%–2%) to obtain compound BB-7. 1 H NMR (400MHz, CDCl3) δppm 7.99-7.95 (m, 1H) 7.14 (m, 1H) 1.48 (s, 18H).

[0425] Step 7: Synthesis of Compound 4-2

[0426] Under nitrogen protection, compound 4-1 (5 g, 23.01 mmol, 1 eq) was added to hydrochloric acid / methanol (100 mL) and reacted at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of compound 4-2. The hydrochloride salt was dissolved in methanol (10 mL) and water (10 mL), and ammonia (2 mL) was added dropwise to adjust the pH to 10. The mixture was extracted with dichloromethane (50 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 4-2. 1HNMR (400MHz, CD3OD) δppm 4.03-3.99(m,2H), 3.80-3.76(m,2H), 3.71-3.69(m,2H), 3.33(s,1H), 3.30-3.21(m,2H).

[0427] Step 8: Synthesis of Compound 4-3

[0428] Under nitrogen protection, compound 4-2 (2.7 g, 23.05 mmol, 1 eq) was dissolved in DCM (54 mL), and triethylamine (4.66 g, 46.10 mmol, 6.42 mL, 2 eq), TBSCl (3.47 g, 23.05 mmol, 2.82 mL, 1 eq), and imidazole (1.88 g, 27.66 mmol, 1.2 eq) were added. The reaction mixture was reacted at 25 °C for 2 hours. The reaction solution was added to a saturated ammonium chloride aqueous solution (50 mL), extracted with dichloromethane (50 mL × 3), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The purified compound 4-3 was obtained by column chromatography (dichloromethane / methanol = 0–1%). 1 H NMR(400MHz,CD3OD)δppm 3.81(m,1H)3.74(m,1H)3.56-3.54(m,2H)3.27-3.26(m,1H)3.24(dd,J=11.2,9.8Hz,1H)2.88-2.85(m,3H)0.92-0.91(m,9H)0.08(s,6H).

[0429] Step 9: Synthesis of Compound 4-4

[0430] Under nitrogen protection, compounds 4-3 (1.6 g, 6.91 mmol, 1 eq) and BB-7 (2.71 g, 6.91 mmol, 1 eq) were added to toluene (32 mL), followed by cesium carbonate (4.51 g, 13.83 mmol, 2 eq), Ruphos (645.29 mg, 1.38 mmol, 0.2 eq), and tris(dibenzylacetone)palladium (949.73 mg, 1.04 mmol, 0.15 eq). The reaction mixture was reacted at 100 °C for 16 hours. The reaction solution was added to water (50 mL), and then extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound 4-4 was separated by column chromatography (ethyl acetate / petroleum ether = 0%–4%).

[0431] Step 10: Synthesis of compounds 4-5

[0432] Under nitrogen protection, compound 4-4 (0.8 g, 1.48 mmol, 1 eq) was added to tetrahydrofuran (45 mL), followed by a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 3.69 mL, 2.5 eq). The reaction mixture was reacted at 50 °C for 3 hours, and then concentrated under reduced pressure. Compound 4-5 was purified by column chromatography (ethyl acetate / petroleum ether = 0%–30%). MS m / z: 408.1 [M+1] + ; 1 HNMR(400MHz,CDCl3)δppm 7.02(d,J=8.2Hz,1H),6.76(d,J=8.2Hz,1H),4.34-4.32(m,1H),4.11-4.09(m,2H),3.94-3.92(m ,1H),3.74-3.73(m,1H),3.43(m,1H),3.28-3.26(m,2H),2.89-2.88(m,1H),1.49-1.45(m,18H).

[0433] Step 11: Synthesis of Compound 4-6 and its trifluoroacetate

[0434] Compounds 4-5 (0.52 g, 1.28 mmol, 1 eq) were added to DCM (12 mL) and trifluoroacetic acid (6 mL), and reacted at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate of compounds 4-6. The trifluoroacetate was dissolved in methanol (5 mL) and water (5 mL), and ammonia (1 mL) was added dropwise to adjust the pH to 10. The mixture was extracted with dichloromethane (20 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compounds 4-6. MS m / z: 208.0 [M+1] + .

[0435] Step 12: Synthesis of compounds 4-7

[0436] Under nitrogen protection, in the first batch: compound BB-6 (0.25 g, 719.23 μmol, 1 eq) and compound 4-6 (277.27 mg, 863.08 μmol, 1.2 eq) were added to dioxane (20 mL), followed by cesium carbonate (703.02 mg, 2.16 mmol, 3 eq), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (62.42 mg, 107.89 μmol, 0.15 eq), and palladium acetate (16.15 mg, 71.92 μmol, 0.1 eq). The reaction was carried out at 110 °C for 2 hours. In the second batch: the process of the first batch was repeated. The reaction solutions from both batches were combined and added to water (30 mL). The mixture was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compounds 4-7 were purified by column chromatography (EA / PE = 0-30%). MS m / z: 474.0 [M+1] + .

[0437] Step 13: Synthesis of compounds 4-8

[0438] To a solution of compound 4-8a (1.3 g, 6.16 mmol) in dioxane (22 mL), neopentyl glycol diboronate (2.09 g, 9.24 mmol) and KOAc (1.21 g, 12.32 mmol) were added. The mixture was purged three times with nitrogen, and Pd(dppf)Cl2 (676.03 mg, 923.92 μmol) was added. The reaction was carried out at 100 °C for 2 hours. Water (30 mL) was added, and the mixture was extracted with EA (30 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The concentrated crude product was purified by column chromatography (EA:PE: 0–20%) to obtain compound 4-8.

[0439] Step 14: Synthesis of compounds 4-9

[0440] Under nitrogen protection, compounds 4-7 (0.2 g, 422.02 μmol, 1 eq) and 4-8 (206.03 mg, 844.04 μmol, 2 eq) were added to dioxane (6 mL) and water (1.2 mL), along with potassium phosphate (268.74 mg, 1.27 mmol, 3 eq) and XPhos Pd G2 (33.20 mg, 42.20 μmol, 0.1 eq). The reaction mixture was reacted at 100 °C for 2 hours. The reaction solution was added to water (30 mL), and the combined organic phases were extracted with ethyl acetate (30 mL × 3). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. A mixture of dichloromethane and methanol (1:10, 30 mL) was added to the crude product, stirred for 0.5 hours, filtered, and the filter cake was dried to give compounds 4-9. MS m / z: 570.2 [M+1] +; 1 H NMR (400MHz, CDCl3) δppm 10.05(s,1H)9.23(s,1H)8.35(d,J=5.0Hz,1H)7.11(d,J=5.0Hz,1H)7.00(d,J=8.4Hz,1H)6.82(m,1H)6.48(d,J=8.4Hz,1H)4.88(s ,2H)4.29(m,1H)3.97-4.13(m,2H)3.79-3.93(m,4H)3.69(m,1H)3.36(m,1H)3.20-3.29(m,1H)3.15(m,1H)2.77(m,1H)1.54(s,9H).

[0441] Step 15: Synthesis of Compound 4 and its trifluoroacetate

[0442] Compound 4-9 (180 mg, 316.01 μmol) was added to DCM (0.5 mL) and trifluoroacetic acid (0.25 mL) and reacted at 25 °C for 2 hours. After concentration under reduced pressure, it was dissolved in 20 mL of dichloromethane and poured into 30 mL of sodium bicarbonate aqueous solution. Extraction was performed with dichloromethane (30 mL x 3). The combined organic phases were concentrated under reduced pressure, and then 10 mL of water was added and stirred for 0.5 hours. The mixture was filtered, and the filter cake was dried under reduced pressure to obtain compound 4. MS m / z: 470.1 [M+1] + .

[0443] Compound 4-9 (5 mg, 8.78 μmol, 1 eq) was added to dichloromethane (0.5 mL) and trifluoroacetic acid (0.25 mL), and reacted at 25 °C for 2 hours. The mixture was concentrated under reduced pressure to give the trifluoroacetate of compound 4. MS m / z: 470.1 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δppm9.85(s,1H)9.45(s,1H)9.15(s,1H)8.35(d,J=5.0H z,1H)7.56(d,J=3.4Hz,1H)7.37(d,J=5.0Hz,1H)7.32(d,J=8.6Hz,1H)6.92(d,J =3.4Hz,1H)6.69(d,J=8.4Hz,1H)4.71(s,2H)4.36-4.44(m,1H)3.90-4.01(m,2H )3.87(s,3H)3.55-3.63(m,2H)3.17-3.25(m,1H)3.02-3.11(m,1H)1.24(s,2H).

[0444] Example 5

[0445]

[0446] Step 1: Synthesis of Compound 5-2

[0447] Under nitrogen protection, compound 5-1 (2 g, 9.25 mmol) was dissolved in DCM (40 mL), and then added to a solution of triethylamine (1.87 g, 18.49 mmol, 2.57 mL), TBSCl (2.09 g, 13.87 mmol, 1.70 mL), and 4-dimethylaminopyridine (112.97 mg, 924.74 μmol, 0.1 eq). The reaction mixture was stirred at 20 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then subjected to column chromatography (dichloromethane / methanol = 5%–10%) to give compound 5-2. 1 H NMR (400MHz, CD3OD) δppm 3.88-4.12(m,2H)3.63(d,J=5.6Hz,2H)3.01(d,J=12.2Hz,1H)2.54-2.94(m,4H)1.48(s,9H)0.95(s,9H)0.12(s,6H).

[0448] Step 2: Synthesis of Compound 5-4

[0449] Under nitrogen protection, cesium carbonate (197.15 mg, 605.08 μmol), Ruphos (14.12 mg, 30.25 μmol), compound 5-2 (0.1 g, 302.54 μmol), compound 5-3 (70.80 mg, 302.54 μmol), and tris(dibenzylacetone)dipalladium (55.41 mg, 60.51 μmol) were added to a toluene (4 mL) solution, and the reaction was stirred at 100 °C for 24 hours. The reaction solution was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then subjected to column chromatography (ethyl acetate / petroleum ether = 16%) to give compound 5-4. MS m / z: 484.3 [M+1] + ;

[0450] Step 3: Synthesis of compound 5-5

[0451] Tetrabutylammonium bromide (1 M, 258.45 μL) and compound 5-4 (50 mg, 103.38 μmol) were added to tetrahydrofuran (4 mL), and the reaction mixture was stirred at 25 °C for 16 hours. The reaction solution was concentrated under reduced pressure to give compound 5-5. MS m / z: 350.2 [M+1] + .

[0452] Step 4: Synthesis of compounds 5-6

[0453] Lithium hydroxide monohydrate (288.26 mg, 6.87 mmol) and compound 5-5 (0.4 g, 1.14 mmol) were added to a mixed solution of tetrahydrofuran (6 mL), methanol (3 mL), and water (3 mL). The reaction mixture was stirred at 25 °C for 0.5 h. The reaction solution was concentrated under reduced pressure to give compound 5-6. MS m / z: 336.2 [M+1] + .

[0454] Step 5: Synthesis of compounds 5-7

[0455] Compound 5-6 (0.4 g, 1.19 mmol) and triethylamine (241.39 mg, 2.39 mmol, 332.04 μL) were added to toluene (6 mL). Water (85.95 mg, 4.77 mmol, 85.95 μL) was added to the reaction solution, followed by diphenyl azide phosphate (656.50 mg, 2.39 mmol, 516.93 μL). The reaction mixture was stirred at 90 °C for 2 hours. The reaction solution was concentrated under reduced pressure to give compound 5-7. MS m / z: 307.0 [M+1] + .

[0456] Step 6: Synthesis of compounds 5-9

[0457] Under nitrogen protection, compounds 5-7 (20 mg, 57.70 μmol), di-tert-butyl[2,4,6-tris(propane-2-yl)-[1,1-diphenyl]-2-yl]phosphine (5.50 mg, 11.54 μmol), and 5-8 (26.52 mg, 86.55 μmol) were added to dioxane (3 mL). Palladium acetate (1.30 mg, 5.77 μmol) was added to the reaction solution, followed by cesium carbonate (56.40 mg, 173.10 μmol). The reaction was stirred at 90 °C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (methanol / ethyl acetate = 10%) to give compound 5-9. MS m / z: 572.1 [M+1] + .

[0458] Step 7: Synthesis of compounds 5-10

[0459] Under nitrogen protection, compounds 5-9 (10.00 mg, 17.48 μmol) and 4-8 (6.15 mg, 34.96 μmol) were added to dioxane (2 mL), potassium phosphate (11.13 mg, 52.44 μmol) was added to the reaction solution, and then XPhosPd G2 (1.38 mg, 1.75 μmol) was added. The reaction was stirred at 100 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (ethyl acetate / petroleum ether = 50%) to obtain compound 5-10. MS m / z: 668.1 [M+1] + .

[0460] Step 8: Synthesis of Compound 5

[0461] Compound 5-10 (6 mg, 8.99 μmol) was added to DCM (2 mL), and trifluoroacetic acid (2.05 mg, 17.97 μmol, 1.33 μL) was added to the reaction solution. The reaction was stirred at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude starting material, which was separated by column chromatography (ethyl acetate / petroleum ether = 50%) to obtain compound 5. MS m / z: 468.0 [M+1] + ; 1 H NMR(400MHz,CD3OD)δppm 8.41(d,J=8.6Hz,1H)8.25(d,J=5.4Hz,1H)7.65(d,J=8.6Hz,1H)7.41(d,J=3.6Hz,1H)7.23-7.33(m,2H)6.55-6.61(m,1H)6.49(d,J=3.6 Hz,1H)4.39(s,2H)4.12(m,1H)3.93(d,J=14.8Hz,1H)3.86(s,3H)3.34-3.43(m,2H)2.82-2.93(m,2H)1.93(d,J=4.2Hz,1H)1.49(s,2H).

[0462] Example 6

[0463]

[0464] Step 1: Synthesis of Compound 6

[0465] Compound 5 (8.00 mg, 17.11 μmol) was added to methanol (5 mL), followed by triethylamine (5.19 mg, 51.33 μmol, 7.15 μL) and acetaldehyde aqueous solution (9.42 mg, 85.56 μmol, 12.00 μL, 40% purity). The reaction mixture was stirred for 10 minutes, and then NaBH(OAc)3 (5.44 mg, 25.67 μmol) was added. The reaction mixture was stirred at 25 °C for 1 hour. The reaction solution was quenched with water (5 mL), and then extracted with dichloromethane (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography using silica gel plates (ethyl acetate / methanol = 1:1, v% = 0.5% triethylamine) to obtain compound 6. MS m / z: 496.2 [M+1] + ; 1 H NMR(400MHz,CD3OD)δppm 8.52(d,J=8.6Hz,1H)8.35(d,J=5.4Hz,1H)7.75(d,J=8.6Hz,1H)7.40-7.54(m,2H)7 .30(d,J=5.2Hz,1H)6.70(d,J=8.2Hz,1H)6.55(d,J=3.6Hz,1H)4.53(m,1H)4.49(s, 2H)4.21-4.30(m,1H)4.12(d,J=13.2Hz,1H)3.96(s,3H)3.74(t,J=12.6Hz,2H)3.50 (s,1H)3.40-3.44(m,2H)3.11-3.27(m,1H)2.93-3.04(m,2H)1.44(t,J=7.4Hz,3H).

[0466] Example 7

[0467]

[0468] Step 1: Synthesis of Compound 7-2

[0469] Under nitrogen protection, compound 7-1 (200 mg, 1.07 mmol, 1 eq) was dissolved in dioxane (5 mL), and compound BB-1 (321.76 mg, 1.07 mmol, 1 eq), cesium carbonate (698.45 mg, 2.14 mmol, 2 eq), Xantphos (186.06 mg, 321.55 μmol, 0.3 eq), and Pd2(dba)3 (196.30 mg, 214.37 μmol, 0.2 eq) were added. The reaction was carried out at 110 °C for 2 hours. After cooling, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Compound 7-2 was purified by column chromatography (methanol / ethyl acetate = 0%–33%). MS m / z: 406.1 [M+1] + .

[0470] Step 2: Synthesis of Compound 7-3

[0471] Under nitrogen protection, compound 7-2 (90 mg, 221.74 μmol, 1 eq) was dissolved in dioxane (2 mL) and water (0.4 mL). Compound 4-8 (64.95 mg, 266.09 μmol, 1.2 eq), potassium carbonate (76.62 mg, 554.35 μmol, 2.5 eq), and Pd(dppf)Cl2 (14.45 mg, 22.17 μmol, 0.1 eq) were added, and the reaction was carried out at 100 °C for 2 hours. After cooling, the reaction solution was separated by thin-layer chromatography (ethyl acetate / methanol = 1:1, v% = 0.5% triethylamine) to obtain compound 7-3. MS m / z: 502.4 [M+1] + .

[0472] Step 3: Synthesis of Compound 7

[0473] Under nitrogen protection, a tetrahydrofuran solution (1 M, 1.28 mL, 8 eq) of lithium bis(trimethylsilyl)aminoacetonitrile was added to a mixture of compound 7-3 (80 mg, 159.50 μmol, 1 eq) and ammonium chloride (51.19 mg, 956.98 μmol, 6 eq), and the reaction was carried out at 20 °C for 0.5 h. The reaction was quenched with methanol (3 mL), and the solvent was concentrated under reduced pressure to obtain the crude product. Compound 7 was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH4HCO3)-acetonitrile]; acetonitrile %: 15%-45%, 8 min). MS m / z: 487.2 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ10.67(s,1H),10.09(s,1H),8.63(s,1H),8.35(d,J=5.2Hz,1H),8.28(s,1H),7.97(s,1H),7.66(d,J=4.8Hz,1H),7. 60-7.52(m,2H),7.11(d,J=3.6Hz,1H),6.95(d,J=8.8Hz,1H),3.87(s,3H),3.77-3.72(m,4H),3.55(s,2H),3.01-2.91(m,4H),2.30(s,6H).

[0474] Example 8

[0475]

[0476] Step 1: Synthesis of Compound 8-2

[0477] Under nitrogen protection, compound 5-8 (300 mg, 865.54 μmol, 1 eq) was dissolved in dioxane (10 mL), and trifluoroacetate of compound 4-6 (452.10 mg, 1.04 mmol, 2.52 eq), cesium carbonate (1.13 g, 3.46 mmol, 4 eq), Xantphos (75.12 mg, 129.83 μmol, 0.15 eq), and palladium acetate (19.43 mg, 86.55 μmol, 0.1 eq) were added. The reaction was carried out at 110 °C for 2 hours. After cooling, the mixture was filtered, washed with dichloromethane (20 mL), and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound 8-1 was purified by column chromatography (ethyl acetate / petroleum ether = 0%–40%). MS m / z: 473.1 [M+1] + ; 1 H NMR(400MHz, CDCl3)δ9.46(s,1H),8.58(d,J=8.8Hz,1H),7.42(d,J=8.8Hz,1H),7 .05(d,J=8.4Hz,1H),6.47(d,J=8.4Hz,1H),4.67(s,2H),4.36-4.33(m,1H),4.20- 4.10(m,1H),4.09-4.02(m,1H),3.94-3.91(m,1H),3.79-3.72(m,1H),3.41(d,J=1 1.6Hz,1H),3.36-3.26(m,1H),3.23-3.14(m,1H),2.85-2.79(m,1H),1.63(s,9H).

[0478] Step 2: Synthesis of Compound 8-2

[0479] Under nitrogen protection, compound 8-1 (211 mg, 446.16 μmol, 1 eq) was dissolved in dioxane (5 mL), and compound 1-2 (339.89 mg, 1.34 mmol, 3 eq), potassium acetate (131.36 mg, 1.34 mmol, 3 eq), Xphos (42.54 mg, 89.23 μmol, 0.2 eq), and XPhos Pd G2 (35.10 mg, 44.62 μmol, 0.1 eq) were added. The mixture was reacted at 110 °C for 2 hours. After cooling, the mixture was filtered, washed with dichloromethane (20 mL), and the filtrate was concentrated under reduced pressure. Compound 8-2 was purified by column chromatography (ethyl acetate / petroleum ether = 0%–30%). MS m / z: 565.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ9.57(s,1H),8.26(d,J=8.8Hz,1H),7.76(d,J=8.4Hz,1H ),7.29(d,J=8.4Hz,1H),6.69(d,J=8.4Hz,1H),4.75(s,2H),4.39-4.35(m,1H), 4.07-4.02(m,1H),4.00-3.93(m,1H),3.91-3.89(m,1H),3.64-3.57(m,2H),3.2 3-3.14(m,1H),3.10-3.00(m,1H),2.67-2.61(m,1H),1.53(s,9H),1.30(s,12H).

[0480] Step 3: Synthesis of Compound 8-3

[0481] Under nitrogen protection, compound 8-2 (107 mg, 189.57 μmol, 1 eq) was dissolved in dioxane (5 mL) and water (1 mL). Compound BB-2-2 (48.91 mg, 227.48 μmol, 1.2 eq), potassium phosphate (80.48 mg, 379.14 μmol, 2 eq), and XPhos Pd G2 (14.92 mg, 18.96 μmol, 0.1 eq) were added, and the reaction was carried out at 100 °C for 2 hours. The reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL × 3), and the organic phase was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give compound 8-3. MS m / z: 573.4 [M+1] + .

[0482] Step 4: Synthesis of Compound 8

[0483] Under nitrogen protection, compound 8-3 (201 mg, 351.04 μmol, 1 eq) was dissolved in DCM (4 mL), and trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL, 76.95 eq) was added. The reaction was carried out at 20 °C for 2 hours. The solvent was concentrated under reduced pressure to obtain the crude product. Compound 8 was purified by prep-HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (NH4HCO3)-acetonitrile]; acetonitrile %: 15%-50%, 8 min). MS m / z: 473.1 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ9.77(s,1H),8.75(s,1H),8.48(d,J=8.4Hz,1H),8.43-8 .39(m,1H),7.80(s,1H),7.68(d,J=8.8Hz,1H),7.53-7.50(m,1H),7.28(d,J=8. 4Hz,1H),6.98-6.94(m,1H),6.59(d,J=8.4Hz,1H),4.36(s,3H),4.07-3.84(m,3 H),3.66-3.53(m,2H),3.23-3.14(m,1H),3.07-2.98(m,1H),2.69-2.64(m,1H).

[0484] Example 9

[0485]

[0486] Step 1: Synthesis of the hydrochloride salt of compound BB-8-2

[0487] Under nitrogen protection, compound BB-8-1 (5 g, 23.01 mmol, 1 eq) was added to a hydrochloric acid / methanol solution (4 M, 100.00 mL, 17.38 eq), and the reaction was carried out at 20 °C for 2 hours. The solvent was concentrated under reduced pressure to obtain the hydrochloride salt of BB-8-2. 1 H NMR (400MHz, DMSO-d6) δ9.50(s,1H),9.27-9.06(m,1H),3.97-3.81(m,2H),3.73-3.47(m,4H),3.28-2.96(m,3H).

[0488] Step 2: Synthesis of compound BB-8-3

[0489] Under nitrogen protection, the hydrochloride salt of compound BB-8-2 (2.7 g, 23.05 mmol, 1 eq) was added to DCM (54 mL), followed by triethylamine (7.00 g, 69.14 mmol, 9.62 mL, 3 eq), imidazole (1.88 g, 27.66 mmol, 1.2 eq), and TBSCl (4.17 g, 27.66 mmol, 3.39 mL, 1.2 eq). The reaction was carried out at 20 °C for 16 hours. The reaction was quenched with saturated ammonium chloride aqueous solution (40 mL), extracted with dichloromethane (50 mL × 3), and the organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The purified compound BB-8-3 was obtained by column chromatography (methanol / dichloromethane = 0–10%). 1 H NMR (400MHz, CDCl3) δ3.81-3.77(m,2H),3.60-3.41(m,3H),3.26-3.23(m,1H),3.02-2.80(m,3H),1.96(s,1H),0.90(s,9H),0.06(s,6H).

[0490] Step 3: Synthesis of compound BB-8-4

[0491] Under nitrogen protection, compound BB-7 (1.7 g, 4.35 mmol, 1 eq) was dissolved in toluene (34 mL), and compound BB-8-3 (1.01 g, 4.35 mmol, 1 eq), cesium carbonate (2.83 g, 8.69 mmol, 2 eq), Ruphos (405.53 mg, 869.05 μmol, 0.2 eq), and Pd2(dba)3 (596.85 mg, 651.79 μmol, 0.15 eq) were added. The reaction was carried out at 100 °C for 16 hours. After cooling, the mixture was filtered, and the residue was washed with dichloromethane (30 mL). The filtrate was concentrated under reduced pressure. The purified compound BB-8-4 was obtained by column chromatography (ethyl acetate / petroleum ether = 0%–10%). MS m / z: 542.3 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ7.57-7.52(m,1H),7.20(d,J=8.0Hz,1H),3.93-3.77(m,3H),3.76-3.69( m,1H),3.66-3.48(m,3H),3.29(s,1H),2.94(d,J=12.4Hz,1H),1.38(s,18H),0.77(s,9H),-0.07 -0.10(d,J=9.6Hz,6H).

[0492] Step 4: Synthesis of compound BB-8-5

[0493] Under nitrogen protection, compound BB-8-4 (484 mg, 893.44 μmol, 1 eq) was dissolved in tetrahydrofuran (10 mL), and a tetrahydrofuran solution of tetrabutylammonium fluoride (1 M, 3.69 mL, 2.5 eq) was added. The reaction was carried out at 50 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure. The mixture was purified by column chromatography (ethyl acetate / petroleum ether = 0%–30%) to obtain compound BB-8-5. MS m / z: 408.1 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ7.24(d,J=8.0Hz,1H),6.79(d,J=8.0Hz,1H),4.37-4.34(m,1H),4.07-3.95( m,2H),3.89(d,J=8.4Hz,1H),3.64-3.52(m,2H),3.21-3.07(m,2H),2.75-2.65(m,1H),1.39(s,18H).

[0494] Step 5: Synthesis of the trifluoroacetate of compound BB-8

[0495] Under nitrogen protection, compound BB-8-5 (269 mg, 660.19 μmol, 1 eq) was dissolved in DCM (5 mL), and trifluoroacetic acid (3.95 g, 34.67 mmol, 2.57 mL, 52.51 eq) was added. The reaction mixture was reacted at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate of compound BB-8. MS m / z: 208.1 [M+1] + .

[0496] Step 6: Synthesis of Compound 9-1

[0497] Under nitrogen protection, compound 5-8 (165 mg, 476.05 μmol, 1 eq) was dissolved in dioxane (5 mL), and trifluoroacetate of compound BB-8 (248.65 mg, 571.26 μmol, 1.2 eq), cesium carbonate (620.42 mg, 1.90 mmol, 4 eq), Xantphos (41.32 mg, 71.41 μmol, 0.15 eq), and palladium acetate (10.69 mg, 47.60 μmol, 0.1 eq) were added. The reaction was carried out at 110 °C for 2 hours. After cooling, the mixture was filtered, and the residue was washed with dichloromethane (20 mL). The filtrate was concentrated under reduced pressure. Compound 9-1 was purified by column chromatography (ethyl acetate / petroleum ether = 0%–35%). MS m / z: 473.1 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ9.28(s,1H),8.40(d,J=8.8Hz,1H),7.59(d,J=8.8Hz,1H),7.28(d,J=8.4Hz,1H),6.67(d,J=8.4Hz,1H),4.69( s,2H),4.37-4.34(m,1H),4.04-3.86(m,3H),3.64-3.53(m,2H),3.23-3.13(m,1H),3.09-2.98(m,1H),2.71-2.63(m,1H),1.53(s,9H).

[0498] Step 7: Synthesis of Compound 9-2

[0499] Under nitrogen protection, compound 9-1 (170 mg, 359.47 μmol, 1 eq) was dissolved in dioxane (4 mL), followed by compound 1-2 (273.85 mg, 1.08 mmol, 3 eq), potassium acetate (105.83 mg, 1.08 mmol, 3 eq), XPhos (34.27 mg, 71.89 μmol, 0.2 eq), and XPhos Pd G2 (28.28 mg, 35.95 μmol, 0.1 eq). The reaction was carried out at 110 °C for 2 hours. After cooling, the mixture was filtered, and the residue was washed with dichloromethane (20 mL). The filtrate was concentrated under reduced pressure. Compound 9-2 was purified by column chromatography (ethyl acetate / petroleum ether = 0%–35%). MS m / z: 565.2 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ9.76 (s, 1H), 8.42 (d, J = 8.8Hz, 1H), 7.89 (d, J = 8.4Hz, 1H), 7.05 (d,J=8.4Hz,1H),6.52(d,J=8.4Hz,1H),4.86(s,2H),4.36-4.33(m,1H),4.19-4.11(m ,1H),4.09-4.05(m,1H),3.94-3.90(m,1H),3.79-3.72(m,1H),3.41(d,J=12.0Hz,1H) ,3.34-3.26(m,1H),3.23-3.14(m,1H),2.90-2.76(m,1H),1.64(s,9H),1.33(s,12H).

[0500] Step 8: Synthesis of Compound 9-3

[0501] Under nitrogen protection, compound 9-2 (134 mg, 237.41 μmol, 1 eq) was dissolved in dioxane (5 mL) and water (1 mL). Compound BB-2-2 (61.26 mg, 284.89 μmol, 1.2 eq), potassium phosphate (100.79 mg, 474.81 μmol, 2 eq), and XPhos Pd G2 (18.68 mg, 23.74 μmol, 0.1 eq) were added, and the reaction was carried out at 100 °C for 2 hours. After cooling, the mixture was filtered, and the residue was washed with dichloromethane (10 mL). The filtrate was concentrated under reduced pressure. Compound 9-3 was purified by column chromatography (ethyl acetate / petroleum ether = 0%–70%). MS m / z: 573.4 [M+1] + .

[0502] Step 9: Synthesis of Compound 9 and its trifluoroacetate

[0503] Under nitrogen protection, compound 9-3 (125 mg, 218.31 μmol, 1 eq) was dissolved in DCM (4 mL), and trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL, 76.95 eq) was added. The reaction was carried out at 20 °C for 2 hours. The solvent was concentrated under reduced pressure to obtain the crude product, which was purified by prep-HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (NH4HCO3)-acetonitrile]; acetonitrile %: 20%-50%, 8 min). Compound 9 was obtained. MS m / z: 473.1 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ9.77 (s, 1H), 8.75 (s, 1H), 8.48 (d, J = 8.4Hz, 1H), 8.43-8. 39(m,1H),7.80(s,1H),7.67(d,J=8.8Hz,1H),7.53-7.50(m,1H),7.28(d,J=8.4H z,1H),6.98-6.94(m,1H),6.59(d,J=8.4Hz,1H),4.40-4.31(m,3H),4.07-3.86(m ,3H),3.66-3.52(m,2H),3.25-3.14(m,1H),3.09-2.99(m,1H),2.68-2.64(m,1H).

[0504] Under nitrogen protection, compound 9-3 (0.4 g, 698.59 μmol) was dissolved in DCM (10 mL), and trifluoroacetic acid (5 mL) was added. The reaction was carried out at 25 °C for 2 hours. The solvent was concentrated under reduced pressure to obtain the crude product, which was purified by prep-HPLC (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (TFA)-acetonitrile]; B%: 10%-35%, 8 min) to obtain the trifluoroacetate salt of compound 9. MS m / z: 473.1 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δppm 9.82(s,1H)8.81(s,1H)8.66(dd,J=7.44,5.32Hz,1H)8.52(d,J=8.64Hz,1H)8.25(s ,1H)7.92(dd,J=8.76,2.24Hz,1H)7.72(d,J=8.62Hz,1H)7.39-7.38(m,1H)7.30(d,J =8.50Hz,1H)6.62(d,J=8.38Hz,1H)4.39-4.36(m,3H)4.07-4.04(m,2H)3.91(dd,J=1 0.94,2.80Hz,1H)3.61-3.56(m,2H)3.20-3.17(m,1H)3.04(s,1H)2.66-2.65(m,1H).

[0505] Example 10

[0506]

[0507] Step 1: Synthesis of compound 10⁻³

[0508] Under nitrogen protection, compound 10⁻¹ (0.7 g, 2.48 mmol, 1 eq) was dissolved in dioxane (6 mL) and water (1.2 mL). Compound 10⁻² (1.24 g, 4.95 mmol, 2 eq), XPhos Pd G₂ (194.81 mg, 247.59 μmol, 0.1 eq), and potassium phosphate (1.05 g, 4.95 mmol, 2 eq) were added, and the reaction was carried out at 100 °C for 1 hour. After cooling, the mixture was extracted with water (5 mL) and ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 50%–100%) to obtain compound 10⁻³. MS m / z: 371.2 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ8.63(s,1H),7.19-7.07(m,1H),6.72-6.62(m,1H),6.49(s,2H),3.81(s,3H),3.29(s,2H),2.15(s,3H),1.43(s,9H).

[0509] Step 2: Synthesis of compound 10⁻⁴

[0510] Under nitrogen protection, compound 10⁻³ (0.2 g, 539.95 μmol, 1 eq) was dissolved in dioxane (10 mL), and BB-1 (194.51 mg, 647.95 μmol, 1.2 eq), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (46.86 mg, 80.99 μmol, 0.15 eq), palladium acetate (12.12 mg, 54.00 μmol, 0.1 eq), and cesium carbonate (527.78 mg, 1.62 mmol, 3 eq) were added. The reaction was carried out at 100 °C for 1 h. After cooling, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 10⁻⁴. MS m / z: 590.3 [M+1] + .

[0511] Step 3: Synthesis of Compound 10

[0512] Under nitrogen protection, compound 10⁻⁴ (0.4 g, 678.33 μmol, 1 eq) was dissolved in hydrochloric acid / methanol solution (40 mL) and reacted at 25 °C for 2 hours. The reaction system was concentrated under reduced pressure to obtain the crude product, which was then purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [water (NH₄HCO₃)-acetonitrile]; acetonitrile %: 10%-60%, 8 min) to obtain compound 10. MS m / z: 490.4 [M+1] + ; 1 H NMR (400MHz, CDCl3) δppm 9.76(s,1H)8.86(d,J=8.6Hz,1H)8.72(s,1H)7.43(d,J=8.6Hz,1H)7.31(s,1H)6.84(d,J=8.6Hz,1H)6.07(s,1H)4.24-4.20(m,1H)4.07 -4.03(m,1H)3.95(s,3H)3.89-3.88(m,4H)3.87-3.73(m,2H)3.30-3.01(m,4H)2.98(s,6H)2.44-2.34(m,3H).

[0513] Examples 11 and 12

[0514]

[0515] Step 1: Synthesis of compound BB-9

[0516] Compound BB-7 (8 g, 20.45 mmol, 1 eq) was dissolved in dioxane (120 mL), and pinacol diboronate (7.79 g, 30.67 mmol, 1.5 eq), potassium acetate (4.01 g, 40.90 mmol, 2 eq), and Pd(dppf)Cl2.CH2Cl2 (1.67 g, 2.04 mmol, 0.1 eq) were added. The mixture was reacted at 120 °C for 12 hours. After cooling, the mixture was filtered, and the filtrate was poured into water (200 mL). The mixture was extracted with ethyl acetate (200 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 0%–4%) to obtain compound BB-9. MS m / z: 200.8 [M-238] + .

[0517] Step 2: Synthesis of compound 11-2

[0518] Compound 11-1 (3 g, 18.97 mmol, 1 eq) was added to tetrahydrofuran (45 mL), cooled to 0 °C, and then sodium hydride (1.14 g, 28.45 mmol, 60% purity, 1.5 eq) was added. After stirring for 0.5 hours, N-phenylbis(trifluoromethanesulfonyl)imide (8.13 g, 22.76 mmol, 1.2 eq) was added, and the mixture was heated to 25 °C and reacted for 12 hours. The reaction solution was slowly added to a saturated ammonium chloride aqueous solution (100 mL), extracted with ethyl acetate (100 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 11-2 was purified by column chromatography (ethyl acetate / petroleum ether = 0%–4%). 1 H NMR (400MHz, CDCl3) δppm 4.38 (t, J = 2.6 Hz, 2H) 3.82 (t, J = 5.6z, 2H) 3.75 (s, 3H) 2.49-2.45 (m, 2H).

[0519] Step 3: Synthesis of Compound 11-3

[0520] Compound 11-2 (2.5 g, 8.61 mmol, 1 eq) and BB-9 (5.85 g, 13.35 mmol, 1.55 eq) were added to dioxane (50 mL) and water (10 mL), along with potassium phosphate (5.49 g, 25.84 mmol, 3 eq) and XPhos Pd G2 (677.78 mg, 861.44 μmol, 0.1 eq). The reaction mixture was reacted at 100 °C for 12 h. The reaction solution was added to water (100 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 11-3 was purified by column chromatography (ethyl acetate / petroleum ether = 0%–5%). MS m / z: 353.1 [M+1] + ; 1 H NMR (400MHz, CDCl3) δppm 7.72(d,J=8.0Hz,1H)7.45(t,J=8.8Hz,1H)7.01(s,1H)4.39(s,2H)3.82(t,J=5.4Hz,2H)3.50(s,3H)2.40(s,2H)1.45(s,9H).

[0521] Step 4: Synthesis of compound 11-4

[0522] Compound 11-3 (1.2 g, 3.41 mmol, 1 eq) was added to tetrahydrofuran (24 mL), cooled to 0 °C, and then lithium aluminum hydride (323.15 mg, 8.51 mmol, 2.5 eq) was added. The reaction was allowed to proceed for 2 hours. Water was added dropwise to the reaction solution until the reaction was completely quenched. Anhydrous sodium sulfate was added and the solution was dried. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 11-4. MS m / z: 325.0 [M+1] + ; 1 H NMR (400MHz, CDCl3) δppm 7.74 -7.72 (m 1H) 7.53-7.48 (m 1H)7.04(s,1H)4.30(t,J=2.2Hz,2H)3.90-3.88(m,2H)3.84-3.82(m,2H)2.30(s,2H)1.45(s,9H).

[0523] Step 5: Synthesis of Compound 11-5

[0524] Compound 11-4 (0.9 g, 2.77 mmol, 1 eq) was added to tetrahydrofuran (20 mL), cooled to 0 °C, and sodium hydride (221.96 mg, 5.55 mmol, 60% purity, 2 eq) was added. The mixture was stirred for 0.5 h, then heated to 50 °C and reacted for 2 h. After the reaction was complete, the reaction solution was slowly added to a saturated ammonium chloride aqueous solution (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give compound 11-5. MS m / z: 305.1 [M+1] + .

[0525] Step 6: Synthesis of Compound 11-6

[0526] Palladium / carbon (0.5 g, 10% purity) was added to a dry hydrogenation flask, followed by methanol (30 mL), compound 11-6 (0.8 g, 2.63 mmol, 1 eq), and the reaction was carried out at 30 °C for 2 hours under hydrogen (15 psi). The mixture was filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (ethyl acetate / petroleum ether = 0%–10%) to obtain compound 11-6. MS m / z: 307.1 [M+1] + ; 1 HNMR(400MHz,CDCl3)δppm 7.43-7.42(m,1H)7.35-7.33(m,1H)6.94(s,1H)4.45-4.39(m,1H)4.24-4.21(m,1H)3.77- 3.74(m,3H)3.50-3.47(m,1H)2.93(m,1H)2.15-2.13(m,1H)1.88-1.79(m,2H)1.45(s,9H).

[0527] Step 7: Synthesis of the hydrochloride salt of compound 11-7

[0528] Compound 11-6 (0.78 g, 2.55 mmol, 1 eq) was added to hydrochloric acid / methanol (4 M, 2 mL) and reacted at 25 °C for 12 hours. The reaction solution was concentrated under reduced pressure to give the hydrochloride salt of compound 11-7. MS m / z: 207.0 [M+1] + .

[0529] Step 8: Synthesis of compounds 11-8

[0530] Compound 5-8 (0.45 g, 1.30 mmol, 1 eq) and the hydrochloride salt of compound 11-7 (378.12 mg, 1.56 mmol, 1.20 eq) were added to dioxane (20 mL), followed by cesium carbonate (1.69 g, 5.19 mmol, 4 eq), Xantphos (112.68 mg, 194.75 μmol, 0.15 eq), and Pd2(dba)3 (118.89 mg, 129.83 μmol, 0.1 eq). The reaction mixture was reacted at 100 °C for 12 h. The reaction solution was added to water (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (ethyl acetate / petroleum ether = 0%–25%) to obtain compound 11-8. MS m / z: 472.1 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δppm 9.48(s,1H)8.64(d,J=9.0Hz,1H)7.65(d,J=8.8Hz,1H)7.56(d,J=8.2Hz,1H)6.65(d,J=8.0Hz,1H)4.71(s,2H)4.37 -4.28(m,2H)3.75-3.68(m,3H)3.47-3.46(m,1H)3.03-3.00(m,1H)2.14-2.10(m,1H)1.85-1.82(m,2H)1.54(s,9H).

[0531] Step 9: Synthesis of compounds 11-9

[0532] Compound 11-8 (0.25 g, 529.74 μmol, 1 eq), bis(phenylephrine)boronic acid (403.56 mg, 1.59 mmol, 3 eq) were added to dioxane (10 mL), followed by potassium acetate (155.97 mg, 1.59 mmol, 3 eq), XPhos Pd G2 (41.68 mg, 52.97 μmol, 0.1 eq), and 2-di-tert-butylphosphine-2',4',6'-triisopropylbiphenyl (50.51 mg, 105.95 μmol, 0.2 eq). The reaction mixture was reacted at 110 °C for 3 hours. The reaction solution was added to water (40 mL), extracted with ethyl acetate (40 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The purified compound 11-9 was obtained by column chromatography (ethyl acetate / petroleum ether = 0%–25%). MS m / z: 564.3 [M+1] + .

[0533] Step 10: Synthesis of compounds 11-10

[0534] Compound 11-9 (275.14 mg, 488.32 μmol, 1.5 eq) and compound BB-2-2 (70 mg, 325.55 μmol, 1 eq) were added to dioxane (10 mL), water (2 mL), XPhos Pd G2 (25.61 mg, 32.55 μmol, 0.1 eq), and potassium phosphate (207.31 mg, 976.64 μmol, 3 eq). The reaction mixture was reacted at 105 °C for 4 hours. The reaction solution was added to water (40 mL), extracted with ethyl acetate (40 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 11-10 was purified by column chromatography (ethyl acetate / petroleum ether = 0%–50%). MS m / z: 572.2 [M+1] + .

[0535] Step 11: Synthesis of trifluoroacetate of compound 11 and trifluoroacetate of compound 12

[0536] Compounds 11-10 (0.15 g, 262.42 μmol, 1 eq) were added to DCM (10 mL) and trifluoroacetic acid (5 mL), and reacted at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure and separated by SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH3H2O ​​IPA]; B%: 58%-58%, 16 min). The separated products were concentrated, and 5 drops of trifluoroacetic acid were added to each to obtain trifluoroacetate salts of compound 11 and 12.

[0537] Trifluoroacetate of compound 11: MS m / z: 472.1 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δppm10.04(s,1H)8.87(s,1H)8.75(d,J=8.6Hz,1H)8.6 9(m,1H)8.30(s,1H)7.95(m,1H)7.77(d,J=8.6Hz,1H)7.56(d,J=7.8Hz,1H)7.4 3-7.41 (m, 1H) 6.59 (d, J = 8.0 Hz, 1H) 4.40-4.38 (m, 3H) 4.35-4.30 (m, 1H) 3.74-3.68 (m, 3H) 3.46 (s, 1H) 3.02-3.00 (m, 1H) 2.13-2.11 (m, 1H) 1.84-1.82 (m, 2H). ee% = 100%, retention time: 1.196 min.

[0538] Trifluoroacetate of compound 12: MS m / z: 472.1 [M+1]+ ; 1 H NMR(400MHz,DMSO-d6)δppm10.06(s,1H)8.88(s,1H)8.76(d,J=8.6Hz,1H)8.72 -8.69(m,1H)8.31(s,1H)7.97(m,1H)7.78(d,J=8.8Hz,1H)7.58(d,J=7.8Hz,1H) 7.46-7.44 (m, 1H) 6.60 (d, J = 7.8 Hz, 1H) 4.41-4.39 (m, 3H) 4.37-4.30 (m, 1H) 3.76-3.70 (m, 3H) 3.48 (s, 1H) 3.03-3.02 (m, 1H) 2.13-2.12 (m, 1H) 1.87-1.84 (m, 2H). ee% = 98.46%, retention time: 1.586 min.

[0539] Analytical method for detecting ee%: Column: Chiralpak AD-3, 50×4.6mm ID, 3μm; Mobile phase: A: Carbon dioxide; B: Isopropanol (0.1% IPAm, v / v).

[0540] Examples 13 and 14

[0541]

[0542]

[0543] Step 1: Synthesis of Compound 13-2

[0544] Compound 13-1 (3 g, 18.97 mmol, 1 eq) was added to tetrahydrofuran (45 mL), cooled to 0 °C, and then sodium hydride (1.14 g, 28.45 mmol, 60% purity, 1.5 eq) was added. After stirring for 0.5 hours, N-phenylbis(trifluoromethanesulfonyl)imide (8.13 g, 22.76 mmol, 1.2 eq) was added, and the mixture was heated to 25 °C and reacted for 12 hours. The reaction solution was slowly added to a saturated ammonium chloride aqueous solution (100 mL), extracted with ethyl acetate (100 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 13-2 was purified by column chromatography (ethyl acetate / petroleum ether = 0%–10%). 1 H NMR (400MHz, CDCl3) δppm 4.85-4.82(m,2H)4.72-4.70(m,2H)4.25-4.20(m,2H)1.28-1.24(m,3H).

[0545] Step 2: Synthesis of compound 13-3

[0546] Compound 13-2 (3.9 g, 13.44 mmol, 1 eq) and BB-9 (8.84 g, 20.16 mmol, 1.5 eq) were added to dioxane (100 mL) and water (20 mL), along with potassium phosphate (8.56 g, 40.32 mmol, 3 eq) and Pd(dppf)Cl2 (983.30 mg, 1.34 mmol, 0.1 eq). The reaction mixture was reacted at 100 °C for 3 hours. The reaction solution was added to water (50 mL), extracted with ethyl acetate (50 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 13-3 was purified by column chromatography (ethyl acetate / petroleum ether = 0%–4%). MS m / z: 297.0 [M-56] + ; 1 H NMR (400MHz, CDCl3) δppm 7.83-7.82(m,1H)7.16(s,1H)5.01(s,4H)4.19-4.14(m,2H)1.54-1.52(m,9H)1.22-1.19(m,3H).

[0547] Step 3: Synthesis of Compound 13-4

[0548] Compound 13-3 (1.2 g, 3.41 mmol, 1 eq) was added to tetrahydrofuran (30 mL), cooled to 0 °C, and then lithium aluminum hydride (323.15 mg, 8.51 mmol, 2.5 eq) was added. The reaction was allowed to proceed for 2 hours. Water was added dropwise to the reaction solution until the reaction was completely quenched. Anhydrous sodium sulfate was added and the solution was dried. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 13-4. MS m / z: 254.9 [M-56] + .

[0549] Step 4: Synthesis of Compounds 13-5

[0550] Compound 13-4 (1 g, 3.22 mmol, 1 eq) was added to tetrahydrofuran (20 mL), cooled to 0 °C, and sodium hydride (257.80 mg, 6.44 mmol, 60% purity, 2 eq) was added. The mixture was stirred for 0.5 h, then heated to 50 °C and reacted for 2 h. After the reaction was complete, the reaction solution was slowly added to a saturated ammonium chloride aqueous solution (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give compound 13-5. MS m / z: 291.0 [M+1] + .

[0551] Step 5: Synthesis of Compounds 13-6

[0552] Palladium / carbon (0.3 g, 10% purity) was added to a dry hydrogenation flask, followed by methanol (30 mL), compound 11-5 (0.8 g, 2.76 mmol, 1 eq), and the reaction was carried out at 25 °C for 4 hours under hydrogen (15 psi). The mixture was filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (ethyl acetate / petroleum ether = 0%–10%) to give compound 13-6. MS m / z: 293.1 [M+1] + ; 1 H NMR (400MHz, CDCl3) δppm 7.50-7.48(m,1H)7.38-7.36(m,1H)6.98-6.93(m,1H)4.22-4.21(m,2H)4.20-4.17(m,1H)4.03- 3.01(m,1H)3.94-3.92(m,1H)3.67-3.57(m,1H)3.55-3.35(m,1H)2.71-2.68(m,1H)1.44(s,9H).

[0553] Step 6: Synthesis of the hydrochloride salt of compound 13-7

[0554] Compound 13-6 (0.18 g, 615.74 μmol, 1 eq) was added to hydrochloric acid / methanol (4 M, 10 mL) and reacted at 25 °C for 2 h. The reaction solution was concentrated under reduced pressure to give the hydrochloride salt of compound 13-7. MS m / z: 193.0 [M+1] + .

[0555] Step 7: Synthesis of compounds 13-8

[0556] Compound 5-8 (0.175 g, 504.90 μmol, 1 eq) and the hydrochloride salt of compound 13-7 (138.55 mg, 605.88 μmol, 1.20 eq) were added to dioxane (10 mL), followed by potassium carbonate (279.13 mg, 2.02 mmol, 4 eq), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (43.82 mg, 75.73 μmol, 0.15 eq), and Pd2(dba)3 (46.23 mg, 50.49 μmol, 0.1 eq). The reaction mixture was reacted at 110 °C for 6 hours. The reaction solution was added to water (30 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography (ethyl acetate / petroleum ether = 0%–25%) to obtain compound 13-8. MS m / z: 458.1 [M+1] + .

[0557] Step 8: Synthesis of compounds 13-9

[0558] Compound 13-8 (0.15 g, 327.58 μmol, 1 eq), bis(phenylephrine)boronic acid (249.55 mg, 982.73 μmol, 3 eq) were added to dioxane (10 mL), followed by potassium acetate (96.45 mg, 982.73 μmol, 3 eq), XPhos Pd G2 (25.77 mg, 32.76 μmol, 0.1 eq), and 2-di-tert-butylphosphine-2',4',6'-triisopropylbiphenyl (31.23 mg, 65.52 μmol, 0.2 eq). The reaction mixture was reacted at 110 °C for 3 hours. The reaction solution was added to water (30 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The purified compound 13-9 was obtained by column chromatography (ethyl acetate / petroleum ether = 0%–50%). MS m / z: 550.2 [M+1] + .

[0559] Step 9: Synthesis of compounds 13-10

[0560] Compound 13-9 (126.48 mg, 230.21 μmol, 1.5 eq) and compound BB-2-2 (33 mg, 153.47 μmol, 1 eq) were added to dioxane (10 mL), water (2 mL), XPhos Pd G2 (12.08 mg, 15.35 μmol, 0.1 eq), and potassium phosphate (97.73 mg, 460.42 μmol, 3 eq). The reaction mixture was reacted at 105 °C for 3 hours. The reaction solution was added to water (20 mL), extracted with ethyl acetate (20 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 13-10 was purified by column chromatography (ethyl acetate / petroleum ether = 0%–50%). MS m / z: 558.2 [M+1] + .

[0561] Step 10: Synthesis of trifluoroacetate of compound 13 and trifluoroacetate of compound 14

[0562] Compounds 13-10 (70 mg, 125.54 μmol, 1 eq) were added to DCM (10 mL) and trifluoroacetic acid (5 mL), and reacted at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure and separated by SFC (column: DAICEL CHIRALCEL OJ (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH3H2O ​​EtOH]; B%: 44%-44%, 12 min). The separated products were concentrated, and 4 drops of trifluoroacetic acid were added to each to obtain trifluoroacetate salts of compound 13 and 14.

[0563] Trifluoroacetate of compound 13: MS m / z: 458.1 [M+1] + ; 1 H NMR (400MHz, CD3OD) δppm 8.82 (d, J=8.4Hz, 1H) 8.69 -8.67(m,1H) 8.21(s,1H) 7.86-7.84(m,1H) 7.76-7.74(m,1H) 7.60(d,J=8.0Hz,1H) 7.48-7.46(m,1H) 6.66(d,J=8.0Hz,1H) 4.42(s,2H) 4.35-4.34(m,1H) 4.27-4.25(m,1H) 4.11-4.09(m,2H) 3.79(m,1H) 3.71-3.74(s,1H) 3.52-3.50(m,1H) 2.86-2.83(m,1H). ee%=100%, retention time: 1.643min.

[0564] Trifluoroacetate of compound 14: MS m / z: 458.1 [M+1] + ; 1 H NMR(400MHz,CD3OD)δppm 8.83(d,J=8.4Hz,1H)8.67(m,1H)8.20(s,1H)7.84(d,J=5.4Hz,1H)7.77-7.75(m,1H)7.60(d,J=7.8Hz,1H)7.47-7.44(m,1H)6.67(d,J=7.8 Hz,1H)4.42(s,2H)4.37-4.35(m,1H)4.27(s,1H)4.11-4.09(m,2H)3. 81-3.80(m,1H)3.79-3.71(m,1H)3.52-3.50(m,1H)2.85-2.83(m,1H). ee% = 98.42%, retention time: 1.827 min.

[0565] Analytical method for detecting ee%: Column: Chiralcel OJ-3, 50×4.6mm ID, 3μm; Mobile phase: A: carbon dioxide; B: ethanol (0.1% IPAm, v / v).

[0566] Example 15

[0567]

[0568] Step 1: Synthesis of Compound 15-3

[0569] Compound 10-1 (0.2 g, 707.41 μmol, 1 eq) and compound 15-2 (240.44 mg, 1.41 mmol, 2 eq) were added to dioxane (4 mL), water (0.8 mL), XPhos Pd G2 (55.66 mg, 70.74 μmol, 0.1 eq), and potassium phosphate (450.48 mg, 2.12 mmol, 3 eq). The reaction mixture was reacted at 100 °C for 2 hours. The reaction solution was added to water (30 mL), extracted with ethyl acetate (30 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 15-3 was obtained by column chromatography (ethyl acetate / petroleum ether = 0%–15%). MS m / z: 273.0 [M-100] + ; 1 H NMR(400MHz,DMSO-d6)δppm 7.41-7.37(m,1H)7.21-7.19(m,1H)6.99-6.89(m 2H)6.70-6.69(m,1H)6.51(s,2H)4.36-4.29(m,2H)3.75(s,3H)1.48(s,9H).

[0570] Step 2: Synthesis of Compound 15-4

[0571] Compound 15-3 (0.18 g, 483.37 μmol, 1 eq) and compound BB-1 (174.12 mg, 580.04 μmol, 1.2 eq) were added to dioxane (10 mL), followed by cesium carbonate (472.47 mg, 1.45 mmol, 3 eq), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (41.95 mg, 72.50 μmol, 0.15 eq), and palladium acetate (10.85 mg, 48.34 μmol, 0.1 eq). The reaction mixture was reacted at 110 °C for 3 h. The reaction solution was added to water (50 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 15-4. MS m / z: 592.3 [M+1] + .

[0572] Step 3: Synthesis of the trifluoroacetate of compound 15

[0573] Compound 15-4 (0.4 g, 676.05 μmol, 1 eq) was added to hydrochloric acid / methanol (4 M, 20 mL) and reacted at 25 °C for 4 hours. The reaction solution was concentrated under reduced pressure and purified by prep-HPLC (column: Phenomenex Lμna 80*30 mm*3 μm; mobile phase: [water (TFA)-acetonitrile]; acetonitrile %: 10%-50%, 8 min) to obtain the trifluoroacetate of compound 15. MS m / z: 492.2 [M+1] + ; 1 H NMR(400MHz,CD3OD)δppm 8.26(d,J=8.4Hz,1H)7.81(d,J=8.8Hz,1H)7.48-7.40(m,2H)7.21(d,J=8.8Hz,1H)6.97(d,J=8.4Hz,1H)6.8 7(t,J=8.8Hz,1H)4.62(s,2H)4.28-4.19(m,2H)3.90-3.88(m,4H)3.81(s,3H)3.05(s,6H)2.93-2.91(m,4H).

[0574] Example 16

[0575]

[0576] Step 1: Synthesis of Compound 16-1

[0577] Under nitrogen protection, at 0°C, compound 4-1 (10 g, 46.03 mmol) was dissolved in DCM (10 mL), and Dys-Martin oxidant (23.43 g, 55.23 mmol, 17.10 mL) was added. The mixture was heated to 20°C and reacted for 16 hours. The mixture was filtered, and the solid was washed with dichloromethane (20 mL). The filtrate was poured into a saturated sodium sulfite solution (200 mL), filtered, and the pH of the filtrate was adjusted to 8 with a saturated sodium bicarbonate solution (200 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered under vacuum, and concentrated under reduced pressure. The purified compound 16-1 was obtained by column chromatography (ethyl acetate / petroleum ether = 0%–15%). 1 H NMR(400MHz,DMSO-d6)δ9.61-9.59(m,1H),4.51-4.34(m,2H),3.79-3.68(m,1H ),3.65-3.52(m,2H),3.40-3.35(m,1H),3.11-2.79(m,1H),1.46-1.37(m,9H).

[0578] Step 2: Synthesis of Compound 16-3

[0579] Under nitrogen protection, compound 16-1 (2.89 g, 13.43 mmol) was added to DCM (60 mL), followed by compound 16-2 (2.44 g, 16.11 mmol) and acetic acid (80.63 mg, 1.34 mmol, 76.79 μL). The reaction was carried out at 20 °C for 1 h. Then, sodium borohydride acetate (5.69 g, 26.85 mmol) was added, and the reaction was carried out at 20 °C for 12 h. The reaction was quenched with saturated sodium bicarbonate aqueous solution (60 mL), extracted with dichloromethane (50 mL × 3), and the organic phases were combined. The organic phase was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. Compound 16-3 was purified by column chromatography (ethyl acetate / petroleum ether = 0%–30%). MS m / z: 351.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ7.18(d,J=8.4Hz,2H),6.85(d,J=8.8Hz,2H),3.82-3.73(m,2H),3.69-3.65(m,4H),3.54-3.51(m,1H ),3.48-3.36(m,3H),3.30-3.24(m,1H),2.85-2.68(m,1H),2.61-2.56(m,1H),2.43-2.38(m,1H),2.14(s,3H),1.40(s,9H).

[0580] Step 3: Synthesis of Compound 16-4

[0581] Under nitrogen protection, compound 16-3 (1.7 g, 4.85 mmol) was dissolved in DCM (2 mL), and hydrochloric acid / methanol (4 M, 50 mL) was added. The reaction was carried out at 20 °C for 6 hours. The solvent was concentrated under reduced pressure, and dichloromethane (20 mL), ammonia (3 mL), and anhydrous sodium sulfate were added. The solution was dried over a vacuum. The mixture was filtered and concentrated under reduced pressure to give compound 16-4. MS m / z: 251.1 [M+1] + ; 1 H NMR(400MHz, DMSO-d6)δ7.20(d,J=8.8Hz,2H),6.87(d,J=8.4Hz,2H),3.73-3.65(m,5H),3.44-3.33(m,3H), 3.09-3.01(m,1H),2.99-2.92(m,1H),2.85-2.74(m,2H),2.33-2.25(m,1H),2.21-2.15(m,1H),2.11(s,3H).

[0582] Step 4: Synthesis of Compound 16-5

[0583] Under nitrogen protection, compound BB-1-1 (600 mg, 2.94 mmol) was dissolved in DMF (12 mL), and compound 16-4 (809.92 mg, 3.24 mmol) and DIEA (1.14 g, 8.82 mmol, 1.54 mL) were added. The reaction was carried out at 100 °C for 6 hours. After cooling, the reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL × 4), and the organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. Compound 16-5 was purified by column chromatography (ethyl acetate / petroleum ether = 0%–20–25%). MS m / z: 434.1 [M+1] + ; 1 H NMR(400MHz, DMSO-d6)δ9.83(s,1H),7.71(d,J=8.8Hz,1H),7.59(d,J=8.8Hz,1H),6.92-6.86(m,2H),6.83-6.78(m,2 H),3.92-3.76(m,3H),3.73(s,3H),3.59-3.55(m,1H),3.55-3.49(m,1H),3.29-3.27(m,1H),3.24-3.19(m,2H),2.95

[0584] -2.87(m,1H),2.64-2.62(m,1H),2.42-2.37(m,1H),1.81(s,3H).

[0585] Step 5: Synthesis of Compound 16-6

[0586] Compound 16-5 (1.24 g, 2.85 mmol) was dissolved in trifluoroacetic acid (15 mL) under nitrogen protection and reacted at 60 °C for 2 h. The mixture was cooled and concentrated under reduced pressure. DCM (30 mL) and NaBH(OAc)3 (1.82 g, 8.56 mmol) were added, and the reaction was continued at 20 °C for 2 h. The reaction was quenched with saturated sodium carbonate solution (30 mL) and saturated sodium hydroxide solution (5 mL), extracted with dichloromethane (20 mL × 5), washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. Compound 16-6 was purified by column chromatography (methanol / ethyl acetate = 0%–5%). MS m / z: 298.0 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ7.36-7.33(m,2H),3.94-3.92(m,1H),3.78-3.62(m,4H),3.46-3.40(m ,1H),3.38-3.35(m,1H),3.25-3.23(m,2H),3.01-2.95(m,1H),2.58-2.52(m,1H),2.33(s,3H).

[0587] Step 6: Synthesis of Compound 16-8

[0588] Under nitrogen protection, compound 16-6 (590 mg, 1.98 mmol) was dissolved in dioxane (12 mL), and compound 16-7 (336.79 mg, 3.96 mmol), cesium carbonate (1.93 g, 5.94 mmol), Xantphos (228.98 mg, 395.74 μmol), and Pd2(dba)3 (181.19 mg, 197.87 μmol) were added. The reaction was carried out at 110 °C for 2 hours. After cooling, the mixture was filtered, and the filter cake was washed with dichloromethane (20 mL). The filtrate was concentrated under reduced pressure. Compound 16-8 was purified by column chromatography (methanol / ethyl acetate = 0%–5%). MS m / z: 303.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ10.55(s,1H),7.86(d,J=8.8Hz,1H),7.37(d,J=8.8Hz,1H),3.87-3.72(m,3H),3.69-3.65(m,2H),3. 45-3.39(m,1H),3.19-3.16(m,3H),2.92-2.86(m,1H),2.55-2.51(m,1H),2.29(s,3H),2.03-1.90(m,1H),0.80-0.71(m,4H).

[0589] Step 7: Synthesis of Compounds 16-9

[0590] Under nitrogen protection, compound 16-8 (500 mg, 1.65 mmol) was dissolved in methanol (10 mL) and water (2.5 mL), and sodium hydroxide (661.39 mg, 16.54 mmol) was added. The reaction was carried out at 80 °C for 16 hours. Then, sodium hydroxide (330.70 mg, 8.27 mmol) was added, and the reaction was carried out at 80 °C for 4 hours. The solvent was concentrated under reduced pressure, extracted with dichloromethane (20 mL × 5), and the organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give compound 16-9. MS m / z: 235.2 [M+1] + ;1 HNMR(400MHz,DMSO-d6)δ7.08(d,J=8.8Hz,1H),6.28(d,J=8.4Hz,1H),5.47(s,2H),3.73-3.56(m,5H),3. 48-3.41(m,1H),3.20-3.14(m,1H),3.06-2.95(m,2H),2.92-2.87(m,1H),2.47-2.45(m,1H),2.26(s,3H).

[0591] Step 8: Synthesis of compounds 16-11

[0592] Under nitrogen protection, compound BB-10 (8.3 g, 23.95 mmol) was dissolved in DMF (83 mL), and BB-2-1 (3.26 g, 23.95 mmol), potassium acetate (4.70 g, 47.89 mmol), and Pd(dppf)Cl2 (1.75 g, 2.39 mmol) were added. The mixture was reacted at 120 °C for 2 hours. After cooling, the mixture was filtered, and the filtrate was poured into water (1000 mL). The extract was then extracted with ethyl acetate (1000 mL), dried over anhydrous sodium sulfate, and concentrated by filtration to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 0%–50%) to obtain compound 16-11. MS m / z: 402.1 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ8.04-7.96(m,1H),7.73-7.70(m,1H),7.67-7.57(m,2H),7.41-7.32(m,1H),6.83-6.72(m,1H),4.64(s,2H),1.58(s,9H).

[0593] Step 9: Synthesis of compounds 16-12

[0594] Under nitrogen protection, compound 16-11 (610 mg, 1.52 mmol) was dissolved in dioxane (12 mL), and compound 16-9 (391.25 mg, 1.67 mmol), cesium carbonate (1.48 g, 4.55 mmol), Xantphos (175.68 mg, 303.62 μmol), and palladium acetate (34.08 mg, 151.81 μmol) were added. The reaction was carried out at 110 °C for 2 hours. After cooling, the mixture was filtered, and the residue was washed with dichloromethane (20 mL). The filtrate was concentrated under reduced pressure. Compound 16-12 was purified by column chromatography (methanol / ethyl acetate = 0%–30%). MS m / z: 600.3 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ9.65 (s, 1H), 8.66 (d, J = 8.4Hz, 1H), 8.43-8.36 (m, 1H), 7.82 (s, 1H), 7.78 (d,J=8.4Hz,1H),7.55-7.52(m,1H),7.41(d,J=8.8Hz,1H),7.02-6.95(m,2H),4.73(s,2H),3.97- 3.88(m,1H),3.83-3.79(m,1H),3.74-3.72(m,1H),3.69-3.63(m,1H),3.49-3.45(m,1H),3.29-3. 20(m,2H),3.17(d,J=5.2Hz,2H),3.09-2.98(m,1H),2.58-2.54(m,1H),2.36(s,3H),1.51(s,9H).

[0595] Step 10: Synthesis of the trifluoroacetate of compound 16

[0596] Under nitrogen protection, compound 16-12 (742 mg, 1.24 mmol) was dissolved in DCM (10 mL), and trifluoroacetic acid (7.70 g, 67.53 mmol, 5 mL) was added. The mixture was reacted at 20 °C for 1 hour. The solvent was concentrated under reduced pressure to obtain the crude product. The crude product was purified by prep-HPLC (column: Phenomenex lμna C18250*50 mm*10 μm; mobile phase: [water (TFA)-acetonitrile]; acetonitrile %: 5%-45%, 10 min) to obtain the trifluoroacetate of compound 16. MS m / z: 500.2 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ10.10(s,1H),8.89(s,1H),8.71-8.56(m,2H),8.24(s,1H) ,7.94-7.92(m,1H),7.72(d,J=8.4Hz,1H),7.59(d,J=8.0Hz,1H),7.44-7.37(m,1H ),7.13(d,J=8.0Hz,1H),4.86-4.67(m,1H),4.56-4.53(m,1H),4.39(s,2H),3.78- 3.64(m,6H),3.42-3.36(m,1H),3.31-3.17(m,1H),2.97(s,3H),2.58-2.56(m,1H).

[0597] Example 17

[0598]

[0599]

[0600] Step 1: Synthesis of compound BB-10-2

[0601] Compound BB-10-1 (23.4 g, 108.82 mmol) was dissolved in DMF (230 mL), and N-chlorosuccinimide (17.44 g, 130.58 mmol) and palladium acetate (12.22 g, 54.41 mmol) were added. The mixture was purged with nitrogen three times, and the reaction was stirred at 110 °C for 16 hours. The reaction solution was poured into water (1 L), and ethyl acetate (300 mL) was added. After stirring, the mixture was filtered, and the filtrate was separated. The aqueous phase was extracted with ethyl acetate (200 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 1%–25%) to give compound BB-10-2. MS m / z: 231.0 [M-17] + ; 1 H NMR (400MHz, CDCl3) δ11.38 (m, 1H), 7.56 (d, J = 8.4Hz, 1H), 7.15 (d, J = 8.4Hz, 1H), 2.48 (s, 3H).

[0602] Step 2: Synthesis of compound BB-10-3

[0603] Compound BB-10-2 (23.7 g, 94.99 mmol) was dissolved in DMF (237 mL), and anhydrous potassium carbonate (32.82 g, 237.49 mmol) was added. The mixture was stirred at 20 °C for 30 minutes, followed by dropwise addition of iodomethane (20.23 g, 142.49 mmol, 8.87 mL). The reaction mixture was stirred at 20 °C for 16 hours. The reaction solution was quenched in 2% dilute ammonia solution (100 mL), diluted with water (1000 mL), and the aqueous phase was extracted with ethyl acetate (200 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0%–10%) to give compound BB-10-3. MS m / z: 263.0 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ7.51 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 3.96 (s, 3H), 2.36 (s, 3H).

[0604] Step 3: Synthesis of compound BB-10-4

[0605] Compound BB-10-3 (7.7 g, 29.22 mmol) was dissolved in 1,2-dichloroethane (150 mL), and N-bromosuccinimide (5.72 g, 32.14 mmol) and benzoyl peroxide (707.80 mg, 2.92 mmol) were added. The mixture was purged with nitrogen three times, and the reaction was carried out under nitrogen protection at 110 °C for 40 hours with stirring. The reaction solution was poured into water (200 mL), and the mixture was separated. The aqueous phase was extracted with dichloromethane (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give compound BB-10-4. MS m / z: 340.9 [M+1] + .

[0606] Step 4: Synthesis of compound BB-10-5

[0607] Compound BB-10-4 (10 g, 29.20 mmol) was dissolved in ammonia-methanol solution (7 M, 208.60 mL), and the reaction was stirred at 20 °C for 16 hours. The reaction solution was filtered directly, and the filter cake was washed with methanol (50 mL). The filter cake was collected, concentrated, and dried to obtain compound BB-10-5. MS m / z: 246.0 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ8.90 (br s, 1H), 7.79 (d, J = 8.4Hz, 1H), 7.43 (d, J = 8.4Hz, 1H), 4.44 (s, 2H).

[0608] Step 5: Synthesis of compound BB-10-6

[0609] Compound BB-10-5 (5.3 g, 21.50 mmol) was dissolved in tetrahydrofuran (80 mL), and di-tert-butyl dicarbonate (7.04 g, 32.25 mmol, 7.41 mL) and 4-dimethylaminopyridine (3.15 g, 25.80 mmol) were added. The reaction mixture was stirred at 20 °C for 16 hours. The reaction solution was poured into water (200 mL), and the mixture was separated. The aqueous phase was extracted with ethyl acetate (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 5%–25%) to give compound BB-10-6. MS m / z: 290.0 [M-55] + ; 1 H NMR (400MHz, CDCl3) δ7.66 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 4.63 (s, 2H), 1.61 (s, 9H).

[0610] Step 6: Synthesis of compound BB-10

[0611] Compound BB-10-6 (5 g, 14.43 mmol) was dissolved in N-methylpyrrolidone (50 mL), and the solution was purged with nitrogen three times. Compound BB-2-1 (1.96 g, 14.43 mmol), potassium acetate (2.83 g, 28.85 mmol), and Pd(dppf)Cl2 (1.06 g, 1.44 mmol) were then added, and the mixture was reacted at 120 °C for 2 hours. The reaction solution was poured into water (200 mL), and a solid precipitated. The solid was filtered, the filter cake was collected, and dried. The solution was purified by column chromatography (ethyl acetate / petroleum ether = 50%–100%) to give compound BB-10. MS m / z: 402.2 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ7.99-7.96(m,1H),7.73(s,1H),7.69-7.64(m,2H),7.40-7.35(m,1H),6.84-6.78(m,1H),4.66(s,2H),1.59(s,9H).

[0612] Step 7: Synthesis of Compound 17-2

[0613] Compound 17-1 (30 g, 251.84 mmol) was dissolved in DCM (300 mL) and methanol (300 mL), then tetrabutylammonium tribromide (145.72 g, 302.21 mmol) was added, and the reaction was carried out at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure, then dichloromethane (600 mL) was added, and the mixture was stirred for 0.5 hours and filtered. The filtrate was concentrated to obtain the crude product, which was dissolved in dichloromethane (50 mL) and reacted at 25 °C for 2 hours. The mixture was filtered, and the filter cake was concentrated to obtain compound 17-2. MS m / z: 197.9 [M+1] + .

[0614] Step 8: Synthesis of Compound 17-3

[0615] Compound 17-2 (8 g, 40.40 mmol) was dissolved in DCM (100 mL), followed by the addition of 4-dimethylaminopyridine (4.94 g, 40.40 mmol), di-tert-butyl dicarbonate (26.45 g, 121.20 mmol, 27.84 mL), and DIEA (15.66 g, 121.20 mmol, 21.11 mL). The reaction mixture was reacted at 25 °C for 16 hours. The reaction solution was poured into a saturated ammonium chloride aqueous solution (200 mL), and extracted with dichloromethane (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 10%–25%) to give compound 17-3. MS m / z: 241.8 [M-155] + ;1 ¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 1.50 (s, 18H). Step 9: Synthesis of compound 17-4

[0616] Compound 17-3 (8.3 g, 20.84 mmol) was dissolved in 1,4-dioxane (100 mL), followed by the addition of potassium acetate (5.11 g, 52.10 mmol) and compound 1-2 (7.94 g, 31.26 mmol). After purging with nitrogen, Pd(dppf)Cl2 (1.52 g, 2.08 mmol) was added. The reaction was carried out at 80 °C for 2 hours. The reaction solution was poured into a saturated ammonium chloride aqueous solution (50 mL), and extracted with ethyl acetate (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 17-4. MS m / z: 207.9 [M-155] + .

[0617] Step 10: Synthesis of Compound 17-5

[0618] Compounds 17-4 (7.5 g, 20.65 mmol) and 13-2 (8.99 g, 30.98 mmol) were dissolved in tetrahydrofuran (100 mL), followed by the addition of anhydrous potassium carbonate (7.14 g, 51.63 mmol) and Pd(PPh3)4 (2.39 g, 2.07 mmol). The reaction was carried out at 65 °C for 1 hour. The reaction mixture was poured into a saturated ammonium chloride aqueous solution (150 mL), and extracted with ethyl acetate (150 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Purification by column chromatography (ethyl acetate / petroleum ether = 10%–50%) yielded compound 17-5. MS m / z: 304.0 [M-155] + ; 1 H NMR (400MHz, CDCl3) δ7.76-7.70(m,2H),5.11-5.04(m,4H),4.18-4.12(m,2H),1.53(s,18H),1.20-1.16(m,3H).

[0619] Step 11: Synthesis of Compound 17-6

[0620] Raney nickel (2 g) was added to a dry hydrogenation flask. After washing three times with methanol, a solution of compound 17-5 (5.1 g, 11.10 mmol) dissolved in methanol (40 mL) and triethylamine (10 mL) was added. After purging with hydrogen three times, the reaction was carried out under a hydrogen atmosphere at 40 Psi and stirred at 25 °C for 16 hours. The reaction solution was directly filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 10%–100%) to obtain compound 17-6. MS m / z: 418.1 [M+1] + .

[0621] Step 12: Synthesis of Compound 17-7

[0622] In a dry vial, 200 mg of wet palladium on carbon (10% purity) was added. Then, under nitrogen protection, a solution of compound 17-6 (1.5 g, 3.59 mmol) dissolved in methanol (20 mL) was slowly added. After three purgings with hydrogen, the reaction was stirred for 16 hours at 20 Psi and 20 °C under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated to give compound 17-7. MS m / z: 420.2 [M+1] + .

[0623] Step 13: Synthesis of Compounds 17-8

[0624] Compound 17-7 (1 g, 2.38 mmol) was dissolved in tetrahydrofuran (20 mL) in a dry vial. Sodium hydride (286.08 mg, 7.15 mmol, 60% purity) was added under nitrogen protection at 0 °C. After stirring for 30 minutes, iodomethane (507.57 mg, 3.58 mmol, 222.62 μL) was added, and the reaction was stirred at 20 °C for 2 hours. The reaction mixture was poured into a saturated ammonium chloride aqueous solution (20 mL), and the aqueous phase was extracted with ethyl acetate (10 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 15%–100). Compound 17-8 was obtained. MS m / z: 434.3 [M+1] + .

[0625] Step 14: Synthesis of Compounds 17-9

[0626] Compound 17-8 (700 mg, 1.61 mmol) was dissolved in DCM (20 mL) in a dry vial, and trifluoroacetic acid (9.21 g, 80.74 mmol, 5.98 mL) was added. The reaction was stirred at 25 °C for 16 hours. The reaction solution was directly concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography using silica gel plates (methanol / dichloromethane = 10%) to give compound 17-9. MS m / z: 234.2 [M+1] + .

[0627] Step 15: Synthesis of Compounds 17-10

[0628] Compound 17-9 (95 mg, 407.26 μmol) was dissolved in tetrahydrofuran (5 mL) in a dry vial. Lithium aluminum hydride (77.28 mg, 2.04 mmol) was added under nitrogen protection at 0 °C, and the reaction was stirred at 60 °C for 2 hours. The reaction mixture was cooled to 20 °C, quenched dropwise with methanol (10 mL), and then concentrated. The crude product was purified by column chromatography (methanol / dichloromethane = 0%–15%) to obtain compound 17-10. MS m / z: 220.0 [M+1] + .

[0629] Step 16: Synthesis of the trifluoroacetate of compound 17

[0630] In a dry vial, compound 17-10 (65 mg, 296.42 μmol) and compound BB-10 (120 mg, 298.64 μmol) were dissolved in 1,4-dioxane (10 mL), and cesium carbonate (291.91 mg, 895.93 μmol) was added. Under nitrogen protection, Pd2(dba)3 (54.69 mg, 59.73 μmol) and Xantphos (43.20 mg, 74.66 μmol) were added, and the reaction was stirred at 110 °C for 2 hours under nitrogen protection. The reaction solution was directly filtered, and the filtrate was concentrated. The crude product was obtained by separation and purification using a thin-layer chromatography silica gel plate (methanol / dichloromethane = 10%). The crude product was then purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3μm; mobile phase: [water (TFA)-acetonitrile]; acetonitrile %: 1%-30%, 8 min) to obtain the trifluoroacetate of compound 17. MS m / z: 485.3 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ10.23(s,1H),8.91(s,1H),8.74(s,1H),8.54(s,1H),8.11(s,1H),7.80-7.78(m,1H),7.39(d,J=8.8Hz,1H),7.57(d,J=8 .4Hz,1H),7.27-7.24(m,1H),7.19-7.17(m,1H),4.91-4.40(m,5H),4.1 9-4.14(m,2H),3.79-3.69(m,4H),3.41-3.00(m,2H),2.83-2.67(m,2H).

[0631] Example 18

[0632]

[0633] Step 1: Synthesis of the trifluoroacetate of compound 18-1

[0634] Compound 17-7 (200 mg, 476.79 μmol) was dissolved in DCM (6 mL) in a dry vial, and trifluoroacetic acid (2.72 g, 23.84 mmol, 1.77 mL) was added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction solution was concentrated to give the trifluoroacetate of compound 18-1. MS m / z: 220.2 [M+1] + .

[0635] Step 2: Synthesis of Compound 18-2

[0636] In a dry vial, the trifluoroacetate of compound 18-1 (109.12 mg) and compound BB-10 (100 mg, 248.87 μmol) were dissolved in 1,4-dioxane (10 mL), and cesium carbonate (243.26 mg, 746.61 μmol) was added. After stirring for 15 minutes and confirming pH > 9, palladium acetate (11.17 mg, 49.77 μmol) and Xantphos (36.00 mg, 62.22 μmol) were added. The reaction was carried out under nitrogen protection at 100 °C with stirring for 4 hours. The reaction solution was filtered, and the filtrate was concentrated. The crude product was purified by preparative thin-layer chromatography using silica gel plates (methanol / dichloromethane, methanol ratio 10%) to obtain compound 18-2. MS m / z: 585.2 [M+1] + .

[0637] Step 3: Synthesis of the trifluoroacetate of compound 18

[0638] Compound 18-2 (65 mg, 111.19 μmol) was dissolved in DCM (1 mL) in a dry vial, and trifluoroacetic acid (633.88 mg, 5.56 mmol, 411.61 μL) was added. The reaction was stirred at 20 °C for 2 hours. The reaction solution was directly concentrated to obtain the crude product. The crude product was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH4HCO3)-acetonitrile]; acetonitrile %: 1%-25%, 8 min). 2-3 drops of trifluoroacetic acid were added dropwise to the fraction, and the mixture was concentrated to obtain the trifluoroacetate of compound 18. MS m / z: 485.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),8.89(s,1H),8.77(d,J=8.4Hz,1H),8.63- 8.62(m,1H),8.34-8.32(m,1H),8.18(s,1H),7.86-7.84(m,1H),7.78-7.76(m,1 H),7.55(d,J=8.4Hz,1H),7.32-7.30(m,1H),6.98-6.96(m,1H),5.03-4.87(m,1 H),4.40-4.35(m,4H),4.15-3.86(m,3H),3.84-3.78(m,1H),3.73-3.65(m,1H).

[0639] Example 20

[0640]

[0641] Step 1: Synthesis of Compound 20-1

[0642] Under nitrogen protection, compound BB-6 (300 mg, 863.08 μmol) was dissolved in 1,4-dioxane (6 mL), and compound BB-8 (196.74 mg, 949.39 μmol), cesium carbonate (843.63 mg, 2.59 mmol), Xantphos (74.91 mg, 129.46 μmol), and palladium acetate (19.38 mg, 86.31 μmol) were added. The reaction was carried out at 110 °C for 2 hours. After cooling, the mixture was filtered, and the residue was washed with dichloromethane (20 mL). The filtrate was concentrated under reduced pressure. The purified compound 20-1 was obtained by column chromatography (ethyl acetate / petroleum ether = 0%–35%). MS m / z: 474.1 [M+1] + ; 1 H NMR(400MHz, DMSO-d6)δ9.49(s,1H),8.92(s,1H),7.30(d,J=8.4Hz,1H),6.78(d,J=8.4Hz,1H),4.73(s,2H),4.39-4.37(m,1H),4.07-4.0 3(m,1H),3.99-3.94(m,1H),3.91-3.89(m,1H),3.65-3.54(m,2H),3.22-3.14(m,1H),3.10-3.02(m,1H),2.69-2.62(m,1H),1.54(s,9H).

[0643] Step 2: Synthesis of compound 20-2

[0644] Under nitrogen protection, compound 20-1 (142 mg, 299.64 μmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL). Compound 4-8 (109.71 mg, 449.45 μmol), potassium phosphate (127.21 mg, 599.27 μmol), and RuPhosPd G2 (23.58 mg, 29.96 μmol) were added, and the reaction was carried out at 100 °C for 2 hours. After cooling, the system was concentrated under reduced pressure. Compound 20-2 was purified by column chromatography (ethyl acetate / petroleum ether = 0%–100%). MS m / z: 570.2 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ10.12(s,1H),9.30(s,1H),8.43(d,J=5.2Hz,1H),7.18(d,J=4.8Hz, 1H),7.08(d,J=8.4Hz,1H),6.88(d,J=3.6Hz,1H),6.57(d,J=8.4Hz,1H),4.38-4.35(m,1H) ,4.21-4.12(m,1H),4.11-4.07(m,1H),3.99-3.91(m,4H),3.80-3.74(m,1H),3.53(s,2H) ,3.45-3.42(m,1H),3.36-3.28(m,1H),3.25-3.17(m,1H),2.89-2.82(m,1H),1.62(s,9H).

[0645] Step 3: Synthesis of the trifluoroacetate of compound 20

[0646] Under nitrogen protection, compound 20-2 (158 mg, 277.38 μmol) was dissolved in DCM (6 mL), and trifluoroacetic acid (4.62 g, 40.52 mmol, 3 mL) was added. The mixture was reacted at 25 °C for 2 hours. The solvent was concentrated under reduced pressure to obtain the crude product. Purification was performed by prep-HPLC (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (TFA)-acetonitrile]; acetonitrile %: 5%-35%, 8 min). The trifluoroacetate salt of compound 20 was obtained. MS m / z: 470.1 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ9.85 (s, 1H), 9.45 (s, 1H), 9.16 (s, 1H), 8.35 (d, J = 4.8Hz, 1H), 7.57 (d, J=3.6Hz,1H),7.38(d,J=4.8Hz,1H),7.31(d,J=8.4Hz,1H),6.92(d,J=3.6Hz,1H),6.69(d,J=8 .4Hz,1H),4.71(s,2H),4.41-4.39(m,1H),4.11-4.01(m,1H),4.01-3.95(m,1H),3.93-3.89(m ,1H),3.87(s,3H),3.66-3.54(m,2H),3.26-3.15(m,1H),3.12-3.02(m,1H),2.71-2.64(m,1H).

[0647] Examples 21 and 22

[0648]

[0649] Step 1: Synthesis of trifluoroacetate of compound 21 and trifluoroacetate of compound 22

[0650] In a dry vial, compound 18-2 (100 mg, 171.06 μmol) was dissolved in DCM (1 mL) and trifluoroacetic acid (975.20 mg, 8.55 mmol, 633.25 μL) was added. The reaction was stirred at 20 °C for 2 hours. The reaction solution was directly concentrated to obtain the crude product, which was purified by preparative thin-layer chromatography using silica gel plates (methanol / dichloromethane = 16%). Further purification was performed by SFC (column: REGIS(S,S)WHELK-O1 (250 mm * 25 mm, 10 μm); mobile phase: A (carbon dioxide), B (ethanol, 0.1% ammonia), B%: 62%-62%, 20 min). The resulting solution was concentrated, and two drops of trifluoroacetic acid were added dropwise to obtain trifluoroacetate salts of compound 21 and 22.

[0651] Trifluoroacetate of compound 21: MS m / z: 485.3 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δppm10.14(s,1H),8.89(s,1H),8.77(d,J=8.8Hz,1H ),8.61(d,J=7.2Hz,1H),8.34-8.32(m,1H),8.16(s,1H),7.84-7.82(m,1H), 7.78-7.76(m,1H),7.56-7.54(m,1H),7.32-7.30(m,1H),6.99-6.97(m,1H), 4.91-4.87(m,1H),4.40-4.36(m,4H),3.92-3.88(m,2H),3.84-3.68(m,3H). ee% = 100%, retention time: 3.070 min.

[0652] Trifluoroacetate of compound 22: MS m / z: 485.3 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δppm10.14(s,1H),8.89(s,1H),8.77(d,J=8.8Hz,1H),8. 63(d,J=6.8Hz,1H),8.33-8.31(m,1H),8.20(s,1H),7.88-7.86(m,1H),7.79-7.7 7(m,1H),7.56-7.54(m,1H),7.34-7.32(m,1H),6.99-6.97(m,1H),4.91-4.87(m, 1H),4.41-4.36(m,4H),3.92-3.85(m,2H),3.81-3.53(m,2H),3.38-3.34(m,1H). ee% = 97.12%, SFC retention time: 5.061 min.

[0653] Analytical method for detecting ee%: Column: (S,S)-WHELK-O1, 50×4.6mm ID, 3.5μm; Mobile phase: A: carbon dioxide, B: ethanol (0.1% isopropylamine, v / v); B% = 50-50%; Flow rate: 4mL / min; Pressure: 1800psi.

[0654] Example 23

[0655]

[0656] Step 1: Synthesis of Compound 23-1

[0657] Under nitrogen protection, compound BB-10-6 (1 g, 2.89 mmol) was dissolved in dioxane (20 mL) and water (4 mL). Compound 4-8 (1.06 g, 4.33 mmol), cesium carbonate (2.82 g, 8.66 mmol), and Pd(dppf)Cl2 (316.66 mg, 432.77 μmol) were added, and the reaction was carried out at 70 °C for 2 hours. After cooling, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0%–50%) to obtain compound 23-1. MS m / z: 398.1 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ8.44(d,J=4.8Hz,1H),7.68(d,J=8.0Hz,1H),7.58(d,J=8.0Hz,1H),7.2 8(s,1H),7.05(d,J=4.8Hz,1H),6.28(d,J=3.6Hz,1H),4.65(s,2H),3.98(s,3H),1.57(s,9H).

[0658] Step 2: Synthesis of compound 23-2

[0659] Under nitrogen protection, compound 23-1 (45 mg, 113.11 μmol) was dissolved in dioxane (2 mL), followed by compound 18-1 (27.28 mg, 124.42 μmol), cesium carbonate (110.56 mg, 339.32 μmol), Xantphos (13.09 mg, 22.62 μmol), and palladium acetate (2.54 mg, 11.31 μmol). The reaction was carried out at 110 °C for 2 hours. After cooling, the solvent was concentrated under reduced pressure. Compound 23-2 was purified by column chromatography (ethyl acetate / petroleum ether = 0%–100%). MS m / z: 581.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ9.87 (s, 1H), 8.81 (d, J = 8.8Hz, 1H), 8.38-8.26 (m, 2H), 7.8 1(d,J=8.4Hz,1H),7.62-7.53(m,2H),7.25(d,J=5.2Hz,1H),7.08(d,J=8.4Hz,1H) ,6.47(d,J=3.6Hz,1H),4.92-4.83(m,1H),4.80(s,2H),4.43-4.39(m,1H),4.38-4 .35(m,1H),3.97-3.86(m,5H),3.86-3.68(m,2H),3.38-3.34(m,1H),1.50(s,9H).

[0660] Step 3: Synthesis of the trifluoroacetate of compound 23

[0661] Under nitrogen protection, compound 23-2 (69 mg, 118.84 μmol) was dissolved in DCM (2 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction was carried out at 25 °C for 2 hours. The solvent was concentrated under reduced pressure to obtain the crude product. The crude product was added to methanol (10 mL), and the reaction was carried out at 25 °C for 0.5 hours. The mixture was filtered, and the residue was washed with methanol (5 mL). The residue was collected and added to water (10 mL). Three drops of trifluoroacetic acid were added, and the mixture was stirred until homogeneous to obtain the trifluoroacetate of compound 23. MS m / z: 481.1 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ10.17(s,1H),8.84(s,1H),8.73(d,J=8.4Hz,1H),8.35-8.26(m, 2H),7.75(d,J=8.4Hz,1H),7.59(d,J=3.2Hz,1H),7.53(d,J=8.4Hz,1H),7.27(d,J=4.8Hz ,1H),6.95(d,J=8.4Hz,1H),6.47(d,J=3.2Hz,1H),4.90-4.84(m,1H),4.46(s,2H),4.42- 4.33(m,2H),3.98-3.86(m,5H),3.84-3.78(m,1H),3.73-3.69(m,1H),3.35-3.33(m,1H).

[0662] Examples 24 and 40

[0663]

[0664] Step 1: Synthesis of Compound 24-1

[0665] Under nitrogen protection, compound 16-9 (145 mg, 618.87 μmol) was dissolved in dioxane (4 mL), and compound BB-6 (236.63 mg, 680.76 μmol), cesium carbonate (604.92 mg, 1.86 mmol), Xantphos (71.62 mg, 123.77 μmol), and palladium acetate (13.89 mg, 61.89 μmol) were added. The reaction was carried out at 110 °C for 2 hours. After cooling, the solvent was concentrated under reduced pressure. The solution was purified by column chromatography (ethyl acetate / petroleum ether = 0%–100%) to give compound 24-1. MS m / z: 501.1 [M+1] + .

[0666] Step 2: Synthesis of compound 24-2

[0667] Under nitrogen protection, compound 24-1 (74 mg, 147.71 μmol) was dissolved in dioxane (4 mL) and water (0.8 mL). Compound 4-8 (54.08 mg, 221.57 μmol), potassium phosphate (94.06 mg, 443.13 μmol), and XPhos Pd G2 (11.62 mg, 14.77 μmol) were added, and the reaction was carried out at 100 °C for 2 hours. After cooling, the system was concentrated under reduced pressure. Compound 24-2 was purified by column chromatography (methanol / ethyl acetate = 0%–10%). MS m / z: 597.2 [M+1] + .

[0668] Step 3: Synthesis of the trifluoroacetate of compound 24-3

[0669] Under nitrogen protection, compound 24-2 (36 mg, 60.33 μmol) was dissolved in DCM (2.5 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction was carried out at 25 °C for 1 hour. The solvent was concentrated under reduced pressure to obtain the crude product. The crude product was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase [water (TFA)-acetonitrile]; acetonitrile %: 1%-30%, 8 min) to obtain the trifluoroacetate of compound 24-3. MS m / z: 497.2 [M+1] + ; 1 H NMR (400MHz, CD3OD) δ10.12(s,1H),8.40(d,J=5.2Hz,1H),7.63(d,J=8.8Hz,1H),7.53-7.47(m,1H),7.40(d,J=5.2Hz,1H),7.14(d,J=8 .8Hz,1H),6.79(d,J=3.6Hz,1H),4.80-4.70(m,2H),4.67(s,2H),3.95-3.82(m,6H),3.74-3.64(m,2H),3.50-3.35(m,4H),3.10(s,3H).

[0670] Step 4: Synthesis of compound 24, its trifluoroacetate, compound 40, and its trifluoroacetate.

[0671] The trifluoroacetate of compound 24-3 was chirally separated by SFC (column: DAICL CHIRALPAK IC (250 mm * 25 mm, 10 μm); mobile phase: A n-heptane, B isopropanol / acetonitrile = 2 / 1, 0.1% ammonia, B%: 40%), yielding compounds 24 and 40.

[0672] Compound 24: 1 H NMR(DMSO-d6,400MHz)δ9.98(s,1H),9.60(s,1H),9.18(s,1H),8.35(d,1H,J=3.6Hz),7 .57(d,1H,J=3.6Hz),7.45(d,1H,J=8.8Hz),7.38(d,1H,J=5.2Hz),7.00(d,1H,J=8.4Hz) ,6.91(d,1H,J=3.2Hz),4.71(s,2H),3.91-4.09(m,2H),3.88(s,3H),3.75-3.77(m,3H),3.50-3.68(m,1H),3.17-3.31(m,5H),2.68-3.10(m,3H);ee%=97.35%;Retention time:3.147min.

[0673] Compound 40: 1 H NMR (DMSO-d6, 400MHz) δ9.99 (s, 1H), 9.64 (s, 1H), 9.20 (s, 1H), 8.35 (d, 1H, J = 3.6Hz), 7.58 (d, 1H, J = 3.5Hz), 7.45(d,1H,J=5.2Hz),7.38(d,1H,J=5.2Hz),7.07(d,1H,J=8.8Hz),6.91(d,1H,J=3.2Hz),4.72(s,2H),3.91 -4.10(m,2H), 3.88(s,3H), 3.70-3.80(m,3H), 3.51-3.62(m,1H), 3.17-3.30(m,5H), 2.66-3.10(m,3H); ee% = 97.65%; retention time: 3.683 min.

[0674] Analytical method for detecting ee%: (Column: DAIICEL CHIRALPAK IC (50*4.6mm 3μm); Mobile phase: A. n-Heptane (0.1% DEA), B. Isopropanol / acetonitrile = 2 / 1, B%: 45%).

[0675] Compound 24 (658 mg, 1.33 mmol) was dissolved in DCM (7 mL), and TFA (492.61 μL) was added. The mixture was stirred at 25 °C for 1 hour. The solution was then concentrated directly under reduced pressure to obtain the trifluoroacetate of compound 24. MS m / z: 497.1 [M+1] + ;ee% = 97.85%; 1HNMR(DMSO-d6,400MHz)δ10.03(s,1H),9.72(s,1H),9.24(s,1H),8.35(d,1H,J=5.2Hz),7.60(m,2H),7.41(d,1H ,J=5.2Hz),7.17-7.24(m,1H),6.92(d,1H,J=3.6Hz),4.60(s,2H),3.88(s,3H),3.36-3.78(m,11H),3.01(s,3H).

[0676] Compound 40 (1.26 g, 2.54 mmol) was dissolved in DCM (13 mL), and TFA (942.43 μL) was added. The mixture was stirred at 25 °C for 1 hour. The solution was then concentrated directly under reduced pressure to obtain the trifluoroacetate of compound 40. MS m / z: 497.1 [M+1] + ;ee% = 97.84%; 1 HNMR (DMSO-d6, 400MHz) δ10.00 (s, 1H), 9.72 (s, 1H), 9.25 (s, 1H), 8.37 (d, 1H, J = 5.2Hz), 7.59 (m, 2H), 7.41 (d, 1H, J = 5. 2Hz),7.21(m,1H),6.92(d,1H,J=3.6Hz),4.73(s,2H),4.65-4.62(m,1H),3.88(s,3H),3.78-3.71(m,5H),3.71-3.35(m 5H),3.00(s,3H).

[0677] Example 25

[0678]

[0679] Step 1: Synthesis of Compound 25-1

[0680] Under nitrogen protection, compound 16-9 (40 mg, 170.72 μmol) was dissolved in dioxane (2 mL), followed by compound 23-1 (67.92 mg, 170.72 μmol), potassium carbonate (70.79 mg, 512.17 μmol), Ruphos (15.93 mg, 34.14 μmol), and Pd2(dba)3 (15.63 mg, 17.07 μmol). The reaction was carried out at 110 °C for 2 hours. After cooling, the solvent was concentrated under reduced pressure. Compound 25-1 was purified by column chromatography (methanol / ethyl acetate = 0%–10%). MS m / z: 596.2 [M+1] + .

[0681] Step 2: Synthesis of the trifluoroacetate of compound 25

[0682] Under nitrogen protection, compound 25-1 (82 mg, 137.66 μmol) was dissolved in DCM (3 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction was carried out at 25 °C for 16 hours. The solvent was concentrated under reduced pressure to obtain the crude product. The crude product was purified by prep-HPLC (column: Phenomenex C18 80*30 mm*3 μm; mobile phase: [water (TFA)-acetonitrile]; acetonitrile %: 1%-30%, 8 min) to obtain the trifluoroacetate of compound 25. MS m / z: 496.1 [M+1] + ; 1 H NMR (400MHz, CD3OD) δ8.76(d,J=8.4Hz,1H),8.35(d,J=5.2Hz,1H),7.77(d,J=8 .4Hz,1H),7.59(d,J=8.8Hz,1H),7.49(d,J=3.6Hz,1H),7.30(d,J=5.2Hz,1H),7 .08(d,J=8.8Hz,1H),6.53(d,J=3.2Hz,1H),4.85-4.60(m,3H),4.49(s,2H),3.9 5(s,3H),3.93-3.82(m,3H),3.76-3.60(m,2H),3.51-3.34(m,3H),3.08(s,3H).

[0683] Example 26

[0684]

[0685] Step 1: Synthesis of Compound 26-1

[0686] Compounds 23-1 (0.1 g, 251.35 μmol) and 4-6 (52.09 mg, 251.35 μmol) were added to anhydrous dioxane (2 mL), followed by potassium carbonate (104.21 mg, 754.05 μmol), Ruphos (17.59 mg, 37.70 μmol), and Pd2(dba)3 (23.02 mg, 25.13 μmol). The reaction mixture was reacted at 110 °C for 2 hours. The reaction solution was added to water (30 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 26-1. MS m / z: 569.2 [M+1] + .

[0687] Step 2: Synthesis of the trifluoroacetate of compound 26

[0688] Compound 26-1 (0.12 g, 211.04 μmol) was added to DCM (2 mL), followed by trifluoroacetic acid (1 mL), and the reaction was carried out at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [water (TFA)-acetonitrile]; acetonitrile %: 10%-40%, 8 min) to obtain the trifluoroacetate of compound 26. MS m / z: 469.1 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δppm 9.85(s,1H),8.74(s,1H),8.47(d,J=8.6Hz,1H),8.31(d,J=5.0Hz,1H) ,7.71(d,J=8.6Hz,1H),7.58(s,1H),7.30-7.26(m,2H),6.60(d,J=8.4H z,1H),6.47(s,1H),4.45(s,2H),4.39-4.36(m,1H),4.06-4.01(m,5H) ,3.92-3.87(m,3H),3.20-3.17(m,1H),3.04(s,1H),2.68-2.65(m,1H).

[0689] Example 27

[0690]

[0691] Step 1: Synthesis of Compound 27-1

[0692] In a dry vial, compounds 17-9 (40 mg, 171.48 μmol) and 23-1 (68.22 mg, 171.48 μmol) were dissolved in dioxane (8 mL), and cesium carbonate (167.62 mg, 514.44 μmol) was added. After stirring for 15 minutes and confirming pH > 9, palladium acetate (7.7 mg, 34.3 μmol) and Xantphos (12.40 mg, 21.43 μmol) were added. The reaction was carried out under nitrogen protection at 110 °C with stirring for 1 hour. The reaction solution was filtered, and the filtrate was concentrated. Compound 27-1 was obtained by column chromatography (ethyl acetate / petroleum ether = 0%–10%).

[0693] Step 2: Synthesis of the trifluoroacetate of compound 27

[0694] Compound 27-1 (70 mg, 117.71 μmol) was dissolved in DCM (1 mL) in a dry vial, and trifluoroacetic acid (671.09 mg, 5.89 mmol, 435.77 μL) was added. The reaction was stirred at 25 °C for 2 hours. The reaction solution was concentrated to obtain a crude product, which was purified by prep-HPLC (column: Phenomenex luna C18 100*40 mm*3 μm; mobile phase: [water (TFA)-acetonitrile]; acetonitrile %: 10%-48%, 8 min) to obtain the trifluoroacetate salt of compound 27. MS m / z: 495.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ10.167(s,1H),8.84(s,1H),8.71(d,J=8.4Hz,1H),8.12(d,J=4.8 Hz,1H),7.77(d,J=8.4Hz,1H),7.59(s,1H),7.50(d,J=8.0Hz,1H),7.28(d,J=5.2Hz,1H),6 .98(d,J=8.4Hz,1H),6.49(s,1H),5.30(d,J=15.2Hz,1H),4.46-4.43(m,4H),4.03-3.99( m,1H),3.97-3.92(m,2H),3.90(s,3H),3.72-3.67(m,1H),3.30-3.27(m,1H),2.94(s,3H).

[0695] Example 28

[0696]

[0697]

[0698] Step 1: Synthesis of compound BB-11-2

[0699] Under nitrogen protection, compound BB-11-1 (40 g, 188.64 mmol) was added to concentrated sulfuric acid (2000 mL), cooled to -10 °C, and concentrated nitric acid (21.55 mL) was slowly added dropwise. The reaction was carried out at -10 °C for 2 hours, and then heated to 20 °C for another 2 hours. The reaction solution was slowly poured into ice water (2000 mL), filtered, and the filter cake was washed with water (200 mL). The filter cake was dried to obtain the crude product. The crude product was added to ethanol (400 mL), stirred for 2 hours, filtered, and the filter cake was concentrated under reduced pressure to obtain compound BB-11-2. 1H NMR (400MHz, CDCl3) δ7.87 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.44 (s, 1H), 4.47 (s, 2H).

[0700] Step 2: Synthesis of compound BB-11-3

[0701] Under nitrogen protection, compound BB-11-2 (51 g, 198.41 mmol) was added to dioxane (510 mL), followed by di-tert-butyl dicarbonate (64.95 g, 297.62 mmol, 68.37 mL), 4-dimethylaminopyridine (2.42 g, 19.84 mmol), and triethylamine (60.23 g, 595.24 mmol, 82.85 mL). The reaction mixture was reacted at 20 °C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was added to methyl tert-butyl ether (250 mL), stirred for 2 hours, filtered, and the filter cake was dried to obtain compound BB-11-3. 1 H NMR (400MHz, CDCl3) δ7.84 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 4.65 (s, 2H), 1.49 (s, 9H).

[0702] Step 3: Synthesis of compound BB-11-4

[0703] Under nitrogen protection, compounds BB-11-3 (15 g, 42.00 mmol) and 4-8 (10.25 g, 42.00 mmol) were added to a mixed solution of dioxane (150 mL) and water (30 mL). Potassium phosphate (17.83 g, 84.00 mmol) and XPhos Pd G2 (4.96 g, 6.30 mmol) were added, and the mixture was heated to 70 °C and reacted for 2 hours. The reaction solution was added to water (200 mL), extracted with ethyl acetate (200 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (ethyl acetate / petroleum ether = 0%–20%) to obtain compound BB-11-4. MS m / z: 409.0 [M+1] + ; 1 HNMR(400MHz, CDCl3)δ8.39(d,J=5.0Hz,1H),7.80(d,J=2.0Hz,2H),7.24-7.19(m,1H) ,6.99(d,J=5.0Hz,1H),6.19(d,J=3.6Hz,1H),4.64(s,2H),3.91(s,3H),1.48(s,9H).

[0704] Step 4: Synthesis of compound BB-11

[0705] Under nitrogen protection, compound BB-11-4 (11.7 g, 28.65 mmol) was added to a mixed solution of ethanol (220 mL) and water (44 mL), along with iron powder (8.00 g, 143.24 mmol) and ammonium chloride (7.66 g, 143.24 mmol). The mixture was heated to 60 °C and reacted for 2 hours. After cooling, the mixture was filtered, and the filter cake was washed with a mixture of dichloromethane and methanol (10:1, 200 mL). The filtrate was concentrated under reduced pressure, and then extracted with water (100 mL) and dichloromethane (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound BB-11. MS m / z: 379.0 [M+1] + .

[0706] Step 5: Synthesis of Compound 28-2

[0707] Under nitrogen protection, compound 28-1 (5 g, 22.48 mmol) was dissolved in DCM (50 mL), and Dys-Martin oxidant (11.44 g, 26.97 mmol, 8.35 mL) was added. The reaction was carried out at 25 °C for 2 hours. A saturated sodium carbonate solution (50 mL) was added, and the aqueous phase was extracted with dichloromethane (50 mL × 3). The mixture was separated, and the organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to obtain the crude product. Compound 28-2 was purified by column chromatography (ethyl acetate / petroleum ether = 0%–50%). MS m / z: 222.0, 220.0 [M+1] + ; 1 HNMR (400MHz, CDCl3) δ10.11 (s, 1H), 7.99 (d, J = 8.4Hz, 1H), 7.41 (d, J = 8.4Hz, 1H).

[0708] Step 6: Synthesis of Compound 28-3

[0709] Methanol (21 mL), compound 28-2 (420 mg, 1.91 mmol), and methylamine hydrochloride (257.27 mg, 3.81 mmol) were added to a thumb flask and stirred. Potassium acetate (392.66 mg, 4.00 mmol) was then added, and the mixture was stirred at 25 °C for 2 hours. NaBH(OAc)3 (1.21 g, 5.72 mmol) was then added, and the mixture was stirred at 25 °C for another hour. The reaction mixture was poured into a saturated sodium carbonate solution (50 mL), and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane:methanol = 2%–10%) to obtain compound 28-3. MS m / z: 234.8, 236.8 [M+1]+ ; 1 H NMR (400MHz, DMSO-d6) δ 8.10 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 3.84 (s, 2H), 2.34 (s, 3H).

[0710] Step 7: Synthesis of Compound 28-5

[0711] Under nitrogen protection, compound 28-3 (400 mg, 1.70 mmol) was dissolved in DMF (4 mL), and compound 28-4 (470.26 mg, 2.18 mmol), HATU (968.70 mg, 2.55 mmol), and DIEA (658.52 mg, 5.10 mmol, 887.50 μL) were added. The reaction mixture was reacted at 25 °C for 0.5 h. The reaction mixture was concentrated, water (5 mL) was added, and the aqueous phase was extracted with ethyl acetate (10 mL). The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Compound 28-5 was purified by column chromatography (ethyl acetate / petroleum ether = 30%–50%). MS m / z: 432.2, 434.2 [M+1] + .

[0712] Step 8: Synthesis of the hydrochloride salt of compound 28-6

[0713] Compound 28-5 (312 mg, 720.99 μmol) was added to hydrochloric acid / ethyl acetate (4 M, 5 mL), and the reaction was carried out at 25 °C for 2 hours. The reaction mixture was concentrated to give the hydrochloride salt of compound 28-6. MS m / z: 332.0, 334.0 [M+1] + .

[0714] Step 9: Synthesis of Compound 28-7

[0715] Under nitrogen protection, the hydrochloride salt (294 mg) of compound 28-6 was dissolved in dioxane (3 mL), and cesium carbonate (1.04 g, 3.19 mmol) and Xantphos Pd G4 (76.66 mg, 79.66 μmol) were added. The reaction mixture was reacted at 110 °C for 2 hours. The reaction mixture was concentrated, water (10 mL) was added, and the aqueous phase was extracted with ethyl acetate (10 mL). The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Compound 28-7 was purified by column chromatography (ethyl acetate / petroleum ether = 30%–60%). MS m / z: 252.1 [M+1] + ; 1H NMR (400MHz, CDCl3) δ6.99(d,J=8.6Hz,1H),6.65(d,J=8.6Hz,1H),5.40(d,J=16.8Hz,1H),4.90 (m,1H),3.98(d,J=17.0Hz,1H),3.23-3.12(m,2H),3.05(s,3H),2.59(m,1H),2.03-1.85(m,3H).

[0716] Step 10: Synthesis of Compound 28-8

[0717] Under nitrogen protection, compound BB-11 (50 mg, 132.13 μmol) was dissolved in dioxane (1 mL), followed by compound 28-7 (39.91 mg, 158.55 μmol), cesium carbonate (86.10 mg, 264.25 μmol), palladium acetate (2.97 mg, 13.21 μmol), and BINAP (12.34 mg, 19.82 μmol). The reaction mixture was reacted at 110 °C for 2 hours. The reaction mixture was concentrated, and water (10 mL) was added. The aqueous phase was extracted with ethyl acetate (10 mL), and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Compound 28-8 was purified by thin-layer chromatography using silica gel plates (ethyl acetate / petroleum ether = 30%). MS m / z: 594.5 [M+1] + .

[0718] Step 11: Synthesis of Compound 28

[0719] Under nitrogen protection, compound 28-8 (30 mg, 50.53 μmol) was dissolved in DCM (1 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was reacted at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure, and saturated sodium bicarbonate (5 mL) was added. The aqueous phase was extracted with ethyl acetate (5 mL), and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Compound 28 was purified by thin-layer chromatography using silica gel plates (ethyl acetate). MS m / z: 494.2 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),8.72(s,1H),8.38(d,J=8.6Hz,1H),8.30(d,J=5.0Hz,1H),7 .70(d,J=8.6Hz,1H),7.57(d,J=3.6Hz,1H),7.25(d,J=5.0Hz,1H),6.99(d,J=8.8Hz,1H),6.93(d, J=8.6Hz,1H),6.47(d,J=3.6Hz,1H),5.67(d,J=16.9Hz,1H),5.01-5.09(m,1H),4.45(s,2H),4.0 5(d,J=17.0Hz,1H),3.87(s,3H),3.02(s,3H),2.42(m,2H),1.84-1.93(m,2H),1.37-1.13(m,2H).

[0720] Example 29

[0721]

[0722] Step 1: Synthesis of Compound 29-2

[0723] Compound 29-1 (5 g, 26.73 mmol), di-tert-butyl dicarbonate (17.50 g, 80.20 mmol, 18.42 mL), and tetrahydrofuran (50 mL) were added. 4-Dimethylaminopyridine (326.59 mg, 2.67 mmol) was then added, and the mixture was reacted at 25 °C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (ethyl acetate / petroleum ether = 0%–1%) to obtain compound 29-2. MS m / z: 386.9, 388.9 [M+1] + .

[0724] Step 2: Synthesis of compound 29-3

[0725] Compound 29-2 (2.5 g, 6.46 mmol) was added to 1,2-dichloroethane (25 mL), followed by N-bromosuccinimide (1.72 g, 9.68 mmol) and azobisisobutyronitrile (106.01 mg, 645.55 μmol). The mixture was heated to 80 °C and reacted for 12 hours. The reaction solution was added to water (50 mL), and the mixture was extracted with dichloromethane (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by column chromatography (ethyl acetate / petroleum ether = 0%–2%) to give compound 29-3. MS m / z: 466.6, 468.7 [M+1] + .

[0726] Step 3: Synthesis of Compound 29-5

[0727] Compound 29-3 (0.9 g, 1.93 mmol) and compound 29-4 (264.45 mg, 2.32 mmol) were added to acetonitrile (27 mL), followed by DIEA (748.57 mg, 5.79 mmol, 1.01 mL). The reaction mixture was reacted at 25 °C for 12 hours. The reaction solution was concentrated under reduced pressure, and the crude product was separated by column chromatography (ethyl acetate / petroleum ether = 0%–50%) to give compound 29-5. MS m / z: 499.0, 501.0 [M+1] + .

[0728] Step 4: Synthesis of Compound 29-6

[0729] Compound 29-5 (0.85 g, 1.70 mmol) was added to dioxane (17 mL), followed by cesium carbonate (1.11 g, 3.40 mmol) and Xantphos Pd G4 (163.80 mg, 170.21 μmol). The mixture was heated to 110 °C and reacted for 4 hours. Water (50 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. This crude product was then separated by column chromatography (ethyl acetate / petroleum ether = 0%–50%) to give compound 29-6. MS m / z: 419.1 [M+1] + .

[0730] Step 5: Synthesis of Compound 29-7

[0731] Compound 29-6 (0.5 g, 1.19 mmol) was added to trifluoroacetic acid (2 mL) and DCM (4 mL), and reacted at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure, dissolved in water (10 mL) and dichloromethane (10 mL), and then added to a saturated sodium carbonate aqueous solution (50 mL). Extraction was performed using a 10:1 dichloromethane:methanol mixture (50 mL × 5), followed by separation. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 29-7. MS m / z: 218.9 [M+1] + .

[0732] Step 6: Synthesis of Compound 29-8

[0733] Compound 23-1 (60 mg, 150.81 μmol) and compound 29-7 (39.50 mg, 180.97 μmol) were added to dioxane (2 mL), followed by potassium carbonate (41.69 mg, 301.62 μmol), Ruphos (14.07 mg, 30.16 μmol), and Pd2(dba)3 (13.81 mg, 15.08 μmol). The mixture was heated to 110 °C and reacted for 2 hours. Water (50 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 29-8. MS m / z: 580.2 [M+1] + .

[0734] Step 7: Synthesis of the trifluoroacetate of compound 29

[0735] Compound 29-8 (60 mg, 103.51 μmol) was added to DCM (2 mL) and trifluoroacetic acid (1 mL), and reacted at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure and purified by prep-HPLC (Phenomenex Luna 80*30 mm*3 μm column; mobile phase: [water (TFA)-acetonitrile]; acetonitrile %: 1%-25%, 8 min) to obtain the trifluoroacetate of compound 29. MS m / z: 480.3 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ11.17(m,1H),10.45(s,1H),8.92-8.89(m,2H),8.34(d,J=4.8Hz,1 H),7.80-7.72(m,2H),7.60(d,J=3.6Hz,1H),7.28(d,J=4.8Hz,1H),6.89(d,J=8.2Hz,1H), 6.45(d,J=3.4Hz,1H),4.60-4.57(m,1H),4.50(s,3H),4.20-4.08(m,2H),3.72-3.70(m,1H ),3.67-3.65(m,2H),3.28-3.27(m,1H),2.17(s,1H),2.16-2.13(m,1H),1.94-1.90(m,2H).

[0736] Example 30

[0737]

[0738] Step 1: Synthesis of Compound 30-2

[0739] Under nitrogen protection, compound 30-1 (75 g, 363.25 mmol) was dissolved in tetrahydrofuran (750 mL), cooled to -65 °C, and a tetrahydrofuran solution of lithium diisopropylamino in 2 M (217.95 mL) was added. The reaction was carried out at -65 °C for 1 hour, followed by the addition of dimethyl carbonate (65.44 g, 726.51 mmol, 61.16 mL), and the temperature was raised to 20 °C for 3 hours. The reaction was quenched with saturated ammonium chloride (200 mL), and the mixture was extracted with water (500 mL) and ethyl acetate (1000 mL). The extract was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Compound 30-2 was purified by column chromatography (ethyl acetate / petroleum ether = 1%–10%). MS m / z: 264.0, 266.0 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ8.20(s,1H),3.93(s,3H),2.04(s,3H).

[0740] Step 2: Synthesis of compound 30-3

[0741] Under nitrogen protection, compound 30-2 (8.2 g, 31.00 mmol) was dissolved in 1,2-dichloroethane (80 mL), and N-bromosuccinimide (16.55 g, 93.00 mmol) and azobisisobutyronitrile (1.02 g, 6.20 mmol) were added. The reaction was carried out at 80 °C for 5 hours. After cooling, the reaction was quenched with saturated sodium sulfite solution (80 mL), extracted with dichloromethane (50 mL × 3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 30-3. MS m / z: 343.8 [M+1] + .

[0742] Step 3: Synthesis of compound 30-4

[0743] Under nitrogen protection, compound 30-3 (11.86 g, 34.54 mmol) was dissolved in an ammonia / methanol solution (7 M, 200 mL), and the reaction was carried out at 25 °C for 16 hours. The mixture was filtered, and the residue was washed with methanol (20 mL). The residue was collected to give compound 30-4. 1 H NMR (400MHz, DMSO-d6) δ8.55 (s, 1H), 4.35 (s, 2H).

[0744] Step 4: Synthesis of compound 30-5

[0745] Under nitrogen protection, compound 30-4 (2.94 g, 11.88 mmol) was dissolved in tetrahydrofuran (30 mL), and di-tert-butyl dicarbonate (3.89 g, 17.82 mmol, 4.09 mL) and 4-dimethylaminopyridine (290.27 mg, 2.38 mmol) were added. The reaction was carried out at 25 °C for 1 hour. The solvent was concentrated under reduced pressure, and the mixture was purified by column chromatography (ethyl acetate / petroleum ether = 0–10%) to give compound 30-5. MS m / z: 347.0 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ8.64(s,1H),4.67(s,2H),1.53(s,9H).

[0746] Step 5: Synthesis of compound 30-6

[0747] Under nitrogen protection, compound 30-5 (3.07 g, 8.83 mmol) was added to dioxane (60 mL), water (12 mL), compound 4-8 (2.16 g, 8.83 mmol), potassium carbonate (2.44 g, 17.66 mmol), and Pd(dppf)Cl2 (646.26 mg, 883.22 μmol). The reaction was carried out at 70 °C for 2 hours. After cooling, the solvent was concentrated under reduced pressure to obtain the crude product. The crude product was added to water (10 mL) and ethyl acetate (20 mL), and stirred for 1 hour. The mixture was filtered, and the residue was washed with ethyl acetate (10 mL). The residue was collected to obtain compound 30-6. MS m / z: 399.1 [M+1] + ; 1 H NMR(400MHz, DMSO-d6)δ8.95(s,1H),8.43(d,J=4.8Hz,1H),7.65(d,J=3.6Hz,1H),7 .41(d,J=4.8Hz,1H),6.69(d,J=3.6Hz,1H),4.92(s,2H),3.89(s,3H),1.51(s,9H).

[0748] Step 6: Synthesis of Compound 30-7

[0749] Compound 30-6 (30 mg, 75.22 μmol) and compound 29-7 (19.70 mg, 90.26 μmol) were added to dioxane (2 mL), followed by Xantphos Pd G4 (7.24 mg, 7.52 μmol) and cesium carbonate (73.52 mg, 225.65 μmol). The mixture was heated to 110 °C and reacted for 2 hours. Water (30 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 30-7. MS m / z: 581.2 [M+1] + .

[0750] Step 7: Synthesis of the trifluoroacetate of compound 30

[0751] Compound 30-7 (50 mg, 86.11 μmol) was added to dioxane (2 mL) and trifluoroacetic acid (1 mL), and reacted at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure. The trifluoroacetate of compound 30 was obtained by prep-HPLC (Phenomenex Luna column 80*30 mm*3 μm; mobile phase: [water (TFA)-acetonitrile]; acetonitrile %: 1%-25%, 8 min). MS m / z: 481.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ11.31(br s,1H),10.23(s,1H),10.03(s,1H),9.30(s,1H),8.38(d,J=4.8Hz,1H),7.82(br d,J=8.4Hz,1H),7.60(d,J=3.4Hz,1H),7.42(d,J=5.0Hz,1H),6.98(d,J=8.2Hz,1H),6.91(d,J=3.6Hz,1H),4.76(s,2H),4.61-4.5 8(m,1H),4.53-4.52(m,1H),4.23-4.18(m,1H),3.88(s,3H),3.32(s,1H),2.61-2.58(m,2H),2.17-2.15(m,1H),1.94-1.88(m,2H).

[0752] Example 31

[0753]

[0754] Step 1: Synthesis of compound 31-1

[0755] Compound 29-7 (50 mg, 229.09 μmol) and methyl iodoform (35.12 mg, 247.42 μmol, 15.40 μL) were added to DMF (1 mL). After cooling to 0 °C, sodium hydride (9.90 mg, 247.42 μmol, 60% purity) was added, and the mixture was stirred at 25 °C for 1 hour. The reaction solution was slowly added to a saturated ammonium chloride aqueous solution (30 mL), and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 31-1. MS m / z: 232.9 [M+1] + .

[0756] Step 2: Synthesis of compound 31-2

[0757] Compound 23-1 (20 mg, 50.27 μmol) and compound 31-1 (14.01 mg, 60.32 μmol) were added to dioxane (2 mL), followed by cesium carbonate (32.76 mg, 100.54 μmol), Pd(OAc)₂ (1.13 mg, 5.03 μmol), and Xantphos (5.82 mg, 10.05 μmol). The mixture was heated to 110 °C and reacted for 2 hours. The reaction solution was added to water (20 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 31-2. MS m / z: 594.4 [M+1] + .

[0758] Step 3: Synthesis of the trifluoroacetate of compound 31

[0759] Compound 31-2 (30 mg, 50.53 μmol) was added to DCM (2 mL) and trifluoroacetic acid (1 mL), and reacted at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure and purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (TFA)-acetonitrile]; acetonitrile %: 20%-50%, 8 min). The organic solvent was removed by concentration, and the solution was added to saturated sodium bicarbonate aqueous solution (10 mL). Extraction was performed with dichloromethane (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The solution was dissolved in methanol (0.2 mL), and trifluoroacetic acid (5 μL) was added, followed by deionized water (3 mL) to obtain the trifluoroacetate salt of compound 31. MS m / z: 494.4 [M+1] + ; 1HNMR(400MHz,DMSO-d6)δ10.50(s,1H),8.94(s,1H),8.62(d,J=8.4Hz,1H),8.33(d ,J=5.0Hz,1H),7.83(d,J=8.4Hz,2H),7.60(d,J=3.6Hz,1H),7.29(d,J=4.8Hz,1H), 7.00(d,J=8.4Hz,1H),6.47(d,J=3.4Hz,1H),4.50(s,3H),3.70-3.65(m,3H),3.54( s,3H),3.17-3.16(m,2H),2.26-2.16(m,2H),1.94-1.84(m,2H),1.26-1.24(m,2H).

[0760] Example 32

[0761]

[0762] Step 1: Synthesis of compound 32-2

[0763] Under nitrogen protection, compound 16-1 (5 g, 23.23 mmol) was added to DCM (120 mL), followed by compound 32-1 (5.98 g, 23.23 mmol) and acetic acid (1.39 g, 23.23 mmol, 1.33 mL). The reaction was carried out at 20 °C for 1 hour. Then, NaBH(OAc)3 (7.38 g, 34.84 mmol) was added, and the reaction was carried out at 20 °C for 16 hours. The reaction was quenched with saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane (50 mL × 3), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Compound 32-2 was obtained by column chromatography (ethyl acetate / petroleum ether = 0%–20%). MS m / z: 457.2 [M+1] + ; 1 H NMR(400MHz, CDCl3) δ7.25(d,J=8.4Hz,4H),6.84(d,J=8.4Hz,4H),4.30-3.96(m,1H),3.9 0(d,J=11.6Hz,1H),3.80(s,6H),3.73-3.42(m,7H),3.41-3.28(m,1H),2.68(s,3H),1.48( S ,9H).

[0764] Step 2: Synthesis of compound 32-3

[0765] Under nitrogen protection, compound 32-2 (8.4 g, 18.40 mmol) was dissolved in DCM (40 mL), and hydrochloric acid / methanol (4 M, 140 mL) was added. The reaction was carried out at 20 °C for 16 hours. The solvent was concentrated under reduced pressure, and dichloromethane (40 mL), ammonia (5 mL), and anhydrous sodium sulfate were added. The mixture was dried over a vacuum. After filtration, the filtrate was concentrated under reduced pressure to give compound 32-3. MS m / z: 357.2 [M+1] + .

[0766] Step 3: Synthesis of compound 32-4

[0767] Under nitrogen protection, compound 32-3 (4 g, 11.22 mmol) was dissolved in DMF (80 mL), and compound BB-1-1 (2.75 g, 13.47 mmol) and DIEA (4.35 g, 33.66 mmol, 5.86 mL) were added. The reaction was carried out at 100 °C for 16 hours. After cooling, the reaction was quenched with water (100 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Compound 32-4 was purified by column chromatography (ethyl acetate / petroleum ether = 0%–50%). MS m / z: 540.1 [M+1] + ; 1 H NMR(400MHz, CDCl3)δ9.83(s,1H),7.45(d,J=8.8Hz,1H),6.98(d,J=8.8Hz,1H),6.92-6.86(m,4H),6.85-6.78(m,4H),4.07-4.03(m,1H), 3.91-3.74(m,8H),3.67-3.56(m,1H),3.54-3.41(m,3H),3.10-2.97(m,3H),2.86-2.81(m,1H),2.67(d,J=12.0Hz,1H),2.53-2.48(m,1H).

[0768] Step 4: Synthesis of compound 32-5

[0769] Under nitrogen protection, compound 32-4 (6 g, 11.10 mmol) was dissolved in trifluoroacetic acid (63.29 g, 555.10 mmol, 41.10 mL) and reacted at 60 °C for 16 h. After cooling, the mixture was concentrated under reduced pressure, and dichloromethane (60 mL) and NaBH(OAc)3 (7.06 g, 33.31 mmol) were added. The reaction was then carried out at 25 °C for 2 h. The reaction was quenched with saturated sodium bicarbonate solution (50 mL), extracted with dichloromethane (50 mL × 3), washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. Compound 32-5 was purified by column chromatography (ethyl acetate / petroleum ether = 0%–50%). MS m / z: 404.0, 406.0 [M+1] + ; 1 HNMR (400MHz, CDCl3) δ7.24(d,J=9.6Hz,3H),7.09(d,J=8.4Hz,1H),6.85(d,J=8.4Hz,2H),4.04(s,2H),3.89-3.81(m, 5H),3.71-3.63(m,3H),3.59-3.51(m,1H),3.35-3.27(m,2H),3.26-3.17(m,1H),3.09-3.01(m,1H),2.63-2.54(m,1H).

[0770] Step 5: Synthesis of Compound 32-6

[0771] Under nitrogen protection, compound 32-5 (50 mg, 132.13 μmol) was dissolved in dioxane (2 mL), and compound BB-11 (53.42 mg, 132.13 μmol), cesium carbonate (129.15 mg, 396.38 μmol), Xantphos (15.29 mg, 26.43 μmol), and palladium acetate (2.97 mg, 13.21 μmol) were added. The reaction was carried out at 110 °C for 2 hours. After cooling, the solvent was concentrated under reduced pressure. Compound 32-6 was purified by column chromatography (ethyl acetate / petroleum ether = 0%–100%). MS m / z: 702.2 [M+1] + .

[0772] Step 6: Synthesis of the trifluoroacetate of compound 32

[0773] Under nitrogen protection, compound 32-6 (60 mg, 85.49 μmol) was dissolved in trifluoroacetic acid (6 mL) and reacted at 80 °C for 72 hours. The mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by prep-HPLC (column: Phenomenex Luna C18 100*40 mm*3 μm; mobile phase: water (TFA(-acetonitrile); B%: 10%-55%, 8 min) to obtain the trifluoroacetate salt of compound 32. MS m / z: 482.2 [M+1] + ; 1 H NMR (400MHz, CD3OD) δ8.75(d,J=8.8Hz,1H),8.35(d,J=5.2Hz,1H),7.77(d,J=8.8 Hz,1H),7.60(d,J=8.8Hz,1H),7.49(d,J=3.6Hz,1H),7.31(d,J=5.2Hz,1H),7.08 (d,J=8.8Hz,1H),6.53(d,J=3.6Hz,1H),4.66-4.52(m,2H),4.49(s,2H),3.98-3. 91(m,4H),3.90-3.82(m,2H),3.77-3.70(m,1H),3.48(s,3H),3.40-3.35(m,2H).

[0774] Example 33

[0775]

[0776] Step 1: Synthesis of Compound 33-1

[0777] Under nitrogen protection, compound 32-5 (1.0 g, 2.47 mmol) was added to trifluoroacetic acid (20.00 mL), and the reaction was carried out at 80 °C for 24 hours. The mixture was concentrated under reduced pressure, methanol (20 mL) was added, and the reaction was quenched with sodium bicarbonate. The mixture was filtered, and the residue was washed with methanol (20 mL). The filtrate was concentrated under reduced pressure. Compound 33-1 was purified by column chromatography (methanol / dichloromethane = 0%–20%). MS m / z: 284.0 [M+1] + .

[0778] Step 2: Synthesis of compound 33-2

[0779] Under nitrogen protection, compound 33-1 (100 mg, 351.92 μmol) was dissolved in DMF (1 mL), and potassium carbonate (97.28 mg, 703.85 μmol) and iodoethane (54.89 mg, 351.92 μmol, 28.15 μL) were added. The reaction was carried out at 25 °C for 16 hours. The reaction was quenched with water (10 mL), extracted with ethyl acetate (10 mL × 3), and the organic phase was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. Compound 33-2 was purified by column chromatography (ethyl acetate / petroleum ether = 0%–70%). MS m / z: 312.2 [M+1] + .

[0780] Step 3: Synthesis of compound 33-3

[0781] Under nitrogen protection, compound BB-11 (40 mg, 105.70 μmol) was dissolved in dioxane (2 mL), and compound 33-2 (33.00 mg, 105.70 μmol), cesium carbonate (103.32 mg, 317.11 μmol), and methanesulfonic acid [9,9-dimethyl-4,5-bis(diphenylphosphine)xanthones](2-methylamino-1,1-biphenyl-2-yl)palladium(II) (10.17 mg, 10.57 μmol) were added. The reaction was carried out at 110 °C for 2 hours. After cooling, the mixture was concentrated under reduced pressure. Compound 33-3 was purified by column chromatography (methanol / ethyl acetate = 0%–10%). MS m / z: 610.2 [M+1] + .

[0782] Step 4: Synthesis of the trifluoroacetate of compound 33

[0783] Under nitrogen protection, compound 33-3 (30 mg, 49.20 μmol) was dissolved in DCM (1.5 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction was carried out at 25 °C for 2 hours. The solution was concentrated under reduced pressure to obtain the crude product. Purification was performed by prep-HPLC (column: Phenomenex Luna C18 150*30 mm*5 μm; mobile phase: [water (TFA)-acetonitrile]; B%: 1%-30%, 8 min). The trifluoroacetate salt of compound 33-3 was obtained. MS m / z: 510.1 [M+1] + ; 1H NMR (400MHz, CD3OD) δ8.75(d,J=8.4Hz,1H),8.36(d,J=5.2Hz,1H),7.78(d,J=8 .4Hz,1H),7.59(d,J=8.8Hz,1H),7.51(d,J=3.6Hz,1H),7.33(d,J=5.2Hz,1H), 7.09(d,J=8.8Hz,1H),6.55(d,J=3.6Hz,1H),4.80-4.62(m,3H),4.49(s,2H),4 .01-3.82(m,7H),3.72-3.59(m,2H),3.53-3.40(m,4H),1.47(t,J=7.2Hz,3H).

[0784] Example 34

[0785]

[0786] Step 1: Synthesis of compound 34-2

[0787] Under nitrogen protection, compound 28-2 (1.5 g, 6.80 mmol) was added to DCM (15 mL), followed by 2,4-dimethoxybenzylamine (1.25 g, 7.48 mmol, 1.13 mL) and AcOH (408.59 mg, 6.80 mmol). The reaction was carried out at 25 °C for 1 hour. Then, NaBH(OAc)3 (1.73 g, 8.17 mmol) was added, and the reaction was carried out at 25 °C for 15 hours. The reaction was quenched with saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane (50 mL × 3), washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The purified compound 34-2 was obtained by column chromatography (ethyl acetate / petroleum ether = 0%–30%). MS m / z: 371.0 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ7.72 (d, J = 8.4Hz, 1H), 7.18 (d, J = 8.8Hz, 1H), 7.06 (d, J = 8. 4Hz,1H),6.46-6.39(m,2H),3.98(s,2H),3.82(s,3H),3.81(s,2H),3.80(s,3H).

[0788] Step 2: Synthesis of compound 34-4

[0789] Under nitrogen protection, compound 34-2 (240 mg, 2.16 mmol) was dissolved in DMF (6 mL), and DIEA (6.48 mmol, 1.13 mL), HATU (1.23 g, 3.24 mmol), and compound 34-3 (802.87 mg, 2.16 mmol) were added. The reaction was carried out at 25 °C for 2 hours. The reaction was quenched with water (20 mL), extracted with ethyl acetate (10 mL × 3), and the organic phase was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Compound 34-4 was purified by column chromatography (ethyl acetate / petroleum ether = 0%–30%). MS m / z: 485.9 [M + Na] + Step 3: Synthesis of compounds 34-5

[0790] Under nitrogen protection, compound 34-4 (604 mg, 1.30 mmol) was dissolved in DMF (6 mL), and 1,10-phenanthroline (46.84 mg, 259.93 μmol), cesium carbonate (1.27 g, 3.90 mmol), and cuprous iodide (24.75 mg, 129.97 μmol) were added. The reaction was carried out at 140 °C for 16 hours. After cooling, the reaction was quenched with water (30 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The organic phases were washed with saturated brine (20 mL × 2) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. Compound 34-5 was purified by column chromatography (ethyl acetate / petroleum ether = 0%–50%). MS m / z: 384.0 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ7.59(d,J=8.4Hz,1H),7.35(d,J=8.4Hz,1H),7.23(d,J=8.4Hz,1H),7.18 -7.16(m,1H),7.06-7.05(m,1H),6.50-6.38(m,3H),4.76(s,2H),4.48(s,2H),3.82(s,3H),3.76(s,3H).

[0791] Step 4: Synthesis of Compounds 34-6

[0792] Under nitrogen protection, compound 34-5 (70 mg, 184.98 μmol) was dissolved in dioxane (4 mL), and compound BB-11 (71.00 mg, 184.98 μmol), cesium carbonate (180.81 mg, 554.93 μmol), 2-dicyclohexylphosphine-2'-N,N-dimethylamino)-biphenyl (14.56 mg, 37.00 μmol), and palladium acetate (4.15 mg, 18.50 μmol) were added. The reaction was carried out at 110 °C for 4 hours. After cooling, the mixture was concentrated under reduced pressure. The solution was purified by column chromatography (ethyl acetate / petroleum ether = 0%–100%) to obtain compound 34-6. MS m / z: 726.1 [M+1] + .

[0793] Step 5: Synthesis of Compound 34

[0794] Under nitrogen protection, compound 34-6 (60 mg, 82.67 μmol) was dissolved in trifluoroacetic acid (4 mL) and reacted at 25 °C for 16 h, followed by a reaction at 60 °C for 6 h. The mixture was concentrated under reduced pressure to obtain the crude product. Purification was performed by prep-HPLC (column: Phenomenex C18 80*30 mm*3 μm; mobile phase: [water (TFA)-acetonitrile]; B%: 10%-40%, 8 min). The mixture was concentrated under reduced pressure, pH adjusted to 8 with ammonia, and extracted with dichloromethane (20 mL × 3). The organic phases were combined and concentrated under reduced pressure to obtain compound 34. MS m / z: 476.1 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ10.40-10.33(m,1H),8.87(s,1H),8.76(d,J=8.4Hz,1H),8.42-8.37 (m,1H),8.32(d,J=4.8Hz,1H),7.91(d,J=8.8Hz,1H),7.78(d,J=8.4Hz,1H),7.59(d,J=3.6H z,1H),7.50(d,J=2.0Hz,1H),7.28(d,J=4.8Hz,1H),7.16(d,J=8.8Hz,1H),6.90-6.89(m,1H ), 6.47 (d, J = 3.6Hz, 1H), 6.44-6.41 (m, 1H), 4.48 (s, 2H), 4.24 (d, J = 4.8Hz, 2H), 3.87 (s, 3H).

[0795] Example 35

[0796]

[0797] Step 1: Synthesis of Compound 35-2

[0798] Under nitrogen protection, compound 35-1 (125 mg, 540.55 μmol) was dissolved in DCM (2 mL), and DIEA (209.59 mg, 1.62 mmol, 282.46 μL), HATU (308.30 mg, 810.83 μmol), and compound 34-2 (200.90 mg, 540.55 μmol) were added. The reaction was carried out at 25 °C for 2 hours. The reaction was quenched with water (20 mL), extracted with ethyl acetate (10 mL × 3), and the organic phase was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Compound 35-2 was purified by column chromatography (ethyl acetate / petroleum ether = 0%–50%). MS m / z: 605.9, 607.9 [M + Na] + .

[0799] Step 2: Synthesis of compound 35-3

[0800] Under nitrogen protection, compound 35-2 (600 mg, 1.03 mmol) was dissolved in DCM (6 mL), and zinc bromide (1.16 g, 5.13 mmol, 256.69 μL) was added. The reaction was carried out at 25 °C for 2 hours. The mixture was filtered, and the residue was washed with dichloromethane (10 mL). The filtrate was collected, and water (10 mL) was added. Extraction was performed with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure. The mixture was purified by column chromatography (ethyl acetate / petroleum ether = 0%–100%) to obtain compound 35-3. MS m / z: 484.0, 486.0 [M+1] + .

[0801] Step 3: Synthesis of compound 35-4

[0802] Under nitrogen protection, compound 35-3 (320 mg, 660.11 μmol) was dissolved in dioxane (6 mL), and cesium carbonate (645.23 mg, 1.98 mmol), 2-di-tert-butylphospho-2'-N,N-dimethylaminobiphenyl (51.96 mg, 132.02 μmol), and palladium acetate (14.82 mg, 66.01 μmol) were added. The reaction was carried out at 110 °C for 2 hours. After cooling, the mixture was filtered, and the residue was washed with dichloromethane (10 mL). The filtrate was concentrated under reduced pressure. Compound 35-4 was purified by column chromatography (ethyl acetate / petroleum ether = 0%–70%). MS m / z: 404.1 [M+1] + .

[0803] Step 4: Synthesis of compound 35-5

[0804] Under nitrogen protection, compound 35-4 (79 mg, 195.61 μmol) was dissolved in dioxane (4 mL), and benzophenone imine (42.54 mg, 234.74 μmol, 39.39 μL), sodium tert-butoxide (37.60 mg, 391.23 μmol), BINAP (24.36 mg, 39.12 μmol), and Pd2(dba)3 (17.91 mg, 19.56 μmol) were added. The reaction was carried out at 110 °C for 2 hours. After cooling, the reaction was quenched with saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 35-5. MS m / z: 549.2 [M+1] + .

[0805] Step 5: Synthesis of Compounds 35-6

[0806] Under nitrogen protection, compound 35-5 (107 mg, 195.03 μmol) was dissolved in DCM (2 mL), and trifluoroacetic acid (667.14 mg, 5.85 mmol, 433.21 μL) was added. The reaction was carried out at 25 °C for 1 hour. The mixture was concentrated under reduced pressure, and extracted with dichloromethane (10 mL), saturated sodium carbonate solution (10 mL), and dichloromethane (10 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure. Compound 35-6 was purified by column chromatography (ethyl acetate / petroleum ether = 0%–100%). MS m / z: 385.2 [M+1] + .

[0807] Step 6: Synthesis of Compounds 35-7

[0808] Under nitrogen protection, compound 30-6 (65 mg, 162.97 μmol) was dissolved in dioxane (3 mL), followed by compound 35-6 (62.65 mg, 162.97 μmol), cesium carbonate (159.30 mg, 488.92 μmol), and methanesulfonic acid [9,9-dimethyl-4,5-bis(diphenylphosphine)xanthone](2-methylamino-1,1-biphenyl-2-yl)palladium(II) (15.68 mg, 16.30 μmol). The reaction was carried out at 110 °C for 2 hours. After cooling, the solvent was concentrated under reduced pressure. The mixture was purified by column chromatography (ethyl acetate / petroleum ether = 0%–100%) to obtain compound 35-7. MS m / z: 747.2 [M+1] + .

[0809] Step 7: Synthesis of the trifluoroacetate of compound 35

[0810] Under nitrogen protection, compound 35-7 (69 mg, 92.39 μmol) was dissolved in trifluoroacetic acid (2.5 mL) and reacted at 60 °C for 16 hours. The solvent was concentrated under reduced pressure to obtain the crude product. The crude product was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; acetonitrile %: 10%-40%, 8 min) to obtain the trifluoroacetate salt of compound 35. MS m / z: 497.2 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ10.01(s,1H),9.68(s,1H),9.20(s,1H),8.40-8.35(m,2H), 7.67-7.54(m,2H),7.39(d,J=4.8Hz,1H),7.13(d,J=8.8Hz,1H),6.90(d,J=3.6Hz,1 H),4.72(s,3H),4.06-4.00(m,1H),3.97-3.90(m,2H),3.87(s,3H),3.78-3.71(m,1 H), 3.70-3.63 (m, 1H), 3.53-3.49 (m, 1H), 3.24-3.21 (m, 1H), 2.99 (d, J = 11.6Hz, 1H).

[0811] Example 36

[0812]

[0813] Step 1: Synthesis of Compound 36-1

[0814] In a dry vial, compound 32-5 (1 g, 2.47 mmol) was dissolved in dioxane (2 mL). Compound 16-7 (421.00 mg, 4.95 mmol) and cesium carbonate (2.42 g, 7.42 mmol) were added to the solution. After stirring for 15 minutes and confirming pH > 9, Pd2(dba)3 (421.00 mg, 4.95 mmol) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (286.23 mg, 494.68 μmol) were added. The reaction was carried out under nitrogen protection at 110 °C with stirring for 2 hours. The reaction solution was filtered, and the filtrate was concentrated. Compound 36-1 was obtained by column chromatography (ethyl acetate / petroleum ether = 0%–5%). MS m / z: 409.1 [M+1] + ; 1H NMR(400MHz, CDCl3)δ8.51(s,1H),8.05-8.01(m,1H),7.35-7.27(m,2H),6.92-6.88(m,2H),3.95-3.78(m,7H),3 .74-3.55(m,4H),3.37-3.18(m,3H),3.07-3.01(m,1H),2.68-2.64(m,1H),1.62-1.57(m,1H),1.11-1.02(m,4H).

[0815] Step 2: Synthesis of compound 36-2

[0816] In a dry vial, compound 36-1 (750 mg, 1.84 mmol) was dissolved in water (5 mL), methanol (20 mL) was added, and sodium hydroxide (1.10 g, 27.54 mmol) was added to the solution. The reaction was carried out under nitrogen protection, heated to 80 °C, and stirred for 16 hours. The solution was concentrated under reduced pressure, extracted with dichloromethane (20 mL × 5), and the organic phases were combined. The organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 36-2. MS m / z: 341.0 [M+1] + ; 1 HNMR(400MHz,CDCl3)δppm 7.27-7.24(m,2H),7.14(d,J=8.4Hz,1H),6.87-6.84(m,2H),6.40(d,J=8. 4Hz,1H),4.19(s,2H),4.02-3.82(m,2H),3.80(s,3H),3.67-3.664(m,1H) ,3.63-3.61(m,1H),3.41-3.39(m,1H),3.11-3.09(m,1H),3.06-3.04(m,2 H),2.85(m,2H),2.61-2.59(m,1H),2.38-2.36(m,1H),2.05-2.03(m,1H).

[0817] Step 3: Synthesis of compound 36-3

[0818] In a dry vial, compound 36-2 (180 mg, 528.76 μmol) and compound 30-6 (210.89 mg, 528.76 μmol) were dissolved in dioxane (3 mL), and cesium carbonate (516.84 mg, 1.59 mmol) was added. After stirring for 15 minutes and confirming pH > 9, methanesulfonic acid (4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (101.77 mg, 105.75 μmol) was added under nitrogen protection. The reaction was stirred at 110 °C for 2 hours under nitrogen protection. The reaction solution was concentrated, and ethyl acetate (20 mL) and water (20 mL) were added. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated by column chromatography (ethyl acetate / petroleum ether = 0%–15%) to give compound 36-3. MS m / z: 703.3 [M+1] + ; 1 H NMR (400MHz, CDCl3) δppm10.30 (s, 1H), 9.42 (s, 1H), 8.45 (d, J = 3.2Hz, 1H), 7.30-7.27 (m, 4H), 7.21-7.19 (m, 1H), 6.89-6.82 (m, 4H), 4.95 (s, 2H) ),4.17-4.11(m,1H),3.97(s,3H),3.95-3.80(m,9H),3.77-3.74(m,1H) ,3.38-3.14(m,3H),3.10-3.00(m,1H),2.68-2.61(m,1H),1.62(s,9H).

[0819] Step 4: Synthesis of the trifluoroacetate of compound 36

[0820] Compound 36-3 (42 mg, 59.76 μmol) was dissolved in trifluoroacetic acid (2 mL) in a dry vial, and the reaction was stirred at 85 °C for 48 hours. The reaction solution was concentrated to obtain a crude product, which was purified by prep-HPLC (column: Phenomenex Luna C1875*30 mm*3 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; acetonitrile %: 5%-35%, 8 min) to obtain the trifluoroacetate salt of compound 36. MS m / z: 483.22 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δppm 10.01(s,1H),9.71(s,1H),9.24-9.16(m,2H),8.36(d,J=4.8Hz,1H),7.60-7.57(m,2H),7.39(d,J=4.8Hz,1H),7.19(d, J=8.8Hz,1H),6.89(d,J=3.2Hz,1H),4.72(s,2H),4.56-4.50(m,2H),3.87(s,3H),3.68-3.46(m,5H),3.27-3.14(m,4H).

[0821] Example 37

[0822]

[0823] Step 1: Synthesis of the trifluoroacetate of compound 37

[0824] In a dry vial, compound 36 (6.00 mg, 12.43 μmol) and acetone (2.17 mg, 37.30 μmol, 2.74 μL) were added to methanol (1 mL). Potassium acetate (2.44 mg, 24.87 μmol) and acetic acid (746.68 μg, 12.43 μmol) were added to the solution. After stirring for 10 minutes, NaBH(OAc)3 (7.91 mg, 37.30 μmol) was added, and the reaction was carried out at 25 °C with stirring for 1 hour. The reaction solution was concentrated to obtain a crude product, which was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; acetonitrile %: 10%-40%, 8 min) to obtain the trifluoroacetate of compound 37. MS m / z: 525.3 [M+1] + .

[0825] Example 38

[0826]

[0827] Step 1: Synthesis of compound BB-12

[0828] Compound BB-12-1 (30 g, 157.07 mmol) and triethylamine (47.68 g, 471.20 mmol, 65.59 mL) were added to DCM (300 mL), cooled to 0 °C, and then compound BB-12-2 (49.26 g, 471.20 mmol, 42.83 mL) was added. The mixture was reacted at 25 °C for 16 hours. The reaction solution was poured into a saturated ammonium chloride aqueous solution (300 mL), separated, and the aqueous phase was extracted with dichloromethane (50 mL × 2). The combined organic phases were washed with water (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was added to acetonitrile (200 mL), stirred for 3 hours, filtered, and the filter cake was dried to obtain compound BB-12. MS m / z: 258.9, 280.9 [M+1] + ; 1 HNMR (400MHz, CDCl3) δ8.06(s,1H),7.94-7.92(m,1H),7.85-7.80(m,1H),1.49-1.47(m,1H),1.07-1.04(m,2H),0.89-0.85(m,2H).

[0829] Step 2: Synthesis of compound 38-2

[0830] Compound BB-12 (0.5 g, 1.93 mmol) and potassium tert-butoxide (866.25 mg, 7.72 mmol) were added to dimethyl sulfoxide (5 mL), followed by compound 5-1 (417.40 mg, 1.93 mmol). The reaction mixture was reacted at 25 °C for 16 hours. The reaction solution was quenched in saturated sodium carbonate aqueous solution (20 mL), and the mixture was separated. The aqueous phase was extracted with ethyl acetate (50 mL), and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to obtain the crude product. The crude product was purified by column chromatography (methanol / dichloromethane = 0%–10%) to obtain compound 38-2. MS m / z: 455.0, 456.9 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ8.17(s,1H),7.76-7.74(m,1H),7.68-7.66(m,1H),4.35-3.93(m,4H),3. 12-2.78(m,5H),2.62(s,1H),1.87(s,1H),1.47(s,9H),1.12-1.09(m,2H).0.89-0.85(m,2H).

[0831] Step 3: Synthesis of compound 38-3

[0832] A solution of compound 38-2 (0.7 g, 1.54 mmol) in dioxane (10 mL) was mixed with 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (177.90 mg, 307.46 μmol) and cesium carbonate (1.00 g, 3.07 mmol). The mixture was purged three times with nitrogen, and then palladium acetate (34.51 mg, 153.73 μmol) was added. The reaction was carried out under nitrogen protection at 110 °C for 2 hours. The reaction solution was concentrated to obtain the crude product. The crude product was purified by column chromatography (methanol / dichloromethane = 0%–10%) to obtain compound 38-3. MS m / z: 375.0 [M+1] + ; 1 H NMR(400MHz, CDCl3)δ7.90(s,1H),7.60-7.40(m,1H),7.09-7.07(m,1H),4.39-4.36(m,1H),4.14-4.09(m,3H),3.59- 3.56(m,1H),3.05-3.00(m,2H),2.70-2.67(m,2H),1.67(s,1H),1.49(s,9H),11.07-1.05(m,2H).0.87-0.83(m,2H).

[0833] Step 4: Synthesis of the hydrochloride salt of compound 38-4

[0834] Compound 38-3 (0.38 g, 1.01 mmol) was added to hydrochloric acid / ethyl acetate (4 M, 7.6 mL), and the reaction was carried out at 25 °C for 2 hours. The reaction mixture was concentrated to give the hydrochloride salt of compound 38-4. MS m / z: 275.4 [M+1] + .

[0835] Step 5: Synthesis of compound 38-5

[0836] The hydrochloride salt (0.33 g) of compound 38-4 was dissolved in DCM (3 mL), and 37% formaldehyde aqueous solution (861.70 mg, 10.62 mmol, 790.56 μL) and acetic acid (637.66 mg, 10.62 mmol, 607.30 μL) were added. The reaction was carried out at 25 °C for 0.5 h. NaBH(OAc)3 (450.10 mg, 2.12 mmol) was added, and the reaction was carried out at 25 °C for 0.5 h. Water (5 mL), dichloromethane (5 mL), and ammonia (5 mL) were added. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 38-5 was purified by column chromatography (methanol / dichloromethane = 10%). MS m / z: 289.4 [M+1] + .

[0837] Step 6: Synthesis of compound 38-6

[0838] Compound 38-5 (50 mg, 173.40 μmol) was added to methanol (1 mL) and water (0.25 mL), followed by sodium hydroxide (69.36 mg, 1.73 mmol). The reaction mixture was reacted at 80 °C for 12 hours. The reaction mixture was concentrated, and water (2 mL) was added. The aqueous phase was extracted with a dichloromethane:methanol mixture (10:1, 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 38-6. MS m / z: 221.4 [M+1] + .

[0839] Step 7: Synthesis of compound 38-7

[0840] Under nitrogen protection, compound 30-6 (50 mg, 125.36 μmol) was added to dioxane (1 mL), followed by compound 38-6 (30.38 mg, 137.90 μmol), methanesulfonic acid [9,9-dimethyl-4,5-bis(diphenylphosphine)oxanthracene](2-methylamino-1,1-biphenyl-2-yl)palladium(II) (12.06 mg, 12.54 μmol), and cesium carbonate (81.69 mg, 250.73 μmol). The reaction was carried out at 110 °C for 2 hours. Water (5 mL) was added, followed by extraction with ethyl acetate (5 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated by filtration. Compound 38-7 was purified by column chromatography (methanol / dichloromethane = 5%–10%). MS m / z: 583.2 [M+1] + .

[0841] Step 8: Synthesis of trifluoroacetic acid from compound 38

[0842] Under nitrogen protection, compound 38-7 (50 mg, 85.81 μmol) was dissolved in DCM (1 mL), and trifluoroacetic acid (1.00 mL) was added. The reaction mixture was reacted at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The trifluoroacetate of compound 38 was purified by prep-HPLC (column: Phenomenex Luna C18100*40 mm*3 μm; mobile phase: [(TFA)-acetonitrile]; acetonitrile %: 1%-40%, 8 min). MS m / z: 483.5 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ9.87 (s, 1H), 9.52 (s, 1H), 9.18 (s, 1H), 8.36 (d, J = 5.0Hz, 1H) ,7.60-7.54(m,1H),7.49-7.43(m,1H),7.38(d,J=5.0Hz,1H),6.94-6.90(m,1H),6.77 (d,J=8.4Hz,1H),4.72(s,2H),4.53-4.46(m,1H),4.21-4.16(m,1H),4.09-4.06(m,1H ),3.88(s,3H),3.58-3.52(m,2H),3.24-3.06(m,2H),2.97-2.93(m,2H),2.89(s,3H).

[0843] Example 39

[0844]

[0845] Step 1: Synthesis of Compound 39-2

[0846] Compound BB-12 (1 g, 3.86 mmol) and potassium tert-butoxide (1.73 g, 15.44 mmol) were added to dimethyl sulfoxide (10 mL), followed by compound 39-1 (834.80 mg, 3.86 mmol). The reaction mixture was reacted at 25 °C for 16 hours. The reaction solution was quenched in saturated sodium carbonate aqueous solution (100 mL), and the mixture was separated. The aqueous phase was extracted with ethyl acetate (50 mL x 3), and the organic phase was washed with saturated brine (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Compound 39-2 was purified by column chromatography (methanol / dichloromethane = 0%–10%). MS m / z: 455.0, 456.9 [M+1] + .

[0847] Step 2: Synthesis of compound 39-3

[0848] A solution of compound 39-2 (1.35 g, 2.96 mmol) in dioxane (10 mL) was mixed with 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (343.10 mg, 592.96 μmol) and cesium carbonate (1.93 g, 5.93 mmol). The mixture was purged three times with nitrogen, and then palladium acetate (66.56 mg, 296.48 μmol) was added. The reaction was carried out under nitrogen protection at 110 °C for 2 hours. The reaction solution was concentrated to obtain the crude product. Compound 39-3 was purified by column chromatography (methanol / dichloromethane = 1%–10%). MS m / z: 375.0 [M+1] + .

[0849] Step 3: Synthesis of the hydrochloride salt of compound 39-4

[0850] Compound 39-3 (0.87 g, 2.32 mmol) was added to hydrochloric acid / ethyl acetate (4 M, 8.70 mL), and the reaction was carried out at 25 °C for 2 hours. The reaction mixture was concentrated to give the hydrochloride salt of compound 39-4. MS m / z: 275.3 [M+1] + .

[0851] Step 4: Synthesis of compound 39-5

[0852] The hydrochloride salt of compound 39-4 (0.4 g, 1.29 mmol) was dissolved in DCM (4 mL), and 37% formaldehyde aqueous solution (1.04 g, 12.87 mmol, 958.38 μL) and acetic acid (772.90 mg, 12.87 mmol, 736.09 μL) were added. The reaction was carried out at 25 °C for 0.5 h. NaBH(OAc)3 (545.57 mg, 2.57 mmol) was added, and the reaction was carried out at 25 °C for 0.5 h. Water (5 mL), dichloromethane (5 mL), and ammonia (5 mL) were added. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated by filtration. Compound 39-5 was purified by column chromatography (methanol / dichloromethane = 10%). MS m / z: 289.4 [M+1] + .

[0853] Step 5: Synthesis of compound 39-6

[0854] Compound 39-5 (50 mg, 173.40 μmol) was added to methanol (1 mL) and water (0.25 mL), followed by sodium hydroxide (69.36 mg, 1.73 mmol). The reaction mixture was reacted at 80 °C for 12 hours. The reaction mixture was concentrated, and water (2 mL) was added. The aqueous phase was extracted with a dichloromethane:methanol mixture (10:1, 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 39-6. MS m / z: 221.4 [M+1] + .

[0855] Step 6: Synthesis of Compound 39-7

[0856] Under nitrogen protection, compound 30-6 (50 mg, 125.36 μmol) was added to dioxane (1 mL), followed by compound 39-6 (30.38 mg, 137.90 μmol), methanesulfonic acid [9,9-dimethyl-4,5-bis(diphenylphosphine)oxanthracene](2-methylamino-1,1-biphenyl-2-yl)palladium(II) (12.06 mg, 12.54 μmol), and cesium carbonate (81.69 mg, 250.73 μmol). The reaction was carried out at 110 °C for 2 hours. Water (5 mL) was added, followed by extraction with ethyl acetate (5 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated by filtration. Compound 39-7 was purified by column chromatography (methanol / dichloromethane = 5%–10%). MS m / z: 583.1 [M+1] + .

[0857] Step 7: Synthesis of the trifluoroacetate of compound 39

[0858] Under nitrogen protection, compound 39-7 (36 mg, 61.79 μmol) was dissolved in DCM (1 mL), and trifluoroacetic acid (719.98 μL) was added. The reaction was carried out at 25 °C for 1 hour. The reaction system was concentrated under reduced pressure to obtain the crude product. The trifluoroacetate of compound 39 was purified by prep-HPLC (column: Phenomenex luna C18100*40 mm*3 μm; mobile phase: [water (TFA)-acetonitrile]; acetonitrile %: 1%-35%, 8 min). MS m / z: 483.5 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ9.88(s,1H),9.52(s,1H),9.18(s,1H),8.36(d,J=5.0Hz,1H),7. 57(d,J=3.4Hz,1H),7.46(d,J=8.8Hz,1H),7.38(d,J=5.0Hz,1H),6.91(d,J=3.6Hz,1H), 6.77(d,J=8.4Hz,1H),4.72(s,2H),4.53-4.47(m,1H),4.21-4.17(m,1H),4.11-4.04(m, 1H),3.88(s,3H),3.61-3.55(m,2H),3.21-3.08(m,2H),3.03-2.92(m,2H),2.89(s,3H).

[0859] Example 41

[0860]

[0861]

[0862] Step 1: Synthesis of compound BB-13-1

[0863] Compound 30-3 (8.9 g, 25.92 mmol) was dissolved in tetrahydrofuran (100 mL) in a bottle. 2,4-Dimethoxybenzylamine (8.67 g, 51.83 mmol) was added dropwise at 0 °C. The reaction was restored to 25 °C and stirred for 5 hours. The solution was directly concentrated to obtain the crude product. The crude product was then reacted with methyl tert-butyl ether, ethyl acetate, and ethanol, stirred for 16 hours (50 mL each), filtered, and the filter cake was dried to give compound BB-13-1. MS m / z: 397.0, 399.0 [M+1, M+3] + .

[0864] Step 2: Synthesis of compound BB-13-2

[0865] Compound 4-8 (2.52 g, 10.31 mmol) and sodium carbonate (2.19 g, 20.62 mmol) were added to a mixed solution of compound BB-13-1 (4.1 g, 10.31 mmol) in dioxane (80 mL) and water (16 mL). The mixture was purged with nitrogen three times, and then Pd(PPh3)4 (1.19 g, 1.03 mmol) was added. The mixture was then reacted under nitrogen protection at 100 °C for 2 hours. After cooling to room temperature, the mixture was filtered, and the residue was washed with dichloromethane (20 mL). The filtrate was concentrated under reduced pressure to obtain the crude product. Methanol (50 mL) was added, and the mixture was stirred and filtered. The filter cake was washed with methanol (20 mL) to obtain BB-13-2. MS m / z: 449.1 [M+1] + .

[0866] Step 3: Synthesis of compound BB-13-3

[0867] To a dioxane (5 mL) solution of compound BB-13-2 (295 mg, 657.16 μmol), BocNH2 (153.97 mg, 1.31 mmol), Pd2(dba)3 (60.18 mg, 65.72 μmol), and RuPhos (61.33 mg, 131.43 μmol) were added. The mixture was purged three times with nitrogen, and potassium phosphate (418.48 mg, 1.97 mmol) was added. The reaction was carried out under nitrogen protection at 110 °C for 2 hours. After cooling to room temperature, the mixture was filtered, and the residue was washed with dichloromethane (10 mL). The filtrate was concentrated under reduced pressure. The mixture was purified by column chromatography (mobile phase: 0–70% EA / PE) to obtain compound BB-13-3. MS m / z: 530.1 [M+1] + .

[0868] Step 4: Synthesis of compound BB-13-4

[0869] TFA (7.70 g, 67.53 mmol) was added to compound BB-13-3 (463 mg, 874.27 μmol), and the reaction was carried out at 25 °C for 16 hours. The crude product was concentrated under reduced pressure, and the pH was adjusted to >10 with dichloromethane (10 mL) and saturated sodium carbonate solution (20 mL). Extraction was performed with dichloromethane (10 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound BB-13-4 was purified by column chromatography (0–100% EA / PE). MS m / z: 430.1 [M+1] + .

[0870] Step 5: Synthesis of Compound 41-2

[0871] In a dry vial, compound 41-1 (10 g, 45.20 mmol) was dissolved in THF (300 mL). Under nitrogen protection, s-BuLi (1.3 M, 62.58 mL) was slowly added dropwise at -30 °C. After the addition was complete, the reaction was stirred at -30 °C for 30 minutes, then carbon dioxide gas was slowly introduced at -30 °C, and the reaction was slowly raised to 25 °C and stirred for 16 hours. The reaction solution was poured into water (200 mL), and the mixture was separated. The aqueous phase was washed with methyl tert-butyl ether (100 mL × 2), then the pH of the aqueous phase was adjusted to 3–4 with 0.5 N dilute hydrochloric acid, and then extracted with ethyl acetate (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1 to 2:1) to give compound 41-2. 1 H NMR (400MHz, CDCl3) δ5.15-4.93(m,1H),4.19-4.07(m,1H),3.34-3.23(m,1H),2.80-2.71(m,1H),2.23-1.78(m,3H),1.49-1.45(m,9H).

[0872] Step 6: Synthesis of compound 41-3

[0873] In a dry vial, compound 28-2 (2.6 g, 11.79 mmol) and p-methoxybenzylamine (1.78 g, 12.97 mmol) were dissolved in DCM (50 mL), and AcOH (708.23 mg, 11.79 mmol) was added. The reaction was stirred at 25 °C for 1 hour, and then NaBH(OAc)3 (3.0 g, 14.15 mmol) was added. The reaction was continued at 25 °C for 2 hours with stirring. 50 mL of saturated sodium carbonate solution was added to the reaction mixture, and the mixture was stirred until the pH was >8. The mixture was separated, and the aqueous phase was extracted with DCM (20 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1 to 1:1) to give compound 41-3. MS m / z: 340.8 [M+1] + ; 1 ¹H NMR (400MHz, CDCl₃) δ=7.75(d, J=8.4Hz, 1H), 7.31–7.27(m, 2H), 7.10(d, J=8.4Hz, 1H), 6.89–6.86(m, 2H), 3.99(s, 2H), 3.81(s, 5H). Step 7: Synthesis of compound 41-4

[0874] In a dry vial, compound 41-3 (1.02 g, 2.99 mmol) and compound 41-2 (793 mg, 2.99 mmol) were dissolved in DMF (30 mL), and DIEA (772.77 mg, 5.98 mmol), HOBt (807.93 mg, 5.98 mmol), and HATU (2.27 g, 5.98 mmol) were added. The reaction was stirred at 25 °C for 16 hours. The solution was adjusted to pH 6 by adding 1 M dilute hydrochloric acid solution (10 mL). The concentrate was extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by column chromatography (dichloromethane:methanol (v / v) = 100:0 to 90:10) to give compound 41-4. MS m / z: 588.0 [M+1] + ; 1¹H NMR (400MHz, CDCl₃) δ 7.78–7.73 (m, 1H), 7.25–7.21 (m, 1H), 7.20–7.04 (m, 2H), 6.92–6.88 (m, 1H), 6.85–6.73 (m, 1H), 5.02–4.50 (m, 5H), 3.99–3.95 (m, 1H), 3.85–3.71 (m, 4H), 2.74–2.57 (m, 1H), 2.49–2.07 (m, 2H), 2.03–1.85 (m, 1H), 1.48–1.38 (m, 9H). Step 8: Synthesis of compounds 41-5

[0875] ZnBr2 (1.91 g, 8.49 mmol) was added to a flask containing a 30 mL solution of DCM containing compound 41-4 (1 g, 1.70 mmol), and the mixture was stirred at 25 °C for 16 hours. The reaction solution was concentrated, and 20 mL of ethyl acetate and 20 mL of water were added and stirred. The mixture was separated, extracted with ethyl acetate (15 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether:ethyl acetate = 100:0 to 30:70) to give compound 41-5. MS m / z: 487.9 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 7.21 (d, J = 8.8Hz, 1H), 7.12 (d, J = 8.8Hz, 2H), 6.92 (d, J = 8.4Hz, 1H), 6.83 (d, J = 8.8H) z,2H),5.07-4.87(m,2H),3.74(s,2H),3.71(s,3H),3.57-3.51(m,1H),3.11-2.99(m,2H),1.92-1.78(m,4H).

[0876] Step 9: Synthesis of Compounds 41-6

[0877] To a flask containing a 1,4-dioxane (5 mL) solution of compound 41-5 (100 mg, 204.60 μmol), Cs₂CO₃ (133.33 mg, 409.20 μmol) was added. The reaction system was found to be alkaline. Under nitrogen protection, BINAP (50.96 mg, 81.84 μmol) and Pd(OAc)₂ (9.19 mg, 40.92 μmol) were added. The reaction was stirred at 110 °C for 16 hours under nitrogen protection. The mixture was concentrated, and 10 mL of ethyl acetate and 10 mL of water were added. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product. Purification by column chromatography (petroleum ether:ethyl acetate (v / v) = 100:0 to 60:40) yielded compound 41-6. MS m / z: 407.9 [M+1] + .

[0878] Step 10: Synthesis of compounds 41-7

[0879] In a round-bottom flask, compound 41-6 (70 mg, 171.64 μmol) was dissolved in 3 mL of THF. BH3·THF (1 M, 1.72 mL) was added under nitrogen protection at 0 °C. The reaction mixture was gradually heated to 60 °C and stirred for 16 hours under nitrogen protection. Methanol (10 mL) was added to the reaction mixture under nitrogen protection to quench the reaction. The mixture was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (petroleum ether:ethyl acetate (v / v) = 100:0 to 70:30) to give compound 41-7. MS m / z: 394.0 [M+1] + .

[0880] Step 11: Synthesis of compounds 41-8

[0881] To a round-bottom flask containing a 2 mL solution of 1,4-dioxane (4 mg, 10.16 μmol) of compound 41-7 and compound BB-13-4 (4.36 mg, 10.16 μmol), Cs₂CO₃ (9.93 mg, 30.48 μmol) was added. The reaction system was found to be alkaline. Xantphos Pd G₄ (1.95 mg, 2.03 μmol) was added under nitrogen protection. The reaction was stirred at 110 °C for 5 hours under nitrogen protection. The crude product was purified by preparative chromatography (dichloromethane:methanol = 10:1, Rf = 0.4) to give compound 41-8. MS m / z: 787.5 [M+1] + .

[0882] Step 12: Synthesis of the trifluoroacetate of compound 41

[0883] TfOH (30.52 mg, 203.34 μmol) was added to a flask containing a 1 mL solution of compound 41-8 (8.00 mg, 10.17 μmol) in DCM. The reaction mixture was stirred at 25 °C for 16 hours. The reaction solution was concentrated, and 2 mL of ammonia was added. The pH of the reaction system was measured to be 9. 1 mL of LDF was added to the solution, and the mixture was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [water (TFA)-acetonitrile; acetonitrile %: 5%-35%, 8 min] to obtain trifluoroacetate of compound 41. MS m / z: 517.2 [M+1] + ;1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),9.72(s,1H),9.22-9.06(m,2H),8.36-8.35(m,1H),7.61-7.58(m,2H),7.38(s,1H),7.12-7.0 9(m,1H),6.95-6.89(m,1H),4.73(s,2H),44.55-4.38(m,2H),3.87(s,3H),3.45-3.42(m,3H),3.26-3.22(m,3H),2.22-2.10(m,3H).

[0884] Example 42

[0885]

[0886] Step 1: Synthesis of Compound 42-1

[0887] Cs₂CO₃ (71.90 mg, 220.67 μmol), BINAP (13.74 mg, 22.07 μmol), and Pd(OAc)₂ (3.30 mg, 14.71 μmol) were added to 1,4-dioxane (5 mL) of compound 41-6 (30 mg, 73.56 μmol) and compound BB-13-4 (29.24 mg, 73.56 μmol). The reaction was carried out under nitrogen protection and stirred at 110 °C for 16 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate (20 mL × 2). The filtrate was concentrated to obtain the crude product. The crude product was purified by preparative chromatography (dichloromethane:methanol = 20:1) to give compound 42-1. MS m / z: 801.2 [M+1] + .

[0888] Step 2: Synthesis of the trifluoroacetate of compound 42

[0889] TfOH (488.00 mg, 3.25 mmol) was added to a flask containing 50 mg (65.03 μmol) of compound 42-1 in DCM (2 mL), and the reaction was stirred at 25 °C for 16 hours. The pH was adjusted to 8–9 with ammonia, and the reaction mixture was concentrated under reduced pressure. The crude product was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [water (TFA)-acetonitrile]; acetonitrile %: 20%–50%, 8 min) to obtain the trifluoroacetate of compound 42. MS m / z: 531.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ10.01(s,1H),9.67(s,1H),9.19(s,1H),8.49(s,1H),8.35-8.34(m,1H),7.61-7.58(m,2H),7.38(s,1H),7.12-7.09(m,1 H),6.90(s,1H),4.77-4.71(m,3H),4.01-3.99(m,1H),3.87(s,3H),3.5 3-3.48(m,2H),3.23-3.16(m,1H),2.38-2.34(m,2H),2.32-2.22(m,2H).

[0890] Example 43

[0891]

[0892] Step 1: Synthesis of Compound 43-2

[0893] Under nitrogen protection, compound 43-1 (248.53 mg, 2.18 mmol) was dissolved in methanol (10 mL), and compound 28-2 (400 mg, 1.81 mmol) and acetic acid (108.96 mg, 1.81 mmol) were added. The reaction was carried out at 20 °C for 1 hour. Sodium borohydride acetate (576.84 mg, 2.72 mmol) was added, and the reaction was carried out at 20 °C for 15 hours. The mixture was concentrated under reduced pressure, the reaction was quenched with saturated sodium carbonate solution (20 mL), and extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The crude product was obtained by filtration and concentration, and separated by column chromatography (methanol / dichloromethane = 0%–10%) to give compound 43-2. ​​MS m / z: 318.0, 320.0 [M+1] + .

[0894] Step 2: Synthesis of compound 43-3

[0895] Under nitrogen protection, compound 43-2 (223 mg, 699.94 μmol) was dissolved in tetrahydrofuran (5 mL), and triethylamine (212.48 mg, 2.10 mmol) and Boc₂O (229.14 mg, 1.05 mmol) were added. The reaction was carried out at 20 °C for 2 hours. The mixture was extracted with saturated sodium bicarbonate solution (20 mL) and ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (ethyl acetate / petroleum ether = 0%–50%) to give compound 43-3. MS m / z: 440.0, 442.0 [M + Na] + .

[0896] Step 3: Synthesis of compound 43-4

[0897] Under nitrogen protection, compound 43-3 (229 mg, 546.91 μmol) was dissolved in 1,4-dioxane (8 mL), and N,N-dimethylethylenediamine (9.64 mg, 109.38 μmol), cesium carbonate (534.59 mg, 1.64 mmol), and cuprous iodide (10.42 mg, 54.69 μmol) were added. The reaction was carried out at 110 °C for 20 hours. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane (10 mL). The filtrate was concentrated under reduced pressure to obtain the crude product. Purification by column chromatography (ethyl acetate / dichloromethane = 0%–40%) yielded compound 43-4. MS m / z: 360.2 [M+Na] + ; 1 H NMR (400MHz, CDCl3) δ7.80(d,J=8.4Hz,1H),7.30(d,J=8.0Hz,1H),4.88(d,J=16.0Hz,1H),4.30-4.06(m,2H) ,3.93-3.81(m,1H),3.22-3.08(m,1H),2.77-2.50(m,2H),2.48-2.32(m,1H),1.97-1.82(m,1H),1.39(s,9H).

[0898] Step 4: Synthesis of Compounds 43-5

[0899] Under nitrogen protection, compound BB-13-4 (100 mg, 232.85 μmol) was dissolved in 1,4-dioxane (4 mL), and compound 43-4 (86.52 mg, 256.13 μmol), cesium carbonate (227.60 mg, 698.54 μmol), Ruphos (21.73 mg, 46.57 μmol), and Pd2(dba)3 (21.32 mg, 23.28 μmol) were added. The mixture was reacted at 110 °C for 2 hours. The mixture was cooled to room temperature and filtered. The filter cake was washed with dichloromethane (20 mL), and the filtrate was concentrated under reduced pressure to obtain the crude product. Purification by column chromatography (ethyl acetate / petroleum ether = 0%–60%) yielded compound 43-5. MS m / z: 731.3 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ10.46(s,1H),9.85(s,1H),8.41(d,J=5.2Hz,1H),7.71(d,J=8.4Hz,1 H),7.47-7.38(m,1H),7.13-7.01(m,1H),6.88(d,J=8.4Hz,2H),6.53-6.41(m,2H),5.02(d, J=15.6Hz,1H),4.76(s,2H),4.59-4.49(m,1H),4.31-4.17(m,2H),4.07-3.90(m,3H),3.84 (s,5H),3.80(s,3H),3.17-3.03(m,1H),2.74-2.53(m,3H),2.52-2.32(m,2H),1.42(s,9H).

[0900] Step 5: Synthesis of the trifluoroacetate of compound 43

[0901] Under nitrogen protection, compound 43-5 (126 mg, 172.41 μmol) was dissolved in TfOH (22.60 mmol, 2 mL) and reacted at 40 °C for 16 hours. The system was slowly poured into dilute ammonia (5% concentration) (10 mL), and extracted with dichloromethane:methanol = 10:1 (V / V, 20 mL × 5). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by prep-HPLC (column: Phenomenex luna C18100 * 40 mm * 3 μm; mobile phase: [A: aqueous phase (0.1% TFA); B: acetonitrile]; B%: 1.00%-30.00%, 8.00 min) to obtain the trifluoroacetate of compound 43. MS m / z: 481.2 [M + H] + ; 1H NMR (400MHz, DMSO-d6) δ10.12(s,1H),9.96(s,1H),9.30(s,1H),8.37(d,J=4.8Hz,1H),7.80(d,J=8.8Hz,1H),7.59(d,J=3.6Hz,1H),7.41(d,J=4 .8Hz,1H),7.25(d,J=8.8Hz,1H),6.90(d,J=3.6Hz,1H),4.74(s,2H),4.5 1-4.47(m,3H),4.00-3.82(m,5H),2.43-2.40(m,4H),1.86-1.84(m,1H). The trifluoroacetate of compound 43 was added to a sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 43.

[0902] Example 44

[0903]

[0904] Step 1: Synthesis of the trifluoroacetate of compound 44

[0905] Compound 43 (30 mg, 62.43 μmol) was dissolved in a round-bottom flask containing 2 mL of MeOH. 37% formaldehyde aqueous solution (25.34 mg, 312.16 μmol, 23.24 μL) and acetic acid (3.75 mg, 62.43 μmol) were added. After stirring at 15°C for 1 hour, NaBH(OAc)3 (26.46 mg, 124.86 μmol) was added, and stirring continued at 15°C for 16 hours. The reaction solution was directly filtered, and the filtrate was concentrated. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 100*40 mm*3 μm; mobile phase: [A: aqueous phase (0.1% TFA); B: acetonitrile]; B%: 1.00%-30.00%, 8.00 min) to obtain the trifluoroacetate of compound 44. MS m / z: 495.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.37-9.96(m,2H),9.29(s,1H),8.37(d,J=4.8Hz,1H),7.81-7.80(m,1H),7.60(d,J=7.6Hz,1H),7.41(d,J=4.8H z,1H),7.27(d,J=8.8Hz,1H),6.90(d,J=3.6Hz,1H),4.78-4.59(m,4H),3.97-3.88(m,4H),3.65-3.54(m,2H),3.39-3.12(m,3H),2.67(br s,1H),2.46-2.33(m,2H),1.83-1.80(m,1H).

[0906] Example 45

[0907]

[0908] Step 1: Synthesis of Compound 45-2

[0909] Compound 45-1 (6.1 g, 18.51 mmol) was dissolved in a round-bottom flask containing DCM (61 mL), purged three times with nitrogen, and then bis-methoxybenzylamine (4.76 g, 18.51 mmol) and acetic acid (1.11 g, 18.51 mmol) were added. The reaction was carried out at 25 °C for 0.5 h. NaBH(OAc)3 (7.85 g, 37.03 mmol) was added, and the reaction was continued for another 0.5 h. Water (50 mL) was added, the mixture was separated, and the organic phase was washed with saturated sodium bicarbonate (50 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Purification by column chromatography (petroleum ether: ethyl acetate = 3:1) yielded compound 45-2. MS m / z: 571.3 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ7.29-7.26(m,4H),6.88-6.82(m,4H),4.11-3.90(m,3H),3.81(s,6H),3.76-3.75( m,2H),3.44-3.10(m,4H),2.68-2.48(m,1H),1.93-1.76(m,2H),1.47(s,9H),0.85(s,9H),0.00(s,6H).

[0910] Step 2: Synthesis of Compound 45-3

[0911] Compound 45-2 (2 g, 3.50 mmol) was dissolved in a 50 mL DCM round-bottom flask, and ZnBr2 (3.95 g, 17.52 mmol) was added. The reaction mixture was stirred at 25 °C for 16 hours. The solution was poured into water (100 mL), and the mixture was separated. The aqueous phase was extracted with DCM (30 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1 to 0:1) to give compound 45-3. MS m / z: 471.1 [M+1] + .

[0912] Step 3: Synthesis of compound 45-4

[0913] Under nitrogen protection, compound 45-3 (400 mg, 849.77 μmol) was dissolved in DMF (5 mL), and compound 28-2 (190.68 mg, 934.74 μmol) and DIEA (329.48 mg, 2.55 mmol) were added. The reaction was carried out at 100 °C for 1 hour. After cooling, the reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The organic phase was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Compound 45-4 was obtained by column chromatography (ethyl acetate / petroleum ether = 0%–15%). MS m / z: 654.2, 656.1 [M+1] + .

[0914] Step 4: Synthesis of compound 45-5

[0915] Compound 45-4 (140 mg, 213.84 μmol) was dissolved in TFA (67.53 mmol, 5 mL) under nitrogen protection and reacted at 60 °C for 16 h. After cooling, the solution was concentrated under reduced pressure. DCM (1 mL) and NaBH(OAc)3 (135.96 mg, 641.51 μmol) were added, and the reaction was carried out at 25 °C for 1 h. The reaction was quenched with saturated sodium carbonate solution (10 mL) and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure to obtain the crude product, and separated by column chromatography (ethyl acetate / petroleum ether = 0%–100%) to give compound 45-5. MS m / z: 404.1, 406.1 [M+1] +；1H NMR (400MHz, DMSO-d6) δ7.30(d,J=8.4Hz,1H),7.21(d,J=8.4Hz,2H),7.04(d,J=8 .8Hz,1H),6.88(d,J=8.8Hz,2H),5.08(d,J=4.0Hz,1H),4.33-4.24(m,1H),4.07( d,J=14.4Hz,1H),3.74(s,4H),3.72-3.64(m,1H),3.56(s,2H),3.50(d,J=14.4Hz ,1H),3.10-3.04(m,1H),2.90-2.87(m,1H),1.93-1.87(m,1H),1.66-1.63(m,1H).

[0916] Step 5: Synthesis of Compounds 45-6

[0917] Under nitrogen protection, compound BB-13-4 (75 mg, 174.63 μmol) was dissolved in 1,4-dioxane (5 mL), and compound 45-5 (70.60 mg, 174.63 μmol), cesium carbonate (170.70 mg, 523.90 μmol), and Xantphos Pd G4 (16.81 mg, 17.46 μmol) were added. The reaction was carried out at 110 °C for 2 hours. After cooling, the mixture was filtered, washed with dichloromethane (10 mL), and the filtrate was concentrated under reduced pressure. Compound 45-6 was obtained by column chromatography (methanol / ethyl acetate = 0%–10%). MS m / z: 753.3 [M+Na] + .

[0918] Step 6: Synthesis of the trifluoroacetate of compound 45

[0919] Under nitrogen protection, compound 45-6 (85 mg, 112.90 μmol) was dissolved in TfOH (45.20 mmol, 4 mL) and reacted at 40 °C for 5 hours. After cooling to room temperature, the system was slowly added to dilute ammonia (10 mL). Extraction was performed using dichloromethane:methanol = 10:1 (20 mL × 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 80*30 mm*3 μm; mobile phase: [A: aqueous phase (0.1% TFA); B: acetonitrile]; acetonitrile %: 1%-20%, 8.00 min) to obtain the trifluoroacetate of compound 45. MS m / z: 483.2 [M+1] + ; 1HNMR(400MHz,DMSO-d6)δ9.99(s,1H),9.63(s,1H),9.19(s,1H),8.36(d,J=4.8Hz,1H),7. 57(d,J=3.6Hz,1H),7.44(d,J=8.8Hz,1H),7.38(d,J=4.8Hz,1H),7.14(d,J=8.8Hz,1H),6. 89 (d, J = 3.6 Hz, 1H), 4.71 (s, 3H), 4.43–4.34 (m, 1H), 4.25–4.16 (m, 1H), 3.87 (s, 3H), 3.37–3.32 (m, 4H), 3.31–3.22 (m, 2H), 3.14–3.05 (m, 1H), 2.11–2.00 (m, 1H), 1.90–1.87 (m, 1H). The trifluoroacetate of compound 45 was added to a sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 45.

[0920] Example 46

[0921]

[0922] Step 1: Synthesis of the trifluoroacetate of compound 46

[0923] Under nitrogen protection, compound 45 (40 mg, 82.90 μmol) was dissolved in methanol (5 mL), and 37% formaldehyde aqueous solution (33.64 mg, 414.48 μmol) and acetic acid (14.93 mg, 248.69 μmol) were added. The reaction was carried out at 25 °C for 1 hour. NaBH(OAc)3 (35.14 mg, 165.79 μmol) was added, and the reaction was carried out at 25 °C for 1 hour. Saturated sodium carbonate solution (10 mL) was added, and the mixture was extracted with dichloromethane:methanol = 10:1 (20 mL × 4). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to obtain the crude product. The trifluoroacetate of compound 46 was obtained by prep-HPLC (column: Phenomenex Luna C18 80*30mm*3μm; mobile phase: [A: aqueous phase (0.1% TFA); B: acetonitrile]; B%: 1%-25%, 8.00 min). MS m / z: 497.2 [M+1] + ; 1HNMR(400MHz,DMSO-d6)δ10.62-10.10(m,1H),10.09-9.90(m,1H),9.80-9.51(m, 1H),9.20(d,J=6.8Hz,1H),8.44-8.25(m,1H),7.58(d,J=2.4Hz,1H),7.52-7.27( m,2H),7.18-7.11(m,1H),6.91(d,J=2.4Hz,1H),4.78-4.57(m,3H),4.51-4.31(m ,3H),3.48-3.21(m,5H),3.18-2.85(m,5H),2.12-1.96(m,1H),1.88-1.75(m,1H).

[0924] Example 47

[0925]

[0926] Step 1: Synthesis of Compound 47-2

[0927] Compounds BB-3-1 (2 g, 13.78 mmol) and 47-1 (2.75 g, 16.53 mmol) were added to DMF (10 mL), followed by DIEA (1.78 g, 13.78 mmol). The reaction mixture was reacted at 100 °C for 16 hours. The reaction solution was then added to semi-saturated brine (50 mL), extracted with methyl tert-butyl ether (50 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Column chromatography (petroleum ether:ethyl acetate (v / v) = 95:5-85:15) was performed to obtain compound 47-2. MS m / z: 292.1 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ8.38-8.37(m,1H),8.29-8.26(m,1H),7.13 -7.10(m,1H),4.73(s,1H),4.46-4.44(m,1H),3.99-3.93(m,2H),3.77-3.73(m,2H),3.71-3.68(m,3H),3.26-3.22(m,1H).

[0928] Step 2: Synthesis of Compound 47-3

[0929] The hydrogenation flask was purged twice with argon. Raney-Ni (441.23 mg, 5.15 mmol) was added, followed by MeOH (2 mL) and compound 47-2 (1.5 g, 5.15 mmol). The reaction was carried out at 50 °C for 12 hours under hydrogen (50 psi). The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 47-3. MS m / z: 266.0 [M+1] + .

[0930] Step 3: Synthesis of compound 47-4

[0931] Compound 47-3 (0.7 g, 2.64 mmol) was added to MeOH (14 mL), followed by sodium tert-butoxide (1.27 g, 13.19 mmol). The reaction was carried out at 25 °C for 16 hours. The crude product was concentrated under reduced pressure and separated by column chromatography (from petroleum ether:ethyl acetate = 100:0 to 0:100 to ethyl acetate:methanol = 97:3) to give compound 47-4. MS m / z: 233.9 [M+1] + .

[0932] Step 4: Synthesis of compound 47-5

[0933] Compound 47-4 (0.2 g, 857.39 μmol) was added to THF (20 mL), cooled to 0 °C, and then BH3·THF (1 M, 8.57 mL) was added. The reaction was carried out under nitrogen protection at 60 °C for 12 hours. Methanol (10 mL) and 2 M dilute hydrochloric acid (20 mL) were added dropwise to the reaction mixture at room temperature under nitrogen protection, and the mixture was stirred at 65 °C for 16 hours. The crude product was concentrated under reduced pressure and added to a saturated sodium carbonate aqueous solution (30 mL) to adjust the pH to 8. Extraction was performed with ethyl acetate (20 mL × 3). The aqueous phase was concentrated under reduced pressure, stirred for 10 min with a mixture of DCM and MeOH (DCM:MeOH = 3:1, 50 mL), and then filtered. The organic phases were combined and concentrated under reduced pressure to obtain compound 47-5. MS m / z: 220.0 [M+1] + .

[0934] Step 5: Synthesis of compound 47-6

[0935] Compound 47-5 (0.2 g, 912.07 μmol) was added to THF (6 mL), along with TEA (276.87 mg, 2.74 mmol) and Boc₂O (199.06 mg, 912.07 μmol). The reaction mixture was reacted at 25 °C for 2 hours. The reaction solution was then added to a saturated ammonium chloride aqueous solution (50 mL), and extracted with ethyl acetate (50 mL × 2). The organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-80:20) to give compound 47-6. MS m / z: 319.6 [M+1] + .

[0936] Step 6: Synthesis of Compound 47-7

[0937] Compounds 30-6 (50 mg, 125.36 μmol) and 47-6 (48.05 mg, 150.44 μmol) were added to dioxane (4 mL), followed by Cs₂CO₃ (81.69 mg, 250.73 μmol), BINAP (15.61 mg, 25.07 μmol), and Pd(OAc)₂ (2.81 mg, 12.54 μmol). The reaction mixture was reacted at 100 °C for 2 hours. The reaction solution was added to water (30 mL), extracted with ethyl acetate (30 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 47-7. MS m / z: 682.4 [M+1] + .

[0938] Step 7: Synthesis of the trifluoroacetate of compound 47

[0939] Compound 47-7 (50 mg, 73.34 μmol) was added to TFA (2 mL) and DCM (4 mL) and reacted at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by prep-HPLC (column: Phenomenex Luna C18 80*30 mm*3 μm; mobile phase: [A: aqueous phase (0.1% TFA); B: acetonitrile]; B%: 5%-45%, 8.00 min) to obtain the trifluoroacetate of compound 47. MS m / z: 482.1 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ9.10 (s, 1H), 8.98-8.92 (m, 2H), 8.76-8.75 (m, 2H), 8.36 (d, J = 4.8Hz, 1H), 7.57-7.56 (m, 1H), 7.48-7.46 (m, 2H), 7 .38-7.36(m,1H),7.16(d,J=8.8Hz,1H),6.89-6.88(m,1H),4.73(s,2H),4.39-4.29(m,3H),3.87(s,3H),3.32-3.20(m,5H),3.05(s,2H).

[0940] Examples 48 and 49

[0941]

[0942] Step 1: Synthesis of Compound 48-1

[0943] Compound 45-5 (255 mg, 630.72 μmol) was dissolved in DCM (5 mL), purged three times with nitrogen, cooled to -78 °C, and DAST (508.32 mg, 3.15 mmol) was added dropwise. The mixture was then heated to 25 °C and reacted for 16 hours. The reaction was quenched with saturated sodium bicarbonate (20 mL), extracted with dichloromethane (20 mL × 3), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound 48-1 was obtained by column chromatography (ethyl acetate / petroleum ether = 0%–30%). MS m / z: 406.1, 408.0 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ7.24(d,J=8.0Hz,3H),6.95-6.84(m,3H),4.31-4.16(m,1H),3.89(d,J=14.4Hz,1H),3.81(s,3H),3.78-3.5 9(m,3H),3.58-3.46(m,1H),3.44-3.25(m,2H),2.98(d,J=11.6Hz,1H),2.76-2.62(m,1H),2.59-2.39(m,1H),1.94-1.78(m,1H).

[0944] Step 2: Synthesis of Compound 48-2

[0945] Under nitrogen protection, compound BB-13-4 (31 mg, 72.18 μmol) was dissolved in 1,4-dioxane (2 mL), and compound 48-1 (29.33 mg, 72.18 μmol), cesium carbonate (70.55 mg, 216.55 μmol), Pd2(dba)3 (6.61 mg, 7.22 μmol), and Ruphos (6.74 mg, 14.44 μmol) were added. The reaction was carried out at 110 °C for 2 hours. After cooling, the mixture was filtered, and the filter cake was washed with dichloromethane (20 mL). The filtrate was concentrated under reduced pressure to obtain the crude product. Compound 48-2 was separated by column chromatography (ethyl acetate / petroleum ether = 0%–100%). MS m / z: 755.3 [M+Na] + .

[0946] Step 3: Synthesis of the trifluoroacetate of compound 48

[0947] Under nitrogen protection, compound 48-2 (49 mg, 64.91 μmol) was dissolved in TfOH (11.30 mmol, 1 mL) and reacted at 40 °C for 5 hours. After cooling to room temperature, the system was slowly added to dilute ammonia (10 mL), and extracted with dichloromethane:methanol = 10:1 (20 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The trifluoroacetate of compound 48 was obtained by prep-HPLC (column: Phenomenexluna C18 80*30 mm*3 μm; mobile phase: [A: aqueous phase (0.1% TFA); B: acetonitrile]; B%: 5%-35%, 8.00 min). MS m / z: 485.2 [M+1] + ; 1 HNMR(400MHz,DMSO-d6)δ10.02(s,1H),9.68(s,1H),9.50-9.36(m,1H),9.23(s,1H) ,8.36(d,J=4.8Hz,1H),7.58(d,J=3.6Hz,1H),7.49-7.33(m,2H),7.17(d,J=8.8Hz, 1H), 6.90 (d, J = 3.6 Hz, 1H), 5.55–5.29 (m, 1H), 4.72 (s, 3H), 4.30–4.25 (m, 1H), 3.87 (s, 3H), 3.49–3.47 (m, 4H), 3.14–2.98 (m, 1H), 2.78–2.65 (m, 1H), 2.07–1.90 (m, 1H). The trifluoroacetate of compound 48 was added to a sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 48.

[0948] Step 4: Synthesis of the trifluoroacetate of compound 49

[0949] Under nitrogen protection, compound 48 (30 mg, 61.92 μmol) was dissolved in methanol (2 mL), and 37% formaldehyde aqueous solution (25.12 mg, 309.58 μmol) and acetic acid (11.15 mg, 185.75 μmol) were added. The reaction was carried out at 20 °C for 1 hour. NaBH(OAc)3 (26.25 mg, 123.83 μmol) was added, and the reaction was carried out at 20 °C for 15 hours. Saturated sodium carbonate solution (10 mL) was added, and the mixture was extracted with dichloromethane:methanol = 10:1 (20 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The crude product was filtered and concentrated to obtain the crude product. The trifluoroacetate of compound 49 was obtained by prep-HPLC (column: Phenomenex C18 80*30 mm*3 μm; mobile phase: [water (TFA)-acetonitrile]; acetonitrile %: 5%-35%, 8 min). MS m / z: 499.2 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ10.11-9.91(m,1H),9.74(s,1H),9.23(s,1H),8.36( d,J=4.8Hz,1H),7.63-7.30(m,3H),7.29-7.10(m,1H),6.91(d,J=3.2Hz,1H) ,5.59-5.30(m,1H),5.08-4.82(m,1H),4.78-4.40(50-1m,4H),3.87(s,6H), 3.54-3.43(m,2H),3.29(d,J=1.6Hz,1H),3.14(s,2H),2.90(d,J=6.0Hz,1H).

[0950] Examples 50A and 50

[0951]

[0952] Step 1: Synthesis of Compound 50-2

[0953] Compound 50-1 (1 g, 5.08 mmol) was added to DMF (20 mL), cooled to 0 °C, and then NaH (405.99 mg, 10.15 mmol, 60% purity) was added. The mixture was stirred at 0 °C for 0.5 h. CD3I (882.84 mg, 6.09 mmol) was added, and the reaction was carried out at 25 °C for 1.5 h. After the reaction was complete, the reaction solution was slowly added to water (50 mL), extracted with ethyl acetate (50 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 50-2 was obtained by column chromatography (PE:EA = 100:0-85:15). MS m / z: 214.1, 216.1 [M+1]+ .

[0954] Step 2: Synthesis of Compound 50-3

[0955] Compound 50-2 (0.2 g, 934.24 μmol), bis(pinnatrol)boronic acid ester (355.86 mg, 1.40 mmol), and dioxane (4 mL) were added to dioxane (275.06 mg, 2.80 mmol), followed by KOAc (275.06 mg, 2.80 mmol) and Pd(dppf)Cl2.CH2Cl2 (76.29 mg, 93.42 μmol). The reaction mixture was reacted at 100 °C for 12 hours. The reaction solution was then added to water (30 mL), extracted with ethyl acetate (30 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Preparative chromatography (PE:EA = 3:1) was used to purify the crude product, yielding compound 50-3. MS m / z: 180.2 [M-81] + .

[0956] Step 3: Synthesis of Compound 50-4

[0957] Compound BB-13-1 (0.18 g, 452.66 μmol) and compound 50-3 (118.21 mg, 452.66 μmol) were added to dioxane (4 mL), water (0.8 mL), Pd(dppf)Cl2 (33.12 mg, 45.27 μmol), and potassium carbonate (125.12 mg, 905.32 μmol). The reaction was carried out at 100 °C for 6 hours. The mixture was then cooled to room temperature and slowly added dropwise to 6 mL of methanol while stirring. After the addition was complete, the mixture was stirred for 10 min, filtered, and the filter cake was dried under reduced pressure to obtain compound 50-4. MS m / z: 452.1 [M+H] + .

[0958] Step 4: Synthesis of Compound 50-5

[0959] Compound 50-4 (0.12 g, 265.53 μmol) and Boc₂O (62.21 mg, 531.07 μmol) were added to dioxane (4 mL), followed by tripotassium phosphate (169.09 mg, 796.60 μmol), RuPhos (24.78 mg, 53.11 μmol), and Pd₂(dba)₃ (24.32 mg, 26.55 μmol). The reaction mixture was reacted at 110 °C for 2 hours. The reaction solution was added to 20 mL of water, and extracted twice with 20 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Preparative chromatography (PE:EA = 1:1) yielded compound 50-5. MS m / z: 533.2 [M+1] + .

[0960] Step 5: Synthesis of compound 50-6

[0961] Compound 50-5 (0.12 g, 225.31 μmol) was added to TFA (3 mL) and reacted at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure and dissolved in 10 mL of dichloromethane. The solution was then poured into 30 mL of saturated sodium carbonate aqueous solution and extracted with 10 mL of dichloromethane twice. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 50-6. MS m / z: 433.2 [M+1] + .

[0962] Step 6: Synthesis of Compound 50-7

[0963] Compound 50-6 (100.00 mg, 231.22 μmol) and compound 45-5 (93.48 mg, 231.22 μmol) were added to dioxane (4 mL), followed by Cs₂CO₃ (150.67 mg, 462.44 μmol) and Xantphos Pd G₄ (22.25 mg, 23.12 μmol). The reaction mixture was reacted at 100 °C for 2 hours. The reaction solution was then added to water (20 mL), extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Preparative chromatography (DCM:MeOH = 20:1) was used to separate compound 50-7. MS m / z: 756.3 [M+1] + .

[0964] Step 7: Synthesis of Compound 50-8

[0965] Compound 50-7 (0.1 g, 132.30 μmol) was added to 2 mL of TfOH and reacted at 40 °C for 2 hours. The reaction solution was slowly added to 10 mL of ammonia water (pH > 10), and extracted with dichloromethane:methanol = 10:1 (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 50A. MS m / z: 486.3 [M+1] + .

[0966] Step 8: Synthesis of Compound 50

[0967] Compound 50A (80 mg, 164.76 μmol) and 37% formaldehyde aqueous solution (823.80 μmol, 61.33 μL) were added to MeOH (2 mL), followed by AcOH (29.68 mg, 494.28 μmol). The reaction was carried out at 25 °C for 1 hour. NaBH(OAc)3 (69.84 mg, 329.52 μmol) was then added, and the reaction was carried out at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The trifluoroacetate of compound 50 was separated by prep-HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (TFA)-acetonitrile]; acetonitrile %: 1%-30%, 8 min). MS m / z: 500.2 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ10.12-9.97(m,2H),9.69-9.49(m,1H),8.39-8.36 (m,1H),7.61-7.58(m,3H),7.40-7.19(m,1H),6.91-6.88(m,1H),4.97-4.8 6(m,1H),4.72(s,1H),4.42-4.41(m,1H),4.38-4.37(m,2H),3.66-3.55(m, 6H),3.09-3.08(m,2H),3.92(s,1H),2.07-2.06(m,1H),1.85-1.81(m,1H).

[0968] Examples 51 and 52

[0969]

[0970] Step 1: Synthesis of Compound 51-2

[0971] Compound 51-1 (0.8 g, 3.37 mmol) was added to DCM (20 mL), cooled to 0 °C, and then Dys-Martin oxidant (1.72 g, 4.05 mmol) was added. The reaction was carried out at 25 °C for 12 hours. 3 g of solid sodium carbonate was added to the reaction mixture, and after stirring for 0.5 hours, the mixture was filtered. The filtrate was added to a saturated sodium bicarbonate solution (20 mL), and extracted with dichloromethane (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Purification by column chromatography (PE:EA = 100:0-85:15) yielded 51-2.

[0972] Step 2: Synthesis of compound 51-3

[0973] Compound 51-2 (0.2 g, 850.24 μmol) and compound 34-2 (347.60 mg, 935.27 μmol) were added to DCM (4 mL), followed by AcOH (25.53 mg, 425.12 μmol), and the reaction was carried out at 25 °C for 1 h. NaBH(OAc)3 (360.40 mg, 1.70 mmol) was then added, and the reaction was continued at 25 °C for 2 h. The reaction mixture was added to a saturated sodium bicarbonate aqueous solution (20 mL), extracted with dichloromethane (30 mL × 2), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 51-3. MS m / z: 590.1, 592.1 [M+1] + .

[0974] Step 3: Synthesis of compound 51-4

[0975] Compound 51-3 (0.38 g, 643.10 μmol) was added to DCM (10 mL), followed by ZnBr2 (724.14 mg, 3.22 mmol). The reaction mixture was reacted at 25 °C for 12 hours. The reaction solution was then added to 20 mL of saturated sodium bicarbonate aqueous solution, extracted with dichloromethane (30 mL × 3), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 51-4. MS m / z: 490.0, 492.0 [M+1] + .

[0976] Step 4: Synthesis of Compound 51-5

[0977] Compound 51-4 (0.2 g, 407.52 μmol) was added to 1,4-dioxane (9 mL), followed by Cs₂CO₃ (265.56 mg, 815.05 μmol), Pd₂(dba)₃ (37.32 mg, 40.75 μmol), and RuPhos (38.03 mg, 81.50 μmol). The reaction mixture was reacted at 105 °C for 2 hours. The reaction solution was added to water (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound 51-5 was obtained by column chromatography (PE:EA = 100:0-80:20). MS m / z: 410.1 [M+1] + .

[0978] Step 5: Synthesis of compounds 51-6

[0979] Compounds BB-13-4 (60 mg, 139.71 μmol) and 51-5 (62.99 mg, 153.68 μmol) were added to 1,4-dioxane (2 mL), followed by Cs₂CO₃ (136.56 mg, 419.12 μmol), Pd₂(dba)₃ (12.79 mg, 13.97 μmol), and RuPhos (13.04 mg, 27.94 μmol). The reaction mixture was reacted at 110 °C for 2 hours. The reaction solution was then added to water (20 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound 51-6 was then separated by column chromatography (PE:EA = 50:50 - 20:80). MS m / z: 803.3 [M+1] + .

[0980] Step 6: Synthesis of the trifluoroacetate of compound 51

[0981] Compound 51-6 (80 mg, 99.64 μmol) was added to TfOH (2 mL) and reacted at 40 °C for 2 hours. The reaction solution was slowly added dropwise to (6 mL) ammonia water, and extracted with dichloromethane (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The trifluoroacetate of compound 51 was separated by prep-HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (TFA)-acetonitrile]; acetonitrile %: 10%-40%, 8 min). MS m / z: 503.2 [M+1] + ; 1 HNMR(400MHz,DMSO-d6)δ10.04(s,1H),9.72(s,1H),9.49-9.10(m,3H),8.39-8.36(m,1H),7.61-7.58(m,1H),7.51(d,J=8.8Hz,1H),7.40-7.39(m ,1H),7.21-7.19(m,1H),6.90-6.89(m,1H),4.76-4.73(m,2H),4.65(s,1 H),4.62-4.61(m,1H),3.88(s,3H),3.70-3.60(m,4H),3.16-3.10(m,2H). The trifluoroacetate of compound 51 was added to a sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 51.

[0982] Step 7: Synthesis of the trifluoroacetate of compound 52

[0983] Compound 51 (35 mg, 69.65 μmol) and 37% formaldehyde aqueous solution (28.26 mg, 348.25 μmol) were added to MeOH (2 mL), followed by AcOH (12.55 mg, 208.95 μmol). The mixture was stirred at 25 °C for 1 hour. NaBH(OAc)3 (29.52 mg, 139.30 μmol) was then added, and the reaction was continued at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The trifluoroacetate of compound 52 was obtained by HLPC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (TFA)-acetonitrile]; acetonitrile %: 10%-40%, 8 min). MS m / z: 517.2 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ10.29-10.10(m,1H),9.74-9.65(m,1H),8.41-8.37(m,1H),7.63-7.60(m,2H),7.41-7.39(m,1H),7.37(s,1H),6.91-6.8 8(m,1H),4.97(s,2H),4.88(s,2H),4.86-4.72(m,1H),4.68-4.55(m,1H ),3.89(s,5H),3.66-3.60(m,3H),3.17-3.14(m,2H),3.10-2.88(m,2H).

[0984] Example 53

[0985]

[0986] Step 1: Synthesis of Compound 53-1

[0987] Compound 33-1 (55 mg, 193.56 μmol) was added to THF (1 mL), purged three times with nitrogen, cooled to -20 °C, and then NaH (23.22 mg, 580.68 μmol, 60% purity) was added and stirred for 0.5 hours. CD3I (22.45 mg, 154.85 μmol, 9.64 μL) was added, and the reaction was carried out at 20 °C for 2.5 hours. The reaction solution was added to (20 mL) of water, extracted with ethyl acetate (20 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound 53-1 was obtained by preparative chromatography (EA:MeOH = 20:1). MS m / z: 301.1, 303.1 [M+1] + .

[0988] Step 2: Synthesis of compound 53-2

[0989] Compound BB-13-4 (20 mg, 46.57 μmol) and compound 53-1 (15.43 mg, 51.23 μmol) were added to dioxane (2 mL), followed by Xantphos Pd G4 (4.48 mg, 4.66 μmol) and Cs₂CO₃ (45.52 mg, 139.71 μmol). The reaction mixture was reacted at 110 °C for 2 hours. The reaction solution was added to water (20 mL), extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 53-2. MS m / z: 650.3 [M+1] + .

[0990] Step 3: Synthesis of the trifluoroacetate of compound 53

[0991] Compound 53-2 (20 mg, 30.78 μmol) was added to TfOH (1 mL) and reacted at 40 °C for 1 hour. The reaction solution was then slowly added dropwise to ammonia (4 mL), and extracted with dichloromethane (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Prep-HPLC separation (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (TFA)-acetonitrile]; acetonitrile %: 5%-35%, 8 min) yielded the trifluoroacetate of compound 53. MS m / z: 500.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ10.28-10.23(m,1H),10.03-10.02(m,1H),9.77-9.72(m,1H),9.23(s,1H),8.37(d,J=5.0Hz,1H),7.63-7.59(m ,2H),7.40(d,J=5.0Hz,1H),7.24-7.19(m,1H),6.91(d,J=3.4Hz,1H),4.78-4.73(m,3H),3.88(s,4H),3.78(s,5H),3.74-3.71(m,3H).

[0992] Examples 54 and 57

[0993]

[0994] Step 1: Synthesis of Compound 54-1

[0995] Compound 50-6 (50 mg, 115.61 μmol) and compound 16-6 (37.92 mg, 127.17 μmol) were added to dioxane (1 mL), followed by Xantphos Pd G4 (22.25 mg, 23.12 μmol) and Cs₂CO₃ (113.00 mg, 346.83 μmol). The reaction mixture was reacted at 110 °C for 2 hours. The reaction solution was then added to water (20 mL), extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 54-1. MS m / z: 650.3 [M+1] + .

[0996] Step 2: Synthesis of the trifluoroacetate of compound 54-2

[0997] Compound 54-1 (50 mg, 76.95 μmol) was added to TfOH (2 mL) and reacted at 40 °C for 12 hours. The reaction solution was added to ammonia (6 mL) and extracted with dichloromethane (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The trifluoroacetate of compound 54-2 was separated by prep-HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (TFA)-acetonitrile]; acetonitrile %: 5%-35%, 8 min). MS m / z: 500.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ10.34-10.28(m,1H),10.02(s,1H),9.76-9.71(m,1H),9.22(s,1H),8.36(d,J=5.0Hz,1H),7.62-7.58(m,2H ),39-7.38(m,1H),7.22-7.18(m,1H),6.90(d,J=3.4Hz,1H),4.75-4.72(m,4H),4.63-4.60(m,1H),3.47-3.26(m,6H),3.05(s,4H).

[0998] Step 3: Synthesis of compounds 54, 57, trifluoroacetate of compound 54, and trifluoroacetate of compound 57

[0999] The trifluoroacetate of compound 54-2 (30.04 g) was chirally separated by SFC (column: DAICELCHIRALPAK IC (250 mm * 25 mm, 10 μm); mobile phase: A n-heptane, B isopropanol / acetonitrile = 2 / 1, 0.1% ammonia, B%: 40%). The separated solution was concentrated to obtain compound 54 and compound 57.

[1000] Compound 54: 1 H NMR(DMSO-d6,400MHz)δ9.97(s,1H),9.59(s,1H),9.18(s,1H),8.35(d,1H,J=4.8Hz ),7.57(d,1H,J=3.6Hz),7.44(d,1H,J=8.8Hz),7.38(d,1H,J=5.0Hz),7.01(d,1H,J= 8.8Hz), 6.91(d,1H,J=3.2Hz), 4.71(s,2H), 3.91-4.09(m,2H), 3.74-3.77(m,3H), 3.67-3.70(m,1H), 3.10-3.40(m,6H), 2.48-2.55(m,2H); ee%=89.99%; retention time: 3.160min.

[1001] Compound 57: 1 H NMR(DMSO-d6,400MHz)δ9.97(s,1H),9.59(s,1H),9.19(s,1H),8.35(d,1H,J=5.0Hz ),7.58(d,1H,J=3.5Hz),7.57(d,1H,J=8.8Hz),7.38(d,1H,J=5.0Hz),7.06-7.08(m ,1H), 6.91(d,1H,J=3.2Hz), 4.71(s,2H), 3.94-4.16(m,2H), 3.67-3.76(m,3H), 3.50-3.52(m,1H), 3.18-3.31(m,6H), 2.48-2.68(m,2H); ee%=95.86%; retention time: 3.681min.

[1002] Analytical method for detecting ee%: (Column: DAIICEL CHIRALPAK IC (50*4.6mm 3μm); Mobile phase: A. n-Heptane (0.1% DEA), B. Isopropanol / acetonitrile = 2 / 1, B%: 45%).

[1003] Compound 54 (440 mg, 880 μmol) was dissolved in DCM (5 mL), and TFA (4.40 mmol, 327.12 μL) was added. The mixture was stirred at 25 °C for 1 hour; the solution was then concentrated under reduced pressure to obtain the trifluoroacetate of compound 54. MS m / z: 250.7 [(M+1) / 2] + ;ee% = 98.97%; 1H NMR(DMSO-d6,400MHz)δ9.97(s,1H),9.72(s,1H),9.23(s,1H),8.37(d,1H,J=5.2Hz),7.59-7.61(m,2H),7.40(d,1H,J=5.2Hz),7.20(br d,1H,J=8.8Hz),6.91(d,1H,J=3.6Hz),4.71(s,2H),3.71-3.79(m,4H),3.36-3.61(m,4H),3.3-3.5(m,3H),3.01(s,3H).

[1004] Compound 57 (1.16 g, 2.32 mmol) was dissolved in DCM (12 mL), and TFA (11.61 mmol, 862.39 μL) was added. The mixture was stirred at 25 °C for 1 hour. The solution was then concentrated under reduced pressure to obtain the trifluoroacetate of compound 57. MS m / z: 250.8 [(M+1) / 2] + ;ee% = 96.40%; 1 H NMR(400MHz,DMSO-d6)δppm 10.02(s,1H),9.73(s,1H),9.26(s,1H),8.38(d,J=4.80Hz,1H),7.57-7.61(m,2H),7.40-7.43(m,2H), 6.93(d,J=3.2Hz,1H),4.73(s,2H),3.71-3.79(m,5H),3.26-3.46(m,4H),3.3-3.5(m,3H),3.01(s,3H).

[1005] Examples 55 and 56

[1006]

[1007] Step 1: Synthesis of Compound 55-1

[1008] Compound 45-5 (300 mg, 742.02 μmol) was dissolved in THF (5 mL) in a dry vial. Under nitrogen protection at 0 °C, NaH (89.04 mg, 2.23 mmol, 60% purity) was slowly added, and the mixture was stirred for 30 minutes. MeI (84.26 mg, 593.62 μmol) was then slowly added dropwise. The reaction mixture was heated to 15 °C and stirred for 16 hours. The reaction solution was poured into a saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Separation by column chromatography (petroleum ether:ethyl acetate = 30–100%) yielded compound 55-1. MS m / z: 417.9 [M+H] + ; 1H NMR (400MHz, CDCl3) δ7.27-7.22(m,3H),6.91-6.85(m,3H),4.31-4.27(m,1H),4.14-4.06(m,1H),3.81-3.76(m,4H),3.69-3.64(m,3H) ,3.48-3.45(m,1H),3.38-3.34(m,3H),3.23-3.21(m,1H),2.97-2.94(m,1H),2.55-2.51(m,1H),2.08-2.05(m,1H),1.76-1.73(m,1H).

[1009] Step 2: Synthesis of Compound 55-2

[1010] In a dry vial, compound 55-1 (179 mg, 427.90 μmol) and compound BB-13-4 (275.65 mg, 641.84 μmol) were dissolved in 1,4-dioxane (5 mL). Cs₂CO₃ (418.25 mg, 1.28 mmol) was added, and the pH was checked to be >9. Xantphos Pd G₄ (82.36 mg, 85.58 μmol) was then added. The mixture was purged with nitrogen three times and stirred at 110 °C for 4 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL × 2). The filtrate was concentrated and separated by column chromatography (dichloromethane:methanol = 100:0–10:1) to obtain compound 55-2. MS m / z: 767.5 [M+1] + .

[1011] Step 3: Synthesis of the trifluoroacetate of compound 55

[1012] Compound 55-2 (50.18 mg, 65.43 μmol) was added to TfOH (1 mL) and reacted at 40 °C for 2 hours. The reaction solution was cooled and then slowly added dropwise to ammonia (4 mL). Extraction was performed with dichloromethane (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Prep-HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (TFA)-acetonitrile]; acetonitrile %: 5%-35%, 8 min) was used to separate the trifluoroacetate of compound 55. MS m / z: 497.2 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),9.64(s,1H),9.30-9.29(m,1H),9.20(s,1H),9.04-9.01(m, 1H),8.36(d,J=5.0Hz,1H),7.57(d,J=3.4Hz,1H),7.47(d,J=9.0Hz,1H),7.38(d,J=5.0Hz,1H),7. 15(d,J=8.8Hz,1H),6.89(d,J=3.6Hz,1H),4.72(s,2H),4.68-4.63(m,1H),4.23-4.18(m,1H),4.1 1-4.08(m,1H),3.87(s,4H),3.33(s,4H),3.10-3.08(m,2H),2.18-2.14(m,1H),1.97-1.93(m,1H).

[1013] Step 4: Synthesis of the trifluoroacetate of compound 56

[1014] The trifluoroacetate of compound 55 (50 mg, 100.69 μmol) and 37% formaldehyde aqueous solution (40.86 mg, 503.46 μmol) were added to MeOH (2 mL), followed by AcOH (18.14 mg, 302.08 μmol). The reaction was carried out at 25 °C for 1 hour. Then, NaBH(OAc)3 (42.68 mg, 201.38 μmol) was added, and the reaction was carried out for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The trifluoroacetate of compound 56 was separated by prep-HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (TFA)-acetonitrile]; acetonitrile %: 5%-35%, 8 min). MS m / z: 511.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.15-9.96(m,2H),9.70-9.60(m,1H),9.21-9.19(m,1H),8.37-8 .36(m,1H),7.59-7.51(m,2H),7.40-7.38(m,1H),7.19-7.14(m,1H),6.91-6.90(m,1H),4 .76-4.72(m,3H),4.46-4.43(m,1H),4.22-4.00(m,2H),3.88(s,3H),3.67-3.60(m,3H),3 .31-3.26(m,3H),3.09-3.08(m,2H),2.91(brs,1H),2.21-2.19(m,1H),1.90-1.88(m,1H).

[1015] Example 58

[1016]

[1017] Step 1: Synthesis of Compound 58-1

[1018] Under nitrogen protection, compound 48-1 (140 mg, 213.84 μmol) was dissolved in DCM (4 mL), and TfOH (2.77 g, 18.46 mmol) was added. The reaction was carried out at 20 °C for 2 hours. Ammonia water (3 mL) was slowly added to the system, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 58-1. MS m / z: 286.0, 288.0 [M+1] + .

[1019] Step 2: Synthesis of Compound 58-2

[1020] Under nitrogen protection, compound 58-1 (67 mg, 234.15 μmol) was dissolved in tetrahydrofuran (1 mL), and sodium hydride (28.10 mg, 702.45 μmol, 60% purity) was added at -20 °C, and the reaction was carried out at -20 °C for 0.5 h. A solution of CD3I (27.15 mg, 187.32 μmol) in tetrahydrofuran (1 mL) was slowly added dropwise, and the reaction was carried out at 20 °C for 15.5 h. The mixture was cooled to 0 °C, and a saturated ammonium chloride solution (5 mL) was added. Extraction was performed with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Compound 58-2 was obtained by column chromatography (methanol / dichloromethane = 0%–5%). MS m / z: 303.1, 305.1 [M+1] + .

[1021] Step 3: Synthesis of Compound 58-3

[1022] Under nitrogen protection, compound BB-13-4 (38 mg, 88.48 μmol) was dissolved in 1,4-dioxane (1 mL), and compound 58-2 (26.83 mg, 88.48 μmol), cesium carbonate (86.49 mg, 265.44 μmol), Ruphos (8.26 mg, 17.70 μmol), and Pd2(dba)3 (8.10 mg, 8.85 μmol) were added. The reaction was carried out at 110 °C for 2 hours. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane (20 mL). The filtrate was concentrated under reduced pressure to obtain the crude product, which was separated by column chromatography (methanol / dichloromethane = 0%–15%) to obtain compound 58-3. MS m / z: 652.3 [M+1] + .

[1023] Step 4: Synthesis of the trifluoroacetate of compound 58

[1024] Under nitrogen protection, compound 58-3 (54.00 mg, 82.85 μmol) was dissolved in DCM (3 mL), and TfOH (1.70 g, 11.30 mmol) was added. The reaction was carried out at 40 °C for 16 hours. After cooling to room temperature, the system was slowly added to ammonia (10 mL), and extracted with dichloromethane:methanol = 10:1 (20 mL × 4). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was then separated into trifluoroacetate of compound 58 by prep-HPLC (column: Phenomenex C18 80*30 mm*3 μm; mobile phase: [water (TFA)-acetonitrile]; acetonitrile %: 1%-30%, 8 min). MS m / z: 502.1 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ9.88-9.60(m,1H),9.39-9.09(m,1H),8.36-8.35(m,1H),7.68-7.28(m,4H),7.24-7.05(m,1H),7.00-6 .80(m,1H),5.60-5.26(m,1H),5.20-4.86(m,1H),4.81-4.58(m,3H),4.57-4.28(m,2H),3.96-3.77(m,6H),2.23-1.66(m,2H).

[1025] Example 61

[1026]

[1027] Step 1: Synthesis of Compound 61-1

[1028] Compound 45-5 (500 mg, 1.24 mmol) was dissolved in DCM (10 mL) in a dry vial, and TfOH (9.28 g, 61.84 mmol) was added. The reaction mixture was stirred at 40 °C for 16 hours. The reaction solution was poured into 5% dilute ammonia water (100 mL), and the aqueous phase was extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 1:1 to dichloromethane:methanol = 10:1) to give compound 61-1. MS m / z: 284.1, 286.1 [M+1] + .

[1029] Step 2: Synthesis of Compound 61-2

[1030] Compound 61-1 (135 mg, 475.10 μmol) was dissolved in THF (5 mL) in a dry vial. Imidazole (97.03 mg, 1.43 mmol) and TBSCl (214.82 mg, 1.43 mmol) were added, and the mixture was stirred at 15 °C for 16 hours. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was then separated by column chromatography (petroleum ether:ethyl acetate = 5:1 to 0:100) to give 61-2. MS m / z: 397.8, 397.9 [M+1] + .

[1031] Step 3: Synthesis of compound 61-3

[1032] Compound 61-2 (100 mg, 251.00 μmol) was dissolved in THF (0.5 mL) in a dry vial. Under nitrogen protection at -20°C, NaH (30.12 mg, 752.99 μmol, 60% purity) was slowly added. After stirring for 15 minutes, a solution of CD3I (28.50 mg, 200.80 μmol) dissolved in THF (0.5 mL) was added dropwise. The reaction mixture was slowly brought back to 15°C and stirred for 16 hours. The reaction solution was poured into a saturated ammonium chloride solution (10 mL). The aqueous phase was extracted with ethyl acetate (5 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Compound 61-3 was purified by preparative chromatography (dichloromethane:methanol = 20:1). MS m / z: 415.0, 416.9 [M+1] + .

[1033] Step 4: Synthesis of compound 61-4

[1034] In a dry vial, compound 61-3 (15 mg, 36.10 μmol) and compound BB-13-4 (18.61 mg, 43.33 μmol) were dissolved in dioxane (1 mL). Cs₂CO₃ (35.29 mg, 108.31 μmol) was added, and the pH was checked to be >9. Then, Xantphos Pd G₄ (6.95 mg, 7.22 μmol) was added, and the mixture was purged with nitrogen three times. The reaction was carried out at 110 °C under nitrogen protection for 4 hours. The reaction solution was directly filtered, and the filter cake was washed with ethyl acetate (10 mL × 2). The filtrate was concentrated to obtain the crude product, which was purified by preparative chromatography (dichloromethane:methanol = 10:1) to obtain compound 61-4. MS m / z: 764.4 [M+1] + .

[1035] Step 5: Synthesis of the trifluoroacetate of compound 61

[1036] Compound 61-4 (25 mg, 32.72 μmol) was dissolved in TfOH (0.5 mL) in a dry vial and stirred at 40 °C for 1 hour. The reaction solution was poured into 5% dilute ammonia water (10 mL), and the aqueous phase was extracted with dichloromethane:methanol = 5:1 (5 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then separated by prep-HPLC (column: Phenomenex C1875 * 30 mm * 3 μm; mobile phase: [water (TFA) - acetonitrile]; acetonitrile %: 5%-35%, 8 min) to obtain the trifluoroacetate of compound 61. MS m / z: 500.1 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ10.49-9.94(m,1H),9.70-9.59(m,1H),9.21-9.19 (m,1H),8.36-8.35(m,1H),7.58-7.49(m,1H),7.39-7.38(m,2H),7.18-7.1 4(m,1H),6.91-6.90(m,1H),4.75-4.45(m,3H),4.39-4.28(m,3H),3.87(s, 4H),3.43-3.35(m,1H),3.17(s,3H),2.14-2.00(m,1H),1.83-1.77(m,1H).

[1037] Example 62

[1038]

[1039] Step 1: Synthesis of Compound 62-2

[1040] Under nitrogen protection, compound 62-1 (1 g, 4.62 mmol) was dissolved in acetonitrile (7 mL), and a solution of sodium bicarbonate (15.12 g, 14.40 mmol) in water (7 mL) and benzyl chloroformate (1.18 g, 6.94 mmol) were added. The reaction was carried out at 25 °C for 2 hours. The solvent was concentrated under reduced pressure, and the mixture was extracted with saturated sodium carbonate aqueous solution (10 mL) and ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure to obtain the crude product, and separated by column chromatography (ethyl acetate / petroleum ether = 0%–50%) to obtain compound 62-2. MS m / z: 373.1 [M + Na] + ; 1HNMR(400MHz, CDCl3)δ7.48-7.27(m,5H),5.17(s,2H),4.31-4.13(m,2H),4 .08-3.94(m,1H),3.93-3.79(m,1H),3.60(s,2H),3.01(s,3H),1.47(s,9H).

[1041] Step 2: Synthesis of Compound 62-3

[1042] Under nitrogen protection, compound 62-2 (1.41 g, 4.02 mmol) was dissolved in DCM (28 mL), and Dys-Martin oxidant (1.88 g, 4.43 mmol) was added. The reaction was carried out at 25 °C for 16 hours. Saturated sodium carbonate solution (20 mL) was added, followed by extraction with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound 62-3 was obtained by column chromatography (ethyl acetate / petroleum ether = 0%–50%). MS m / z: 371.1 [M + Na] + .

[1043] Step 3: Synthesis of compound 62-4

[1044] Under nitrogen protection, compound 62-3 (1.33 g, 3.82 mmol) was added to DCM (25 mL), followed by (PMB)₂NH (982.35 mg, 3.82 mmol) and acetic acid (229.25 mg, 3.82 mmol). The reaction was carried out at 25 °C for 1 hour. Sodium borohydride acetate (1.21 g, 5.73 mmol) was then added, and the reaction was carried out at 25 °C for 1 hour. The mixture was extracted with saturated sodium carbonate aqueous solution (20 mL) and dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound 62-4 was obtained by column chromatography (ethyl acetate / petroleum ether = 0%–40%). MS m / z: 590.4 [M+1] + .

[1045] Step 4: Synthesis of Compound 62-5

[1046] Compound 62-4 (1.85 g, 3.14 mmol) was dissolved in hydrogen chloride / methanol (4 M, 100 mL) under nitrogen protection and reacted at 25 °C for 2 h. The solvent was concentrated under reduced pressure, and the mixture was extracted with dichloromethane (20 mL), saturated sodium carbonate aqueous solution (20 mL), and dichloromethane (20 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 62-5. MS m / z: 490.2 [M+1] + .

[1047] Step 5: Synthesis of compound 62-6

[1048] Under nitrogen protection, compound 62-5 (1.47 g, 3.00 mmol) was dissolved in DMF (15 mL), and compound BB-1-1 (734.98 mg, 3.60 mmol) and DIEA (1.16 g, 9.01 mmol) were added. The mixture was reacted at 100 °C for 16 hours. After cooling, water (20 mL) and saturated sodium carbonate solution (20 mL) were added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound 62-6 was obtained by column chromatography (ethyl acetate / petroleum ether = 0%–30%). MS m / z: 673.0, 675.0 [M+1] + .

[1049] Step 6: Synthesis of Compounds 62-7

[1050] Compound 62-6 (480 mg, 712.59 μmol) was dissolved in trifluoroacetic acid (15.40 g, 135.06 mmol) under nitrogen protection and reacted at 60 °C for 16 h. After cooling, the solution was concentrated under reduced pressure, and DCM (10 mL) and sodium borohydride acetate (453.08 mg, 2.14 mmol) were added. The mixture was reacted at 25 °C for 1 h. Saturated sodium carbonate solution (30 mL) was added, followed by extraction with dichloromethane (20 mL × 5), washing with saturated brine (20 mL), and drying over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound 62-7 was obtained by column chromatography (methanol / dichloromethane = 0%–20%). MS m / z: 403.0, 405.0 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ7.30 (d, J = 8.4Hz, 1H), 7.25 (d, J = 8.8Hz, 2H), 7.06 (d, J = 8. 4Hz,1H),6.86(d,J=8.4Hz,2H),4.16(d,J=14.4Hz,1H),3.96(d,J=14.4Hz,1H), 3.80(s,3H),3.75-3.69(m,1H),3.65-3.58(m,1H),3.49(s,1H),3.21-3.13(m,2 H),3.10-3.02(m,2H),3.00-2.90(m,2H),2.86-2.81(m,1H),2.63-2.89(m,1H).

[1051] Step 7: Synthesis of Compounds 62-8

[1052] Under nitrogen protection, compound 62-7 (150 mg, 371.92 μmol) was dissolved in methanol (3 mL), followed by the addition of 37% formaldehyde aqueous solution (150.91 mg, 1.86 mmol) and acetic acid (67.00 mg, 1.12 mmol), and the reaction was carried out at 25 °C for 1 hour. Sodium borohydride acetate (157.65 mg, 743.84 μmol) was added, and the reaction was carried out at 25 °C for 1 hour. The mixture was extracted with saturated sodium carbonate aqueous solution (10 mL) and dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound 62-8 was obtained by column chromatography (methanol / ethyl acetate = 0%–10%). MS m / z: 417.0, 419.0 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ7.30(s,1H),7.27-7.22(m,2H),7.06(d,J=8.4Hz,1H),6.86(d,J=8.4Hz,2H),4.18-4.07(m,1H),4.03-3.93(m, 1H),3.81(s,3H),3.75-3.57(m,2H),3.46-3.32(m,2H),2.90-2.77(m,1H),2.70-2.57(m,2H),2.48-2.33(m,3H),1.87-1.66(m,4H).

[1053] Step 8: Synthesis of compounds 62-9

[1054] Under nitrogen protection, compound BB-13-4 (70 mg, 162.99 μmol) was dissolved in 1,4-dioxane (2 mL), and compound 62-8 (81.63 mg, 195.59 μmol), cesium carbonate (159.32 mg, 488.97 μmol), and Xantphos Pd G4 (15.69 mg, 16.30 μmol) were added. The mixture was reacted at 110 °C for 2 hours. After cooling, the mixture was filtered, and the residue was washed with dichloromethane (20 mL). The filtrate was concentrated under reduced pressure to obtain the crude product. Compound 62-9 was separated by column chromatography (methanol / dichloromethane = 0%–20%). MS m / z: 766.2 [M+1] + .

[1055] Step 9: Synthesis of the trifluoroacetate of compound 62

[1056] Under nitrogen protection, compound 62-9 (50 mg, 65.28 μmol) was dissolved in TfOH (4.25 g, 28.32 mmol) and reacted at 40 °C for 16 hours. After cooling to room temperature, the system was slowly added to dilute ammonia (5%, 10 mL), and extracted with dichloromethane (20 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The trifluoroacetate of compound 62 was separated by prep-HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (TFA)-acetonitrile]; acetonitrile %: 1%-25%, 8 min). MS m / z: 496.3 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ10.04(s,1H),9.75(s,1H),9.23(s,1H),8.36(d,J=5.2Hz,1H),7.73-7.48(m,2H),7.39(d,J=4.8Hz,1H),7.29(d,J=8.8Hz, 1H),6.89(d,J=3.6Hz,1H),4.73(s,2H),4.57-4.48(m,1H),4.45-4.35(m ,1H),3.87(s,3H),3.55(d,J=3.8Hz,6H),3.26-3.16(m,4H),2.91(s,3H).

[1057] Example 63

[1058]

[1059] Step 1: Synthesis of Compound 63-1

[1060] Under nitrogen protection, compound 4-6 (1 g, 4.83 mmol) was added to 1,2-dibromoethane (10 mL), followed by copper bromide (538.90 mg, 2.41 mmol), and then isoamyl nitrite (621.85 mg, 5.31 mmol). The reaction was carried out at 20 °C for 2 hours. Copper bromide (1.08 g, 4.83 mmol) was added, and the reaction was continued at 20 °C for 2 hours. The mixture was filtered, and the filter cake was washed with dichloromethane (20 mL). The filtrate was collected and concentrated under reduced pressure to obtain the crude product. Compound 63-1 was obtained by column chromatography (ethyl acetate / petroleum ether = 0%–40%). MS m / z: 271.1, 273.1 [M+1] + .

[1061] Step 2: Synthesis of Compound 63-2

[1062] Under nitrogen protection, compound 50-6 (160 mg, 369.95 μmol) was dissolved in 1,4-dioxane (4 mL), and compound 63-1 (100.30 mg, 369.95 μmol), potassium phosphate (157.06 mg, 739.90 μmol), Ruphos (51.79 mg, 110.99 μmol), and Pd2(dba)3 (67.75 mg, 73.99 μmol) were added. The reaction was carried out at 110 °C for 2 hours. After cooling, the mixture was concentrated under reduced pressure to obtain the crude product. Compound 63-2 was obtained by column chromatography (methanol / ethyl acetate = 0%–100%). MS m / z: 623.2 [M+1] + .

[1063] Step 3: Synthesis of the trifluoroacetate of compound 63

[1064] Under nitrogen protection, compound 63-2 (218 mg, 350.10 μmol) was dissolved in DCM (5 mL), and TfOH (3.39 g, 22.60 mmol) was added. The reaction was carried out at 40 °C for 16 hours. The reaction was quenched with ammonia (5 mL), and extracted with dichloromethane:methanol = 10:1 (V / V, 20 mL × 4). The organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to obtain the crude product. The trifluoroacetate of compound 63 was separated by prep-HPLC (column: Phenomenex C1875 * 30 mm * 3 μm; mobile phase: [water (TFA) - acetonitrile]; acetonitrile %: 15%-45%, 8 min). MS m / z: 473.0 [M + H] + ; 1 H NMR (400MHz, DMSO-d6) δ9.85(s,1H),9.47(s,1H),9.18(s,1H),8.36(s,1H),7.58(s,1H),7.43-7.24(m,2H),6.94(s,1H),6.69(d,J=6.8Hz,1 H), 4.71 (s, 2H), 4.39 (d, J = 9.6Hz, 1H), 4.12-3.84 (m, 3H), 3.60 (d, J = 4.8Hz, 2H), 3.22-3.18 (m, 1H), 3.06 (d, J = 0.8Hz, 1H), 2.71-2.59 (m, 1H).

[1065] Example 64

[1066]

[1067] Step 1: Synthesis of Compound 64-2

[1068] Under nitrogen protection, compound 64-1 (8.5 g, 40.27 mmol) was dissolved in DMF (85 mL), and Select-F (14.27 g, 40.27 mmol) was added. The mixture was stirred at 60 °C for 16 hours. The solution was poured into water (300 mL), and the aqueous phase was extracted with MTBE (50 mL × 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then separated by column chromatography (PE:EA = 100:0–4:1) to give compound 64-2. MS m / z: 229.1, 231.1 [M+1] + .

[1069] Step 2: Synthesis of Compound 64-3

[1070] Under nitrogen protection, compound 64-2 (1 g, 4.37 mmol) was dissolved in 1,4-dioxane (20 mL), followed by the addition of dipinacolborate (1.66 g, 6.55 mmol) and Pd(dppf)Cl. 2. CH₂Cl₂ (356.53 mg, 436.59 μmol) and potassium acetate (1.29 g, 13.10 mmol) were stirred at 85 °C for 16 hours. The mixture was poured into water (50 mL), extracted with EA (30 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then separated by column chromatography (PE:EA = 100:0–2:1) to give compound 64-3. MS m / z: 195.2 [M-81] + ; 1 H NMR (400MHz, DMSO-d6) δ8.35(d,J=4.4Hz,1H),7.41(d,J=4.4Hz,1H),7.01(s,1H),3.84(s,3H),1.41(s,12H).

[1071] Step 3: Synthesis of compound 64-4

[1072] Under nitrogen protection, compound 64-3 (360 mg, 1.30 mmol) and compound BB-13-1 (518.46 mg, 1.30 mmol) were dissolved in 1,4-dioxane (20 mL), and a solution of Pd(dppf)Cl2 (190.80 mg, 260.76 μmol) and K3PO4 (830.28 mg, 3.91 mmol) / H2O (4 mL) was added. The mixture was stirred at 60 °C for 2 hours. The mixture was filtered, and the filter cake was washed with EA (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by filtration to obtain the crude product. Compound 64-4 was obtained by column chromatography (DCM:MeOH = 100:0–95:5). MS m / z: 467.1 [M+1] + .

[1073] Step 4: Synthesis of Compound 64-5

[1074] Under nitrogen protection, compound 64-4 (120 mg, 257.02 μmol) and BocNH2 (60.22 mg, 514.04 μmol) were dissolved in 1,4-dioxane (10 mL), and K3PO4 (163.67 mg, 771.06 μmol) was added. The pH of the system was checked and found to be >9. Pd2(dba)3 (47.07 mg, 51.40 μmol) and RuPhos (35.98 mg, 77.11 μmol) were added, and the mixture was stirred at 110 °C for 3 hours. The mixture was filtered, and the filter cake was washed with EA (20 mL × 3). The organic phases were combined and concentrated to obtain the crude product, which was separated by preparative chromatography (EA) to obtain compound 64-5. MS m / z: 548.2 [M+1] + .

[1075] Step 5: Synthesis of compound 64-6

[1076] Compound 64-5 (55 mg, 100.44 μmol) was dissolved in DCM (2 mL), and TFA (25.35 mmol, 1.88 mL) was added. The mixture was stirred at 15 °C for 2 hours. The solution was then poured into a saturated sodium carbonate solution (20 mL). The pH of the system was >8. The aqueous phase was extracted with DCM:MeOH at a ratio of 5:1 (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 64-6. MS m / z: 448.0 [M+1] + .

[1077] Step 6: Synthesis of compounds 64-7

[1078] Compounds 64-6 (45 mg, 100.57 μmol) and 63-1 (27.26 mg, 100.57 μmol) were dissolved in 1,4-dioxane (5 mL), and K3PO4 (64.04 mg, 301.70 μmol) was added. Then, Pd2(dba)3 (18.42 mg, 20.11 μmol) and RuPhos (14.08 mg, 30.17 μmol) were added. The mixture was stirred at 110 °C for 3 hours under nitrogen protection. The mixture was filtered, and the filter cake was washed with ethyl acetate (20 mL). The organic phases were combined and concentrated to obtain the crude product, which was separated by preparative chromatography (DCM:MeOH = 20:1) to give compound 64-7. MS m / z: 638.2 [M+1] + .

[1079] Step 7: Synthesis of Compound 64

[1080] Compound 64-7 (50 mg, 78.41 μmol) was dissolved in TfOH (53.67 mmol, 4.75 mL) and stirred at 40 °C for 1 hour. The solution was poured into 20 mL of 5% dilute ammonia solution, and the aqueous phase was extracted with DCM:MeOH at a ratio of 10:1 (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was then separated by prep-HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (0.1% TFA)-acetonitrile]; acetonitrile %: 15%-45%) to obtain the trifluoroacetate of compound 64. MS m / z: 488.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ9.78 (s, 1H), 9.34 (s, 1H), 9.08 (s, 1H), 8.38 (d, J = 4.8Hz, 1H),7.59(s,1H),7.36(d,J=4.8Hz,1H),7.31(d,J=8.4Hz,1H),6.68(d,J=8.4Hz,1 H),4.53(s,2H),4.39-4.36(m,1H),4.05-4.00(m,1H),3.89-3.88(m,1H),3.87-3 .86(m,1H),3.82(s,3H),3.60-3.45(m,3H),3.22-3.17(m,1H),2.66-2.64(m,1H).

[1081] Example 65

[1082]

[1083] Step 1: Synthesis of Compound 65-1

[1084] Compounds 16-6 (70 mg, 234.76 μmol) and 64-6 (105.05 mg, 234.76 μmol) were dissolved in 1,4-dioxane (5 mL), and K3PO4 (149.50 mg, 704.28 μmol), Pd2(dba)3 (42.99 mg, 46.95 μmol), and RuPhos (32.86 mg, 70.43 μmol) were added. The mixture was stirred at 110 °C for 3 hours under nitrogen protection. The mixture was filtered, and the filter cake was washed with EA (10 mL × 2). The combined organic phases were concentrated to obtain the crude product, which was separated by preparative chromatography (DCM:MeOH = 10:1) to give compound 65-1. MS m / z: 665.3 [M+1] + .

[1085] Step 2: Synthesis of Compound 65

[1086] Compound 65-1 (60 mg, 90.26 μmol) was dissolved in DCM (2 mL) and TfOH (1.61 g, 10.76 mmol) was added. The mixture was stirred at 40 °C for 16 hours. The solution was poured into 5% dilute ammonia water (20 mL), and extracted with DCM:MeOH = 10:1 (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then separated by prep-HPLC (column: Phenomenex C18 80*30 mm*3 μm; mobile phase: [water (0.1% TFA)-acetonitrile]; acetonitrile %: 10%-40%) to obtain the trifluoroacetate of compound 65. MS m / z: 515.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ9.98-9.96(m,1H),9.66-9.60(m,1H),9.16(s,1H),8.40(d,J=4.8Hz,1H),7.61-7.58(m,2H),7.37-7.36(m, 1H),7.22-7.17(m,1H),4.75-7.73(m,1H),4.59-4.55(m,3H),3.83(s,3H),3.71-3.60(m,3H),3.35-2.99(m,6H),2.98-2.97(m,3H).

[1087] Example 66

[1088]

[1089] Step 1: Synthesis of Compound 66-2

[1090] Under nitrogen protection, compound 30-1 (38.5 g, 186.47 mmol) was dissolved in THF (500 mL), and LDA (2 M, 111.88 mL) was added at -78 °C. The mixture was stirred for 1 hour, and then CO2 was bubbled through until no significant temperature change was observed. The mixture was slowly heated to 25 °C and reacted for 2 hours. The solution was poured into water (1000 mL), and extracted with EA (200 mL × 3). The pH of the aqueous phase was adjusted to 1 with 2 M hydrochloric acid. The extract was then extracted with DCM (200 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 66-2.

[1091] Step 2: Synthesis of Compound 66-3

[1092] Under nitrogen protection, compound 66-2 (26 g, 103.80 mmol) was dissolved in DMF (300 mL), and K2CO3 (43.04 g, 311.41 mmol) and MeI (29.47 g, 207.60 mmol) were added. The mixture was stirred at 15 °C for 2 hours. The solution was poured into water (3000 mL), and the mixture was extracted with EA (1000 mL × 3). The organic phases were combined, washed with semi-saturated brine (500 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Compound 66-3 was obtained by column chromatography (EA / PE = 0%–10%).

[1093] Step 3: Synthesis of Compound 66-4

[1094] Under nitrogen protection, compound 66-3 (7 g, 26.46 mmol) was dissolved in 1-methyl-2-pyrrolidone (70 mL). 1,3,5-triazine (4.29 g, 52.93 mmol) was slowly added dropwise at 0 °C. After stirring at 0 °C for 0.5 hours, potassium tert-butoxide (5.94 g, 52.93 mmol) was added, and the mixture was heated to 110 °C and stirred for 1 hour. The solution was poured into water (100 mL), extracted with EA (30 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was then separated by column chromatography (EA / PE = 0%–10%–MeOH / EA = 0%–5%) to give compound 66-4. MS m / z: 258.7, 260.7 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ11.98 (s, 1H), 8.40-8.36 (m, 1H), 6.63 (d, J = 7.6Hz, 1H).

[1095] Step 4: Synthesis of Compound 66-5

[1096] Under nitrogen protection, compound 66-4 (2.5 g, 6.74 mmol) was dissolved in 1,4-dioxane (30 mL) and water (6 mL), followed by compound 66-4a (1.74 g, 6.74 mmol), potassium phosphate (4.29 g, 20.23 mmol), and Pd(dppf)Cl. 2. CH2Cl2 (550.75 mg, 674.41 μmol) was stirred at 90 °C for 1 hour. The mixture was poured into water (200 mL), extracted with EA (50 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then separated by column chromatography (EA / PE = 10%–100%) to give compound 66-5. MS m / z: 310.8 [M+1] + .

[1097] Step 5: Synthesis of compound 66-6

[1098] Under nitrogen protection, compound 66-5 (1.5 g, 4.83 mmol) was dissolved in tetrahydrofuran (5 mL). 1,8-diazabicyclo[5.4.0]undec-7-ene (3.67 g, 24.14 mmol, 3.64 mL) was slowly added dropwise at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Then, 2-(trimethylsilyl)ethoxymethyl chloride (3.22 g, 19.31 mmol) was slowly added, and the mixture was heated to 15 °C and stirred for 16 h. The solution was poured into water (100 mL), extracted with EA (30 mL × 3), and the organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound 66-6 was obtained by column chromatography (EA / PE = 10%–50%). MS m / z: 441.0 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ8.76 (s, 1H), 8.49 (d, J = 4.8Hz, 1H), 7.27-7.23 (m, 3H), 6.50 (d, J = 7.6Hz, 1H) ,6.27(d,J=3.2Hz,1H),5.41(s,2H),3.97(s,3H),3.71-3.66(m,2H),0.99-0.95(m,2H),0.01(s,9H).

[1099] Step 6: Synthesis of Compounds 66-7

[1100] Under nitrogen protection, compound 66-6 (100 mg, 226.76 μmol) was dissolved in 1,4-dioxane (2 mL), followed by compound 4-6 (46.99 mg, 226.76 μmol), potassium phosphate (144.40 mg, 680.28 μmol), Ruphos (21.16 mg, 45.35 μmol), and Pd2(dba)3 (20.76 mg, 22.68 μmol). The mixture was stirred at 110 °C for 2 hours. After cooling to room temperature, the mixture was filtered, and the residue was washed with DCM (20 mL). The filtrate was concentrated under reduced pressure. Compound 66-7 was obtained by column chromatography (MeOH / EA = 0%–2%). MS m / z: 612.2 [M+1] + .

[1101] Step 7: Synthesis of Compound 66

[1102] Under nitrogen protection, compound 66-7 (80 mg, 130.77 μmol) was dissolved in TFA (26.93 mmol, 2.00 mL) and stirred at 20 °C for 16 hours. The solution was concentrated under reduced pressure, and DCM (10 mL) was added. The pH was adjusted to 8 with dilute ammonia (5%, 3 mL). The aqueous phase was extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was then separated into trifluoroacetate of compound 66 by prep-HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (0.1% TFA)-acetonitrile]; acetonitrile %: 15%-45%). MS m / z: 482.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ12.03-11.93(m,1H),11.86(s,1H),9.79(s,1H),8.39(d,J =4.4Hz,1H),7.56(d,J=3.6Hz,1H),7.37-7.28(m,1H),7.21(d,J=3.6Hz,2H),6.73 -6.60(m,1H),6.41-6.30(m,1H),6.26(d,J=3.6Hz,1H),4.41-4.32(m,2H),4.10-3 .94(m,3H),3.88(s,4H),3.62-3.57(m,1H),3.23-3.15(m,1H),3.12-3.03(m,1H).

[1103] Example 68

[1104]

[1105] Step 1: Synthesis of Compound 68-1

[1106] Under nitrogen protection, compound 66-6 (100 mg, 226.76 μmol) was dissolved in 1,4-dioxane (1 mL), and compound 16-9 (58.44 mg, 249.43 μmol), potassium phosphate (144.40 mg, 680.28 μmol), Ruphos (21.16 mg, 45.35 μmol), and Pd2(dba)3 (20.76 mg, 22.68 μmol) were added. The mixture was stirred at 110 °C for 2 hours. After cooling to room temperature, the mixture was filtered, and the residue was washed with DCM (20 mL). The filtrate was concentrated under reduced pressure to obtain the crude product. Compound 68-1 was obtained by rapid column chromatography (MeOH / EA = 0%–15%). MS m / z: 639.3 [M+1] + .

[1107] Step 2: Synthesis of the trifluoroacetate of compound 68

[1108] Compound 68-1 (120 mg, 187.84 μmol) was dissolved in TFA (67.31 mmol, 5 mL), and the reaction was stirred at 15 °C for 16 hours. The solvent was concentrated under reduced pressure, and dichloromethane (20 mL) and dilute ammonia (5%, 20 mL) were added. The mixture was separated, and the aqueous phase was extracted with DCM:MeOH = 10:1 (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then separated by prep-HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (0.1% TFA)-acetonitrile]; acetonitrile %: 10%-40%) to obtain the trifluoroacetate of compound 68. MS m / z: 509.1 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ=12.31-12.26(m,1H),11.96-11.95(m,1H),10.05 (s,1H),8.40(d,J=5.2Hz,1H),7.62-7.56(m,2H),7.28-7.21(m,2H),7.16-7 .14(m,1H),6.36-6.34(m,1H),6.24-6.23(m,1H),4.75-4.73(m,1H),4.65-4 .33(m,1H),3.89(s,3H),3.78-3.61(m,5H),3.43-3.26(m,4H),2.98(s,3H).

[1109] Example 69

[1110]

[1111] Step 1: Synthesis of Compound 69-2

[1112] Under nitrogen protection, compound 30-5 (2.1 g, 6.04 mmol) was dissolved in 1,4-dioxane (30 mL) and water (6 mL), followed by compound BB-2 (5.86 g, 6.04 mmol), potassium carbonate (2.50 g, 18.12 mmol), and Pd(dppf)Cl. 2. CH2Cl2 (442.06 mg, 604.16 μmol) was stirred at 70 °C for 2 hours. After cooling to room temperature, the mixture was filtered, and the residue was washed with DCM (20 mL). The filtrate was concentra...

Claims

1. The compound represented by formula (V), its stereoisomers, or pharmaceutically acceptable salts thereof, in, X is selected from O and S; T is selected from CH and N; T1 is selected from CH and N; R2 is selected from 5-membered 6-membered heteroaryl groups, wherein the 5-membered 6-membered heteroaryl group is optionally surrounded by 1, 2, or 3 R groups. a replace; R3 and R4, along with the carbon atoms bonded to them, constitute... E and E1 are independently selected from -C(R7)2-, -O-, and -N(R5)-, respectively; n and m are independently selected from 0 and 1, respectively; R5 is selected from H and C. 1-3 alkyl; R6 is selected from H and -C. 1-3 Alkyl-C 1-3 Alkylamino; R7 is selected from H, F, Cl, Br, I, OH, NH2, and C. 1-3 alkyl; Each R a Selected independently from D, halogen, and C 1-3 Alkyl and C 1-3 Alkoxy; Each R b Selected independently from H, D and C respectively. 1-3 alkyl; Or, 2 Rs b The carbon atoms that are connected to them form C=O.

2. The compound according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, Each R a They are selected independently from D, F and CH3 respectively.

3. The compound according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, Each R b They are selected independently from H, D and CH3 respectively.

4. The compound according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, R2 is selected from pyrrolopyridyl and imidazopyridyl, wherein the pyrrolopyridyl and imidazopyridyl are optionally surrounded by 1, 2 or 3 R2 groups. a replace.

5. The compound according to claim 4, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, R2 is selected from 6. The compound according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, R6 is selected from H and -CH2-N(CH3)2.

7. The compound according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, R5 is selected from H, CH3, CH2CH3 and CH(CH3)2.

8. The compound according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, R7 is selected from H, F and CH3.

9. The compound according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, E and E1 are independently selected from -CH2-, -CH(OH)-, -CH(CH3)-, -O-, -NH-, -N(CH3)- and -N(CH2CH3)-, respectively.

10. The compound according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, R3 and R4, along with the carbon atoms bonded to them, constitute...

11. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, selected from, in, E, E1, T, T1, R2, and m are as defined in claim 1. E2 is selected from N and CH.

12. The following compounds, their stereoisomers, or pharmaceutically acceptable salts, 13. The compound according to claim 12, its stereoisomers, or pharmaceutically acceptable salts thereof, selected from:

14. Use of the compound of any one of claims 1 to 13, its stereoisomer, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diseases related to HPK1 kinase inhibition.

15. The application of claim 14, wherein the HPK1 kinase inhibition-related disease is a solid tumor.

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