Nitrogen-containing compound and application thereof

Abstract

The invention discloses a nitrogen-containing compound and application thereof. Specifically provided are a nitrogen-containing compound represented by formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof. The nitrogen-containing compound can effectively inhibit the overexpression of the KIF18A protein in part of human tumor cells.

Description

A nitrogen-containing compound and its application

[0001] This application claims priority to Chinese patent application No. 2022107730353, filed on June 30, 2022. This application claims priority to Chinese patent application No. 202310066234.5, filed on January 16, 2023. This application claims priority to Chinese patent application No. 2023107394075, filed on June 21, 2023. This application incorporates the entirety of the aforementioned Chinese patent applications. Technical Field

[0002] The invention relates to a nitrogen-containing compound and application thereof. Background Art

[0003] Humans have 46 chromosomes (two sets of 23), but in cancer, this number changes because chromosomes separate during cell division, leading to a phenomenon called aneuploidy. Aneuploidy, the presence of an abnormal number of chromosomes in a cell, not only causes common genetic diseases but is also a hallmark of cancer cells. Not all cancers exhibit aneuploidy, but approximately 90% of solid tumors and 75% of blood cancers exhibit aneuploidy to some extent.

[0004] KIF18A, a member of the kinesin-8 family of kinesins, is a mitotic motor protein that uses the energy released by ATP hydrolysis to move along microtubules toward the positive pole within the cell. KIF18A is localized at the positive end of microtubules, where it regulates microtubule dynamic instability, exerting an activity similar to that of a microtubule depolymerase. During mitosis, KIF18A regulates spindle microtubule dynamics and chromosome amplitude, playing a key role in ensuring the timely alignment of chromosomes during mitosis, maintaining genomic stability, and enabling the successful completion of mitosis.

[0005] KIF18A protein is overexpressed in some human tumor cells (e.g., breast cancer, ovarian cancer, and colorectal cancer) and is associated with tumor invasion and metastasis. After inhibition of KIF18A protein, tumor cells with chromosomal instability exhibit mitotic delay, multipolar spindles, and increased cell death. Many antimitotic drugs have been used clinically for cancer treatment, including microtubule inhibitors, which can stabilize microtubules or prevent microtubule assembly. Since microtubules are the main component of the mitotic spindle, the disruption of microtubule movement by these drugs can lead to mitotic arrest and tumor cell growth inhibition. However, since microtubule inhibitors also have inhibitory effects on normal cells, this type of drug has more toxic side effects. The proliferation of aneuploid cancer cells characterized by chromosomal instability (CIN) depends on the KIF18A protein, but the proliferation in diploid cells is not dependent on the KIF18A protein. As a result, inhibiting KIF18A protein activity has less impact on normal cells and selectively inhibits tumor cell proliferation. Therefore, the selectivity of KIF18A inhibitors between normal cells and tumor cells can create a better therapeutic window and have good clinical application prospects for tumor treatment.

[0006] Summary of the Invention

[0007] The technical problem to be solved by the present invention is that the KIF18A inhibitors in the prior art have a single structure, and a nitrogen-containing compound and its application are provided. The nitrogen-containing compound of the present invention can effectively inhibit the overexpression of KIF18A protein in some human tumor cells.

[0008] The present invention provides a nitrogen-containing compound as shown in Formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its metabolite, its prodrug, its isotope-labeled derivative, its solvate or its pharmaceutically acceptable salt solvate,

[0009] Among them, R x is a 3-6 membered monocyclic cycloalkyl, a 5-6 membered monocyclic heterocycloalkyl, a 6-9 membered bridged heterocycloalkyl, a 7-9 membered spiro heterocycloalkyl, or one or more R x-1 substituted 5-6 membered monocyclic heterocycloalkyl, x-2 Substituted 6-9 membered bridged heterocyclic alkyl, one or more R x-3 substituted 7-9 membered spirocyclic heterocyclic alkyl or one or more R x-4 substituted 3-6 membered monocyclic cycloalkyl; the “5-6 membered monocyclic heterocycloalkyl”, the “6-9 membered bridged heterocycloalkyl”, the “7-9 membered spiro heterocycloalkyl”, the “substituted one or more R x-1 substituted 5-6 membered monocyclic heterocycloalkyl", said "substituted by one or more R x-2substituted 6-9 membered bridged heterocyclic alkyl" and the "substituted by one or more R x-3 In the "substituted 7-9 membered spiro heterocycloalkyl", the heteroatoms are independently composed of 1 N atom and 0, 1 or 2 X atoms, and the X atoms are independently selected from 1 or 2 of N, O and S; the "5-6 membered monocyclic heterocycloalkyl", the "6-9 membered bridged heterocycloalkyl", the "7-9 membered spiro heterocycloalkyl", the "substituted one or more R x-1 substituted 5-6 membered monocyclic heterocycloalkyl", said "substituted by one or more R x-2 substituted 6-9 membered bridged heterocyclic alkyl" and the "substituted by one or more R x-3 The substituted 7-9 membered spirocyclic heterocycloalkyl is connected to ring A via an N atom;

[0010] Each R x-1 、R x-2 、R x-3 and R x-4 are independently halogen, R N-10k 、R N-10l 、C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, -OR N-a , C substituted by one or more halogens 1-6 Alkoxy, CN, -NR N-a R N-a or oxo;

[0011] R 1 -LR 1-1 ;

[0012] L is *-NHSO2-, -NH-, *-NHC(O)-, -NHC(O)NH-, *-SO2NH- or -SO2-; * represents the end connected to ring A;

[0013] R 1-1 C 1-6 Alkyl, 3-6 membered monocyclic cycloalkyl, 4-8 membered monocyclic heterocycloalkyl, a Substituted C 1-6 Alkyl or one or more R b Substituted 3-6 membered monocyclic cycloalkyl; in the 4-8 membered monocyclic heterocycloalkyl, the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0014] Each R a are independently hydroxy, halogen or -NH(R a-1 );

[0015] R a-1 C1-6 alkyl;

[0016] Each R b Each independently is C 1-6 Alkyl or C substituted by one or more hydroxyl groups 1-6 alkyl;

[0017] G is C(R 10 ) or N; R 10 H, halogen, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, -OH, -OR N- 8a OR N-8b ;

[0018] M is phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 9-10-membered heteroaryl, 6-membered heterocycloalkenyl, substituted by one or more R 2 substituted 6-membered heteroaryl, one or more R 3 substituted 9-10 membered heteroaryl, substituted by one or more R 4 substituted 6-membered heterocycloalkenyl, one or more R 5 Substituted phenyl, one or more R 5 substituted naphthyl or one or more R 6 substituted 5-membered heteroaryl; the "5-membered heteroaryl", "6-membered heteroaryl", "9-10-membered heteroaryl", "6-membered heterocycloalkenyl", "substituted by one or more R 2 substituted 6-membered heteroaryl, "substituted by one or more R 3 substituted 9-10 membered heteroaryl, "substituted by one or more R 4 substituted 6-membered heterocycloalkenyl" and "substituted by one or more R 6 In the "substituted 5-membered heteroaryl", the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0019] Each R 2 、R 3 、R 4 、R 5 and R 6 are independently oxo, halogen, R N-4a 、R N-4b 、C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, cyano, C 1-6 Alkoxy, -OR N-6a or -YR N-13 ;

[0020] R N-6ais a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S;

[0021] Y is -C 1-6 Alkyl-, -N(C 1-6 alkyl)-C 1-6 Alkyl-, -C(=O)NR N-a R N-a (C 1-6 Alkyl), -O-, -OC 1-6 Alkyl-, S, S=O, S(=O)2, -S(=O)(=NR N-13 )- or -S(=O)(=NH)-;

[0022] R N-13 R N-13a or R N-13b ;

[0023] Each R N-4a 、R N-8a 、R N-10k and R N-13a are independently selected from the group consisting of: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, which is substituted by 0, 1, 2 or 3 groups selected from the group consisting of halogen, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, -OR N-a , C substituted by one or more halogens 1-6 Alkoxy, CN, -C(=O)R N-b 、-C(=O)OR N-a 、-C(=O)NR N-a R N-a 、-C(=NR N-a )NR N-a R N-a 、-OC(=O)R N- b 、-OC(=O)NR N-a R N-a 、-OC 1-6 Alkyl NR N-a R N-a 、-OC 1-6 Alkyl OR N-a 、-SR N-a 、-S(=O)R N-b 、-S(=O)2R N-b 、-S(=O)2NR N-a R N-a 、-NR N-a R N-a 、-N(R N-a )C(=O)R N-b 、-N(R N-a )C(=O)OR N-b 、-N(R N-a )C(=O)NR N-a R N- a 、-N(R N-a )C(=NR N-a )NR N-a R N-a 、-N(R N-a )S(=O)2R N-b 、-N(R N-a )S(=O)2NR N-a R N-a 、-NR N-a C 1-6 Alkyl NR N- a R N-a 、-NR N-a C 1-6 Alkyl OR N-a 、-C 1-6 Alkyl NR N-a R N-a 、-C 1-6 Alkyl OR N-a 、-C 1-6 Alkyl N(R N-a )C(=O)R N-b 、-C 1-6 Alkyl OC(=O)R N-b 、-C 1-6 Alkyl C(=O)NR N-a R N-a 、-C 1-6 Alkyl C(=O)OR N-a 、R N-14 and oxo;

[0024] Each R N-4b 、R N-8b 、R N-10l and R N-13b are independently selected from halogen, -OR N-a , C substituted by one or more halogens 1- 6 alkoxy and C substituted with 0, 1, 2, 3, 4 or 5 groups in CN 1-6 alkyl;

[0025] Each RN-14 are independently selected from the group consisting of: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, which is substituted by 0, 1, 2 or 3 groups selected from the following: halogen, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, -OR N-a , C substituted by one or more halogens 1-6 Alkoxy, CN, -C(=O)R N- b 、-C(=O)OR N-a 、-C(=O)NR N-a R N-a 、-C(=NR N-a )NR N-a R N-a 、-OC(=O)R N-b 、-OC(=O)NR N-a R N-a 、-OC 1-6 Alkyl NR N-a R N-a 、-OC 1-6 Alkyl OR N-a 、-SR N-a 、-S(=O)R N-b 、-S(=O)2R N-b 、-S(=O)2NR N-a R N-a 、-NR N-a R N- a 、-N(R N-a )C(=O)R N-b 、-N(R N-a )C(=O)OR N-b 、-N(R N-a )C(=O)NR N-a R N-a 、-N(R N-a )C(=NR N-a )NR N-a R N- a 、-N(R N-a )S(=O)2R N-b 、-N(R N-a )S(=O)2NR N-a R N-a 、-NR N-a C 1-6 Alkyl NRN-a R N-a 、-NR N-a C 1-6 Alkyl OR N-a 、-C 1-6 Alkyl NR N-a R N-a 、-C 1-6 Alkyl OR N-a 、-C 1-6 Alkyl N(R N-a )C(=O)R N-b 、-C 1-6 Alkyl OC(=O)R N-b 、-C 1-6 Alkyl C(=O)NR N-a R N-a 、-C 1-6 Alkyl C(=O)OR N-a and oxo;

[0026] Each R N-a are independently H or R N-b ;

[0027] Each R N-b Each independently is C 1-6 alkyl, phenyl or benzyl, wherein the C 1-6 The alkyl group is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -OC(=O)C 1-6 Alkyl or -N(C 1-6 Alkyl)C 1-6 Alkyl; and the phenyl or benzyl is substituted by 0, 1, 2 or 3 substituents selected from the group consisting of halogen, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, -OH, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -OC(=O)C 1-6 Alkyl or -N(C 1-6 Alkyl)C 1-6 alkyl;

[0028] W and X 2 is defined as follows:

[0029] Solution 1: W is *-CONR W -;X 2 R W-1 ; * indicates the end connected to ring A;

[0030] Solution 2: W is *-NRW CO-;X 2 R W-1 ; * indicates the end connected to ring A;

[0031] Solution 3: W is *-C(=X 1 )NR W -;X 1 、X 2 and the C atoms therebetween together form a 6-membered heteroaryl group; in the 6-membered heteroaryl group, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; * represents the end connected to ring A;

[0032] R W H, C 1-6 Alkyl or C substituted by one or more halogen 1-6 alkyl;

[0033] R W-1 H, halogen, C 1-6 Alkyl or C substituted by one or more halogen 1-6 alkyl;

[0034] Furthermore, the compound as shown in Formula I satisfies one, two or three of the following conditions:

[0035] Condition 1: R x is a 6-9 membered bridged heterocyclic alkyl group or is replaced by one or more R x-2 substituted 6-9 membered bridged heterocycloalkyl;

[0036] Condition 2: M is naphthyl, 5-membered heteroaryl, 9-10-membered heteroaryl, 6-membered heterocycloalkenyl, or one or more R 5 Substituted naphthyl, one or more R 6 substituted 5-membered heteroaryl, one or more R 3 9-10 membered heteroaryl substituted or one or more R 4 substituted 6-membered heterocycloalkenyl;

[0037] Condition 3: W is *-C(=X 1 )NR W -;X 1 、X 2 and the intervening C atoms together form a 6-membered heteroaryl group.

[0038] The present invention provides a nitrogen-containing compound as shown in Formula II, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its metabolite, its prodrug, its isotope-labeled derivative, its solvate or its pharmaceutically acceptable salt solvate,

[0039] Among them, Rx is a 3-6 membered monocyclic cycloalkyl, a 5-6 membered monocyclic heterocycloalkyl, a 6-9 membered bridged heterocycloalkyl, a 7-9 membered spiro heterocycloalkyl, or one or more R x-1 substituted 5-6 membered monocyclic heterocycloalkyl, x-2 Substituted 6-9 membered bridged heterocyclic alkyl, one or more R x-3 substituted 7-9 membered spirocyclic heterocyclic alkyl or one or more R x-4 substituted 3-6 membered monocyclic cycloalkyl; the “5-6 membered monocyclic heterocycloalkyl”, the “6-9 membered bridged heterocycloalkyl”, the “7-9 membered spiro heterocycloalkyl”, the “substituted one or more R x-1 substituted 5-6 membered monocyclic heterocycloalkyl", said "substituted by one or more R x-2 substituted 6-9 membered bridged heterocyclic alkyl" and the "substituted by one or more R x-3 In the "substituted 7-9 membered spiro heterocycloalkyl", the heteroatoms are independently composed of 1 N atom and 0, 1 or 2 X atoms, and the X atoms are independently selected from 1 or 2 of N, O and S; the "5-6 membered monocyclic heterocycloalkyl", the "6-9 membered bridged heterocycloalkyl", the "7-9 membered spiro heterocycloalkyl", the "substituted one or more R x-1 substituted 5-6 membered monocyclic heterocycloalkyl", said "substituted by one or more R x-2 substituted 6-9 membered bridged heterocyclic alkyl" and the "substituted by one or more R x-3 The substituted 7-9 membered spirocyclic heterocycloalkyl is connected to ring A via an N atom;

[0040] Each R x-1 、R x-2 、R x-3 and R x-4 are independently halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C substituted by one or more halogen 1-6 Alkyl or C substituted by one or more halogen 1-6 alkoxy;

[0041] R 1 -LR 1-1 ;

[0042] L is *-NHSO2-, -NH-, *-NHC(O)-, -NHC(O)NH-, *-SO2NH- or -SO2-; * represents the end connected to ring A;

[0043] R 1-1 C 1-6 Alkyl, 3-6 membered monocyclic cycloalkyl, 4-8 membered monocyclic heterocycloalkyl, aSubstituted C 1-6 Alkyl or one or more R b Substituted 3-6 membered monocyclic cycloalkyl; in the 4-8 membered monocyclic heterocycloalkyl, the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0044] Each R a are independently hydroxy, halogen or -NH(R a-1 );

[0045] R a-1 C 1-6 alkyl;

[0046] Each R b Each independently is C 1-6 Alkyl, C substituted by one or more hydroxyl groups 1-6 alkyl;

[0047] B is phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 9-10-membered heteroaryl, 6-membered heterocycloalkenyl, substituted by one or more R 2 substituted 6-membered heteroaryl, one or more R 3 substituted 9-10 membered heteroaryl, substituted by one or more R 4 substituted 6-membered heterocycloalkenyl, one or more R 5 Substituted phenyl, one or more R 5 substituted naphthyl or one or more R 6 substituted 5-membered heteroaryl; the "5-membered heteroaryl", "6-membered heteroaryl", "9-10-membered heteroaryl", "6-membered heterocycloalkenyl", "substituted by one or more R 2 substituted 6-membered heteroaryl, "substituted by one or more R 3 substituted 9-10 membered heteroaryl, "substituted by one or more R 4 substituted 6-membered heterocycloalkenyl" and "substituted by one or more R 6 In the "substituted 5-membered heteroaryl", the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0048] Each R 2 、R 3 、R 4 、R 5 、R 6 are independently halogen, cyano, oxo (=O), C 1-6 Alkyl or C substituted by one or more halogen 1-6 alkyl;

[0049] U is a 3-10 membered cycloalkyl, a 4-10 membered heterocycloalkyl, a 6-10 membered aryl, a 5-10 membered heteroaryl, or a 6-10 membered aryl group. 2-1 Substituted 3-10 membered cycloalkyl, one or more R 2-2 substituted 4-10 membered heterocycloalkyl or one or more R 2-3 substituted 5-10 membered heteroaryl; the "5-10 membered heteroaryl", "4-10 membered heterocycloalkyl", "substituted by one or more R 2-2 substituted 4-10 membered heterocycloalkyl" and "substituted by one or more R 2-3 In the "substituted 5-10 membered heteroaryl", the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0050] Each R 2-1 、R 2-2 and R 2-3 are independently halogen, C 1-6 Alkyl, oxo, CN, hydroxy, 3-6 membered monocyclic cycloalkyl, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkoxy, 3-6 membered monocyclic cycloalkyl substituted by one or more halogens or C 1-6 alkoxy;

[0051] W and X 2 is defined as follows:

[0052] (1)W is *-CONR W -;X 2 R W-1 ; * indicates the end connected to ring A;

[0053] (2)W is *-NR W CO-;X 2 R W-1 ; * indicates the end connected to ring A;

[0054] (3)W is *-C(=X 1 )NR W -;X 1 、X 2 and the C atoms therebetween together form a 6-membered heteroaryl group; in the 6-membered heteroaryl group, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; * represents the end connected to ring A;

[0055] R W H, C 1-6 Alkyl or C substituted by one or more halogen 1-6 alkyl;

[0056] R W-1 H, halogen, C 1-6 Alkyl or C substituted by one or more halogen 1-6 alkyl;

[0057] G is C(R 10 ) or N;

[0058] R 10 H, halogen, C 1-6 Alkyl, hydroxy or C substituted by one or more halogen 1-6 alkyl;

[0059] Furthermore, the compound represented by Formula II satisfies one, two or three of the following conditions:

[0060] (1)R x is a 6-9 membered bridged heterocyclic alkyl group or is replaced by one or more R x-2 substituted 6-9 membered bridged heterocycloalkyl;

[0061] (2) B is naphthyl, 5-membered heteroaryl, 9-10-membered heteroaryl, 6-membered heterocycloalkenyl, or one or more R 5 Substituted naphthyl, one or more R 6 substituted 5-membered heteroaryl, one or more R 3 9-10 membered heteroaryl substituted or one or more R 4 substituted 6-membered heterocycloalkenyl;

[0062] (3)W is *-C(=X 1 )NR W -;X 1 、X 2 and the intervening C atoms together form a 6-membered heteroaryl group.

[0063] In a certain embodiment, in the nitrogen-containing compound represented by Formula II, its pharmaceutically acceptable salts, its stereoisomers, its tautomers, its metabolites, its prodrugs, its isotope-labeled derivatives, its solvates, or solvates of its pharmaceutically acceptable salts, the definitions of certain groups in the nitrogen-containing compound represented by Formula II are as follows, and the definitions of the remaining groups are as described in any other embodiment (hereinafter referred to as "in a certain embodiment"):

[0064] R x is a 6-9 membered bridged heterocycloalkyl, a 7-9 membered spiro heterocycloalkyl, or one or more R x-2 Substituted 6-9 membered bridged heterocycloalkyl; the “6-9 membered bridged heterocycloalkyl”, the “7-9 membered spiro heterocycloalkyl” and the “substituted by one or more R x-2In the "substituted 6-9 membered bridged heterocycloalkyl", the heteroatoms are independently composed of 1 N atom and 0, 1 or 2 X atoms, and the X atoms are independently selected from 1 or 2 of N, O and S; the "6-9 membered bridged heterocycloalkyl", the "7-9 membered spiro heterocycloalkyl" and the "substituted by one or more R x-2 The substituted 6-9 membered bridged heterocycloalkyl is connected to the ring A through the N atom;

[0065] Each R x-2 Each independently is C 1-6 alkyl;

[0066] R 1 -LR 1-1 ;

[0067] L is *-NHSO2-; * represents the end connected to ring A;

[0068] R 1-1 C 1-6 Alkyl, one or more R a Substituted C 1-6 Alkyl or one or more R b substituted 3-6 membered monocyclic cycloalkyl;

[0069] Each R a are independently hydroxyl groups;

[0070] Each R b Each independently is C 1-6 alkyl;

[0071] B is a 5-membered heteroaryl, a 9-10-membered heteroaryl, or a 5-membered heteroaryl, 2 substituted 6-membered heteroaryl, one or more R 3 substituted 9-10 membered heteroaryl; the "5-membered heteroaryl", "9-10 membered heteroaryl", "substituted by one or more R 2 substituted 6-membered heteroaryl" and "substituted by one or more R 3 In the "substituted 9-10 membered heteroaryl", the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0072] Each R 2 Each independently is C 1-6 alkyl;

[0073] Each R 3 are independently halogen, C 1-6 Alkyl or C substituted by one or more halogen 1-6 alkyl;

[0074] U is a 3-10 membered cycloalkyl, a 4-10 membered heterocycloalkyl, 2-1 substituted 3-10 membered cycloalkyl or one or more R 2-2 substituted 4-10 membered heterocycloalkyl; the “4-10 membered heterocycloalkyl” or “substituted by one or more R 2-2 In the "substituted 4-10 membered heterocycloalkyl", the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0075] Each R 2-1 、R 2-2 and R 2-3 are each independently halogen;

[0076] W and X 2 is defined as follows:

[0077] (1)W is *-CONR W -;X 2 R W-1 ; * indicates the end connected to ring A;

[0078] (2)W is *-C(=X 1 )NR W -;X 1 、X 2 and the C atoms therebetween together form a 6-membered heteroaryl group; in the 6-membered heteroaryl group, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; * represents the end connected to ring A;

[0079] R W H; R W-1 is H;

[0080] G is C(R 10 ) or N;

[0081] R 10 is H;

[0082] Furthermore, the compound represented by Formula II satisfies one, two or three of the following conditions:

[0083] (1)R x is a 6-9 membered bridged heterocyclic alkyl group or is replaced by one or more R x-2 substituted 6-9 membered bridged heterocycloalkyl;

[0084] (2) B is naphthyl, 5-membered heteroaryl, 9-10-membered heteroaryl, 6-membered heterocycloalkenyl, or one or more R 5 Substituted naphthyl, one or more R 6 substituted 5-membered heteroaryl, one or more R 39-10 membered heteroaryl substituted or one or more R 4 substituted 6-membered heterocycloalkenyl;

[0085] (3)W is *-C(=X 1 )NR W -;X 1 、X 2 and the intervening C atoms together form a 6-membered heteroaryl group.

[0086] In one scenario, R x is a 6-9 membered bridged heterocycloalkyl, a 7-9 membered spiro heterocycloalkyl, or one or more R x-2 Substituted 6-9 membered bridged heterocycloalkyl; the “6-9 membered bridged heterocycloalkyl”, the “7-9 membered spiro heterocycloalkyl” and the “substituted by one or more R x-2 In the "substituted 6-9 membered bridged heterocycloalkyl", the heteroatoms are independently composed of 1 N atom and 0, 1 or 2 X atoms, and the X atoms are independently selected from 1 or 2 of N, O and S; the "6-9 membered bridged heterocycloalkyl", the "7-9 membered spiro heterocycloalkyl" and the "substituted by one or more R x-2 The substituted 6-9 membered bridged heterocycloalkyl is connected to the ring A through the N atom;

[0087] Each R x-2 Each independently is C 1-6 alkyl;

[0088] R 1 -LR 1-1 ;

[0089] L is *-NHSO2-; * represents the end connected to ring A;

[0090] R 1-1 C 1-6 Alkyl, one or more R a Substituted C 1-6 Alkyl or one or more R b substituted 3-6 membered monocyclic cycloalkyl;

[0091] Each R a are independently hydroxyl groups;

[0092] Each R b Each independently is C 1-6 alkyl;

[0093] B is a 9-10 membered heteroaryl group, 2 substituted 6-membered heteroaryl, one or more R 3 substituted 9-10 membered heteroaryl; the "5-membered heteroaryl", "9-10 membered heteroaryl", "substituted by one or more R2 substituted 6-membered heteroaryl" and "substituted by one or more R 3 In the "substituted 9-10 membered heteroaryl", the heteroatoms are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; when the 9-10 membered heteroaryl is a 9-membered heteroaryl and the number of heteroatoms is 2, the heteroatoms are independently selected from one or two of N or O; when the 9-10 membered heteroaryl is a 9-membered heteroaryl and the number of heteroatoms is 3, the heteroatom is N; when the 9-10 membered heteroaryl is a 10-membered heteroaryl and the heteroatom is N, and the number of heteroatoms is 2, the heteroatoms are located on different rings;

[0094] When B is occupied by one or more R 2 When the 6-membered heteroaryl group is substituted, R x is an 8-9 membered bridged heterocycloalkyl group; in the “8-9 membered bridged heterocycloalkyl group”, the heteroatoms are independently composed of 1 N atom and 0, 1 or 2 X atoms, and the X atoms are independently selected from 1 or 2 of N, O and S; the “8-9 membered bridged heterocycloalkyl group” is connected to ring A via the N atom;

[0095] Each R 2 Each independently is C 1-6 alkyl;

[0096] Each R 3 are independently halogen or C 1-6 alkyl;

[0097] U is a 4-10 membered heterocycloalkyl group or is replaced by one or more R 2-2 substituted 4-10 membered heterocycloalkyl; the “4-10 membered heterocycloalkyl” or “substituted by one or more R 2-2 In the "substituted 4-10 membered heterocycloalkyl", the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 2, 3 or 4;

[0098] Each R 2-2 are each independently halogen;

[0099] W is *-CONR W -;X 2 R W-1 ; * indicates the end connected to ring A;

[0100] R W H; R W-1 is H;

[0101] G is C(R 10 ) or N;

[0102] R 10 is H;

[0103] Furthermore, the compound as shown in Formula II satisfies one or two of the following conditions:

[0104] (1)R x is a 6-9 membered bridged heterocyclic alkyl group or is replaced by one or more R x-2 substituted 6-9 membered bridged heterocycloalkyl;

[0105] (2) B is a 9-10 membered heteroaryl group, supported by one or more R 3 Substituted 9-10 membered heteroaryl.

[0106] In one scenario, R x is a 6-9 membered bridged heterocyclic alkyl group, x-2 substituted 6-9 membered bridged heterocycloalkyl or 7-9 membered spiro heterocycloalkyl;

[0107] Each R x-2 Each independently is C 1-6 alkyl;

[0108] R 1 -LR 1-1 ;

[0109] L is *-NHSO2-;

[0110] R 1-1 C 1-6 Alkyl, one or more R a Substituted C 1-6 Alkyl or one or more R b substituted 3-6 membered monocyclic cycloalkyl;

[0111] R a is hydroxyl group;

[0112] Each R b Each independently is C 1-6 alkyl;

[0113] B is a 5-membered heteroaryl, a 9-10-membered heteroaryl, or a 5-membered heteroaryl, 2 substituted 6-membered heteroaryl or one or more R 3 substituted 9-10 membered heteroaryl;

[0114] Each R 2 Each independently is C 1-6 alkyl;

[0115] Each R 3 Each independently is C 1-6 alkyl;

[0116] U is a 4-10 membered heterocycloalkyl group, 2-1substituted 3-10 membered cycloalkyl or one or more R 2-2 substituted 4-10 membered heterocycloalkyl;

[0117] Each R 2-1 are each independently halogen;

[0118] Each R 2-2 are each independently halogen;

[0119] W is *-CONH-; X 2 is H;

[0120] Furthermore, the compound as shown in Formula II satisfies one or two of the following conditions:

[0121] (1)R x is a 6-9 membered bridged heterocycloalkyl group;

[0122] (2) B is a 5-membered heteroaryl, naphthyl, 9-10-membered heteroaryl, or one or more R 5 substituted naphthyl or one or more R 3 Substituted 9-10 membered heteroaryl.

[0123] In one scenario, R x is a 6-9 membered bridged heterocyclic alkyl group, x-2 substituted 6-9 membered bridged heterocycloalkyl or 7-9 membered spiro heterocycloalkyl;

[0124] Each R x-2 Each independently is C 1-6 alkyl;

[0125] R 1 -LR 1-1 ;

[0126] L is *-NHSO2-;

[0127] R 1-1 C 1-6 Alkyl, one or more R a Substituted C 1-6 Alkyl or one or more R b substituted 3-6 membered monocyclic cycloalkyl;

[0128] R a is hydroxyl group;

[0129] Each R b Each independently is C 1-6 alkyl;

[0130] B is naphthyl, 5-membered heteroaryl, 9-10-membered heteroaryl, or one or more R 5 Substituted naphthyl, one or more R2 substituted 6-membered heteroaryl or one or more R 3 substituted 9-10 membered heteroaryl;

[0131] Each R 2 Each independently is C 1-6 alkyl;

[0132] Each R 3 Each independently is C 1-6 alkyl;

[0133] U is a 4-10 membered heterocycloalkyl group, 2-1 substituted 3-10 membered cycloalkyl or one or more R 2-2 substituted 4-10 membered heterocycloalkyl;

[0134] Each R 2-1 are each independently halogen;

[0135] Each R 2-2 are each independently halogen;

[0136] W is *-CONH-; X 2 is H;

[0137] Furthermore, the compound as shown in Formula II satisfies one or two of the following conditions:

[0138] (1)R x is a 6-9 membered bridged heterocycloalkyl group;

[0139] (2) B is a 5-membered heteroaryl, a 9-10-membered heteroaryl, or is replaced by one or more R 3 Substituted 9-10 membered heteroaryl.

[0140] In one scenario, R x is a 6-9 membered bridged heterocycloalkyl, a 7-9 membered spiro heterocycloalkyl, or one or more R x-2 substituted 6-9 membered bridged heterocyclic alkyl or one or more R x-3 substituted 7-9 membered spirocyclic heterocycloalkyl; preferably substituted by one or more R x-2 The substituted 6- to 9-membered bridged heterocycloalkyl group, 6- to 9-membered bridged heterocycloalkyl group, or 7- to 9-membered spiro heterocycloalkyl group is more preferably a 6- to 9-membered bridged heterocycloalkyl group or a 7- to 9-membered spiro heterocycloalkyl group.

[0141] In a certain scheme, each R x-1 、R x-2 、R x-3 and R x-4 are independently halogen, C 1-6 Alkyl or C substituted by one or more halogen 1-6 Alkyl, preferably halogen or C1-6 Alkyl, more preferably C 1-3 Alkyl, F, Cl or Br.

[0142] In one scenario, R x is a 6-9 membered bridged heterocycloalkyl, a 7-9 membered spiro heterocycloalkyl, or one or more R x-2 substituted 6-9 membered bridged heterocyclic alkyl or one or more R x-3 substituted 7-9 membered spirocyclic heterocycloalkyl;

[0143] Each R x-1 、R x-2 、R x-3 and R x-4 are independently halogen, C 1-6 Alkyl or C substituted by one or more halogen 1-6 Alkyl, preferably halogen or C 1-6 Alkyl, more preferably C 1-3 Alkyl, F, Cl or Br.

[0144] In one scenario, R x is a 6-9 membered bridged heterocycloalkyl, a 7-9 membered spiro heterocycloalkyl, or one or more R x-2 substituted 6-9 membered bridged heterocycloalkyl;

[0145] Each R x-2 Each independently is C 1-6 alkyl.

[0146] In a certain scheme, each R x-1 、R x-2 、R x-3 and R x-4 Each independently is C 1-6 alkyl.

[0147] In one embodiment, L is *-NHSO2-.

[0148] In one embodiment, L is *-NHSO2- or -NH-.

[0149] In one scenario, R 1-1 C 1-6 Alkyl, 3-6 membered monocyclic cycloalkyl, b substituted 3-6 membered monocyclic cycloalkyl or one or more R a Substituted C 1-6 Alkyl, preferably C 1-3 Alkyl, one or more R a Substituted C 1-3 Alkyl or one or more R b In one embodiment, Ra It is a hydroxyl group.

[0150] In a certain scheme, each R b Each independently is C 1-6 alkyl.

[0151] In one scenario, R 1-1 C 1-6 Alkyl, one or more R b substituted 3-6 membered monocyclic cycloalkyl or one or more R a Substituted C 1-6 alkyl;

[0152] R a is hydroxyl group;

[0153] Each R b Each independently is C 1-6 alkyl.

[0154] In one embodiment, B is phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 9-10-membered heteroaryl, 6-membered heterocycloalkenyl, substituted by one or more R 5 Substituted naphthyl, one or more R 2 substituted 6-membered heteroaryl, one or more R 3 9-10 membered heteroaryl substituted or one or more R 4 substituted 6-membered heterocycloalkenyl; preferably 5-membered heteroaryl, 9-10-membered heteroaryl, substituted by one or more R 2 substituted 6-membered heteroaryl or one or more R 3 substituted 9-10 membered heteroaryl, more preferably 9-10 membered heteroaryl or substituted by one or more R 3 Substituted 9-10 membered heteroaryl.

[0155] In one embodiment, B is a 5-membered heteroaryl, a 9-10-membered heteroaryl, a 2 substituted 6-membered heteroaryl, one or more R 3 Substituted 9-10 membered heteroaryl.

[0156] In one embodiment, in B, the 9-10 membered heteroaryl group is a 9-membered heteroaryl group having 2 heteroatoms, and the heteroatoms are independently selected from one or two of N and O.

[0157] In one embodiment, in B, the 9-10 membered heteroaryl group is a 9-membered heteroaryl group, the number of heteroatoms is 3, and the heteroatom is N.

[0158] In one embodiment, in B, the 9-10 membered heteroaryl group is a 10 membered heteroaryl group, the heteroatom is N, the number of heteroatoms is 2, and the heteroatoms are located on different rings.

[0159] In a certain scheme, when B is occupied by one or more R 2 When the 6-membered heteroaryl group is substituted, R x It is an 8-9 membered bridged heterocycloalkyl group.

[0160] In a certain scheme, each R 2 、R 3 、R 4 、R 5 、R 6 are independently halogen, oxo or C 1-6 Alkyl; preferably C 1-3 alkyl.

[0161] In a certain scheme, each R 2 、R 3 、R 4 、R 5 、R 6 are independently halogen, C 1-6 Alkyl or C substituted by one or more halogen 1-6 alkyl.

[0162] In a certain scheme, each R 2 Each independently is C 1-6 alkyl.

[0163] In a certain scheme, each R 3 are independently halogen, C 1-6 Alkyl or C substituted by one or more halogen 1-6 alkyl.

[0164] In a certain scheme, each R 3 are independently halogen or C 1-6 alkyl.

[0165] In one embodiment, B is a 9-10 membered heteroaryl group, 2 substituted 6-membered heteroaryl or one or more R 3 substituted 9-10 membered heteroaryl;

[0166] Each R 2 Each independently is C 1-6 alkyl;

[0167] Each R 3 are independently halogen or C 1-6 alkyl.

[0168] In one embodiment, B is a 5-membered heteroaryl, a 9-10-membered heteroaryl, a 2 substituted 6-membered heteroaryl or one or more R 3 substituted 9-10 membered heteroaryl;

[0169] Each R 2 、R 3 are independently halogen or C 1-6 alkyl.

[0170] In one embodiment, U is a 3-10 membered cycloalkyl, a 4-10 membered heterocycloalkyl, or a 2-1 substituted 3-10 membered cycloalkyl or one or more R 2-2 substituted 4-10 membered heterocycloalkyl, preferably 4-9 membered heterocycloalkyl, substituted by one or more R 2-1 substituted 3-8 membered cycloalkyl or one or more R 2-2 substituted 4-9 membered heterocycloalkyl, more preferably 4-9 membered heterocycloalkyl or substituted by one or more R 2-2 Substituted 4-9 membered heterocycloalkyl.

[0171] In one embodiment, in U, the 4-10 membered heterocycloalkyl group is a 4-6 membered monocyclic heterocycloalkyl group, a 6-9 membered bridged heterocycloalkyl group, or a 7-9 membered spirocyclic heterocycloalkyl group.

[0172] In a certain scheme, each R 2-1 、R 2-2 and R 2-3 are independently halogen, C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy or C substituted by one or more halogen 1-6 The alkyl group is preferably halogen, more preferably F, Cl or Br.

[0173] In one embodiment, U is a 4-10 membered heterocycloalkyl group or is replaced by one or more R 2-2 substituted 4-10 membered heterocycloalkyl;

[0174] Each R 2-2 are each independently halogen.

[0175] In one embodiment, U is a 3-10 membered cycloalkyl, a 4-10 membered heterocycloalkyl, or a 2-1 substituted 3-10 membered cycloalkyl or one or more R 2-2 substituted 4-10 membered heterocycloalkyl;

[0176] Each R 2-1 and R 2-2 are independently halogen, C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy or C substituted by one or more halogen 1-6 Alkyl, preferably F, Cl or Br.

[0177] In one embodiment, G is C(R10 ).

[0178] In one embodiment, G is C(R 10 ) or N; R 10 For H.

[0179] In one scenario, R 10 H, halogen, C 1-6 Alkyl or C substituted by one or more halogen 1-6 Alkyl, preferably H.

[0180] In one embodiment, G is C(R 10 );R 10 For H.

[0181] In one scenario, R W For H.

[0182] In one scenario, R W-1 For H.

[0183] In one embodiment, W is *-CONR W -;X 2 R W-1 ;

[0184] R W-1 is H or halogen, preferably H;

[0185] R W For H.

[0186] In one embodiment, the compound of formula II satisfies one or two of the following conditions:

[0187] (a)R x is a 6-9 membered bridged heterocycloalkyl group;

[0188] (b) B is a 5-membered heteroaryl, a 9-10-membered heteroaryl, a 6-membered heterocycloalkenyl, or a 6-membered heteroaryl group. 4 substituted 6-membered heterocycloalkenyl or one or more R 3 substituted 9-10 membered heteroaryl, preferably 9-10 membered heteroaryl or substituted by one or more R 3 Substituted 9-10 membered heteroaryl.

[0189] In a certain embodiment, in the compound shown in Formula II, R x is a 6-9 membered bridged heterocyclic alkyl group or is replaced by one or more R x-2 Substituted 6-9 membered bridged heterocycloalkyl.

[0190] In a certain embodiment, in the compound shown in Formula II, B is a 9-10 membered heteroaryl group, 3Substituted 9-10 membered heteroaryl.

[0191] In one embodiment, the nitrogen-containing compound represented by Formula II is the following compound:

[0192] Each V1 is independently C or N;

[0193] V2 is N or CR 11 ; preferably N;

[0194] D is a partially saturated or unsaturated 5-6 membered carbocyclic ring, or a partially saturated or unsaturated 5-6 membered heterocyclic ring, wherein the 5-6 membered carbocyclic ring or the 5-6 membered heterocyclic ring is optionally substituted by 0, 1, 2 or 3 R 11 Substitution; in the "5-6 membered heterocycle", the heteroatom is N, O, S, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0195] R 11 For hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C substituted by one or more halogen 1-6 alkyl.

[0196] In one embodiment, the "5-6 membered monocyclic heterocycloalkyl" is independently a 5-6 membered heterocycloalkyl containing 1 or 2 heteroatoms, preferably

[0197] In a certain embodiment, the “6-9 membered bridged heterocycloalkyl” is independently a 6-9 membered bridged heterocycloalkyl containing 1 or 2 heteroatoms, preferably selected from any of the following fragments: More preferred

[0198] In one embodiment, the “6-9 membered bridged heterocycloalkyl” is independently a 6-9 membered bridged heterocycloalkyl containing 1 or 2 heteroatoms, preferably any of the following fragments: More preferred

[0199] In a certain embodiment, the “7-9 membered spiro heterocycloalkyl” is independently a 7-9 membered spiro heterocycloalkyl containing 1 or 2 heteroatoms, preferably any of the following fragments: More preferred

[0200] In one embodiment, the "halogen" is independently fluorine, chlorine, bromine or iodine, preferably fluorine.

[0201] In one embodiment, the “C 1-6The "alkyl" groups are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or ethyl.

[0202] In one scenario, R 1-1 In the C 1-6 The alkyl group is ethyl or isopropyl.

[0203] In a certain embodiment, the "3-6 membered monocyclic cycloalkyl" is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl.

[0204] In one embodiment, the “C 1-6 The "alkoxy" groups are each independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, preferably methoxy or ethoxy.

[0205] In one embodiment, the "4-8 membered monocyclic heterocycloalkyl" is a "4-8 membered monocyclic heterocycloalkyl" containing one O atom, preferably

[0206] In a certain embodiment, the “5-membered heteroaryl group” is independently a 5-membered heteroaryl group wherein “the heteroatom is selected from one or two of N and S”, and is preferably any of the following fragments:

[0207] More preferred (For example, the one connected to U by the dotted line on the right ).

[0208] In a certain embodiment, the “6-membered heteroaryl” is independently any of the following fragments: Preferably connected to U by the left dotted line More preferably, it is connected to U by the left dotted line

[0209] In one embodiment, the “9-10 membered heteroaryl” is independently any of the following fragments:

[0210] Preferably connected to U by the left dotted line More preferably, it is connected to U by the left dotted line

[0211] In one embodiment, the “9-10 membered heteroaryl” is independently any of the following fragments:

[0212] Preferably connected to U by the left dotted line More preferably, it is connected to U by the left dotted line

[0213] In a certain embodiment, the “6-membered heterocycloalkenyl” is independently a 6-membered heterocycloalkenyl group wherein the heteroatom is N and the number of heteroatoms is 1 or 2, and is preferably any of the following fragments: More preferably, it is connected to U by the left dotted line

[0214] In a certain embodiment, the "3-10 membered cycloalkyl" are independently 3-6 membered monocyclic cycloalkyl or 6-8 membered spirocyclic cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, More preferred

[0215] In a certain embodiment, the "4-10 membered heterocycloalkyl" are independently 4-6 membered monocyclic heterocycloalkyl, 6-8 membered spirocyclic heterocycloalkyl or 7-9 membered bridged heterocycloalkyl, preferably More preferred

[0216] In a certain embodiment, the "4-10 membered heterocycloalkyl" are independently 4-6 membered monocyclic heterocycloalkyl, 6-8 membered spirocyclic heterocycloalkyl or 7-9 membered bridged heterocycloalkyl, preferably More preferred

[0217] In one embodiment, the "6-10 membered aryl" is phenyl.

[0218] In one embodiment, the "5-10 membered heteroaryl" is a 5-6 membered heteroaryl group wherein the heteroatom is N and the number of heteroatoms is 1 or 2.

[0219] In one embodiment, when W is *-C(X 1 )NR W -;X 1 、X 2 When the carbon atoms therebetween form a 6-membered heteroaryl group, the heteroatom in the “6-membered heteroaryl group” is N, and the number of heteroatoms is 1 or 2.

[0220] In one scenario, R x For any of the following fragments:

[0221] Preferably

[0222] In one scenario, R x For any of the following fragments:

[0223] Preferably

[0224] In one embodiment, R1 is any of the following fragments:

[0225] Preferably

[0226] In one embodiment, B is any of the following fragments (the left dashed line in the following fragments represents the bond to U):

[0227] Preferably

[0228] In one embodiment, B is any of the following fragments (the left dashed line in the following fragments represents the bond to U):

[0229] Preferably

[0230] In one embodiment, U is selected from any of the following fragments:

[0231] Preferably

[0232] In one embodiment, U is any of the following fragments:

[0233] Preferably

[0234] The present invention also provides any of the following nitrogen-containing compounds:

[0235] The present invention also provides a pharmaceutical composition, comprising:

[0236] (1) the nitrogen-containing compound represented by formula I, the nitrogen-containing compound represented by formula II, the nitrogen-containing compound, its (referring to the nitrogen-containing compound represented by formula I, the nitrogen-containing compound represented by formula II or the nitrogen-containing compound) pharmaceutically acceptable salt, its (referring to the nitrogen-containing compound represented by formula I, the nitrogen-containing compound represented by formula II or the nitrogen-containing compound) stereoisomer, its (referring to the nitrogen-containing compound represented by formula I, the nitrogen-containing compound represented by formula II or the nitrogen-containing compound) tautomer, its (referring to the nitrogen-containing compound represented by formula I, the nitrogen-containing compound represented by formula II or the nitrogen-containing compound) tautomer, its (referring to the nitrogen-containing compound represented by formula I, the nitrogen-containing compound represented by formula II a compound or the above-mentioned nitrogen-containing compound) metabolite, a prodrug thereof (referring to the aforementioned nitrogen-containing compound as shown in Formula I, the aforementioned nitrogen-containing compound as shown in Formula II, or the above-mentioned nitrogen-containing compound), an isotope-labeled derivative thereof (referring to the aforementioned nitrogen-containing compound as shown in Formula I, the aforementioned nitrogen-containing compound as shown in Formula II, or the above-mentioned nitrogen-containing compound), a solvate thereof (referring to the aforementioned nitrogen-containing compound as shown in Formula I, the aforementioned nitrogen-containing compound as shown in Formula II, or the above-mentioned nitrogen-containing compound), or a solvate of a pharmaceutically acceptable salt thereof (referring to the aforementioned nitrogen-containing compound as shown in Formula I, the aforementioned nitrogen-containing compound as shown in Formula II, or the above-mentioned nitrogen-containing compound), and

[0237] (2) Pharmaceutically acceptable excipients.

[0238] The present invention also provides the nitrogen-containing compound as shown in formula I, the nitrogen-containing compound as shown in formula II, the nitrogen-containing compound, its (referring to the nitrogen-containing compound as shown in formula I, the nitrogen-containing compound as shown in formula II or the nitrogen-containing compound) pharmaceutically acceptable salt, its (referring to the nitrogen-containing compound as shown in formula I, the nitrogen-containing compound as shown in formula II or the nitrogen-containing compound) stereoisomer, its (referring to the nitrogen-containing compound as shown in formula I, the nitrogen-containing compound as shown in formula II or the nitrogen-containing compound) tautomer, its (referring to the nitrogen-containing compound as shown in formula I, the nitrogen-containing compound as shown in formula II or the nitrogen-containing compound) tautomer, Use of a metabolite thereof (referring to the aforementioned nitrogen-containing compound as shown in Formula I, the aforementioned nitrogen-containing compound as shown in Formula II, or the aforementioned nitrogen-containing compound), an isotope-labeled derivative thereof (referring to the aforementioned nitrogen-containing compound as shown in Formula I, the aforementioned nitrogen-containing compound as shown in Formula II, or the aforementioned nitrogen-containing compound), a solvate thereof (referring to the aforementioned nitrogen-containing compound as shown in Formula I, the aforementioned nitrogen-containing compound as shown in Formula II, or the aforementioned nitrogen-containing compound), or a solvate of a pharmaceutically acceptable salt thereof (referring to the aforementioned nitrogen-containing compound as shown in Formula I, the aforementioned nitrogen-containing compound as shown in Formula II, or the aforementioned nitrogen-containing compound) in the preparation of a KIF18A inhibitor.

[0239] The present invention also provides the nitrogen-containing compound shown in Formula I, the nitrogen-containing compound shown in Formula II, the nitrogen-containing compound, its (referring to the nitrogen-containing compound shown in Formula I, the nitrogen-containing compound shown in Formula II, or the nitrogen-containing compound) pharmaceutically acceptable salt, its (referring to the nitrogen-containing compound shown in Formula I, the nitrogen-containing compound shown in Formula II, or the nitrogen-containing compound) stereoisomer, its (referring to the nitrogen-containing compound shown in Formula I, the nitrogen-containing compound shown in Formula II, or the nitrogen-containing compound) tautomer, its (referring to the nitrogen-containing compound shown in Formula I, the nitrogen-containing compound shown in Formula II, or the nitrogen-containing compound) Use of a metabolite, a prodrug thereof (referring to the aforementioned nitrogen-containing compound as shown in Formula I, the aforementioned nitrogen-containing compound as shown in Formula II, or the aforementioned nitrogen-containing compound), an isotope-labeled derivative thereof (referring to the aforementioned nitrogen-containing compound as shown in Formula I, the aforementioned nitrogen-containing compound as shown in Formula II, or the aforementioned nitrogen-containing compound), a solvate thereof (referring to the aforementioned nitrogen-containing compound as shown in Formula I, the aforementioned nitrogen-containing compound as shown in Formula II, or the aforementioned nitrogen-containing compound), or a solvate of a pharmaceutically acceptable salt thereof (referring to the aforementioned nitrogen-containing compound as shown in Formula I, the aforementioned nitrogen-containing compound as shown in Formula II, or the aforementioned nitrogen-containing compound) in the preparation of a medicament, wherein the medicament is used to treat a disease related to the mechanism of action of the KIF18A protein, such as cancer, or another example of a cancer related to the mechanism of action of the KIF18A protein.

[0240] In one embodiment, the cancer is ovarian cancer, colon cancer, or ductal carcinoma.

[0241] The present invention also provides the nitrogen-containing compound as shown in formula I, the nitrogen-containing compound as shown in formula II, the nitrogen-containing compound, its (referring to the nitrogen-containing compound as shown in formula I, the nitrogen-containing compound as shown in formula II or the nitrogen-containing compound) pharmaceutically acceptable salt, its (referring to the nitrogen-containing compound as shown in formula I, the nitrogen-containing compound as shown in formula II or the nitrogen-containing compound) stereoisomer, its (referring to the nitrogen-containing compound as shown in formula I, the nitrogen-containing compound as shown in formula II or the nitrogen-containing compound) tautomer, its (referring to the nitrogen-containing compound as shown in formula I, the nitrogen-containing compound as shown in formula II or the nitrogen-containing compound) tautomer, its (referring to the nitrogen-containing compound as shown in formula I, the nitrogen-containing compound as shown in formula II or the nitrogen-containing compound) Use of a metabolite thereof (referring to the aforementioned nitrogen-containing compound as shown in Formula I, the aforementioned nitrogen-containing compound as shown in Formula II, or the aforementioned nitrogen-containing compound), an isotope-labeled derivative thereof (referring to the aforementioned nitrogen-containing compound as shown in Formula I, the aforementioned nitrogen-containing compound as shown in Formula II, or the aforementioned nitrogen-containing compound), a solvate thereof (referring to the aforementioned nitrogen-containing compound as shown in Formula I, the aforementioned nitrogen-containing compound as shown in Formula II, or the aforementioned nitrogen-containing compound), or a solvate of a pharmaceutically acceptable salt thereof (referring to the aforementioned nitrogen-containing compound as shown in Formula I, the aforementioned nitrogen-containing compound as shown in Formula II, or the aforementioned nitrogen-containing compound) in the preparation of a medicament for treating cancer.

[0242] In one embodiment, the cancer is ovarian cancer, colon cancer, or ductal carcinoma.

[0243] Terminology

[0244] As used herein, the term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. For details, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0245] In the present invention, the structural fragment This refers to the bond through which the structural fragment is connected to the rest of the molecule. For example, It refers to cyclohexyl.

[0246] In the present invention, the term "one or more" refers to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18.

[0247] In the present invention, the term "saturated" refers to a group that is completely saturated with hydrogen.

[0248] In the present invention, the term "partially saturated" refers to a group that is partially saturated with hydrogen.

[0249] In the present invention, the term "unsaturated" refers to an aromatic group.

[0250] In the present invention, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0251] As used herein, the term "alkyl" refers to a linear or branched, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C1-C6). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl.

[0252] In the present invention, the term "alkoxy" refers to a group R Y -O-, R Y The same definition as the term "alkyl". Alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.

[0253] In the present invention, the term "cycloalkyl" refers to a monocyclic cycloalkyl, a bridged cycloalkyl or a spirocyclic cycloalkyl.

[0254] In the present invention, the term "monocyclic cycloalkyl" refers to a cyclic, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C3-C6), which is a single ring. Monocyclic cycloalkyl groups include, but are not limited to: wait.

[0255] In the present invention, the term "carbocycle" refers to a cyclic hydrocarbon group having a specified number of carbon atoms (e.g., C5-C6) and sharing two atoms and one bond with the rest of the molecule, e.g. ( represents a bond to the rest of the molecule).

[0256] In the present invention, the term "heterocycle" refers to a cyclic group having a specified number of ring atoms (e.g., 5-6 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatom (one or more of N, O, and S), and sharing two atoms and one bond with the rest of the molecule, for example ( represents a bond to the rest of the molecule).

[0257] In the present invention, the term "bridged ring cycloalkyl" refers to a group having a specified number of carbon atoms (e.g., C4 to C 10 ) is a cyclic, saturated, monovalent hydrocarbon group, which is polycyclic (e.g., 2 or 3) and has two or more carbon atoms shared between the single rings. Bridged ring cycloalkyl includes but is not limited to: wait.

[0258] In the present invention, the term "spirocyclic cycloalkyl" refers to a cyclic, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C5-C9), which is polycyclic (e.g., 2 or 3) and has one carbon atom shared between the rings. Spirocyclic cycloalkyl groups include, but are not limited to: wait.

[0259] In the present invention, the term "heterocycloalkenyl" refers to a cyclic, partially unsaturated hydrocarbon group having a specified number of ring atoms (e.g., 5-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (one or more of N, O, and S), which has one or more (e.g., 1, 2, or 3) carbon-carbon sp 2 Double bond, it is a single ring, not aromatic. Heterocycloalkenyl is connected to the rest of the molecule through a carbon atom or a heteroatom. Heterocycloalkenyl includes but is not limited to: wait.

[0260] In the present invention, the term "cycloalkenyl" refers to a cyclic, partially unsaturated hydrocarbon group having a specified number of carbon atoms (e.g., 5-6 members) and having one or more (e.g., 1, 2, or 3) carbon-carbon sp 2 Double bond, it is a single ring, not aromatic. The cycloalkenyl group is attached to the rest of the molecule through a carbon atom.

[0261] In the present invention, the term "heterocycloalkyl" refers to a monocyclic heterocycloalkyl, a bridged heterocycloalkyl or a spirocyclic heterocycloalkyl.

[0262] In the present invention, the term "monocyclic heterocycloalkyl" refers to a cyclic, saturated, monovalent group having a specified number of ring atoms (e.g., 3 to 10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), which is a single ring. Monocyclic heterocycloalkyl groups are attached to the rest of the molecule through a carbon atom or a heteroatom. Monocyclic heterocycloalkyl groups include, but are not limited to: wait.

[0263] In the present invention, the term "bridged heterocycloalkyl" refers to a cyclic, saturated, monovalent group with a specified number of ring atoms (e.g., 4 to 10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). It is polycyclic (e.g., 2 or 3), and the single rings share two or more carbon atoms and / or heteroatoms. The bridged heterocycloalkyl is connected to the rest of the molecule through a ring with heteroatoms or a ring without heteroatoms; the bridged heterocycloalkyl is connected to the rest of the molecule through a carbon atom or a heteroatom. Bridged heterocycloalkyl includes but is not limited to: wait.

[0264] In the present invention, the term "spirocyclic heterocycloalkyl" refers to a cyclic, saturated, monovalent group with a specified number of ring atoms (e.g., 7-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). It is polycyclic (e.g., 2 or 3) and the monocyclic rings share one carbon atom. Spirocyclic heterocycloalkyl is connected to the rest of the molecule through a ring with heteroatoms or a ring without heteroatoms; spirocyclic heterocycloalkyl is connected to the rest of the molecule through a carbon atom or a heteroatom. Spirocyclic heterocycloalkyl includes but is not limited to: wait.

[0265] In the present invention, the term "heteroaryl" refers to a cyclic, unsaturated group with a specified number of ring atoms (e.g., 5 to 10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatom (one or more of N, O, and S), which is monocyclic or polycyclic. When it is polycyclic, the monocyclic rings share two atoms and one bond, and at least one ring is aromatic. The heteroaryl group is connected to the rest of the molecule through a carbon atom or a heteroatom; the heteroaryl group is connected to the rest of the molecule through a ring with heteroatoms or a ring without heteroatoms; the heteroaryl group is connected to the rest of the molecule through a ring with aromatic properties or a ring without aromatic properties. Heteroaryl groups include but are not limited to wait.

[0266] In the present invention, the term "aryl" refers to a group having a specified number of carbon atoms (e.g., C6 to C 10 ) is a cyclic, unsaturated hydrocarbon group, which may be monocyclic or polycyclic (e.g., two or three). In the case of polycyclic rings, the rings share two atoms and one bond, and at least one ring is aromatic. The aryl group is attached to the rest of the molecule through an aromatic or non-aromatic ring. Aryl groups include, but are not limited to, phenyl and naphthyl.

[0267] As used herein, the term "pharmaceutical excipients" refers to all substances contained in a pharmaceutical formulation other than the active pharmaceutical ingredient, and is generally classified into two categories: excipients and additives. For details, see the Pharmacopoeia of the People's Republic of China (2020 Edition) and the Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0268] As used herein, the term "solvate" refers to a compound formed by the combination of a solvent (including but not limited to water, methanol, ethanol, etc.). Solvates are categorized into stoichiometric and non-stoichiometric types. Solvates include but are not limited to monohydrates.

[0269] In the present invention, the term "stereoisomer" refers to cis-trans isomers or optical isomers. Cis-trans isomers are isomers caused by the inability of double bonds or single bonds of ring carbon atoms to rotate freely. Optical isomers are stereoisomers with different optical properties caused by the lack of anti-axis symmetry in the molecule.

[0270] In the present invention, the term "isotope-labeled derivative" refers to a compound in which the isotopic abundance of one or more atoms is different from its natural abundance. For example, one or more atoms in the compound are replaced by atoms with a lower mass number in nature - a hydrogen atom in the compound is replaced by deuterium. For example, a compound having the structure of the present invention, except that hydrogen is replaced by "deuterium" or "tritium", or by 18 F-fluorine labeling ( 18 F isotope) instead of fluorine, or with 11 C-, 13 C-, or 14 C-enriched carbon ( 11 C-, 13 C-, or 14 C-carbon labeling; 11 C-, 13 C-, or 14 Compounds in which carbon atoms are replaced by C-isotopes are within the scope of the present invention.

[0271] In the present invention, the term "prodrug" refers to any compound that can be converted in vivo to provide a bioactive substance (i.e., a compound shown in Formula I). ​​For example, a compound containing a carboxyl group can form a physiologically hydrolyzable ester, which acts as a prodrug by being hydrolyzed in vivo to obtain the compound shown in Formula I itself. The prodrug is preferably administered orally because hydrolysis occurs primarily under the influence of digestive enzymes in many cases. When the ester itself is active or hydrolysis occurs in the blood, parenteral administration can be used. In addition, the prodrug can be converted to the compound of the present invention by chemical or biochemical methods in an in vivo environment.

[0272] In the present invention, the term "tautomer" refers to a functional group isomer resulting from the rapid shift of an atom in a molecule between two positions.

[0273] In the present invention, the term "metabolite" refers to a substance produced or consumed through a metabolic process.

[0274] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0275] The reagents and raw materials used in the present invention are commercially available.

[0276] The positive improvement effect of the present invention is that the nitrogen-containing compound of the present invention can effectively inhibit the overexpression of KIF18A protein in some human tumor cells. DETAILED DESCRIPTION

[0277] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0278] Example 1: Preparation of Compound 1

[0279] The synthetic route of compound 1 is:

[0280] The specific preparation method of compound 1 includes:

[0281] Step 1: Synthesis of compound 1B

[0282] Compound 1A (2.0 g, 9.7 mmol) was dissolved in tert-butanol (20 mL), followed by the addition of triethylamine (1.95 g, 19.4 mmol) and diphenylphosphoryl azide (4.0 g, 14.55 mmol). After the additions were complete, the atmosphere was replaced with nitrogen three times and then heated to 80°C under nitrogen for 16 hours. After TLC indicated the reaction was complete, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried, and spin-dried. The residue was purified by silica gel column chromatography to afford compound 1B (500 mg, white solid, 18.5% yield).

[0283] MS (ESI): m / z 278.9 [M+1] + .

[0284] Step 2: Synthesis of Compound 1C

[0285] Compound 1B (200 mg, 0.72 mmol) was dissolved in a mixture of 1,4-dioxane (4 mL) and water (0.5 mL). 2-(4,4-difluorocyclohex-1-en-1-yl)boronic acid pinacol ester (264 mg, 1.1 mmol), cesium carbonate (469 mg, 1.44 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (20 mg, 0.033 mmol) were added sequentially at room temperature. After the additions were complete, the reaction solution was purged with nitrogen three times and then heated to 90°C under nitrogen for 16 hours. After TLC indicated the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried, and spin-dried. The residue was purified by silica gel column chromatography to obtain compound 1C (200 mg, off-white solid, 55.5% yield).

[0286] MS (ESI): m / z 317.1[M+1] + .

[0287] Step 3: Synthesis of Compound 1D

[0288] Compound 1C (200 mg, 0.63 mmol) was dissolved in methanol (5 mL), and 10% wet palladium on carbon (50 mg) was added. After the addition was complete, the reaction solution was replaced with hydrogen three times and allowed to react at 15 psi and 50°C for 4 hours. After TLC indicated the reaction was complete, the mixture was cooled to room temperature and filtered. The filter cake was washed with methanol (5 mL), and the filtrate was dried to afford compound 1D (200 mg, light yellow solid, 99.4% yield).

[0289] MS (ESI): m / z 263.1[M-55] + .

[0290] Step 4: Synthesis of Compound 1E

[0291] Compound 1D (190 mg, 0.63 mmol) was dissolved in 8% hydrochloric acid in ethanol (2 mL). The reaction solution was purged with nitrogen three times and then reacted at 40°C for 2 hours. After TLC indicated completion of the reaction, the solvent was concentrated to provide compound 1E (100 mg, yellow solid, 76.7% yield).

[0292] Step 5: Synthesis of Compound 1F

[0293] Compound 1E1 (141 mg, 0.46 mmol) was dissolved in dichloromethane (2 mL), followed by the dropwise addition of oxalyl chloride (233 mg, 1.82 mmol) and N,N-dimethylformamide (0.5 drop). The mixture was allowed to react at room temperature for 30 minutes. After TLC indicated completion of the reaction, the concentrated residue was added with toluene (2 mL), 4-dimethylaminopyridine (223 mg, 1.82 mmol), and compound 1E (100 mg, 0.46 mmol). After the additions were complete, the reaction mixture was purged with nitrogen three times and allowed to react at 100°C for 1 hour. After TLC indicated completion of the reaction, the mixture was cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried and spin-dried, and the residue was purified by thin-layer chromatography to afford compound 1F (40 mg, yellow oil, 17.1% yield).

[0294] MS (ESI): m / z 510.1[M+1] + .

[0295] Step 6: Synthesis of Compound 1

[0296] Compound 1F (40 mg, 0.08 mmol) and 2-hydroxyethane-1-sulfonamide (20 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (0.5 mL). Cuprous iodide (30 mg, 0.16 mmol), potassium phosphate (50 mg, 0.24 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (11 mg, 0.08 mmol) were added sequentially. The reaction mixture was heated to 120°C for 4 hours. After TLC indicated the reaction was complete, the mixture was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), dried, and spin-dried. The residue was purified by TLC chromatography to yield the crude compound, which was then purified by preparative HPLC to afford compound 1 (15 mg, light yellow solid, 18.5% yield).

[0297] MS (ESI): m / z 555.2[M+1] + .

[0298] 1 H NMR(300MHz,dmso)δ13.49(s,1H),10.15(br.s,1H),8.03(d,J=8.6Hz,1H), 7.52(s,1H),7.26(d,J=1.9Hz,1H),7.11(dd,J=8.6,2.0Hz,1H),4.93(br.s, 1H),3.75(t,J=6.5Hz,2H),3.33(t,J=6.6Hz,2H),3.22(ddd,J=8.9,4.2,1.7 Hz,1H),2.95(t,J=5.0Hz,4H),2.19–1.78(m,8H),1.67(s,4H),0.37(s,4H).

[0299] Example 2: Preparation of Compound 2

[0300] The synthetic route of compound 2 is:

[0301] The specific preparation method of compound 2 includes:

[0302] Step 1: Synthesis of compound 2B

[0303] Compound 2A (500 mg, 2.78 mmol) was dissolved in N-methylpyrrolidone (5 mL), and 4,4-difluoropiperidine hydrochloride (530 mg, 3.34 mmol) and N,N-diisopropylethylamine (720 mg, 5.56 mmol) were added. After the addition was complete, the reaction solution was purged with nitrogen three times and reacted at 120°C for 16 hours. After TLC showed the reaction was complete, water (50 mL) was added for dilution, followed by extraction with ethyl acetate (50 mL x 3). The organic phases were combined, dried, and spin-dried. The residue was purified by silica gel column chromatography to obtain compound 2B (700 mg, yellow oil, 95.2% yield).

[0304] MS (ESI): m / z 265.1[M+1] + .

[0305] Step 2: Synthesis of Compound 2C

[0306] Compound 1E1 (117 mg, 0.38 mmol) was dissolved in dichloromethane (2 mL), followed by the dropwise addition of oxalyl chloride (192 mg, 1.52 mmol) and N,N-dimethylformamide (1 drop). The mixture was allowed to react at room temperature for 30 minutes. The solvent was then removed, and toluene (2 mL), 4-dimethylaminopyridine (184 mg, 1.52 mmol), and compound 2B (100 mg, 0.38 mmol) were added. After the addition was complete, the reaction solution was purged with nitrogen three times and reacted at 100°C for 1 hour. After TLC indicated the reaction was complete, the mixture was cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried, and spin-dried. The residue was purified by TLC chromatography to afford compound 2C (50 mg, yellow solid, 23.8% yield).

[0307] MS (ESI): m / z 556.1 [M+1] + .

[0308] Step 3: Synthesis of Compound 2

[0309] Compound 2C (50 mg, 0.09 mmol) and 2-hydroxyethane-1-sulfonamide (23 mg, 0.18 mmol) were dissolved in N,N-dimethylformamide (0.5 mL). Cuprous iodide (34 mg, 0.18 mmol), potassium phosphate (58 mg, 0.27 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (13 mg, 0.09 mmol) were added sequentially. The reaction mixture was heated to 120°C for 4 hours. After TLC indicated the reaction was complete, the mixture was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (30 mL x 3), dried, and spin-dried. The residue was purified by TLC to afford the crude compound, which was then purified by preparative HPLC to afford compound 2 (10 mg, light yellow solid, 18.5% yield).

[0310] MS (ESI): m / z 601.2 [M+1] + .

[0311] 1H NMR(300MHz,dmso)δ12.04(s,1H),10.10(br.s,1H),8.12(d,J=8.2Hz,1H),7.79–7.64(m,2H),7.47(d,J=8.3Hz,1H),7.24(t,J=7.6Hz,1H), 7.11–6.96(m,2H),4.97(br.s,1H),3.76(t,J=6.4Hz,6H),3.34(d,J=6.5Hz,2H),2.85(s,4H),2.04–1.79(m,4H),1.28(s,4H),0.21(s,4H).

[0312] Example 3: Preparation of Compound 3

[0313] The synthetic route of compound 3 is:

[0314] The specific preparation method of compound 3 includes:

[0315] Step 1: Synthesis of compound 3B

[0316] Compound 3A (500 mg, 1.17 mmol, synthesized according to the preparation method in WO2020132648A1) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of compound 3A1 (344 mg, 2.34 mmol) and potassium carbonate (323 mg, 2.34 mmol). The mixture was reacted at 120°C for 16 hours. After TLC showed completion of the reaction, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 2), dried, and spin-dried. The residue was purified by thin-layer chromatography to afford compound 3B (350 mg, white solid, 57.6% yield).

[0317] MS (ESI): m / z 260.5 [M / 2+1] + .

[0318] Step 2: Synthesis of Compound 3

[0319] 3B (143.0 mg, 0.3 mmol) was dissolved in N,N-dimethylformamide (3.0 mL), followed by the addition of potassium phosphate (116.9 mg, 0.6 mmol), 2-hydroxyethane-1-sulfonamide (69.0 mg, 0.6 mmol), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (19.6 mg, 0.1 mmol), and cuprous iodide (52.5 mg, 0.3 mmol). The mixture was reacted at 120°C for 3 hours under a nitrogen atmosphere. After TLC indicated completion of the reaction, the reaction solution was diluted with saturated brine (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic phases were washed with saturated brine (4.0 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain a residue which was purified by thin-layer chromatography to afford compound 3 (21.3 mg, white solid, 13.7% yield).

[0320] MS (ESI): m / z 565.2[M+1] + .

[0321] 1 H NMR(300MHz,dmso)δ11.02(s,1H),10.08(br.s,1H),7.73(d,J=8.5Hz,1H),7.45(s ,1H),7.19(s,1H),7.00(dd,J=8.5,1.9Hz,1H),4.91(br.s,1H),3.92–3.78(m,4H) ,3.73(t,J=6.5Hz,2H),3.31(t,J=6.6Hz,2H),2.93(dd,J=10.6,3.1Hz,2H),2.80( d,J=10.4Hz,2H),2.29(s,3H),2.24(s,2H),2.03–1.81(m,6H),1.69–1.42(m,4H).

[0322] Example 4: Preparation of Compound 4

[0323] The synthetic route of compound 4 is:

[0324] The specific preparation method of compound 4 includes:

[0325] Step 1: Synthesis of compound 4B

[0326] Compound 3A (500 mg, 1.17 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of compound 4A1 (344 mg, 2.34 mmol) and potassium carbonate (323 mg, 2.34 mmol). The mixture was allowed to react at 120°C for 16 hours. After TLC indicated completion of the reaction, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 2), dried, and spin-dried. The residue was purified by thin-layer chromatography to afford compound 4B (75 mg, white solid, 12.7% yield).

[0327] MS (ESI): m / z 253.5 [M / 2+1] + .

[0328] Step 2: Synthesis of compound 4

[0329] 4B (75.0 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (2.0 mL), followed by the addition of potassium phosphate (58.4 mg, 0.3 mmol), 2-hydroxyethane-1-sulfonamide (34.5 mg, 0.3 mmol), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (10.0 mg, 0.05 mmol), and cuprous iodide (27.0 mg, 0.15 mmol). The mixture was reacted at 120°C for 3 hours under a nitrogen atmosphere. After TLC indicated completion of the reaction, the reaction solution was diluted with saturated brine (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic phases were washed with saturated brine (10.0 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain a residue that was purified by thin-layer chromatography. The resulting product was then purified by preparative HPLC to afford compound 4 (28.0 mg, white solid, 30% yield).

[0330] MS (ESI): m / z 551.2 [M+1] + .

[0331] 1H NMR(300MHz,dmso)δ11.58(s,1H),10.03(br.s,1H),7.65(d,J=7.5Hz,1H),7.37 (s,1H),7.15(s,1H),6.91(d,J=8.8Hz,1H),4.97(br.s,1H),3.82(s,4H),3.74(t ,J=6.6Hz,2H),3.39(s,4H),3.31(t,J=6.6Hz,2H),2.46-2.42(m,2H),2.28(s,3H ),2.18–2.04(m,2H),1.94(ddd,J=20.2,13.6,6.3Hz,4H),1.71(d,J=5.6Hz,2H).

[0332] Example 5: Preparation of Compound 5

[0333] The synthetic route of compound 5 is:

[0334] The specific preparation method of compound 5 includes:

[0335] Step 1: Synthesis of compound 5B

[0336] Compound 3A (500 mg, 1.17 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of compound 5A1 (302 mg, 2.34 mmol) and potassium carbonate (323 mg, 2.34 mmol). The mixture was allowed to react at 120°C for 16 hours. After TLC indicated completion of the reaction, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 2), dried, and spin-dried. The residue was purified by thin-layer chromatography to afford compound 5B (130 mg, white solid, 22.6% yield).

[0337] MS (ESI): m / z 246.5 [M / 2+1] + .

[0338] Step 2: Synthesis of compound 5

[0339] Compound 5B (100 mg, 0.203 mmol) and 2-hydroxyethane-1-sulfonamide (38.12 mg, 0.305 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cuprous iodide (38.8 mg, 0.203 mmol), potassium phosphate (86.5 mg, 0.406 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (14.45 mg, 0.101 mmol) were added sequentially. After complete addition, the mixture was reacted at 120°C under a nitrogen atmosphere for 4 h. After TLC indicated completion of the reaction, the mixture was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), dried, and spin-dried. The residue was purified by thin-layer chromatography to afford compound 5 (5 mg, light yellow solid, 4.59% yield).

[0340] MS (ESI): m / z 537.2[M+1] + .

[0341] 1 H NMR(300MHz,dmso)δ10.91(s,1H),10.03(br.s,1H),7.67(d,J=8.5Hz,1H),7. 35(s,1H),6.92(s,1H),6.85(d,J=8.3Hz,1H),4.91(br.s,1H),4.11(d,J=6.7 Hz,1H),3.91–3.77(m,4H),3.73(t,J=6.5Hz,2H),3.28-3.26(m,1H),3.09(s, 2H),2.90–2.80(m,1H),2.29(s,3H),2.08–1.82(m,7H),1.48(d,J=4.2Hz,2H).

[0342] Example 6: Preparation of Compound 6

[0343] The synthetic route of compound 6 is:

[0344] The specific preparation method of compound 6 includes:

[0345] Step 1: Synthesis of compound 6B

[0346] 6A (500.0 mg, 2.3 mmol) was dissolved in N,N-dimethylpyrrolidone (5.0 mL), followed by the addition of N,N-diisopropylethylamine (1.4 g, 9.0 mmol) and 4,4-difluoropiperidine hydrochloride (722.2 mg, 4.6 mmol). The mixture was allowed to react in a sealed container at 150°C for 5 hours. After the reaction mixture cooled, it was diluted with saturated brine (20.0 mL) and extracted with ethyl acetate (40.0 mL x 2). The combined organic phases were washed with saturated brine (10.0 mL x 2), dried over anhydrous sodium sulfate, and the organic solution was evaporated to dryness. The resulting residue was purified by silica gel column chromatography and evaporated to dryness under reduced pressure to afford 6B (452 ​​mg, yellow solid, 76.3% yield).

[0347] MS (ESI): m / z 264.1[M+1] + .

[0348] Step 2: Synthesis of compound 6D

[0349] Compound 6C (5.0 g, 22.8 mmol) was dissolved in methanol (50 mL). Thionyl chloride (3.5 g, 29.6 mmol) was added dropwise to the reaction mixture at 0°C. After complete addition, the reaction mixture was stirred at 60°C for 5 hours. After TLC indicated completion of the reaction, the mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography to obtain compound 6D (5.0 g, white solid, 94.0% yield).

[0350] MS (ESI): m / z 232.0 [M+1] + .

[0351] Step 3: Synthesis of compound 6E

[0352] Compound 6D (1.0 g, 4.29 mmol) was weighed and poured into a sealed jar. N-methylpyrrolidone (10 mL), 6-aza-spiro[2.5]octane hydrochloride (760 mg, 5.15 mmol), and N,N-diisopropylethylamine (1.7 g, 12.9 mmol) were then added. After complete addition, the reaction mixture was heated to 120°C for 16 hours. After TLC indicated the reaction was complete, the mixture was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (80 mL x 3), dried, and spin-dried. The residue was purified by silica gel column chromatography to afford compound 6E (1.2 g, light yellow oil, 86.3% yield).

[0353] MS (ESI): m / z 324.1[M+1] + ,326.1[M+3] + .

[0354] Step 4: Synthesis of compound 1E1

[0355] Compound 6E (1.2 g, 3.70 mmol) was dissolved in methanol (10 mL), water (10 mL), and tetrahydrofuran (5 mL). Lithium hydroxide monohydrate (156 mg, 3.70 mmol) was then added under ice-cooling. After complete addition, the reaction mixture was allowed to react at room temperature for 16 hours. After TLC indicated completion of the reaction, the methanol and tetrahydrofuran were removed, and 1N hydrochloric acid was added to adjust the pH to 5-6. The mixture was then extracted with dichloromethane / methanol (10:1) (100 mL x 3), dried, and spin-dried. The residue was purified by silica gel column chromatography to yield compound 1E1 (1.0 g, white solid, 87.1% yield).

[0356] MS (ESI): m / z 310.0 [M+1] + .

[0357] Step 5: Synthesis of Compound 6G

[0358] Compound 1E1 (50.0 mg, 0.2 mmol) was dissolved in anhydrous dichloromethane (2.0 mL). Oxalyl chloride (50.0 mg, 0.4 mmol) was added at room temperature, followed by a half-drop of N,N-dimethylformamide. The mixture was allowed to react at 25°C for 10 minutes. After TLC indicated the reaction was complete, the residue was dried and dissolved in anhydrous tetrahydrofuran (2.0 mL). A solution of N,N-dimethyl-4-aminopyridine (79.1 mg, 0.6 mmol) and compound 6B (42.5 mg, 0.2 mmol) dissolved in toluene (1.0 mL) was then added. The reaction solution was stirred at 100°C for 1 hour. After TLC showed that the reaction was complete, saturated brine (20.0 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (20.0 mL × 2). The combined organic phases were washed with saturated brine (10.0 mL × 2) and dried over anhydrous sodium sulfate. The residue obtained by concentration was purified by silica gel column chromatography and dried under reduced pressure to give compound 6G (63 mg, yellow solid, yield 70.3%).

[0359] MS (ESI): m / z 555.2[M+1] + .

[0360] Step 6: Synthesis of Compound 6

[0361] Compound 6G (63.0 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (1.5 mL), followed by the addition of anhydrous potassium phosphate (48.3 mg, 0.2 mmol), 2-hydroxyethane-1-sulfonamide (21.3 mg, 0.2 mmol), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (8.1 mg, 0.06 mmol), and cuprous iodide (21.7 mg, 0.1 mmol). The mixture was reacted at 120°C under a nitrogen atmosphere for 3 hours. After TLC indicated the reaction was complete, the mixture was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), dried, and spin-dried. The residue was purified by TLC chromatography to give the crude compound, which was then purified by preparative HPLC to afford compound 6 (19.4 mg, white solid, 28.5% yield).

[0362] MS (ESI): m / z 600.2[M+1] + .

[0363] 1 H NMR(300MHz,dmso)δ13.13(s,1H),10.22(br.s,1H),8.26(s,1H),8.09(d,J=8.5Hz,1H),8.05(d,J=8 .5Hz,1H),7.84(d,J=8.0Hz,1H),7.65(t,J=7.5Hz,1H),7.45(t,J=7.6Hz,1H),7.27(d,J=1.8Hz,1H), 7.13(dd,J=8.6,1.9Hz,1H),4.94(br.s,1H),3.75(t,J=6.5Hz,2H),3.57–3.44(m,4H),3.36(d,J=6. 4Hz, 2H), 3.00 (d, J=3.6Hz, 4H), 2.27 (ddd, J=19.7, 14.4, 5.5Hz, 4H), 2.14–1.34 (m, 4H), 0.39 (s, 4H).

[0364] Example 7: Preparation of Compound 7

[0365] The synthetic route of compound 7 is:

[0366] The specific preparation method of compound 7 includes:

[0367] Step 1: Synthesis of compound 7B

[0368] Compound 7A (500 mg, 2.29 mmol) was dissolved in acetonitrile (10 mL). N,N-diisopropylethylamine (739.7 mg, 5.73 mmol) and 4,4-difluoropiperidine hydrochloride (400 mg, 2.52 mmol) were added sequentially at room temperature. The reaction mixture was allowed to react at room temperature for 16 hours. After TLC indicated the reaction was complete, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate to obtain compound 7B (757 mg, white solid, yield: 108.9%).

[0369] MS (ESI): m / z 304.1[M+1] + .

[0370] Step 2: Synthesis of compound 7C

[0371] Compound 7B (300 mg, 0.99 mmol) was added to aqueous ammonia (6 mL) and the mixture was allowed to react at 160°C for 4 hours. After TLC indicated completion of the reaction, the reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and dried by spin drying. The residue was purified by silica gel column chromatography to obtain compound 7C (94 mg, white solid, yield: 33.4%).

[0372] MS (ESI): m / z 285.1[M+1] + .

[0373] Step 3: Synthesis of Compound 7D

[0374] Compound 1E1 (80.5 mg, 0.26 mmol) was dissolved in dichloromethane (2 mL). Oxalyl chloride (58 mg, 0.65 mmol) and N,N-dimethylformamide (0.5 drop) were added dropwise in an ice bath. The mixture was allowed to react at room temperature for 30 minutes. After TLC indicated the reaction was complete, the mixture was dried by rotary evaporation. Toluene (2 mL), 4-dimethylaminopyridine (127.3 mg, 1.04 mmol), and a toluene solution of compound 7C (74 mg, 0.26 mmol) in 2 mL were added sequentially. The reaction mixture was allowed to react at 100°C under nitrogen for 1 hour. After TLC indicated the reaction was complete, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried, and rotary evaporation. The residue was purified by thin-layer chromatography to yield compound 7D (55 mg, yellow solid, yield: 36.7%).

[0375] MS (ESI): m / z 576.1[M+1] + .

[0376] Step 6: Synthesis of Compound 7

[0377] Compound 7D (45 mg, 0.078 mmol) and 2-hydroxyethane-1-sulfonamide (14.7 mg, 0.117 mmol) were dissolved in N,N-dimethylformamide (1 mL). Cuprous iodide (15.0 mg, 0.078 mmol), potassium phosphate (33.2 mg, 0.156 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5.6 mg, 0.039 mmol) were added sequentially. After the additions were complete, the reaction mixture was incubated at 120°C under nitrogen for 2 hours. After TLC indicated the reaction was complete, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried, and spin-dried. The mixture was then purified by HPLC to afford compound 7 (2 mg, yellow solid, 4.1% yield).

[0378] MS (ESI): m / z 621.2[M+1] + .

[0379] Example 8: Preparation of Compound 8

[0380] The synthetic route of compound 8 is:

[0381] The specific preparation method of compound 8 includes:

[0382] Step 1: Synthesis of compound 8-B

[0383] Compound 8-A (2.0 g, 7.27 mmol) was dissolved in N-methylpyrrolidone (50 mL), and N,N-diisopropylethylamine (2.8 g, 21.9 mmol) and 4,4-difluoropiperidine hydrochloride (1.5 g, 9.4 mmol) were added. The mixture was stirred at 100°C for 3 hours. After TLC indicated completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 8-B (2.0 g, yellow solid, yield: 87.1%).

[0384] MS (ESI): m / z 317.0 [M+1] +

[0385] Step 2: Synthesis of compound 8-C

[0386] Compound 8-B (860.0 mg, 2.72 mmol) was dissolved in dioxane (10.0 mL), and tert-butyl carbamate (640.0 mg, 5.44 mmol), cesium carbonate (1.78 g, 5.44 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (235.0 mg, 0.41 mmol), and palladium acetate (50.0 mg, 0.21 mmol) were added. The mixture was then reacted at 100°C under nitrogen for 4 hours. After TLC indicated the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (50.0 mL), and extracted with ethyl acetate (30.0 mL x 2). The combined organic phases were washed with saturated brine (20.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography and dried under reduced pressure to afford compound 8-C (800 mg, brown solid, yield: 83.3%).

[0387] MS (ESI): m / z 354.2[M+1] + .

[0388] Step 3: Synthesis of compound 8-D

[0389] Compound 8-C (400.0 mg, 1.13 mmol) was dissolved in anhydrous dichloromethane (10.0 mL). 2,6-Lutidine (364 mg, 3.4 mmol) and trimethylsilyl trifluoromethanesulfonate (755 mg, 3.4 mmol) were added sequentially at room temperature, followed by stirring at room temperature for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with ice water (40 mL) and extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated brine (20.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure to yield crude compound 8-D (300 mg).

[0390] MS (ESI): m / z 254.1[M+1] + .

[0391] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.20 (s, 1H), 7.91 (d, J = 1.2Hz, 1H), 7.58 (d, J = 1.2Hz, 1H), 4.35 (t, J = 8.0Hz, 4H), 2.14-2.04 (m, 4H).

[0392] Step 4: Synthesis of compound 8-E

[0393] Compound 1E1 (330.0 mg, 1.1 mmol) was dissolved in dichloromethane (10 mL). Oxalyl chloride (415 mg, 3.3 mmol) and N,N-dimethylformamide (0.5 drop) were added dropwise in an ice bath, followed by stirring at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by vortexing and then dissolved in anhydrous tetrahydrofuran (6 mL). A solution of compound 8-D (300 mg, 1.1 mmol) and N,N-diisopropylethylamine (426 mg, 3.3 mmol) in tetrahydrofuran (8 mL) was added at room temperature, and the mixture was stirred at 50°C under nitrogen for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and desolventized under reduced pressure. The residue was purified by silica gel column to give compound 8-E (300 mg, bright yellow solid, yield: 50.1%).

[0394] MS (ESI): m / z 273.1 [M / 2+1] + .

[0395] Step 5: Synthesis of Compound 8

[0396] Compound 8-E (100 mg, 0.18 mmol) and 2-hydroxyethane-1-sulfonic acid (46.3 mg, 0.37 mmol) were dissolved in N,N-dimethylformamide (3 mL). Cuprous iodide (35.0 mg, 0.18 mmol), potassium phosphate (78 mg, 0.37 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (26 mg, 0.18 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 3 hours. After TLC indicated completion of the reaction, the reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 8 (60 mg, off-white solid).

[0397] MS (ESI): m / z 590.2[M+1] + .

[0398] 1H NMR(300MHz,DMSO-d6)δ(ppm)12.88(s,1H),10.20(br.s,1H),8.82(s,1H),8.10 –8.02(m,2H),7.54(d,J=1.0Hz,1H),7.26(d,J=2.1Hz,1H),7.12(dd,J=8.7,2.1 Hz,1H),4.99(br.s,1H),4.51-4.35(m,4H),3.74(t,J=6.5Hz,2H),3.35(t,J=6. 5Hz,2H),3.03-2.89(m,4H),2.26-2.00(m,5H),1.91-1.50(m,3H),0.39(s,4H).

[0399] Example 9: Preparation of Compound 9

[0400] The synthetic route of compound 9 is:

[0401] The preparation method of compound 9 specifically includes:

[0402] Step 1: Synthesis of compound 9-B

[0403] Compound 6C (50 mg, 0.23 mmol) was dissolved in thionyl chloride (1 mL) and stirred at 80°C for 2 hours. After TLC showed that the reaction was complete, the reaction solution was pressurized and desolvated to obtain the crude intermediate. Compound 6B (60 mg, 0.23 mmol) and N,N-diisopropylethylamine (0.16 mL, 0.91 mmol) were dissolved in tetrahydrofuran (1 mL), and the tetrahydrofuran (0.5 mL) solution of the intermediate was added dropwise to the above reaction solution, followed by stirring at 50°C for 2 hours. After TLC showed that the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (10 mL), and then extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by column chromatography to obtain compound 9-B (110 mg, yellow solid).

[0404] MS (ESI): m / z 464.1[M+1] +

[0405] Step 2: Synthesis of compound 9-C

[0406] Compound 9-B (110 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (1 mL), and compound 3A1 (70 mg, 0.47 mmol) and potassium carbonate (66 mg, 0.47 mmol) were added, followed by stirring at 120°C for 12 hours. After TLC indicated completion of the reaction, the mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by column chromatography to afford compound 9-C (80 mg, yellow solid, 60% yield).

[0407] MS (ESI): m / z 555.2[M+1] +

[0408] Step 3: Synthesis of Compound 9

[0409] Compound 9-C (80 mg, 0.14 mmol) and 2-hydroxyethane-1-sulfonamide (37 mg, 0.28 mmol) were dissolved in anhydrous N,N-dimethylformamide (2 mL). Cuprous iodide (3 mg, 0.01 mmol), potassium phosphate (61 mg, 0.28 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (11 mg, 0.07 mmol) were added. The reaction mixture was purged with nitrogen three times and then stirred at 120°C for 16 hours. After TLC indicated completion of the reaction, the mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by column chromatography to obtain the crude compound, which was then purified by prep-HPLC to yield compound 9 (23 mg, light yellow solid).

[0410] MS (ESI): m / z 600.2[M+1] +

[0411] 1H NMR (300MHz, DMSO-d6) δ (ppm) 10.73 (s, 1H), 10.05 (br.s, 1H), 8.32 (s, 1H), 8.11–7.99 (m, 1H), 7.85 (d, J=8.3Hz, 1H),7.72(d,J=8.5Hz,1H),7.65(ddd,J=8.1,6.8,1.2Hz,1H),7.46(ddd,J=8.3,6.8,1.2Hz,1H),7.16(d,J=2.1H z,1H),7.00(dd,J=8.5,2.0Hz,1H),4.95(br.s,1H),3.74(t,J=6.6Hz,2H),3.51-3.40(m,4H),3.31–3.26(m,2H) ,3.01(dd,J=10.7,3.5Hz,2H),2.80(d,J=10.6Hz,2H),2.28-2.16(m,6H),2.03-1.92(m,2H),1.63-1.44(m,4H).

[0412] Example 10 Preparation of Compound 10

[0413] Synthesis route:

[0414] Preparation method:

[0415] Step 1: Synthesis of compound 10

[0416] Compound 8-E (70 mg, 0.128 mmol) and methanesulfonamide (16 mg, 0.384 mmol) were dissolved in N,N-dimethylformamide (1 mL). Cuprous iodide (15 mg, 0.077 mmol), potassium phosphate (77 mg, 0.371 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (15 mg, 0.110 mmol) were added sequentially. The reaction mixture was then purged with nitrogen three times and stirred at 100°C for 16 hours. After LCMS indicated completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 10 (10 mg, off-white solid).

[0417] MS (ESI): m / z 560.2[M+1] + .

[0418] 1H NMR (300MHz, DMSO-d6) δ (ppm) 12.88 (s, 1H), 10.24 (br.s, 1H), 8.83 (s, 1H), 8.08 (dd, J = 4.9, 3.8Hz, 2H), 7.54 (d, J = 1.1Hz, 1H), 7.25 (d, J = 2. 1Hz,1H),7.13(dd,J=8.7,2.1Hz,1H),4.48-4.37(m,4H),3.11(s,3H),3.03-2.95(m,4H),2.23-1.99(m,5H),1.88-1.59(m,3H),0.39(s,4H).

[0419] Example 11 Preparation of Compound 11

[0420] Synthesis route:

[0421] Preparation method:

[0422] Step 1: Synthesis of compound 11-B

[0423] Compound 8-A (1.0 g, 3.61 mmol) was dissolved in N-methylpyrrolidone (10 mL), and N,N-diisopropylethylenediamine (1.4 g, 10.8 mmol) and morpholine (410 mg, 4.69 mmol) were added. The mixture was stirred at 100°C under nitrogen for 4 hours. After TLC indicated completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 11-B (1 g, yellow oil, yield: 97.8%).

[0424] MS (ESI): m / z 283.0 [M+1] + .

[0425] Step 2: Synthesis of Compound 11-C

[0426] Compound 11-B (1.0 g, 3.53 mmol) was dissolved in dioxane (10 mL), and tert-butyl carbamate (833 mg, 7.06 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (340 mg, 0.71 mmol), cesium carbonate (2.3 g, 7.06 mmol), and palladium acetate (80 mg, 0.35 mmol) were added. The mixture was then stirred at 100°C under nitrogen for 16 hours. After TLC indicated completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 11-C (1.0 g, yellow solid, yield: 88.7%).

[0427] MS (ESI): m / z 320.2[M+1] + .

[0428] Step 3: Synthesis of compound 11-D

[0429] Compound 11-C (500 mg, 1.57 mmol) was dissolved in anhydrous dichloromethane (5.0 mL). 2,6-Lutidine (504 mg, 4.71 mmol) and trimethylsilyl trifluoromethanesulfonate (1.1 g, 4.71 mmol) were added sequentially at room temperature, followed by stirring at room temperature for 1 hour. After TLC indicated completion of the reaction, the reaction solution was diluted with ice water (50 mL), adjusted to pH 7-8 with saturated ammonium bicarbonate solution, and then extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure to yield crude compound 11-D (300 mg, yellow oil).

[0430] MS (ESI): m / z 220.1[M+1] + .

[0431] Step 4: Synthesis of compound 11-E

[0432] Compound 1E1 (214 mg, 0.68 mmol) was dissolved in dichloromethane (5.0 mL), and oxalyl chloride (263 mg, 2.04 mmol) was added dropwise. The mixture was then stirred at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation and then dissolved in anhydrous tetrahydrofuran (10 mL). Compound 11-D (150 mg, 0.68 mmol) and N,N-diisopropylethylenediamine (268 mg, 2.04 mmol) were added sequentially at room temperature. The reaction solution was then stirred at 50°C for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 11-E (110 mg, yellow solid, 34.3% yield).

[0433] MS (ESI): m / z 511.1[M+1] + .

[0434] Step 5: Synthesis of Compound 11

[0435] Compound 11-E (100 mg, 0.20 mmol) and 2-hydroxyethane-1-sulfonamide (30 mg, 0.24 mmol) were dissolved in N,N-dimethylformamide (3 mL). Cuprous iodide (4 mg, 0.02 mmol), potassium phosphate (84 mg, 0.40 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (6 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 3 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 11 (15 mg, yellow solid).

[0436] MS (ESI): m / z 556.2[M+1] + .

[0437] 1H NMR(300MHz,DMSO-d6)δ(ppm)12.95(s,1H),10.19(s,1H),8.79(s,1H),8.12–8.03( m,2H),7.52(d,J=1.1Hz,1H),7.27(d,J=2.1Hz,1H),7.13(dd,J=8.6,2.2Hz,1H),4.9 2(s,1H),4.29-4.23(m,4H),3.79-3.76(m,4H),3.34(t,J=6.4Hz,2H),3.16(t,J=9. 3,4.4Hz,2H),3.00-2.94(m,4H),1.83-1.61(m,3H),1.44-1.39(m,1H),0.38(s,4H).

[0438] Example 12 Preparation of Compound 12

[0439] Synthesis route:

[0440] Preparation method:

[0441] Step 1: Synthesis of compound 12-B

[0442] Compound 8-A (500 mg, 1.81 mmol) was dissolved in N-methylpyrrolidone (30 mL), and N,N-diisopropylethylenediamine (938 mg, 13.0 mmol) and piperidine hydrochloride (308 mg, 3.62 mmol) were added. The mixture was then stirred at 100°C under nitrogen for 4 hours. After TLC indicated the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 12-B (400 mg, yellow oil, yield: 78.8%).

[0443] MS (ESI): m / z 281.0 [M+1] + .

[0444] Step 2: Synthesis of Compound 12-C

[0445] Compound 12-B (400 mg, 1.42 mmol) was dissolved in dioxane (5.0 mL), and tert-butyl carbamate (336 mg, 2.84 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (145 mg, 0.28 mmol), cesium carbonate (932 mg, 2.84 mmol), and palladium acetate (32 mg, 0.14 mmol) were added. The mixture was then stirred at 100°C under nitrogen for 16 hours. After TLC indicated the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (50.0 mL x 2). The combined organic phases were washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography and dried under reduced pressure to afford compound 12-C (200 mg, yellow solid, yield: 44.3%).

[0446] MS (ESI): m / z 318.2[M+1] + .

[0447] Step 3: Synthesis of Compound 12-D

[0448] Compound 12-C (200.0 mg, 0.63 mmol) was dissolved in anhydrous dichloromethane (5.0 mL). 2,6-Lutidine (203 mg, 1.89 mmol) and trimethylsilyl trifluoromethanesulfonate (420 mg, 1.89 mmol) were added sequentially at room temperature, followed by stirring at room temperature for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with ice water (20 mL), adjusted to pH 7-8 with saturated sodium bicarbonate solution, and then extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure to yield crude compound 12-D (150 mg, yellow oil).

[0449] MS (ESI): m / z 218.1[M+1] + .

[0450] Step 4: Synthesis of compound 12-E

[0451] Compound 1E1 (214 mg, 0.69 mmol) was dissolved in dichloromethane (5 mL). Oxalyl chloride (263 mg, 2.07 mmol) was added dropwise under an ice bath, and the mixture was stirred at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation and then dissolved in anhydrous tetrahydrofuran (10 mL). Compound 12-D (150 mg, 0.69 mmol) and N,N-diisopropylethylenediamine (268 mg, 2.07 mmol) were added sequentially at room temperature, and the reaction solution was stirred at 50°C for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 12-E (110 mg, yellow solid, yield: 31.3%).

[0452] MS (ESI): m / z 509.2[M+1] + .

[0453] Step 5: Synthesis of Compound 12

[0454] Compound 12-E (100 mg, 0.20 mmol) and 2-hydroxyethane-1-sulfonamide (30 mg, 0.24 mmol) were dissolved in N,N-dimethylformamide (3 mL). Cuprous iodide (4 mg, 0.02 mmol), potassium phosphate (84 mg, 0.40 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (6 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120°C for 3 hours under nitrogen. After TLC indicated completion of the reaction, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 12 (28 mg, off-white solid).

[0455] MS (ESI): m / z 554.3 [M+1] + .

[0456] 1H NMR(300MHz,DMSO-d6)δ(ppm)12.80(s,1H),10.15(br.s,1H),8.72(s,1H),8.07( d,J=8.6Hz,1H),8.00(d,J=1.1Hz,1H),7.49(d,J=1.0Hz,1H),7.27(d,J=2.1Hz,1H ),7.12(dd,J=8.6,2.1Hz,1H),4.94(br.s,1H),4.34-4.21(m,4H),3.75(t,J=6.5H z,2H),3.34(t,J=6.5Hz,2H),3.02-2.93(m,4H),1.83-1.58(m,10H),0.38(s,4H).

[0457] Example 13 Preparation of Compound 13

[0458] Synthesis route:

[0459] Preparation method:

[0460] Step 1: Synthesis of compound 13

[0461] Compound 8-E (70 mg, 0.128 mmol) and 1-methylcyclopropane-1-sulfonamide (23 mg, 0.384 mmol) were dissolved in N,N-dimethylformamide (1 mL). Cuprous iodide (15 mg, 0.077 mmol), potassium phosphate (77 mg, 0.371 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (15 mg, 0.110 mmol) were added sequentially. The reaction mixture was then purged with nitrogen three times and stirred at 100°C for 16 hours. After LCMS indicated completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 13 (25 mg, off-white solid, 32.59%).

[0462] MS (ESI): m / z 600.3[M+1] + .

[0463] 1H NMR(300MHz,DMSO-d6)δ(ppm)12.92(s,1H),10.25(br.s,1H),8.84(s,1H),8 .12–8.00(m,2H),7.55(d,J=1.1Hz,1H),7.36(d,J=2.1Hz,1H),7.17(dd,J=8. 6,2.1Hz,1H),4.48-4.39(m,4H),3.01-2.92(m,4H),2.22-2.01(m,5H),1.90- 1.61(m,3H),1.40(s,3H),1.25-1.17(m,2H),0.88–0.79(m,2H),0.41(s,4H).

[0464] Example 14 Preparation of Compound 14

[0465] Synthesis route:

[0466] Preparation method:

[0467] Step 1: Synthesis of compound 14B

[0468] Compound 14A (900 mg, 4.74 mmol) was dissolved in N-methylpyrrolidone (10 mL), and N,N-diisopropylethylenediamine (1.2 g, 9.48 mmol) and 4,4-difluoropiperidine hydrochloride (900 mg, 5.69 mmol) were added. The mixture was then stirred at 120°C under nitrogen for 16 hours. After TLC indicated completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (80 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 14B (1.0 g, yellow solid, yield: 76.9%).

[0469] MS (ESI): m / z 275.1[M+1] + .

[0470] Step 2: Synthesis of Compound 14C

[0471] Compound 14B (1.0 g, 3.64 mmol) was dissolved in dioxane (10.0 mL), and tert-butyl carbamate (854 mg, 7.28 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (348 mg, 0.73 mmol), cesium carbonate (2.37 mg, 7.28 mmol), and palladium acetate (81 mg, 0.36 mmol) were added. The mixture was then reacted at 100°C under nitrogen for 16 hours. After TLC indicated completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 14C (1.0 g, yellow solid, yield: 77.3%).

[0472] MS (ESI): m / z 356.2[M+1] + .

[0473] Step 3: Synthesis of Compound 14D

[0474] Compound 14C (100 mg, 0.28 mmol) was dissolved in ethyl acetate (2 mL, 8%) and stirred at room temperature for 16 hours. After TLC showed the reaction was complete, the reaction solution was evaporated to dryness under reduced pressure to obtain crude compound 14D (100 mg).

[0475] MS (ESI): m / z 256.1[M+1] + .

[0476] Step 4: Synthesis of compound 14E

[0477] Compound 1E1 (87 mg, 0.28 mmol) was dissolved in dichloromethane (2 mL), and oxalyl chloride (90 mg, 0.70 mmol) was added dropwise under an ice bath, followed by stirring at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation. The residue was dissolved in anhydrous tetrahydrofuran (10 mL), and compound 14D (72 mg, 0.28 mmol) and N,N-diisopropylethylenediamine (146 mg, 1.12 mmol) were added sequentially at room temperature, followed by stirring at 50°C for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 14E (80 mg, yellow solid, yield: 51.8%).

[0478] MS (ESI): m / z 547.1[M+1] + .

[0479] Step 5: Synthesis of Compound 14

[0480] Compound 14E (70 mg, 0.13 mmol) and 2-hydroxy-1-sulfonamide (20 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). Cuprous iodide (3 mg, 0.01 mmol), potassium phosphate (56 mg, 0.26 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (4 mg, 0.03 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 3 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (8 mL x 3). The combined organic phases were washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure to yield compound 14 (14 mg, off-white solid).

[0481] MS (ESI): m / z 592.2[M+1] + .

[0482] 1 H NMR(300MHz,DMSO-d6)δ12.86(s,1H),10.21(br.s,1H),8.05(d,J=8.6Hz,1H), 7.69(s,1H),7.25(d,J=2.2Hz,1H),7.11(dd,J=8.6,2.1Hz,1H),5.08-5.05(m, 2H),4.98-4.89(m,3H),3.75(t,J=6.5Hz,2H),3.60-3.54(m,4H),3.35(t,J=6. 5Hz,2H),3.00-2.94(m,4H),2.10-1.96(m,5H),1.81-1.56(m,3H),0.38(s,4H).

[0483] Example 15 Preparation of Compound 15

[0484] Synthesis route:

[0485] Preparation method:

[0486] Step 1: Synthesis of compound 15B

[0487] Compound 15A (900 mg, 5.31 mmol) was dissolved in dichloromethane (10 mL), and m-chloroperbenzoic acid (1.8 g, 10.6 mmol) was added, followed by stirring at room temperature for 12 hours. After TLC indicated completion of the reaction, the reaction solution was decompressed and the solvent removed. The residue was purified by silica gel column chromatography to afford crude compound 15B (1.15 g, yellow solid).

[0488] MS (ESI): m / z 186.0 [M+1] + .

[0489] Step 2: Synthesis of compound 15C

[0490] The crude product, Compound 15B (1.15 g), was dissolved in phosphorus oxychloride (7 mL) and stirred at 115° C. for 12 hours. After TLC indicated completion of the reaction, the reaction solution was desolvated under reduced pressure, and the residue was dissolved in dichloromethane (50 mL), adjusted to pH 8 with saturated sodium bicarbonate solution, and then extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to afford Compound 15C (350 mg, yellow solid).

[0491] MS (ESI): m / z 203.9[M+1] + .

[0492] Step 3: Synthesis of Compound 15D

[0493] Compound 15C (350 mg, 1.72 mmol) was dissolved in N-methylpyrrolidone (5 mL), and potassium carbonate (711 mg, 5.15 mmol) and 4,4-difluoropiperidine hydrochloride (406 mg, 2.57 mmol) were added, followed by stirring at 120°C for 12 hours. After TLC indicated completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 15D (380 mg, yellow liquid, yield: 76.5%).

[0494] MS (ESI): m / z 289.0 [M+1] + .

[0495] Step 4: Synthesis of compound 15E

[0496] Compound 15D (350 mg, 1.21 mmol) was dissolved in dioxane (5.0 mL), and tert-butyl carbamate (284 mg, 2.42 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (116 mg, 0.24 mmol), cesium carbonate (792 mg, 2.42 mmol), and palladium acetate (27 mg, 0.12 mmol) were added. The mixture was stirred at 110°C under nitrogen for 16 hours. After TLC indicated the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 15E (400 mg, yellow solid, yield: 89.3%).

[0497] MS (ESI): m / z 370.1[M+1] + .

[0498] Step 5: Synthesis of Compound 15F

[0499] Compound 15E (100 mg, 0.27 mmol) was dissolved in a hydrochloric acid and ethyl acetate solution (2.0 mL, 8%) and stirred at room temperature for 2 hours. After TLC showed the reaction was complete, the solvent was removed under reduced pressure to give crude compound 15F (100 mg, yellow oil).

[0500] MS (ESI): m / z 270.1[M+1] + .

[0501] Step 6: Synthesis of Compound 15G

[0502] Compound 1E1 (84 mg, 0.27 mmol) was dissolved in dichloromethane (2.0 mL), and oxalyl chloride (86 mg, 0.675 mmol) was added dropwise. The mixture was then stirred at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation, and the residue was dissolved in anhydrous tetrahydrofuran (5 mL). Compound 15F (73.0 mg, 0.27 mmol) and N,N-diisopropylethylenediamine (105 mg, 0.81 mmol) were added sequentially at room temperature, and the mixture was stirred at 50°C for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 15G (110 mg, yellow solid, yield: 72.3%).

[0503] MS (ESI): m / z 561.1[M+1] + .

[0504] Step 7: Synthesis of Compound 15

[0505] Compound 15G (50.0 mg, 0.09 mmol) and 2-hydroxy-1-sulfonamide (14 mg, 0.18 mmol) were dissolved in N,N-dimethylformamide (3 mL). Cuprous iodide (2 mg, 0.01 mmol), potassium phosphate (38 mg, 0.18 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (2.5 mg, 0.02 mmol) were added sequentially. The mixture was then stirred at 120°C for 3 hours under nitrogen. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 15 (38 mg, yellow solid).

[0506] MS (ESI): m / z 606.2[M+1] + .

[0507] 1 H NMR(300MHz,DMSO-d6)δ(ppm)12.91(s,1H),10.20(br.s,1H),8.29(s,1H),8.08 (d,J=8.6Hz,1H),8.00(d,J=5.4Hz,1H),7.49(d,J=5.5Hz,1H),7.26(d,J=2.1Hz, 1H),7.12(dd,J=8.6,2.1Hz,1H),4.95(br.s,1H),3.83-3.74(m,6H),3.35(t,J=6 .4Hz,2H),3.02-2.94(m,4H),2.24-2.05(m,5H),1.89-1.60(m,3H),0.38(s,4H).

[0508] Example 16 Preparation of Compound 16

[0509] Synthesis route:

[0510] Preparation method:

[0511] Step 1: Synthesis of compound 16B

[0512] Compound 16A (5.0 g, 25.1 mmol) was dissolved in methanol (25 mL), and potassium hydroxide solution (50 mL, 2 mol / L) was added, followed by stirring at 70°C for 2 hours. After TLC indicated completion of the reaction, the mixture was cooled to room temperature, desolvated under reduced pressure, and the residue was purified on a silica gel column to afford compound 16B (3.0 g, yellow solid, 70.5% yield).

[0513] MS (ESI): m / z 170.0 [M+1] + .

[0514] Step 2: Synthesis of Compound 16C

[0515] Compound 16B (3.0 g, 17.7 mmol) was dissolved in phosphorus oxychloride (30 mL) and stirred at 120°C for 16 hours. After TLC indicated completion of the reaction, the mixture was cooled to room temperature and desolventized. The residue was adjusted to pH 8 with saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and desolventized under reduced pressure. The residue was purified on a silica gel column to afford compound 16C (3.0 g, yellow solid, 90.4% yield).

[0516] MS (ESI): m / z 188.0 [M+1] + .

[0517] Step 3: Synthesis of Compound 16D

[0518] Compound 16C (3.0 g, 16.0 mmol) was dissolved in N-methylpyrrolidone (30 mL), and N,N-diisopropylethylamine (6.2 g, 48.0 mmol) and 4,4-difluoropiperidine hydrochloride (3.3 g, 20.8 mmol) were added. The mixture was then stirred at 100°C for 3 hours. After TLC indicated completion of the reaction, the reaction solution was cooled to room temperature, poured into ice water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to afford compound 16D (4.0 g, yellow oil, yield: 91.8%).

[0519] MS (ESI): m / z 273.1[M+1] + .

[0520] Step 4: Synthesis of compound 16E

[0521] Compound 16D (200 mg, 0.74 mmol) was dissolved in dioxane (3 mL), and tert-butyl carbamate (130 mg, 1.11 mmol), cesium carbonate (479 mg, 1.48 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (35 mg, 0.07 mmol), and tris(dibenzylideneacetone)dipalladium (34 mg, 0.04 mmol) were added. The mixture was then stirred at 100°C under nitrogen for 4 hours. After TLC indicated the reaction was complete, the mixture was cooled to room temperature, poured into ice water (10 mL), and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to afford compound 16E (150 mg, yellow oil, yield: 56.8%).

[0522] MS (ESI): m / z 354.2[M+1] + .

[0523] Step 5: Synthesis of Compound 16F

[0524] Compound 16E (700 mg, 1.98 mmol) was dissolved in ethyl acetate (10 mL, 8%) hydrochloric acid and stirred at room temperature for 2 hours. After TLC indicated completion of the reaction, the reaction solution was diluted with water (50 mL), then adjusted to pH 8 with aqueous ammonia, and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure to yield crude compound 16F (400 mg, yellow solid).

[0525] MS (ESI): m / z 254.1[M+1] + .

[0526] Step 6: Synthesis of Compound 16G

[0527] Compound 1E1 (487 mg, 1.58 mmol) was dissolved in dichloromethane (10 mL), and oxalyl chloride (500 mg, 3.95 mmol) was added dropwise under ice-cooling, followed by stirring at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was desolvated under reduced pressure. The residue was dissolved in anhydrous tetrahydrofuran (10 mL), and compound 16F (400 mg, 1.58 mmol) and N,N-diisopropylethylenediamine (609 mg, 4.74 mmol) were added sequentially at room temperature, followed by stirring at 50°C for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 16G (70 mg, yellow solid, yield: 8.1%).

[0528] MS (ESI): m / z 545.1 547.1 [M+1] + .

[0529] Step 7: Synthesis of Compound 16

[0530] Compound 16G (70 mg, 0.13 mmol) and 2-hydroxy-1-sulfonamide (20 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cuprous iodide (3 mg, 0.01 mmol), potassium phosphate (56 mg, 0.26 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (4 mg, 0.03 mmol) were added sequentially. The mixture was then stirred at 120°C for 2 hours under nitrogen. After TLC indicated completion of the reaction, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (8 mL x 3). The combined organic phases were washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 16 (7 mg, yellow solid).

[0531] MS (ESI): m / z 590.2[M+1] + .

[0532] 1 H NMR (300MHz, DMSO-d6) δ (ppm) 13.30 (s, 1H), 10.24 (br.s, 1H), 8.16–7.74 (m, 3H), 7.67–7.48 (m, 1H), 7.26 (s, 1H), 7.12 (d, J=8.6Hz, 1H), 5.05 (b r.s,1H),3.75(t,J=6.5Hz,2H),3.61-3.54(m,4H),3.34(t,J=6.5Hz,2H ),3.00-2.93(m,4H),2.33-2.16(m,5H),1.85-1.60(m,3H),0.38(s,4H).

[0533] Example 17 Preparation of Compound 17

[0534] Synthesis route:

[0535] Preparation method:

[0536] Step 1: Synthesis of compound 17B

[0537] 2-Fluoro-4-bromobenzoic acid (173 mg, 0.79 mmol) was dissolved in thionyl chloride (5 mL) and stirred at 80°C for 2 hours. After TLC indicated the reaction was complete, the reaction solution was desolvated under reduced pressure. The residue was dissolved in anhydrous tetrahydrofuran (2 mL), and compound 8-D (200 mg, 0.79 mmol) and N,N-diisopropylethylenediamine (408 mg, 3.16 mmol) were added sequentially at room temperature, followed by stirring at 50°C for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1 (volume ratio)) to yield compound 17B (110 mg, yellow solid, yield: 30.7%).

[0538] MS (ESI): m / z 454.0 [M+1] + .

[0539] Step 2: Synthesis of compound 17C

[0540] Compound 17B (100 mg, 0.22 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 3-azabicyclo[3.2.1]octane hydrochloride (38 mg, 0.26 mmol) and potassium carbonate (60 mg, 0.44 mmol) were added. The mixture was then stirred at 120°C under nitrogen for 16 hours. After TLC indicated completion of the reaction, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to afford compound 17C (70 mg, yellow solid, yield: 66.2%).

[0541] MS (ESI): m / z 545.1[M+1] + .

[0542] Step 3: Synthesis of Compound 17

[0543] Compound 17C (70 mg, 0.13 mmol) and 2-hydroxy-1-sulfonamide (20 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cuprous iodide (3 mg, 0.01 mmol), potassium phosphate (56 mg, 0.26 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (4 mg, 0.03 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 2 hours. After TLC indicated completion of the reaction, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (8 mL x 3). The combined organic phases were washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 17 (16 mg, yellow solid).

[0544] MS (ESI): m / z 590.2[M+1] + .

[0545] 1 H NMR (300MHz, DMSO-d6) δ (ppm) 10.54 (s, 1H), 10.04 (br.s, 1H), 8.89 (s, 1H), 8.09 (d, J = 1.1Hz, 1H),7.70(d,J=8.4Hz,1H),7.55(d,J=1.1Hz,1H),7.16(d,J=2.1Hz,1H),7.00(dd,J=8.5,2.0H z,1H),4.95(br.s,1H),4.44-4.36(m,4H),3.75(t,J=6.6Hz,2H),3.31(t,J=6.6Hz,2H),3.06– 2.95(m,2H),2.80(d,J=10.5Hz,2H),2.29-2.21(m,2H),2.14–1.95(m,6H),1.63–1.47(m,4H).

[0546] Example 18 Preparation of Compound 18

[0547] Synthesis route:

[0548] Preparation method:

[0549] Step 1: Synthesis of compound 18B

[0550] Compound 18A (5 g, 25.9 mmol) was dissolved in isopropanol (50 mL). Sodium carbonate (6.84 g, 64.8 mmol) and 4,4-difluoropiperidine hydrochloride (4.09 g, 25.9 mmol) were added sequentially under an ice bath, and the mixture was stirred at room temperature for 12 hours. After TLC indicated completion of the reaction, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1 (volume ratio)) to afford compound 18B (4.4 g, yellow solid, yield: 61.2%).

[0551] MS (ESI): m / z 278.0 [M+1] + .

[0552] Step 2: Synthesis of Compound 18C

[0553] Compound 18B (4.4 g, 15.8 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL). Under nitrogen, vinylmagnesium bromide solution (55.3 mL, 55.3 mmol) was added dropwise to the reaction mixture at -70°C, and the mixture was allowed to warm to room temperature naturally over one hour. After TLC indicated completion of the reaction, the reaction mixture was slowly poured into saturated ammonium chloride (100 mL) under an ice bath, followed by extraction with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to afford compound 18C (1.9 g, yellow oil, 44.3% yield).

[0554] MS (ESI): m / z 272.1[M+1] + .

[0555] Step 3: Synthesis of Compound 18D

[0556] Compound 18C (1.9 g, 7.0 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and sodium hydroxide (420 mg, 10.5 mmol) was added under ice-cooling, followed by stirring under ice-cooling for 10 minutes. Methyl iodide (1.19 g, 8.4 mmol) was then added dropwise to the reaction mixture under ice-cooling, followed by stirring at room temperature for 1 hour. After TLC indicated completion of the reaction, the reaction mixture was slowly poured into saturated ammonium chloride (100 mL) under ice-cooling, followed by extraction with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 18D (1.2 g, yellow oil, yield: 60%).

[0557] MS (ESI): m / z 286.1[M+1] + .

[0558] Step 4: Synthesis of compound 18E

[0559] Compound 18D (1.15 g, 4.0 mmol) was dissolved in anhydrous dioxane (50 mL), and tert-butyl carbamate (707 mg, 6.0 mmol), cesium carbonate (2.62 g, 8.0 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (192 mg, 0.4 mmol), and tris(dibenzylideneacetone)dipalladium (184 mg, 0.2 mmol) were added. The mixture was then stirred at 100°C under nitrogen for 4 hours. After TLC indicated the reaction was complete, the mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to afford compound 18E (1.2 g, yellow oil, yield: 81.9%).

[0560] MS (ESI): m / z 367.2[M+1] + .

[0561] Step 5: Synthesis of Compound 18F

[0562] Compound 18E (500 mg, 1.36 mmol) was dissolved in ethyl acetate (10 mL, 8%) hydrochloric acid and stirred at room temperature for 2 hours. After TLC indicated completion of the reaction, the reaction solution was diluted with water (50 mL), and aqueous ammonia was added until the pH reached 8. The mixture was then extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure to yield crude compound 18F (400 mg, yellow solid).

[0563] MS (ESI): m / z 267.1[M+1] + .

[0564] Step 6: Synthesis of Compound 18G

[0565] Compound 1E1 (468 mg, 1.50 mmol) was dissolved in dichloromethane (10 mL), and oxalyl chloride (477 mg, 3.75 mmol) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was desolvated under reduced pressure. The residue was dissolved in anhydrous tetrahydrofuran (10 mL), and compound 18F (400 mg, 1.50 mmol) and N,N-diisopropylethylenediamine (582 mg, 4.50 mmol) were added sequentially at room temperature. The mixture was then stirred at 50°C for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 18G (500 mg, yellow solid, yield: 59.6%).

[0566] MS (ESI): m / z 558.2[M+1] + .

[0567] Step 7: Synthesis of Compound 18

[0568] Compound 18G (100 mg, 0.18 mmol) and 2-hydroxy-1-sulfonamide (27 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cuprous iodide (3 mg, 0.02 mmol), potassium phosphate (76 mg, 0.39 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 2 hours. After TLC indicated completion of the reaction, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 18 (7 mg, pale yellow solid).

[0569] MS (ESI): m / z 603.3 [M+1] + .

[0570] 1H NMR (300MHz, DMSO-d6) δ (ppm) 12.87 (s, 1H), 10.14 (br.s, 1H), 8.14 (s, 1H), 8.07 (d, J = 8.6 Hz,1H),7.44(d,J=3.0Hz,1H),7.24(d,J=2.1Hz,1H),7.10(dd,J=8.6,2.1Hz,1H),6.45(d ,J=3.0Hz,1H),4.94(br.s,1H),4.03(s,3H),3.74(t,J=6.5Hz,2H),3.34(t,J=6.5Hz,2H) ,3.29–3.24(m,4H),3.00-2.93(m,4H),2.31–2.13(m,5H),1.94-1.51(m,3H),0.37(s,4H).

[0571] Example 19 Preparation of Compound 19

[0572] Synthesis route:

[0573] Preparation method:

[0574] Step 1: Synthesis of compound 19

[0575] Compound 17C (70 mg, 0.13 mmol) and methanesulfonamide (15 mg, 0.38 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cuprous iodide (3 mg, 0.01 mmol), potassium phosphate (55 mg, 0.26 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (4 mg, 0.03 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 16 hours. After TLC indicated completion of the reaction, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 19 (16 mg, pale yellow solid).

[0576] MS (ESI): m / z 280.7 [1 / 2M+1] + .

[0577] 1H NMR(300MHz,DMSO-d6)δ(ppm)10.53(s,1H),10.10(br.s,1H),8.89(s,1H), 8.09(s,1H),7.71(d,J=8.4Hz,1H),7.55(s,1H),7.15(d,J=2.1Hz,1H),7.01 (dd,J=8.5,2.0Hz,1H),4.44-4.34(m,4H),3.07(s,3H),3.05-2.95(m,2H), 2.86-2.77(m,2H),2.28-2.21(m,2H),2.17-1.95(m,6H),1.66-1.44(m,4H).

[0578] Example 20 Preparation of Compound 20

[0579] Synthesis route:

[0580] Preparation method:

[0581] Step 1: Synthesis of compound 20B

[0582] Methyl 2-fluoro-4-bromobenzoate (1.6 g, 6.87 mmol) was dissolved in N,N-dimethylformamide (10 mL). 6,6-dimethyl-3-azabicyclo[3.1.0]hexane (940 mg, 8.24 mmol) and potassium carbonate (2.0 g, 13.7 mmol) were added, and the mixture was stirred at 120°C under nitrogen for 16 hours. After TLC indicated completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (80 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 20B (2.1 g, yellow oil, 94.3% yield).

[0583] MS (ESI): m / z 324.0 [M+1] + .

[0584] Step 2: Synthesis of Compound 20C

[0585] Compound 20B (2.0 g, 6.17 mmol) was dissolved in methanol (20 mL), water (20 mL), and tetrahydrofuran (10 mL). Lithium hydroxide monohydrate (260 mg, 6.17 mmol) was added under ice-cooling, and the mixture was allowed to react at 70°C for 16 hours. After TLC indicated completion of the reaction, the reaction solution was concentrated under reduced pressure to remove methanol and tetrahydrofuran. The pH was then adjusted to 5-6 with 1N hydrochloric acid under ice-cooling, and the mixture was filtered. The filter cake was washed with water (50 mL) and dried to afford compound 20C (1.5 g, pale yellow solid, 78.4% yield).

[0586] MS (ESI): m / z 310.0 [M+1] + .

[0587] Step 3: Synthesis of Compound 20D

[0588] Compound 20C (122 mg, 0.39 mmol) was dissolved in dichloromethane (5 mL), and oxalyl chloride (125 mg, 0.98 mmol) was added dropwise under an ice bath. The mixture was then stirred at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation and dissolved in anhydrous tetrahydrofuran (10 mL). Compound 8-D (100 mg, 0.39 mmol) and N,N-diisopropylethylamine (191 mg, 1.56 mmol) were added sequentially at room temperature. The reaction solution was then stirred at 50°C for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 20D (120 mg, yellow solid, yield: 55.9%).

[0589] Step 3: Synthesis of Compound 20

[0590] Compound 20D (120 mg, 0.22 mmol) and 2-hydroxy-1-sulfonamide (33 mg, 0.29 mmol) were dissolved in N,N-dimethylformamide (4 mL). Cuprous iodide (4 mg, 0.02 mmol), potassium phosphate (94 mg, 0.44 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (6 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 16 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 20 (30 mg, yellow solid).

[0591] MS (ESI): m / z 295.6 [1 / 2M+1] + .

[0592] 1 H NMR(300MHz,DMSO-d6)δ(ppm)10.34(s,1H),9.67(br.s,1H),8.69(s,1H),8.05( d,J=1.1Hz,1H),7.50(d,J=1.1Hz,1H),7.13(d,J=8.7Hz,1H),6.55-6.47(m,2H), 4.92(br.s,1H),4.38-4.29(m,4H),3.71(t,J=6.8Hz,2H),3.43-3.35(m,2H),3. 25-3.15(m,4H),2.12-1.96(m,4H),1.47-1.37(m,2H),0.95(s,3H),0.80(s,3H).

[0593] Example 21 Preparation of Compound 21

[0594] Synthesis route:

[0595] Preparation method:

[0596] Step 1: Synthesis of compound 21B

[0597] Compound 21A (100 mg, 0.45 mmol) was dissolved in N-methylpyrrolidone (3 mL), and N,N-diisopropylethylamine (230 mg, 1.80 mmol) and 4,4-difluoropiperidine hydrochloride (114 mg, 0.90 mmol) were added. The mixture was then stirred at 150°C under nitrogen for 5 hours. After TLC indicated completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 21B (110 mg, yellow solid, yield: 93.3%).

[0598] MS (ESI): m / z 265.1[M+1] + .

[0599] Step 2: Synthesis of Compound 21C

[0600] Compound 1E1 (152 mg, 0.49 mmol) was dissolved in dichloromethane (5 mL), and oxalyl chloride (156 mg, 1.23 mmol) was added dropwise under an ice bath. The mixture was then stirred at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation and dissolved in anhydrous tetrahydrofuran (10 mL). Compound 21B (130 mg, 0.49 mmol) and N,N-diisopropylethylamine (191 mg, 1.47 mmol) were added sequentially at room temperature. The reaction solution was then stirred at 50°C for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 21C (200 mg, yellow solid, 73.1% yield).

[0601] MS (ESI): m / z 279.4 [1 / 2M+1] + .

[0602] Step 3: Synthesis of Compound 21

[0603] Compound 21C (100 mg, 0.18 mmol) and 2-hydroxy-1-sulfonamide (20 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cuprous iodide (4 mg, 0.02 mmol), potassium phosphate (76 mg, 0.36 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 16 hours. After TLC indicated completion of the reaction, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 21 (20 mg, white solid).

[0604] MS (ESI): m / z 301.3 [1 / 2M+1] + .

[0605] 1H NMR (300MHz, DMSO-d6) δ (ppm) 12.90 (s, 1H), 10.21 (br.s, 1H), 8.72 (dd, J = 4.2, 1.7Hz, 1H), 8.24(dd,J=8.5,1.7Hz,1H),8.13–8.07(m,2H),7.61(dd,J=8.4,4.1Hz,1H),7.28(d,J=2.1Hz,1H),7.14(dd,J=8.6,2.1Hz,1H),4.96(br.s, 1H),4.23-4.16(m,4H),3.76(t,J=6.5Hz,2H),3.36(t,J=6.5Hz,2H),3.04-2.97(m,4H),2.28–2.06(m,5H),1.93-1.58(m,3H),0.41(s,4H).

[0606] Example 22 Preparation of Compound 22

[0607] Synthesis route:

[0608] Preparation method:

[0609] Step 3: Synthesis of Compound 22A

[0610] Compound 18C (550 mg, 2.0 mmol) was dissolved in dioxane (7 mL), and tert-butyl carbamate (352 mg, 3.0 mmol), cesium carbonate (1.32 g, 4.0 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (99 mg, 0.2 mmol), and tris(dibenzylideneacetone)dipalladium (88 mg, 0.1 mmol) were added. The mixture was then stirred at 100°C under nitrogen for 16 hours. After TLC indicated the reaction was complete, the reaction solution was cooled to room temperature, washed with water (20 mL), and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to afford compound 22A (550 mg, yellow oil, 80% yield). MS (ESI): m / z 353.1 [M+1] + .

[0611] Step 4: Synthesis of compound 22B

[0612] Compound 22A (322 mg, 0.9 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at 25°C for 16 hours. After TLC showed that the reaction was complete, the reaction solution was desolvated under reduced pressure, and the residue was dissolved in methanol (2 mL) and water (2 mL). Solid sodium hydroxide (182 mg, 4.5 mmol) was slowly added under an ice bath, and the mixture was stirred at 25°C for 16 hours. After TLC showed that the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, desolvated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 22B (130 mg, brown oil, 55.6% yield). MS (ESI): m / z 253.1 [M+1] + .

[0613] Step 5: Synthesis of Compound 22C

[0614] Compound 1E1 (120 mg, 0.4 mmol) was dissolved in dichloromethane (10 mL), and oxalyl chloride (130 mg, 1.0 mmol) was added dropwise under an ice bath, followed by stirring at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation, and the residue was dissolved in anhydrous tetrahydrofuran (10 mL). Compound 22B (100 mg, 0.4 mmol) and N,N'-diisopropylethylamine (200 mg, 1.6 mmol) were added at room temperature, and the mixture was stirred at 50°C for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and desolventized under reduced pressure. The residue was purified on a silica gel column to yield compound 22C (20 mg, yellow solid, 10% yield). MS (ESI): m / z 544.1 [M+1] + .

[0615] Step 6: Synthesis of Compound 22

[0616] Compound 22C (20 mg, 0.04 mmol) and 2-hydroxy-1-sulfonamide (6 mg, 0.52 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cuprous iodide (4 mg, 0.02 mmol), potassium phosphate (23 mg, 0.12 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.03 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 22 (0.62 mg, light yellow solid). MS (ESI): m / z 589.2 [M+1] + .

[0617] Example 23 Preparation of Compound 23

[0618] Synthesis route:

[0619] Preparation method:

[0620] Step 1: Synthesis of compound 23B

[0621] Compound 23A (500 mg, 1.59 mmol) was added to trifluoroacetic acid (1.5 mL) in an ice bath and stirred for 1.5 hours. After TLC indicated the reaction was complete, an ice-water mixture (20 mL) was added to the reaction solution, followed by stirring at room temperature for 5 minutes. The suspension was filtered, and the filter cake was washed with water until the filtrate had a pH of 6. The filter cake was collected and dissolved in dichloromethane (30 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and desolvated under reduced pressure to afford compound 23B (290 mg, white solid, yield: 84.8%).

[0622] Step 2: Synthesis of Compound 23D

[0623] Compound 23B (290 mg, 1.35 mmol) was dissolved in dichloromethane (10 mL), and compound 23C (341 mg, 1.35 mmol) was added at room temperature. The mixture was stirred at room temperature for 16 hours. After LCMS showed that the reaction was complete, the reaction solution was filtered, and the filter cake was washed with dichloromethane (1 mL x 3). The filter cake was dried to obtain crude compound 23D (500 mg, white solid). MS (ESI): m / z 268.9 [M] + .

[0624] Step 3: Synthesis of Compound 23E

[0625] Crude compound 23D (500 mg) was dissolved in triethyl orthoformate (5 mL) and stirred at 100°C for 1 hour. LCMS showed that the reaction was complete. The reaction solution was desolvated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 23E (300 mg, yellow solid). MS (ESI): m / z 278.8 [M+1] + .

[0626] Step 4: Synthesis of compound 23F

[0627] Compound 23E (300 mg, 1.08 mmol) was dissolved in N-methylpyrrolidone (5 mL), and N,N-diisopropylethylamine (230 mg, 4.32 mmol) and 4,4-difluoropiperidine hydrochloride (170 mg, 2.16 mmol) were added. The mixture was then stirred at 100°C under nitrogen for 16 hours. After TLC indicated the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (60 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and desolventized under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 23F (220 mg, brown solid, yield: 64.1%). MS (ESI): m / z 318.0 [M+1] +

[0628] Step 5: Synthesis of Compound 23G

[0629] Compound 23F (200 mg, 0.63 mmol) was dissolved in dioxane (5 mL), and tert-butyl carbamate (148 mg, 1.26 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (30 mg, 0.06 mmol), cesium carbonate (411 mg, 1.26 mmol), and tris(dibenzylideneacetone)dipalladium (29 mg, 0.03 mmol) were added. The mixture was then stirred at 100°C under nitrogen for 16 hours. After TLC indicated the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and desolventized under reduced pressure. The residue was purified by silica gel column chromatography and dried under reduced pressure to afford compound 23G (190 mg, yellow solid, yield: 75.3%). MS (ESI): m / z 355.2[M+1] + .

[0630] Step 6: Synthesis of compound 23H

[0631] Compound 23G (200 mg, 0.56 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. After TLC showed the reaction was complete, the reaction solution was concentrated under reduced pressure to give crude compound 23H (200 mg, yellow oil). MS (ESI): m / z 255.1 [M+1] + .

[0632] Step 7: Synthesis of compound 23I

[0633] Compound 1E1 (182 mg, 0.59 mmol) was dissolved in dichloromethane (5 mL), and oxalyl chloride (188 mg, 1.48 mmol) was added dropwise under an ice bath. The mixture was then stirred at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation, and the residue was dissolved in anhydrous tetrahydrofuran (10 mL). Compound 23H (150 mg, 0.59 mmol) and N,N'-diisopropylethylamine (305 mg, 2.36 mmol) were added sequentially at room temperature, and the mixture was stirred at 50°C for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 23I (100 mg, yellow solid, yield: 31.0%). MS(ESI):m / z 273.6 274.4[1 / 2M+1] + .

[0634] Step 8: Synthesis of Compound 23

[0635] Compound 23I (90 mg, 0.16 mmol) and 2-hydroxy-1-sulfonamide (21 mg, 0.19 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cuprous iodide (3 mg, 0.02 mmol), potassium phosphate (70 mg, 0.32 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 16 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 23 (30 mg, white solid). MS (ESI): m / z 591.4 [M+1] + . 1H NMR(300MHz,DMSO-d6)δ(ppm)13.30(s,1H),10.17(br.s,1H),8.97(s,1H),8. 50(s,1H),8.10(d,J=8.6Hz,1H),7.30(d,J=2.1Hz,1H),7.14(dd,J=8.7,2.1Hz ,1H),4.92(br.s,1H),4.42-4.36(m,4H),3.76(t,J=6.5Hz,2H),3.35(t,J=6.2 Hz,2H),3.02-2.96(m,4H),2.23-2.09(m,5H),1.81-1.68(m,3H),0.42(s,4H).

[0636] Example 24 Preparation of Compound 24

[0637] Step 1: Synthesis of compound 24B

[0638] Compound 24A (50 g, 335.6 mmol) was dissolved in ethanol, and hydrazine hydrate (39.5 g, 671.3 mmol, 85% purity) was added, followed by stirring at 90°C for 12 hours. After the reaction was complete, LCMS indicated that the reaction solution was cooled to room temperature and filtered. The filter cake was washed with icy ethanol and dried to yield crude compound 24B (54 g, yellow solid). MS (ESI): m / z 145.0 [M+1] +

[0639] Step 2: Synthesis of compound 24C

[0640] Crude compound 24B (54 g, 373.5 mmol) was dissolved in tetrahydrofuran, and trifluoroacetic anhydride (86.3 g, 410.9 mmol) was added dropwise in an ice bath, followed by stirring in an ice bath for 3 hours. After the reaction was completed, LCMS showed that the reaction solution was desolvated under reduced pressure, then diluted with water (200 mL), and extracted with dichloromethane (200 mL × 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure to obtain crude compound 24C (40 g, orange liquid). MS (ESI): m / z 241.0 [M+1] +

[0641] Step 3: Synthesis of Compound 24D

[0642] Crude compound 24C (40 g, 166.3 mmol) was dissolved in dichloromethane (400 mL). NBS (86.3 g, 182.9 mmol) was added portionwise at -40°C, and the temperature was naturally raised to 0°C over 1 hour. After completion of the reaction, LCMS showed that the reaction was quenched with water (200 mL) in an ice bath and extracted with dichloromethane (200 mL x 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 24D (15 g, yellow liquid). MS (ESI): m / z 318.8 320.8 [M+1] +

[0643] Step 4: Synthesis of compound 24E

[0644] Compound 24D (15 g, 47.0 mmol) was dissolved in ethanol (160 mL), hydrochloric acid (12 mL, 12 mol / L) was added, and the mixture was stirred at 100°C for 8 hours. After the reaction was completed, ethanol was removed from the reaction solution under reduced pressure, and the reaction was quenched with solid sodium bicarbonate until pH = 7, followed by extraction with dichloromethane / methanol (80 mL × 3, 10:1). The combined organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure to obtain crude compound 24E (7 g, gray solid). MS (ESI): m / z 222.9 224.9 [M+1] +

[0645] Step 5: Synthesis of compound 24F

[0646] Compound 24E (7 g, 31.3 mmol) was dissolved in triethyl orthoformate (70 mL) and stirred at 130°C for 2 hours. LCMS indicated that the reaction was complete. The solvent was removed from the reaction solution under reduced pressure, and the residue was purified by silica gel column chromatography to yield compound 24F (5.2 g, yellow solid). MS (ESI): m / z 232.8 234.8 [M+1] +

[0647] Step 6: Synthesis of Compound 24G

[0648] Compound 24F (800 mg, 3.43 mmol) was dissolved in N-methylpyrrolidone (10 mL), and N,N-diisopropylethylamine (1.8 g, 13.7 mmol) and 4,4-difluoropiperidine hydrochloride (1.1 g, 6.86 mmol) were added. The mixture was then stirred at 60°C under nitrogen for 4 hours. After TLC indicated the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (80 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 24G (220 mg, brownish-red solid, yield: 20.2%). MS (ESI): m / z 318.0 320.0 [M+1] +

[0649] Step 7: Synthesis of compound 24H

[0650] Compound 24G (400 mg, 1.26 mmol) was dissolved in dioxane (10 mL), and tert-butyl carbamate (298 mg, 2.52 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (60 mg, 0.13 mmol), cesium carbonate (823 mg, 2.52 mmol), and tris(dibenzylideneacetone)dipalladium (21 mg, 0.06 mmol) were added. The mixture was then stirred at 110°C under nitrogen for 16 hours. After TLC indicated the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (40 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 24H (150 mg, brown solid, yield: 24.6%). MS (ESI): m / z 355.1 [M+1] + .

[0651] Step 8: Synthesis of Compound 24J

[0652] Compound 24H (100 mg, 0.56 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. After TLC showed that the reaction was complete, the mixture was concentrated under reduced pressure, the solvent was removed, and the mixture was diluted with water (20 mL). The pH was adjusted to 7-8 with solid sodium bicarbonate and extracted with ethyl acetate (20 mL x 4). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure to obtain crude compound 24J (100 mg, dark green solid). MS (ESI): m / z 255.1 [M+1] + .

[0653] Step 9: Synthesis of Compound 24K

[0654] Compound 1E1 (122 mg, 0.39 mmol) was dissolved in dichloromethane (5 mL), and oxalyl chloride (125 mg, 0.98 mmol) was added dropwise under an ice bath. The mixture was then stirred at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was spun down to dryness and then dissolved in anhydrous tetrahydrofuran (5 mL). Compound 24J (100 mg, 0.39 mmol) and N,N-diisopropylethylamine (152 mg, 1.17 mmol) were added sequentially at room temperature, and the reaction solution was stirred at 50°C for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 24K (100 mg, yellow solid, purity: 53.8%, yield: 25.0%). MS (ESI): m / z 273.6 274.4 [M / 2+1] + .

[0655] Step 10: Synthesis of Compound 24

[0656] Compound 24K (100 mg, 0.18 mmol) and 2-hydroxy-1-sulfonamide (28 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cuprous iodide (4 mg, 0.02 mmol), potassium phosphate (78 mg, 0.36 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 24 (40 mg, off-white solid). MS (ESI): m / z 591.1 [M+1] + . 1 H NMR(300MHz,DMSO-d6)δ(ppm)13.05(s,1H),10.20 (br.s,1H),9.34(s,1H),8.76(s,1H),8.05(d,J=8.6Hz,1H),7.26(d,J=2.1Hz,1H),7.11(dd,J=8.7,2.1Hz,1H),4.91(br.s,1H),4. 48-4.35(m,4H),3.73(t,J=6.5Hz,2H),3.33(t,J=6.4Hz,2H),3.00-2.93(m,4H),2.22-2.07(m,5H),1.81-1.56(m,3H),0.38(s,4H).

[0657] Example 25 Preparation of Compound 25

[0658] Step 1: Synthesis of compound 25B

[0659] Compound 25A (5.0 g, 35.1 mmol) was dissolved in glacial acetic acid (50 mL). N-chlorosuccinimide (5.6 g, 42.1 mmol) was added portionwise in an ice bath, and stirring was continued at room temperature for 16 hours. After TLC indicated completion of the reaction, the reaction solution was diluted with water (300 mL), adjusted to pH 7-8 with sodium bicarbonate, and extracted with ethyl acetate (150 mL x 3). The combined organic phases were washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 25B (3.7 g, light red solid, yield: 56.9%). MS (ESI): m / z 176.9 [M+1] + .

[0660] Step 2: Synthesis of compound 25C

[0661] Compound 25B (3.5 g, 19.8 mmol) was dissolved in glacial acetic acid (35 mL). A solution of sodium nitrite (1.5 g, 21.8 mmol) dissolved in water (5 mL) was slowly added dropwise under an ice bath. After the addition was complete, stirring was continued at room temperature for 16 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with 150 mL of ethanol, then adjusted to pH 7-8 with sodium bicarbonate. The solution was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (80 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 25C (500 mg, light red solid, yield: 64.1%). MS (ESI): m / z 187.9 [M+1] + .

[0662] Step 3: Synthesis of compound 25D

[0663] Compound 25C (800 mg, 4.26 mmol) was dissolved in N-methylpyrrolidone (10 mL), and N,N-diisopropylethylamine (2.2 g, 17.0 mmol) and 4,4-difluoropiperidine hydrochloride (1.3 g, 8.52 mmol) were added. The mixture was then stirred at 80°C under nitrogen for 16 hours. After TLC indicated the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 25D (800 mg, brown solid, yield: 62.5%). MS (ESI): m / z 273.1 [M+1] + .

[0664] Step 4: Synthesis of compound 25E

[0665] Compound 25D (1.0 g, 3.49 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL). Sodium hydride (300 mg, 6.98 mmol) was then added portionwise under ice-cooling. The mixture was stirred for 30 minutes. Iodomethane (785 mg, 5.24 mmol) was then added dropwise to the reaction mixture. After the addition was complete, the mixture was slowly warmed to room temperature and stirred for 2 hours. After TLC indicated the reaction was complete, the mixture was quenched with saturated ammonium chloride solution (30 mL) under ice-cooling and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 25E (600 mg, brown oil, purity: 70.5%, yield: 40.2%). MS (ESI): m / z 287.0 [M+1] +

[0666] Step 5: Synthesis of compound 25F

[0667] Compound 25E (600 mg, 2.09 mmol) was dissolved in dioxane (10 mL), and tert-butyl carbamate (492 mg, 4.18 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (198 mg, 0.42 mmol), cesium carbonate (1.37 g, 4.18 mmol), and palladium acetate (192 mg, 0.21 mmol) were added. The mixture was then stirred at 110°C under nitrogen for 16 hours. After TLC indicated the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (80 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 25F (600 mg, yellow solid, yield: 70.2%). MS (ESI): m / z 368.2 [M+1] +

[0668] Step 6: Synthesis of Compound 25G

[0669] Compound 25F (800 mg, 2.18 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. After TLC showed the reaction was complete, the reaction solution was concentrated under reduced pressure and the solvent was removed to obtain crude compound 25G (800 mg, yellow oil). MS (ESI): m / z 268.1 [M+1] + .

[0670] Step 7: Synthesis of compound 25H

[0671] Compound 1E1 (578 mg, 1.87 mmol) was dissolved in dichloromethane (5 mL). Oxalyl chloride (594 mg, 4.68 mmol) was added dropwise under an ice bath, and the mixture was stirred at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation and then dissolved in anhydrous tetrahydrofuran (10 mL). Compound 25G (500 mg, 1.87 mmol) and N,N-diisopropylethylamine (966 mg, 7.48 mmol) were added at room temperature, and the reaction solution was stirred at 50°C for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 25H (400 mg, khaki solid, yield: 36.7%). MS(ESI):m / z 280.1 281.1[M / 2+1] + .

[0672] Step 8: Synthesis of Compound 25

[0673] Compound 25H (400 mg, 0.71 mmol) and 2-hydroxy-1-sulfonamide (108 mg, 0.85 mmol) were dissolved in N,N-dimethylformamide (6 mL). Cuprous iodide (14 mg, 0.07 mmol), potassium phosphate (304 mg, 1.42 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (20 mg, 0.14 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 25 (60 mg, light yellow solid). MS (ESI): m / z 302.7 [M / 2+1] + . 1 H NMR(300MHz,DMSO-d6)δ(ppm)12.51(s,1H),10.26(br.s,1H),8.24(s,1H),8.07 (d,J=8.6Hz,1H),7.82(s,1H),7.25(d,J=2.1Hz,1H),7.11(dd,J=8.6,2.1Hz,1H) ,4.95(s,1H),4.33-4.24(m,4H),4.14(s,3H),3.76(t,J=6.5Hz,2H),3.35(t,J=6 .5Hz,2H),3.04-2.93(m,4H),2.23-1.99(m,5H),1.90-1.61(m,3H),0.40(s,4H).

[0674] Example 26 Preparation of Compound 26

[0675] Preparation method:

[0676] Step 1: Synthesis of compound 26A

[0677] 2-Fluoro-4-bromobenzoic acid (165 mg, 0.76 mmol) was dissolved in thionyl chloride (4 mL) and stirred at 80°C for 2 hours. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation and then dissolved in anhydrous tetrahydrofuran (2 mL). Compound 21B (100 mg, 0.76 mmol) and N,N-diisopropylethylamine (391 mg, 3.04 mmol) were added sequentially at room temperature, followed by stirring at 50°C for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 26A (200 mg, yellow solid, purity: 85.8%, yield: 48.7%). MS (ESI): m / z 465.0 466.9 [M+1] + .

[0678] Step 2: Synthesis of compound 26B

[0679] Compound 26A (100 mg, 0.21 mmol) was dissolved in N,N-dimethylformamide (2 mL), followed by the addition of 3-azabicyclo[3.2.1]octane hydrochloride (32 mg, 0.25 mmol) and potassium carbonate (60 mg, 0.42 mmol). The mixture was stirred at 120°C under nitrogen for 16 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The residue was purified on a silica gel column to yield compound 26B (120 mg, yellow solid, purity: 63.1%, yield: 63.3%). MS (ESI): m / z 278.6 279.7 [M / 2+1] + .

[0680] Step 3: Synthesis of Compound 26

[0681] Compound 26B (100 mg, 0.18 mmol) and 2-hydroxy-1-sulfonamide (27 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (4 mL). Cuprous iodide (3 mg, 0.02 mmol), potassium phosphate (76 mg, 0.36 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120°C for 2 hours under nitrogen. After TLC indicated the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (8 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 26 (27 mg, off-white solid). MS (ESI): m / z 301.1 [M / 2+1] + . 1 H NMR (300MHz, DMSO-d6) δ (ppm) 10.50 (s, 1H), 10.02 (br.s, 1H), 8.71 (dd, J = 4.1, 1.7Hz, 1H), 8.24 (dd,J=8.5,1.7Hz,1H),8.12(s,1H),7.69–7.55(m,2H),7.12(d,J=2.0Hz,1H),6.98(dd,J=8.4,2 .0Hz,1H),4.95(br.s,1H),4.20-4.10(m,4H),3.76(t,J=6.6Hz,2H),3.31(t,J=6.6Hz,2H),3.0 9–2.98(m,2H),2.79(d,J=10.5Hz,2H),2.27–2.02(m,6H),1.98-1.88(m,2H),1.58-1.44(m,4H).

[0682] Example 27 Preparation of Compound 27

[0683] Step 1: Synthesis of compound 27B

[0684] Compound 27A (5 g, 28.7 mmol) was dissolved in acetic acid (50 mL), and Raney nickel (2 g) was added. The mixture was then stirred at 55°C under hydrogen (40 psi) for 48 hours. LCMS indicated the reaction was complete. The reaction solution was filtered through celite, and the filtrate was decompressed to obtain crude compound 27B (6 g, brown oil). MS (ESI): m / z 178.0 [M+1] + .

[0685] Step 2: Synthesis of compound 27C

[0686] Acetic anhydride (25 mL) was added to formic acid (25 mL), and then stirred at 50 ° C for 2 hours. The above solution was then cooled to room temperature, and a solution of compound 27B (6 g) in dichloromethane (50 mL) was added dropwise to the above reaction solution at room temperature, and then stirred at room temperature for 3 hours. LCMS showed that after the reaction was completed, the reaction solution was decompressed and desolvated, and the residue was quenched with saturated sodium bicarbonate until pH = 7, and then extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and desolvated to give crude compound 27C (5 g, brown solid). MS (ESI): m / z 205.8 [M+1] + .

[0687] Step 3: Synthesis of compound 27D

[0688] The crude compound 27C (5 g, 24.3 mmol) was dissolved in acetonitrile (50 mL), and dichlorothionyl (4.33 g, 36.4 mmol) was added at room temperature, followed by stirring at 80°C for 0.5 hours. After the reaction was completed, LCMS showed that the reaction solution was desolvated under reduced pressure, and the residue was quenched with saturated sodium bicarbonate until pH = 7, and then extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, desolvated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 27D (3.2 g, brown solid). MS (ESI): m / z 187.9 [M+1] + .

[0689] Step 4: Synthesis of compound 27E

[0690] Compound 27D (270 mg, 1.44 mmol) was dissolved in N-methyl-2-pyrrolidone (6 mL), and 4,4-difluoropiperidine hydrochloride (296 mg, 1.87 mmol) and N,N-diisopropylethylamine (558 mg, 4.32 mmol) were added. After the addition was complete, the mixture was stirred at 80°C under nitrogen for 4 hours. After TLC showed the reaction was complete, the reaction solution was diluted with water (20 mL) at 0°C and then extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (15 mL x 3), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and desolventized under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 27E (383 mg, 1.40 mmol, yellow oil, 97.2% yield). MS (ESI): m / z 273.0 [M+1] + .

[0691] Step 5: Synthesis of compound 27F

[0692] Compound 27E (383 mg, 1.40 mmol) was dissolved in dioxane (7 mL), and tert-butyl carbamate (247 mg, 2.1 mmol), cesium carbonate (1.4 g, 4.2 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (67 mg, 0.14 mmol), and tris(dibenzylideneacetone)dipalladium (65 mg, 0.07 mmol) were added. The mixture was then stirred at 100°C under nitrogen for 5 hours. After TLC indicated the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (15 mL x 2). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to afford compound 27F (220 mg, yellow oil, 44% yield). MS (ESI): m / z 354.2 [M+1] + .

[0693] Step 6: Synthesis of Compound 27G

[0694] Compound 27F (220 mg, 0.62 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (1.5 mL) was added, and the mixture was stirred at room temperature for 5 hours. After TLC showed the reaction was complete, the solvent was removed under reduced pressure to obtain crude compound 27G (151 mg, yellow oil). MS (ESI): m / z 254.1 [M+1] + .

[0695] Step 7: Synthesis of compound 27H

[0696] Compound 1E1 (184 mg, 0.6 mmol) was dissolved in dichloromethane (2 mL), and oxalyl chloride (189 mg, 1.5 mmol) was added dropwise under ice-cooling, followed by stirring at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation, and the residue was dissolved in anhydrous tetrahydrofuran (2 mL). Compound 27G (151 mg, 0.6 mmol) and N,N-diisopropylethylamine (309 mg, 2.4 mmol) were added to the reaction solution under ice-cooling, and the mixture was stirred at room temperature for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 27H (98 mg, yellow solid, 30% yield). MS (ESI): m / z 545.2 547.1 [M+1] + .

[0697] Step 8: Synthesis of Compound 27

[0698] Compound 27H (98 mg, 0.18 mmol) and 2-hydroxy-1-sulfonamide (27 mg, 0.24 mmol) were dissolved in N,N-dimethylformamide (5 mL). Cuprous iodide (18 mg, 0.11 mmol), potassium phosphate (99 mg, 0.52 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (20 mg, 0.15 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 27 (6 mg, yellow solid). MS (ESI): m / z 590.2 [M+1] + . 1 H NMR(300MHz,DMSO-d6)δ(ppm)12.81(s,1H),10.20(br.s,1H),8.71(s,1H),8.53( s,1H),8.07(d,J=8.6Hz,1H),7.87(s,1H),7.28(d,J=2.2Hz,1H),7.14(dd,J=8.7, 2.1Hz,1H),4.94(br.s,1H),4.01-3.93(m,4H),3.76(t,J=6.5Hz,2H),3.35(t,J= 6.5Hz,2H),3.01-2.94(m,4H),2.23-2.04(m,5H),1.82-1.59(m,3H),0.40(s,4H).

[0699] Example 28 Preparation of Compound 28

[0700] Step 1: Synthesis of compound 28B

[0701] Compound 28A (8.0 g, 38.5 mmol) was dissolved in ethanol (160 mL) and water (30 mL), and iron powder (10.7 g, 192.5 mmol) and concentrated hydrochloric acid (20 mL) were added. The mixture was stirred at 95°C for 16 hours. After TLC showed that the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filtrate was diluted with water (150 mL), and the pH was adjusted to 7 with solid sodium bicarbonate. The mixture was then extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and desolventized under reduced pressure to obtain crude compound 28B (10.0 g, yellow solid). MS (ESI): m / z 178.0 [M+1] + .

[0702] Step 2: Synthesis of compound 28C

[0703] Crude compound 28B (10.0 g, 56.1 mmol) was dissolved in hydrochloric acid (25 mL, 2 mol / L) and water (20 mL). Solid sodium nitrite (3.26 g, 56.1 mmol) was added portionwise at 0°C, and the mixture was stirred at 0°C for 4 hours. After TLC indicated the reaction was complete, ice water (150 mL) was added to the reaction solution, causing solid precipitation. The solid was filtered, and the filter cake was washed twice with water. The filter cake was collected and dried to obtain crude compound 28C (6.5 g, yellow solid). MS (ESI): m / z 188.9 [M+1] + .

[0704] Step 3: Synthesis of compound 28D

[0705] Compound 28C (2.0 g, 10.6 mmol) was dissolved in N-methyl-2-pyrrolidone (20 mL), and N,N-diisopropylethylamine (4.1 g, 31.8 mmol) and 4,4-difluoropiperidine hydrochloride (2.2 g, 13.8 mmol) were added. The mixture was then stirred at 100°C for 16 hours. After TLC indicated the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (50 mL), and then extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and desolventized under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 28D (2.6 g, yellow oil, 89.6% yield).

[0706] MS (ESI): m / z 274.1[M+1] + .

[0707] Step 4: Synthesis of compound 28E

[0708] Compound 28D (1.0 g, 3.7 mmol) was dissolved in tetrahydrofuran (10 mL), and 3,4-dihydro-2H-pyran (615 mg, 7.4 mmol) and p-toluenesulfonic acid monohydrate (69 mg, 0.37 mmol) were added. The mixture was then stirred at room temperature for 5 hours. After TLC showed that the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and desolventized under reduced pressure. The residue was purified by silica gel column chromatography to obtain crude compound 28E (1.6 g, yellow solid). MS (ESI): m / z 358.1 [M+1] + .

[0709] Step 5: Synthesis of compound 28F

[0710] Compound 28E (1.6 g, 4.5 mmol) was dissolved in dioxane (16 mL), and tert-butyl carbamate (787 mg, 6.8 mmol), cesium carbonate (4.38 g, 13.5 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (213 mg, 0.45 mmol), and tris(dibenzylideneacetone)dipalladium (205 mg, 0.23 mmol) were added. The mixture was then stirred at 100°C under nitrogen for 16 hours. After TLC indicated the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to afford compound 28F (1.7 g, yellow oil, 88% yield). MS (ESI): m / z 439.3 [M+1] + .

[0711] Step 6: Synthesis of Compound 28G

[0712] Compound 28F (1.7 g, 4.0 mmol) was dissolved in toluene (20 mL) and 300-400 mesh silica gel (1.7 g) was added. The mixture was then stirred at 120°C for 16 hours. After TLC indicated the reaction was complete, the reaction mixture was filtered, and the filter cake was washed with dichloromethane / methanol = 5:1 (30 mL). The filtrate was desolvated under reduced pressure to yield crude compound 28G (860 mg, brown oil). MS (ESI): m / z 339.2 [M+1] + .

[0713] Step 7: Synthesis of compound 28H

[0714] Compound 28G (860 mg, 2.5 mmol) and compound 1E1 (732 mg, 2.4 mmol) were dissolved in pyridine (8 mL). Phosphorus oxychloride (1.92 g, 12.5 mmol) was added dropwise under an ice bath, and then stirred at room temperature for 3 hours. After TLC showed that the reaction was complete, the reaction solution was dried, diluted with ice water (20 mL), and the pH was adjusted to 5 with 4N hydrochloric acid. Then, the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to obtain compound 28H (162 mg, yellow solid, 12% yield). MS (ESI): m / z 273.7 274.8 [(M-84) / 2+1] +

[0715] Step 8: Synthesis of compound 28I

[0716] Compound 28H (162 mg, 0.3 mmol) and 2-hydroxy-1-sulfonamide (53 mg, 0.4 mmol) were dissolved in N,N-dimethylformamide (5 mL). Cuprous iodide (37 mg, 0.18 mmol), potassium phosphate (200 mg, 0.87 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (40 mg, 0.26 mmol) were added sequentially. The mixture was then stirred at 120°C for 2 hours under nitrogen. After TLC showed the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (8 mL x 3). The combined organic phases were washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to obtain compound 28I (25 mg, white solid). MS (ESI): m / z 675.2 [M+1] + .

[0717] Step 9: Synthesis of Compound 28

[0718] Compound 28I (25 mg) was dissolved in ethanolic hydrochloride (2 mL, 4 mol / L) and stirred at 25°C for 0.5 hours. After TLC indicated the reaction was complete, the solvent was removed under reduced pressure and the residue was purified by HPLC to give compound 28 (8 mg, white solid). MS (ESI): m / z 591.3 [M+1] + . 1 H NMR(300MHz,DMSO-d6)δ(ppm)12.97(s,1H),10.29(br.s,1H),8.09(d,J=8.6Hz,1H),7.85(s,1H),7.28(d,J=2.2Hz,1H),7.13(dd,J=8.6,2.1Hz,1H),4 .99(br.s,1H),4.50-4.28(m,4H),3.76(t,J=6.4Hz,2H),3.36(t,J=6.4Hz, 2H),3.05-2.94(m,4H),2.45-2.02(m,5H),1.87-1.61(m,3H),0.41(s,4H).

[0719] Example 29 Preparation of Compound 29

[0720] Step 1: Synthesis of compound 29A

[0721] Compound 8-A (1.1 g, 3.9 mmol) was dissolved in N-methyl-2-pyrrolidone (12 mL), and N,N-diisopropylethylamine (2.06 g, 15.6 mmol) and 2-azaspiro[3.3]heptane hemioxalate (792 mg, 2.7 mmol) were added. The mixture was then stirred at 100°C under nitrogen for 5 hours. After TLC indicated completion of the reaction, the reaction solution was diluted with water (30 mL) at 0°C and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 29A (1.1 g, yellow oil, 94.8% yield). MS (ESI): m / z 293.0 295.0 [M+1] + .

[0722] Step 2: Synthesis of compound 29B

[0723] Compound 29A (600 mg, 2.1 mmol) was dissolved in dioxane (7 mL), and tert-butyl carbamate (360 mg, 3.2 mmol), cesium carbonate (1.33 g, 4.2 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (92 mg, 0.2 mmol), and palladium acetate (24 mg, 0.1 mmol) were added. The mixture was then stirred at 100°C under nitrogen for 5 hours. After TLC indicated the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and desolventized under reduced pressure. The residue was purified on a silica gel column to yield compound 29B (550 mg, yellow oil, 80.9% yield). MS (ESI): m / z 330.2 [M+1] + .

[0724] Step 3: Synthesis of Compound 29C

[0725] Compound 29B (550 mg, 1.7 mmol) was dissolved in dichloromethane (7 mL), trifluoroacetic acid (1.5 mL) was added, and the mixture was stirred at room temperature for 2 hours. After TLC showed the reaction was complete, the solvent was removed under reduced pressure to obtain crude compound 29C (330 mg, brown oil). MS (ESI): m / z 230.1 [M+1] + .

[0726] Step 4: Synthesis of compound 29D

[0727] Compound 1E1 (440 mg, 1.4 mmol) was dissolved in dichloromethane (5 mL), and oxalyl chloride (451 mg, 3.5 mmol) was added dropwise under an ice bath, followed by stirring at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation, and the residue was dissolved in anhydrous tetrahydrofuran (5 mL). Compound 29C (330 mg, 1.4 mmol) and N,N-diisopropylethylamine (737 mg, 5.6 mmol) were added to the reaction solution at room temperature, and the mixture was stirred at room temperature for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 29D (648 mg, yellow solid, 85.7% yield). MS (ESI): m / z 261.3 262.4 [M / 2+1] +

[0728] Step 5: Synthesis of Compound 29

[0729] Compound 29D (120 mg, 0.23 mmol) and 2-hydroxy-1-sulfonamide (37 mg, 0.3 mmol) were dissolved in N,N-dimethylformamide (5 mL). Cuprous iodide (26 mg, 0.13 mmol), potassium phosphate (144 mg, 0.67 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (28 mg, 0.2 mmol) were added sequentially. The mixture was then stirred at 120°C for 2 hours under nitrogen. After TLC indicated the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (8 mL x 3). The combined organic phases were washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 29 (5 mg, white solid). MS (ESI): m / z 566.0 [M+1] + . 1H NMR (300MHz, DMSO-d6) δ (ppm) 13.07 (s, 1H), 10.19 (s, 1H), 8.62 (s, 1H), 8.06 (d, J = 8.6 Hz,1H),7.99(d,J=1.0Hz,1H),7.49(d,J=1.0Hz,1H),7.28(d,J=2.1Hz,1H),7.14(dd,J =8.6,2.1Hz,1H),4.94(br.s,1H),4.43-4.31(m,4H),3.76(t,J=6.4Hz,2H),3.37(t,J =6.4Hz,2H),3.03-2.94(m,4H),2.22(t,J=7.5Hz,5H),1.93–1.69(m,5H),0.43(s,4H).

[0730] Example 30 Preparation of Compound 30

[0731] Step 1: Synthesis of compound 30A

[0732] Compound 8-A (1 g, 3.9 mmol) was dissolved in N-methyl-2-pyrrolidone (12 mL), and N,N-diisopropylethylamine (2.06 g, 15.6 mmol) and 3-azabicyclo[3.2.1]octane hydrochloride (1.6 g, 11.7 mmol) were added. The mixture was then stirred at 100°C under nitrogen for 5 hours. After TLC indicated completion of the reaction, the reaction solution was diluted with water (30 mL) at 0°C and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and desolventized under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 30A (260 mg, yellow oil, 24% yield). MS (ESI): m / z 307.0 309.0 [M+1] + .

[0733] Step 2: Synthesis of compound 30B

[0734] Compound 30A (260 mg, 0.85 mmol) was dissolved in dioxane (7 mL), and tert-butyl carbamate (148 mg, 1.27 mmol), cesium carbonate (559 mg, 1.7 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (39 mg, 0.09 mmol), and palladium acetate (13 mg, 0.04 mmol) were added. The mixture was then stirred at 100°C under nitrogen for 5 hours. After TLC indicated the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and desolventized under reduced pressure. The residue was purified on a silica gel column to yield compound 30B (234 mg, yellow oil, 80% yield). MS (ESI): m / z 344.2 [M+1] + .

[0735] Step 3: Synthesis of Compound 30C

[0736] Compound 30B (234 mg, 0.68 mmol) was dissolved in dichloromethane (7 mL), trifluoroacetic acid (1.5 mL) was added, and the mixture was stirred at room temperature for 2 hours. After TLC showed the reaction was complete, the solvent was removed under reduced pressure to obtain crude compound 30C (164 mg, brown oil). MS (ESI): m / z 244.1 [M+1] + .

[0737] Step 4: Synthesis of compound 30D

[0738] Compound 1E1 (207 mg, 0.67 mmol) was dissolved in dichloromethane (5 mL), and oxalyl chloride (214 mg, 1.67 mmol) was added dropwise under an ice bath, followed by stirring at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation, and the residue was dissolved in anhydrous tetrahydrofuran (5 mL). Compound 30C (164 mg, 0.67 mmol) and N,N-diisopropylethylamine (348 mg, 2.68 mmol) were added to the reaction solution at room temperature, and the mixture was stirred at room temperature for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 30D (132 mg, yellow solid, 37.3% yield). MS(ESI):m / z 268.3 269.0[M / 2+1] +

[0739] Step 5: Synthesis of Compound 30

[0740] Compound 30D (132 mg, 0.25 mmol) and 2-hydroxy-1-sulfonamide (33 mg, 0.25 mmol) were dissolved in N,N-dimethylformamide (5 mL). Cuprous iodide (26 mg, 0.15 mmol), potassium phosphate (152 mg, 0.73 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (20 mg, 0.22 mmol) were added sequentially. The mixture was then stirred at 120°C for 2 hours under nitrogen. After TLC indicated the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (8 mL x 3). The combined organic phases were washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 30 (25 mg, white solid). MS (ESI): m / z 290.7 [M / 2+1] + . 1 H NMR(300MHz,DMSO-d6)δ(ppm)12.83(s,1H),10.34(br.s,1H),8.71(s,1H),8. 20–7.93(m,2H),7.50(s,1H),7.27(s,1H),7.13(d,J=8.4Hz,1H),5.27(s,2H), 4.98(br.s,1H),3.76(t,J=6.5Hz,2H),3.35(t,J=6.4Hz,2H),3.09(d,J=12.6H z,2H),3.03-2.92(m,4H),2.39-2.28(m,2H),1.97–1.42(m,10H),0.39(s,4H).

[0741] Example 31 Preparation of Compound 31

[0742] Step 1: Synthesis of compound 31A

[0743] Compound 8-A (1.0 g, 3.61 mmol) was dissolved in N-methylpyrrolidone (10 mL), and N,N-diisopropylethylamine (930 mg, 7.22 mmol) and 6-aza-spiro[2.5]octane hydrochloride (640 mg, 4.33 mmol) were added. The mixture was then stirred at 100°C for 16 hours. After TLC indicated completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (70 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography and dried under reduced pressure to afford compound 31A (1.0 g, pink solid, yield: 86.2%). MS (ESI): m / z 307.0 309.0 [M+1] +.

[0744] Step 2: Synthesis of compound 31B

[0745] Compound 31A (500 mg, 1.63 mmol) was dissolved in dioxane (5 mL), and tert-butyl carbamate (382 mg, 3.26 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (156 mg, 0.33 mmol), cesium carbonate (1.06 mg, 3.26 mmol), and palladium acetate (37 mg, 0.16 mmol) were added. The mixture was then reacted at 100°C under nitrogen for 16 hours. After TLC indicated completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (60 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 31B (400 mg, yellow solid, yield: 71.6%). MS (ESI): m / z 344.1 [M+1] + .

[0746] Step 3: Synthesis of Compound 31C

[0747] Compound 31B (100 mg, 0.29 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.4 mL) was added, and the mixture was stirred at room temperature for 16 hours. After TLC showed the reaction was complete, the mixture was concentrated under reduced pressure and the solvent was removed to obtain crude compound 31C (100 mg, yellow oil). MS (ESI): m / z 244.1 [M+1] + .

[0748] Step 4: Synthesis of compound 31D

[0749] Compound 1E1 (89 mg, 0.29 mmol) was dissolved in dichloromethane (2 mL). Oxalyl chloride (91 mg, 0.73 mmol) was added dropwise under an ice bath, and the mixture was stirred at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation and then dissolved in anhydrous tetrahydrofuran (5 mL). A mixture of compound 31C (70 mg, 0.29 mmol) and N,N-diisopropylethylamine (148 mg, 1.16 mmol) in tetrahydrofuran was added at room temperature, and the reaction solution was stirred at 50°C for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 31D (80 mg, yellow solid, purity: 65.8%, yield: 31.7%). MS(ESI):m / z 268.1 269.1[M / 2+1] + .

[0750] Step 5: Synthesis of compound 31

[0751] Compound 31D (70 mg, 0.13 mmol) and 2-hydroxy-1-sulfonamide (20 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cuprous iodide (3 mg, 0.01 mmol), potassium phosphate (56 mg, 0.26 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.03 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 31 (15 mg, off-white solid). MS (ESI): m / z 290.7 [M / 2+1] + . 1 H NMR(300MHz,DMSO-d6)δ(ppm)12.77(s,1H),10.19(br.s,1H),8.74(s,1H),8. 14-7.93(m,2H),7.51(d,J=1.1Hz,1H),7.27(d,J=2.1Hz,1H),7.13(dd,J=8.6, 2.1Hz,1H),4.94(br.s,1H),4.40-4.29(m,4H),3.76(t,J=6.5Hz,2H),3.35(t, J=6.5Hz,2H),3.02-2.93(m,4H),1.91–1.40(m,8H),0.39(s,4H),0.36(s,4H).

[0752] Example 32 Preparation of Compound 32

[0753] Step 1: Synthesis of compound 32

[0754] Compound 21C (100 mg, 0.18 mmol) and methanesulfonamide (21 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cuprous iodide (4 mg, 0.02 mmol), potassium phosphate (78 mg, 0.36 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (15 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 32 (30 mg, white solid). MS (ESI): m / z 286.2 [M / 2+1] + . 1 H NMR (300MHz, DMSO-d6) δ (ppm) 12.90 (s, 1H), 10.25 (s, 1H), 8.72 (dd, J = 4.1, 1.7 Hz,1H),8.24(dd,J=8.5,1.7Hz,1H),8.17–8.04(m,2H),7.61(dd,J=8.4,4.1Hz, 1H),7.27(d,J=2.1Hz,1H),7.14(dd,J=8.6,2.1Hz,1H),4.24-4.16(m,4H),3.1 3(s,3H),3.05-2.96(m,4H),2.27-2.07(m,5H),1.86-1.61(m,3H),0.40(s,4H).

[0755] Example 33 Preparation of Compound 33

[0756] Step 3: Synthesis of Compound 33

[0757] Compound 26B (800 mg, 0.14 mmol) and methanesulfonamide (17 mg, 0.17 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cuprous iodide (3 mg, 0.01 mmol), potassium phosphate (61 mg, 0.28 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (4 mg, 0.03 mmol) were added sequentially. The mixture was stirred at 120°C under nitrogen for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 33 (15 mg, white solid).

[0758] MS (ESI): m / z 286.2 [M / 2+1] + .

[0759] 1 H NMR (300MHz, DMSO-d6) δ (ppm) 10.49 (s, 1H), 10.04 (s, 1H), 8.71 (dd, J = 4.1, 1.7Hz, 1 H),8.25(dd,J=8.5,1.8Hz,1H),8.12(s,1H),7.71–7.54(m,2H),7.11(d,J=2.1Hz,1 H),6.99(dd,J=8.4,2.0Hz,1H),4.21-4.10(m,4H),3.07(s,3H),3.06-3.01(m,2H), 2.80(d,J=10.5Hz,2H),2.27–2.03(m,6H),1.93(d,J=7.6Hz,2H),1.58-1.44(m,4H).

[0760] Example 34 Preparation of Compound 34

[0761] Step 1: Synthesis of compound 34A

[0762] Compound 8-A (20 g, 72.2 mmol) was dissolved in acetonitrile (180 mL), and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (28.1 g, 79.4 mmol) was added at room temperature. The mixture was then stirred at 80°C for 5 hours. LCMS indicated that the reaction was complete. The reaction solution was desolvated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a crude product. The crude product was then purified by reverse phase column chromatography to obtain 34A (3.1 g, yellow solid, yield: 14.5%). MS (ESI): m / z 295.8 [M+1] +

[0763] Step 2: Synthesis of compound 34B

[0764] Compound 34A (1.0 g, 3.39 mmol) was dissolved in N-methylpyrrolidone (10 mL), and N,N-diisopropylethylamine (884 mg, 6.78 mmol) and 4,4-difluoropiperidine hydrochloride (650 mg, 4.07 mmol) were added, followed by stirring at 100°C for 16 hours. After TLC indicated the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (80 mL), and extracted with ethyl acetate (80 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 34B (1.0 g, light yellow solid, purity: 73.5%, yield: 64.7%). MS (ESI): m / z 335.0 337.0 [M+1] +

[0765] Step 3: Synthesis of Compound 34C

[0766] Compound 34B (400 mg, 1.19 mmol) was dissolved in dioxane (10 mL), and tert-butyl carbamate (280 mg, 2.38 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (57 mg, 0.12 mmol), cesium carbonate (340 mg, 2.38 mmol), and palladium acetate (13 mg, 0.06 mmol) were added. The mixture was then stirred at 100°C under nitrogen for 16 hours. After TLC indicated the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (40 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 34C (300 mg, off-white solid, purity: 75.2%, yield: 50.9%). MS (ESI): m / z 372.1 [M+1] + .

[0767] Step 4: Synthesis of compound 34D

[0768] Compound 34C (300 mg, 0.81 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. After TLC showed the reaction was complete, the mixture was concentrated under reduced pressure and the solvent was removed to obtain crude compound 34D (300 mg, yellow oil). MS (ESI): m / z 272.1 [M+1] + .

[0769] Step 5: Synthesis of compound 34E

[0770] Compound 1E1 (228 mg, 0.74 mmol) was dissolved in dichloromethane (5 mL), and oxalyl chloride (234 mg, 1.85 mmol) was added dropwise under an ice bath. The mixture was then stirred at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation, and the residue was dissolved in anhydrous tetrahydrofuran (5 mL). A mixture of compound 34D (200 mg, 0.74 mmol) and N,N-diisopropylethylamine (381 mg, 2.96 mmol) was added at room temperature, and the mixture was stirred at 50°C for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 34E (200 mg, pale yellow solid, purity: 65.8%, yield: 31.7%). MS(ESI):m / z 282.8 283.9[M / 2+1] + .

[0771] Step 6: Synthesis of compound 34

[0772] Compound 34E (100 mg, 0.18 mmol) and 2-hydroxy-1-sulfonamide (27 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cuprous iodide (3 mg, 0.02 mmol), potassium phosphate (75 mg, 0.36 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120°C for 2 hours under nitrogen. After LCMS showed completion of the reaction, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 34 (40 mg, light yellow solid). MS (ESI): m / z 304.5 [M / 2+1] + . 1H NMR(300MHz,DMSO-d6)δ(ppm)13.03(s,1H),10.30(br.s,1H),8.43(s,1H),8.08 (d,J=8.6Hz,1H),7.40(d,J=7.2Hz,1H),7.29(d,J=2.2Hz,1H),7.14(dd,J=8.6,2 .1Hz,1H),4.95(br.s,1H),4.46-4.36(m,4H),3.76(t,J=6.5Hz,2H),3.36(t,J=6 .5Hz,2H),3.03-2.94(m,4H),2.21-2.02(m,5H),1.85-1.61(m,3H),0.41(s,4H).

[0773] Example 35 Preparation of Compound 35

[0774] Preparation method:

[0775] Step 1: Synthesis of compound 35B

[0776] Compound 42B (1 g, 2.26 mmol) was dissolved in N,N-dimethylformamide (10 mL), and cuprous iodide (2.15 g, 11.3 mmol), cesium fluoride (1.03 g, 6.78 mmol), and (trifluoromethyl)trimethylsilane (963 mg, 6.78 mmol) were added. The mixture was then stirred at 95°C for 12 hours under nitrogen. LCMS indicated that the reaction was complete. The reaction solution was cooled to room temperature, added to water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to afford compound 35B (110 mg, yellow solid, 12.6% yield). MS (ESI): m / z 384.9 387.0 [M+1] +

[0777] Step 2: Synthesis of compound 35C

[0778] Compound 35B (110 mg, 0.29 mmol) was dissolved in dioxane (6 mL), and tert-butyl carbamate (55 mg, 0.44 mmol), cesium carbonate (187 g, 0.58 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (14 mg, 0.03 mmol), and palladium acetate (4 mg, 0.02 mmol) were added. The mixture was then stirred at 100°C under a nitrogen atmosphere for 5 hours. After TLC indicated the reaction was complete, the mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (15 mL x 2). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to afford compound 35C (69 mg, yellow oil, 55.1% yield). MS (ESI): m / z 422.1 [M+1] +

[0779] Step 4: Synthesis of compound 35D

[0780] Compound 35C (69 mg, 0.16 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) was added. After the addition was complete, the mixture was stirred at 25°C for 2 hours. After TLC indicated the reaction was complete, the solvent was removed under reduced pressure to obtain crude compound 35D (50 mg, brown oil). MS (ESI): m / z 322.1 [M+1] + .

[0781] Step 4: Synthesis of compound 35E

[0782] Compound 1E1 (48 mg, 0.16 mmol) was dissolved in dichloromethane (2 mL), and oxalyl chloride (49 mg, 0.4 mmol) was added dropwise under an ice bath. The mixture was then stirred at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation and then dissolved in anhydrous tetrahydrofuran (2 mL). Compound 35D (50 mg, 0.16 mmol) and N,N-diisopropylethylamine (80 mg, 0.64 mmol) were added at room temperature, and the mixture was stirred at room temperature for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 35E (50 mg, yellow solid, 50% yield).

[0783] Step 5: Synthesis of Compound 35

[0784] Compound 35E (50 mg, 0.08 mmol) and 2-hydroxy-1-sulfonamide (13 mg, 0.10 mmol) were dissolved in N,N-dimethylformamide (5 mL). Cuprous iodide (9 mg, 0.05 mmol), potassium phosphate (50 mg, 0.23 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (10 mg, 0.07 mmol) were added sequentially. The mixture was then stirred at 120°C for 2 hours under nitrogen. After TLC indicated the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 35 (15 mg, white solid). MS (ESI): m / z 329.7 [M / 2+1] +1 H NMR(300MHz,DMSO-d6)δ(ppm)13.22(s,1H),10.27(br.s,1H),8.80(s,1H),8.21–8.01(m,2H),7.29(s,1H),7.14(d,J=8.3Hz,1H),4.95(br.s ,1H),4.41-4.33(m,4H),3.76(t,J=6.4Hz,2H),3.36(t,J=6.4Hz,2H), 3.05-2.92(m,4H),2.28-2.04(m,5H),1.87-1.59(m,3H),0.41(s,4H).

[0785] Example 36 Preparation of Compound 36

[0786] Preparation method:

[0787] Step 1: Synthesis of compound 36B

[0788] Compound 36A (1.0 g, 3.95 mmol) was dissolved in N,N-dimethylacetamide (10 mL), and 3-bromo-1,1,1-trifluoroacetone (1.9 g, 9.88 mmol) was added, followed by stirring at 90°C for 16 hours. After TLC showed the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to obtain crude compound 36B (600 mg, brown oil). MS (ESI): m / z 345.8 [M+1] +

[0789] Step 2: Synthesis of compound 36C

[0790] Compound 36B (600 mg, 1.74 mmol) was dissolved in N-methylpyrrolidone (10 mL), and N,N-diisopropylethylamine (451 mg, 3.48 mmol) and 4,4-difluoropiperidine hydrochloride (332 mg, 2.09 mmol) were added, followed by stirring at 100°C for 4 hours. After TLC indicated the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (80 mL), and extracted with ethyl acetate (40 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 36C (400 mg, light yellow solid, purity: 71.8%, yield: 42.9%). MS (ESI): m / z 385.0 387.0 [M+1] +

[0791] Step 3: Synthesis of compound 36D

[0792] Compound 36C (200 mg, 0.52 mmol) was dissolved in dioxane (5 mL), and tert-butyl carbamate (122 mg, 1.04 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (25 mg, 0.05 mmol), cesium carbonate (340 mg, 1.04 mmol), and palladium acetate (6 mg, 0.03 mmol) were added. The mixture was then stirred at 100°C under nitrogen for 16 hours. After TLC indicated the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (40 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 36D (160 mg, yellow solid, purity: 81.4%, yield: 59.5%). MS (ESI): m / z 366.1 [M-55] + .

[0793] Step 4: Synthesis of compound 36E

[0794] Compound 36D (180 mg, 0.43 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. After TLC showed the reaction was complete, the mixture was concentrated under reduced pressure and the solvent was removed to obtain crude compound 36E (180 mg, yellow oil). MS (ESI): m / z 322.1 [M+1] + .

[0795] Step 5: Synthesis of compound 36F

[0796] Compound 1E1 (135 mg, 0.44 mmol) was dissolved in dichloromethane (5 mL), and oxalyl chloride (139 mg, 1.10 mmol) was added dropwise under an ice bath, followed by stirring at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was spun down to dryness and then dissolved in anhydrous tetrahydrofuran (5 mL). Compound 36E (140 mg, 0.44 mmol) and N,N-diisopropylethylamine (225 mg, 1.76 mmol) were added at room temperature, and the mixture was stirred at 50°C for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 36F (200 mg, light yellow solid, purity: 81.3%, yield: 60.8%). MS (ESI): m / z 307.1 308.2 [M / 2+1] +

[0797] Step 6: Synthesis of compound 36

[0798] Compound 36F (100 mg, 0.16 mmol) and 2-hydroxy-1-sulfonamide (25 mg, 0.19 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cuprous iodide (3 mg, 0.02 mmol), potassium phosphate (69 mg, 0.32 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.03 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 36 (38 mg, light yellow solid). MS (ESI): m / z 329.7 [M / 2+1] + . 1 H NMR(300MHz,DMSO-d6)δ(ppm)13.03(s,1H),10.21(br.s,1H),8.88(s,1H),8.71 (d,J=1.0Hz,1H),8.08(d,J=8.6Hz,1H),7.29(d,J=2.1Hz,1H),7.15(dd,J=8.6,2 .1Hz,1H),4.95(br.s,1H),4.44-4.32(m,4H),3.76(t,J=6.5Hz,2H),3.36(t,J=6 .4Hz,2H),3.03-2.92(m,4H),2.29-1.99(m,5H),1.83-1.58(m,3H),0.41(s,4H).

[0799] Example 37 Preparation of Compound 37

[0800] Preparation method:

[0801] Step 1: Synthesis of compound 37B

[0802] Compound 37A (900 mg, 4.1 mmol) was dissolved in methanol (10 mL), and thionyl chloride (974 mg, 8.2 mmol) was added dropwise under an ice bath. The mixture was then stirred at room temperature for 12 hours. After TLC indicated the reaction was complete, the reaction solution was dried, the residue was adjusted to pH 7 with saturated sodium bicarbonate, and then extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure to yield crude compound 37B (300 mg, off-white solid).

[0803] Step 2: Synthesis of compound 37C

[0804] Crude compound 37B (900 mg, 3.8 mmol) was dissolved in N-methylpyrrolidone (10 mL), and 6-aza-spiro[2.5]octane hydrochloride (681 g, 4.6 mmol) and N,N-diisopropylethylamine (2.7 mL, 15.4 mmol) were added, followed by stirring at 120°C for 3 hours. LCMS showed that the reaction was completed. The reaction solution was diluted with water (60 mL) in an ice bath and extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to obtain compound 37C (1.4 g, yellow solid). MS (ESI): 325.0 327.0 m / z [M+1] + .

[0805] Step 3: Synthesis of compound 37D

[0806] Compound 37C (1.34 g, 4.1 mmol) was dissolved in methanol (5 mL) and water (5 mL), and sodium hydroxide (330 mg, 8.2 mmol) was added, followed by stirring at room temperature for 12 hours. LCMS showed that after the reaction was completed, the reaction solution was adjusted to pH 6 with hydrochloric acid solution (1 mol / L) in an ice bath, extracted with ethyl acetate (60 mL × 3), and the combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and desolventized. The residue was purified on a silica gel column to obtain compound 37D (1 g, off-white solid). MS (ESI): 311.0313.0 m / z [M+1] + .

[0807] Step 4: Synthesis of compound 37E

[0808] Compound 37D (372 mg, 1.18 mmol) was dissolved in dichloromethane (5 mL), and oxalyl chloride (378 mg, 2.96 mmol) was added dropwise under an ice bath. The mixture was then stirred at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation and then dissolved in anhydrous tetrahydrofuran (8 mL). A mixture of compound 8-D (300 mg, 1.18 mmol) and N,N-diisopropylethylamine (462 mg, 4.72 mmol) was added at room temperature, and the reaction solution was stirred at 50°C for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 37E (300 mg, khaki solid, purity: 77.5%, yield: 24.0%). MS (ESI): 273.6 274.5 m / z [M / 2+1] + .

[0809] Step 5: Synthesis of Compound 37

[0810] Compound 37E (5 mg, 0.009 mmol) and 2-hydroxy-1-sulfonamide (1.4 mg, 0.011 mmol) were dissolved in N,N-dimethylformamide (0.5 mL). Cuprous iodide (0.2 mg, 0.001 mmol), cesium carbonate (3.9 mg, 0.018 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (0.3 mg, 0.002 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 2 hours. After TLC indicated the reaction was complete, the reaction mixture was combined and filtered. The filtrate was then stripped of solvent under reduced pressure, and the residue was purified by HPLC to yield compound 37 (8 mg, yellow solid, formate salt). MS (ESI): 591.1 m / z [M+1] + . 1 H NMR (300MHz, DMSO-d6) δ (ppm) 11.38 (s, 1H), 10.37 (s, 1H), 8.80 (s, 1H), 8.12 (d, J = 1.1Hz, 1H), 7.60–7.47 (m, 2H), 4.99 (br.s, 1H), 4. 51-4.28(m,4H),3.78(t,J=6.6Hz,2H),3.40(t,J=6.2Hz,2H),3.09-2.99(m,4H),2.22–1.97(m,5H),1.80-1.58(m,4H),0.36(s,4H).

[0811] Example 38 Preparation of Compound 38

[0812] Step 1: Synthesis of compound 38B

[0813] Compound 38A (5 g, 24.3 mmol) was dissolved in 33% hydrobromic acid acetic acid solution (40 mL) and then stirred at 60 ° C for 5 hours. LCMS showed that after the reaction was completed, the reaction solution was diluted with water (60 mL) under ice bath and then stirred under ice bath for 10 minutes. The suspension was filtered and the filter cake was washed with ice water (10 mL×2). The filter cake was dissolved in ethyl acetate (60 mL) and water (30 mL), and then neutralized with sodium hydroxide aqueous solution (1 mol / L) until pH = 7. The aqueous phase was extracted with ethyl acetate (60 mL×3), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure to give crude compound 38B (2.5 g, off-white solid). MS (ESI): m / z 295.9[M+1] +

[0814] Step 2: Synthesis of compound 38C

[0815] Compound 38B (2 g, 6.78 mmol) was dissolved in N-methylpyrrolidone (20 mL), and 6-aza-spiro[2.5]octane hydrochloride (1.2 g, 8.14 mmol) and N,N-diisopropylethylamine (3.6 mL, 20.3 mmol) were added, followed by stirring at 120°C for 12 hours. LCMS showed that the reaction was completed. The reaction solution was diluted with water (60 mL) in an ice bath and extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to obtain compound 38C (1.1 g, off-white solid). MS (ESI): m / z 325.0 327.0 [M+1] +

[0816] Step 3: Synthesis of compound 38D

[0817] Compound 38C (1.1 g, 3.4 mmol) was dissolved in methanol (5 mL) and water (5 mL), and sodium hydroxide (271 mg, 6.8 mmol) was added, followed by stirring at room temperature for 12 hours. LCMS showed that after the reaction was completed, the reaction solution was adjusted to pH 6 with hydrochloric acid solution (1 mol / L) in an ice bath, extracted with ethyl acetate (60 mL × 3), and the combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and desolventized. The residue was purified on a silica gel column to obtain compound 38D (800 mg, white solid). MS (ESI): m / z 311.0 313.0 [M+1] +

[0818] Step 4: Synthesis of compound 38E

[0819] Compound 38D (100 mg, 0.32 mmol) was dissolved in dichloromethane (2 mL). Oxalyl chloride (102 mg, 0.8 mmol) and one drop of N,N-dimethylformamide were added dropwise under an ice bath, followed by stirring at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was spun down to dryness and then dissolved in anhydrous tetrahydrofuran (2 mL). Compound 8-D (81 mg, 0.32 mmol) and N,N-diisopropylethylamine (165 mg, 1.28 mmol) were added at room temperature, followed by stirring at room temperature for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 38E (130 mg, yellow solid, 75% yield). MS (ESI): m / z 273.6 274.5 [M / 2+1] +

[0820] Step 5: Synthesis of Compound 38

[0821] Compound 38E (70 mg, 0.13 mmol) and 2-hydroxy-1-sulfonamide (21 mg, 0.17 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cuprous iodide (14 mg, 0.08 mmol), potassium phosphate (77 mg, 0.38 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (15 mg, 0.11 mmol) were added sequentially. The mixture was then stirred at 120°C for 2 hours under nitrogen. After TLC indicated the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 38 (5 mg, white solid, formate salt). MS (ESI): m / z 591.3 [M+1] + . 1 H NMR (300MHz, DMSO-d6) δ (ppm) 10.80 (br.s, 1H), 8.72 (s, 1H), 8.05 (s, 1H), 7.52 (d, J = 1.1Hz, 1H), 6.69 (s, 1H), 4.83 (br.s, 1H), 4. 42-4.31(m,4H),3.73(t,J=6.8Hz,2H),3.52-3.34(m,2H),3.01-2.99(m,5H),2.16-2.00(m,5H),1.64-1.51(m,4H),0.31(s,4H).

[0822] Example 39 Preparation of Compound 39

[0823] Step 1: Synthesis of compound 39B

[0824] Compound 39A (500 mg, 2.50 mmol) was dissolved in tetrahydrofuran (5 mL), and triethylamine (508 mg, 5.00 mmol) and 4,4-difluoropiperidine hydrochloride (476 mg, 3.00 mmol) were added, followed by stirring at room temperature for 16 hours. After TLC indicated the reaction was complete, the solvent was removed under reduced pressure to yield crude compound 39B (1 g, yellow solid). MS (ESI): m / z 285.0 [M+1] +

[0825] Step 2: Synthesis of compound 39C

[0826] Compound 39B (400 mg, 1.41 mmol) was dissolved in dioxane (10 mL), and tert-butyl carbamate (330 mg, 2.82 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (63 mg, 0.14 mmol), cesium carbonate (918 mg, 2.82 mmol), and palladium acetate (16 mg, 0.07 mmol) were added. The mixture was then stirred at 100°C under nitrogen for 16 hours. After TLC indicated the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (80 mL), and extracted with ethyl acetate (40 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 39C (400 mg, orange-yellow solid, yield: 75.7%). MS (ESI): m / z 366.1 [M+1] + .

[0827] Step 3: Synthesis of compound 39D

[0828] Compound 39C (300 mg, 0.82 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. After TLC showed the reaction was complete, the mixture was concentrated under reduced pressure, the solvent was removed, and the mixture was diluted with water (20 mL). The pH was then adjusted to 7-8 with solid sodium bicarbonate and extracted with ethyl acetate (20 mL x 4). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure to obtain crude compound 39D (180 mg, brownish-red solid). MS (ESI): m / z 266.0 [M+1] + .

[0829] Step 4: Synthesis of compound 39E

[0830] Compound 1E1 (211 mg, 0.68 mmol) was dissolved in dichloromethane (5 mL), and oxalyl chloride (215 mg, 1.70 mmol) was added dropwise under an ice bath. The mixture was then stirred at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation and then dissolved in anhydrous tetrahydrofuran (5 mL). Compound 39D (180 mg, 0.68 mmol) and N,N-diisopropylethylamine (350 mg, 2.04 mmol) were added sequentially at room temperature, and the mixture was stirred at 50°C for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield crude compound 39E (200 mg, brownish-red solid).

[0831] Step 5: Synthesis of Compound 39

[0832] Compound 39E (100 mg, 0.18 mmol) and 2-hydroxy-1-sulfonamide (27 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cuprous iodide (3 mg, 0.02 mmol), potassium phosphate (76 mg, 0.36 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 39 (8 mg, yellow solid). MS (ESI): m / z 301.7 [M / 2+1] + . 1 H NMR (300MHz, DMSO-d6) δ (ppm) 13.10 (s, 1H), 10.27 (br.s, 1H), 8.93 (d, J = 1.9Hz, 1H),8.69(d,J=1.9Hz,1H),8.20–8.05(m,2H),7.28(d,J=2.1Hz,1H),7.13(dd,J= 8.7,2.1Hz,1H),4.99(br.s,1H),4.28-4.20(m,4H),3.76(t,J=6.5Hz,2H),3.36( t,J=6.5Hz,2H),3.06-2.97(m,4H),2.31-2.05(m,5H),1.75(s,3H),0.41(s,4H).

[0833] Example 40 Preparation of Compound 40

[0834] Step 1: Synthesis of compound 40B

[0835] Compound 40A (550 mg, 2.7 mmol) was dissolved in N-methyl-2-pyrrolidone (7 mL), and N,N-diisopropylethylamine (1.06 g, 8.1 mmol) and 4,4-difluoropiperidine hydrochloride (561 mg, 3.5 mmol) were added. The mixture was then stirred at 80°C for 5 hours under nitrogen. After TLC showed the reaction was complete, the reaction solution was diluted with water (30 mL) at 0°C and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (15 mL x 3), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and desolventized under reduced pressure. The residue was purified by silica gel column chromatography to obtain crude compound 40B (990 mg, yellow oil). MS (ESI): m / z 284.1 286.1 [M+1] + .

[0836] Step 2: Synthesis of Compound 40C

[0837] Crude compound 40B (990 mg, 3.5 mmol) was dissolved in dioxane (12 mL), and tert-butyl carbamate (616 mg, 5.3 mmol), cesium carbonate (2.3 mg, 7.0 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (165 mg, 0.35 mmol), and tris(dibenzylideneacetone)dipalladium (165 mg, 0.18 mmol) were added. The mixture was then stirred at 100°C under nitrogen for 5 hours. After TLC indicated the reaction was complete, the mixture was cooled to room temperature, diluted with water (40 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield crude compound 40C (1.4 g, yellow oil). MS (ESI): m / z 365.2 [M+1] + .

[0838] Step 3: Synthesis of Compound 40D

[0839] Compound 40C (500 mg, 1.4 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at 25°C for 2 hours. After TLC showed the reaction was complete, the solvent was removed under reduced pressure to obtain crude compound 40D (400 mg, brown oil). MS (ESI): m / z 265.1 [M+1] + .

[0840] Step 4: Synthesis of compound 40E

[0841] Compound 1E1 (468 mg, 1.5 mmol) was dissolved in dichloromethane (5 mL), and oxalyl chloride (480 mg, 3.8 mmol) was added dropwise under an ice bath, followed by stirring at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation, and the residue was dissolved in anhydrous tetrahydrofuran (5 mL). Compound 40D (400 mg, 1.5 mmol) and N,N-diisopropylethylamine (781 mg, 6.0 mmol) were then added to the reaction solution, followed by stirring at 65°C for 16 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 40E (280 mg, yellow solid, 33.3% yield). MS (ESI): 278.6 279.6 [M / 2+1] +

[0842] Step 5: Synthesis of Compound 40

[0843] Compound 40E (280 mg, 0.5 mmol) and 2-hydroxy-1-sulfonamide (84 mg, 0.65 mmol) were dissolved in N,N-dimethylformamide (6 mL). Cuprous iodide (57 mg, 0.3 mmol), potassium phosphate (308 mg, 1.45 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (60 mg, 0.43 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 40 (41 mg, yellow solid). MS (ESI): m / z 601.2 [M+1] +1H NMR (300MHz, DMSO-d6) δ (ppm) 13.30 (s, 1H), 10.06 (br.s, 1H), 8.95 (dd, J = 4.2, 1.6Hz, 1H), 8.44 ( d,J=8.4Hz,1H),8.32(s,1H),8.13(d,J=8.5Hz,1H),7.43(dd,J=8.4,4.3Hz,1H),7.29(d,J=2.1Hz ,1H),7.15(dd,J=8.6,2.1Hz,1H),4.98(br.s,1H),3.77(t,J=6.4Hz,2H),3.61-3.51(m,4H),3.3 7(t,J=6.4Hz,2H),3.01(d,J=6.4Hz,4H),2.25(d,J=16.0Hz,5H),1.94-1.74(m,3H),0.40(s,4H).

[0844] Example 41 Preparation of Compound 42

[0845] Step 1: Synthesis of compound 42A

[0846] Compound 8-A (5 g, 18.1 mmol) was dissolved in DMF (40 mL), and N-iodosuccinimide (4.47 g, 19.9 mmol) was added, followed by stirring at 60°C for 3 hours. After the reaction was completed as determined by LCMS, the reaction solution was cooled to room temperature, quenched with saturated sodium thiosulfate solution (80 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (60 mL × 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 42A (6.8 g, yellow solid, yield: 93.5%). MS (ESI): m / z 403.7 [M+1] + .

[0847] Step 2: Synthesis of Compound 42B

[0848] Compound 42A (1 g, 2.5 mmol) was dissolved in N-methylpyrrolidone (40 mL), and 4,4-difluoropiperidine hydrochloride (430 mg, 2.7 mmol) was added, followed by stirring at 100°C for 3 hours. After completion of the reaction, LCMS indicated that the reaction solution was cooled to room temperature, diluted with water (60 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and desolventized under reduced pressure. The residue was purified by silica gel column chromatography and dried under reduced pressure to afford compound 42B (900 mg, off-white solid, yield: 81.8%). MS (ESI): m / z 442.9 444.9 [M+1]+ .

[0849] Step 3: Synthesis of Compound 42C

[0850] Compound 42B (3.5 g, 7.9 mmol) was dissolved in dioxane (40 mL) and water (4 mL). Trimethylboroxane (6.8 mL, 23.7 mmol, 3.5 mol / L tetrahydrofuran solution), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (320 mg, 0.4 mmol), and potassium carbonate (2.18 g, 15.8 mmol) were added, and the mixture was stirred at 75°C under nitrogen for 3 hours. After LCMS showed completion of the reaction, the reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by reverse phase preparative chromatography to afford compound 42C (290 mg, off-white solid, yield: 11.1%). MS (ESI): m / z 331.0 333.0 [M+1] + .

[0851] Step 4: Synthesis of compound 42D

[0852] Compound 42C (280 mg, 0.85 mmol) was dissolved in dioxane (5 mL), and tert-butyl carbamate (200 mg, 1.70 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (40 mg, 0.09 mmol), cesium carbonate (553 mg, 1.70 mmol), and trisdibenzylideneacetone dipalladium (40 mg, 0.04 mmol) were added. The mixture was then reacted at 110°C under nitrogen for 16 hours. After TLC indicated completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (40 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography and dried under reduced pressure to afford compound 42D (250 mg, yellow solid, purity: 94.1%, yield: 75.7%). MS (ESI): m / z 368.2 [M+1] + .

[0853] Step 5: Synthesis of compound 42E

[0854] Compound 42D (250 mg, 0.68 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. After TLC showed the reaction was complete, the mixture was concentrated under reduced pressure and the solvent was removed to obtain crude compound 42E (250 mg, yellow oil). MS (ESI): m / z 268.1 [M+1] + .

[0855] Step 5: Synthesis of Compound 42F

[0856] Compound 1E1 (208 mg, 0.67 mmol) was dissolved in dichloromethane (5 mL), and oxalyl chloride (218 mg, 1.68 mmol) was added dropwise under an ice bath. The mixture was then stirred at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation and then dissolved in anhydrous tetrahydrofuran (10 mL). Compound 42E (180 mg, 0.67 mmol) and N,N-diisopropylethylamine (350 mg, 2.68 mmol) were added sequentially at room temperature, and the reaction solution was stirred at 50°C for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 42F (110 mg, yellow solid, purity: 63.2%, yield: 18.5%). MS(ESI):m / z 280.1 281.1[M / 2+1] +

[0857] Step 3: Synthesis of Compound 42

[0858] Compound 42F (100 mg, 0.18 mmol) and 2-hydroxy-1-sulfonamide (27 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cuprous iodide (3 mg, 0.02 mmol), potassium phosphate (76 mg, 0.44 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120°C for 2 hours under nitrogen. After TLC indicated the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (8 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 42 (20 mg, white solid). MS (ESI): m / z 604.3 [M+1] + . 1H NMR(300MHz,DMSO-d6)δ12.90(s,1H),10.21(br.s,1H),8.50(s,1H),8.08(d,J= 8.6Hz,1H),7.38(s,1H),7.28(d,J=2.2Hz,1H),7.14(dd,J=8.7,2.1Hz,1H),4.9 7(br.s,1H),4.49-4.33(m,4H),3.76(t,J=6.5Hz,2H),3.36(t,J=6.4Hz,2H),3. 05-2.94(m,4H),2.42(s,3H),2.21-1.98(m,5H),1.87-1.61(m,3H),0.40(s,4H).

[0859] Example 42 Preparation of Compound 43

[0860] Step 1: Synthesis of compound 43B

[0861] Compound 43A (2.0 g, 9.17 mmol) was dissolved in dimethyl sulfoxide (20 mL), and 6-aza-spiro[2.5]octane hydrochloride (1.6 g, 11.0 mmol) and N,N-diisopropylethylamine (3.4 g, 22.9 mmol) were added. The mixture was then stirred at room temperature under nitrogen for 16 hours. After TLC indicated completion of the reaction, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (80 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 43B (2.8 g, white solid, yield: 97.7%). MS (ESI): m / z 308.9 311.0 [M+1] + .

[0862] Step 2: Synthesis of Compound 43C

[0863] Compound 43B (2.9 g, 9.38 mmol) was dissolved in N-methylpyrrolidone (30 mL), and 4-methoxybenzylamine (1.6 g, 11.3 mmol) and N,N-diisopropylethylamine (2.4 g, 18.8 mmol) were added. The mixture was then stirred at 120°C under nitrogen for 16 hours. After TLC indicated completion of the reaction, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (80 mL × 3). The combined organic phases were washed with saturated brine (80 mL × 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 43C (3.7 g, yellow oily solid, yield: 83.0%).

[0864] Step 3: Synthesis of Compound 43D

[0865] Compound 43C (3.7 g, 8.68 mmol) was dissolved in trifluoroacetic acid (20 mL), trifluoromethanesulfonic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. After TLC showed that the reaction was complete, the reaction solution was diluted with water (100 mL), the pH was adjusted to 7-8 with solid sodium bicarbonate, and then extracted with ethyl acetate (80 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and desolventized under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 43D (2.0 g, yellow oil, yield: 73.0%). MS (ESI): m / z 306.1 308.0 [M+1] +

[0866] Step 4: Synthesis of compound 43E

[0867] Compound 43D (500 mg, 1.63 mmol) was dissolved in triethyl orthoformate (5 mL), and acetic anhydride (167 mg, 1.39 mmol) was added, followed by stirring at 145°C for 3 hours. After TLC indicated the reaction was complete, the solvent was removed under reduced pressure to yield crude compound 43E (500 mg, brown solid). MS (ESI): m / z 362.1-364.0 [M+1] +

[0868] Step 5: Synthesis of compound 43F

[0869] Compound 43E (500 mg, 1.38 mmol) and compound 8-D (350 mg, 1.38 mmol) were dissolved in glacial acetic acid (5 mL) and stirred at 125°C for 1 hour. After TLC indicated completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (50 mL), and then adjusted to pH 7-8 with solid sodium bicarbonate. The mixture was then extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 43F (200 mg, yellow solid, purity: 83.2%, yield: 21.2%). MS (ESI): m / z 285.1 286.2 [M / 2+1] + .

[0870] Step 6: Synthesis of Compound 43

[0871] Compound 43F (200 mg, 0.35 mmol) and 2-hydroxy-1-sulfonamide (53 mg, 0.42 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cuprous iodide (7 mg, 0.04 mmol), potassium phosphate (149 mg, 0.70 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (10 mg, 0.07 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 16 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 43 (30 mg, yellow solid). MS (ESI): m / z 614.2.[M+1] + . 1 H NMR(300MHz,DMSO-d6)δ(ppm)12.88(s,1H),10.30(br.s,1H),9.21(s,1H),8.60(s,1H),8. 13(d,J=1.1Hz,1H),7.56(d,J=1.1Hz,1H),7.36(d,J=2.1Hz,2H),5.03(br.s,1H),4.51-4.3 9(m,4H),3.78(t,J=6.4Hz,2H),3.40(t,J=6.4Hz,2H),3.20(d,J=10.9Hz,2H),2.86(t,J=11 .4Hz,2H),2.64-2.53(m,2H),2.22-2.06(m,4H),1.04(d,J=12.9Hz,2H),0.52-0.37(m,4H).

[0872] Example 43 Preparation of Compound 44

[0873] Step 1: Synthesis of compound 44A

[0874] Compound 3A (500 mg, 1.17 mmol) was dissolved in N-methyl-2-pyrrolidone (6 mL), and potassium carbonate (325 mg, 2.34 mmol) and isoindoline (220 mg, 1.4 mmol) were added. The mixture was then stirred at 120°C for 16 hours under nitrogen protection. After TLC showed that the reaction was complete, water (30 mL) was added to the reaction solution at 0°C, followed by extraction with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and desolventized under reduced pressure. The residue was purified by silica gel column chromatography to obtain crude compound 44A (330 mg, 0.62 mmol, brown oil). MS (ESI): 264.6 265.6 [M / 2+1] +

[0875] Step 2: Synthesis of Compound 44

[0876] Compound 44A (330 mg, 0.62 mmol) and 2-hydroxy-1-sulfonamide (99 mg, 0.81 mmol) were dissolved in N,N-dimethylformamide (6 mL). Cuprous iodide (71 mg, 0.4 mmol), potassium phosphate (385 mg, 1.8 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (77 mg, 0.53 mmol) were added sequentially. The mixture was then stirred at 120°C for 2 hours under nitrogen. After TLC indicated the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 44 (25 mg, yellow solid). MS (ESI): m / z 573.1 [M+1] +1 H NMR(300MHz,DMSO-d6)δ(ppm)11.15(s,1H),9.93(s,1H),7.51–7.19(m,6H),6.90(s,1H),6.72(d,J=8.5Hz,1H) ,4.96(t,J=5.6Hz,1H),4.59(s,4H),3.83–3.67(m,6H),3.33(t,J=5.6Hz,2H),2.30(s,3H),1.98-1.83(m,4H).

[0877] Example 44 Preparation of Compound 45

[0878] Preparation method:

[0879] Step 1: Synthesis of Compound 45

[0880] Compound 15G (400 mg, 0.71 mmol) and methanesulfonamide (79 mg, 0.85 mmol) were dissolved in N,N-dimethylformamide (8 mL). Cuprous iodide (13 mg, 0.07 mmol), potassium phosphate (295 mg, 1.42 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (20 mg, 0.14 mmol) were added sequentially. The mixture was then stirred at 120°C for 2 hours under nitrogen. After TLC indicated the reaction was complete, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 45 (150 mg, off-white solid). MS (ESI): m / z 288.5 [M / 2+1] + . 1 H NMR (300MHz, DMSO-d6) δ (ppm) 12.92 (s, 1H), 10.25 (s, 1H), 8.30 (s, 1H), 8.10 (d, J = 8.6Hz, 1H), 8.01 (d, J = 5.4Hz, 1H), 7.51 (d, J = 5.5Hz, 1H), 7.26 (d, J = 2.1Hz,1H),7.13(dd,J=8.6,2.1Hz,1H),3.86-3.76(m,4H),3.12(s,3H),3.04-2.95(m,4H),2.27-2.05(m,5H),1.89-1.64(m,3H),0.39(s,4H).

[0881] Example 45 Preparation of Compound 46

[0882] Step 5: Synthesis of Compound 46

[0883] Compound 34E (600 mg, 1.07 mmol) and methanesulfonamide (132 mg, 1.4 mmol) were dissolved in N,N-dimethylformamide (6 mL). Cuprous iodide (120 mg, 0.64 mmol), potassium phosphate (654 mg, 3.1 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (132 mg, 0.92 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 46 (101 mg, off-white solid). MS (ESI): m / z 289.7 [M / 2+1] + . 1 H NMR (300MHz, DMSO-d6) δ13.03(s,1H),10.27(s,1H),8.43(s,1H),8.09(d,J=8.6Hz,1H),7.40(d,J=7.2Hz,1H),7.27(d,J=2 .2Hz,1H),7.14(dd,J=8.6,2.1Hz,1H),4.41(s,4H),3.13(s,3H),2.99(s,4H),2.23-1.99(m,5H),1.73(s,3H),0.41(s,4H).

[0884] Example 46 Preparation of Compound 47

[0885] Step 1: Synthesis of Compound 47

[0886] Compound 22F (200 mg, 0.4 mmol) and methanesulfonamide (45 mg, 0.52 mmol) were dissolved in N,N-dimethylformamide (4 mL). Cuprous iodide (42 mg, 0.24 mmol), potassium phosphate (226 mg, 1.16 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (45 mg, 0.34 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 47 (81 mg, yellow solid). MS (ESI): m / z 559.1 [M+1] + . 1H NMR (300MHz, DMSO-d6) δ (ppm) 12.69 (s, 1H), 11.34 (s, 1H), 10.19 (s, 1H), 8.15–8.04 (m, 2H), 7.46 (t, J = 2.8Hz, 1H), 7.24 (d, J = 2.1Hz, 1H), 7.11 ( dd,J=8.6,2.1Hz,1H),6.50–6.43(m,1H),3.59-3.51(m,4H),3.11(s,3H) ),3.04-2.95(m,4H),2.29-2.10(m,5H),1.94-1.59(m,3H),0.39(s,4H).

[0887] Example 47 Preparation of Compound 48

[0888] Preparation method:

[0889] Step 1: Synthesis of Compound 48

[0890] Compound 25H (400 mg, 0.71 mmol) and methanesulfonamide (82 mg, 0.85 mmol) were dissolved in N,N-dimethylformamide (8 mL). Cuprous iodide (14 mg, 0.07 mmol), potassium phosphate (304 mg, 1.42 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (20 mg, 0.14 mmol) were added sequentially. The mixture was then stirred at 120°C for 2 hours under nitrogen. After TLC indicated the reaction was complete, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 48 (180 mg, off-white solid). MS (ESI): m / z 287.7 [M / 2+1] + . 1 H NMR (300MHz, DMSO-d6) δ (ppm) 12.52 (s, 1H), 10.24 (br.s, 1H), 8.24 (s, 1H), 8.08 (d, J = 8.6Hz, 1H), 7.82 (s, 1H), 7.23 (d, J = 2.2Hz, 1H), 7.10 (dd,J=8.6,2.1Hz,1H),4.34-4.23(m,4H),4.14(s,3H),3.10(s,3H),3.03-2.96(m,4H),2.19-1.98(m,5H),1.89-1.58(m,3H),0.40(s,4H).

[0891] Example 48 Preparation of Compound 49

[0892] Step 1: Synthesis of compound 49-2

[0893] Compound 49-1 (50 g, 232.2 mmol) was dissolved in diethylene glycol (600 mL). Potassium hydroxide (59.8 g, 1.07 mol) and hydrazine hydrate (62.9 g, 1.07 mol) were added under ice-cooling, followed by stirring at 180°C for 5 hours. LCMS indicated completion of the reaction. The reaction solution was cooled to room temperature, diluted with water (500 mL), and extracted with methyl tert-butyl ether (500 mL x 3). The combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure to yield crude compound 49-2 (50 g, light yellow oil).

[0894] MS (ESI): m / z 202.2[M+1] + .

[0895] Step 2: Synthesis of compound 49-3

[0896] To the crude product 49-2 (50 g, 248.4 mmol) was added ethyl acetate hydrochloride (200 mL, 4 mol / L) under an ice bath, followed by methanol (200 mL). The mixture was then stirred at 45°C under a hydrogen balloon for 96 hours. After LCMS indicated completion of the reaction, the reaction solution was filtered through celite, and the filtrate was then decompressed to remove the solvent to afford the crude product 49-3 (20 g, light yellow solid).

[0897] Step 3: Synthesis of Compound 49-4

[0898] Compound 6D (20 g, 85.8 mmol) was dissolved in N-methylpyrrolidone (200 mL), and compound 49-3 (40 g, 257 mmol) and potassium carbonate (71 g, 515 mmol) were added. The mixture was then stirred at 120°C for 16 hours. After TLC indicated completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (1000 mL), and extracted with ethyl acetate (300 mL x 3). The combined organic phases were washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 49-4 (20 g, light yellow oil, purity: 80.2%, yield: 57.6%).

[0899] MS (ESI): m / z 324.0 326.0 [M+1] + .

[0900] Step 4: Synthesis of Compound 49A

[0901] Compound 49-4 (20 g, 61.7 mmol) was dissolved in methanol (150 mL), water (150 mL), and tetrahydrofuran (150 mL). Lithium hydroxide monohydrate (5.2 g, 123 mmol) was then added under ice-cooling, followed by stirring at 50°C for 16 hours. After TLC indicated completion of the reaction, the methanol and tetrahydrofuran were removed from the reaction solution under reduced pressure. 1N hydrochloric acid was then added to adjust the pH to 5-6, resulting in the precipitation of a white solid. The filter cake was filtered, washed with water (200 mL), and dried to afford compound 49A (17.5 g, white solid, purity: 90.8%, yield: 83.0%).

[0902] MS (ESI): m / z 310.0 312.0 [M+1] + .

[0903] 1 H NMR(300MHz,Chloroform-d)δ(ppm)8.16(d,J=8.4Hz,1H),7.61(d,J=1.9Hz,1H),7.54(dd,J=8.4,1.8H z,1H),3.08-3.01(m,2H),2.95-2.89(m,2H),2.44-2.37(m,2H),1.99–1.80(m,5H),1.71-1.69(m,1H).

[0904] Step 5: Synthesis of Compound 49B

[0905] Compound 49A (1.0 g, 3.27 mmol) was dissolved in dichloromethane (10 mL), and oxalyl chloride (1.0 g, 8.18 mmol) was added dropwise under an ice bath. The mixture was then stirred at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation and then dissolved in anhydrous tetrahydrofuran (10 mL). A mixture of compound 15F (880 mg, 1.80 mmol) and N,N-diisopropylethylamine (1.7 g, 13.1 mmol) was added at room temperature, and the reaction solution was stirred at 50°C for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with water (80 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 49B (1.2 g, yellow solid, purity: 70.2%, yield: 45.9%). MS (ESI): m / z 281.0282.3 [M / 2+1] + .

[0906] Step 6: Synthesis of Compound 49

[0907] Compound 49B (100 mg, 0.18 mmol) and methanesulfonamide (20 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cuprous iodide (3 mg, 0.02 mmol), potassium phosphate (76 mg, 0.36 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 49 (30 mg, off-white solid). MS (ESI): m / z 288.7 [M / 2+1] + . 1 H NMR(300MHz,DMSO-d6)δ(ppm)10.57(s,1H),10.04(s,1H),8.32(s,1H),8.00( d,J=5.4Hz,1H),7.68(d,J=8.4Hz,1H),7.51(d,J=5.4Hz,1H),7.12(d,J=2.1H z,1H),6.99(dd,J=8.4,2.0Hz,1H),3.81-3.70(m,4H),3.09-2.96(m,5H),2.8 0(d,J=10.6Hz,2H),2.29–2.02(m,6H),1.98-1.88(m,2H),1.62-1.43(m,4H).

[0908] Example 49 Preparation of Compound 50

[0909] Preparation method:

[0910] Step 1: Synthesis of Compound 50

[0911] Compound 49B (100 mg, 0.18 mmol) and 2-hydroxy-1-sulfonamide (27 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (4 mL). Cuprous iodide (3 mg, 0.02 mmol), potassium phosphate (76 mg, 0.36 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120°C for 2 hours under nitrogen. After TLC indicated the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 50 (30 mg, off-white solid). MS (ESI): m / z 303.6 [M / 2+1] + . 1 H NMR (300MHz, DMSO-d6) δ (ppm) 10.58 (s, 1H), 10.02 (br.s, 1H), 8.32 (s, 1H), 8.00 (d, J = 5. 4Hz,1H),7.67(d,J=8.4Hz,1H),7.51(d,J=5.4Hz,1H),7.13(d,J=2.0Hz,1H),6.98(dd,J =8.4,1.9Hz,1H),4.95(br.s,1H),3.78–3.73(m,6H),3.31(t,J=6.7Hz,2H),3.06-2.98( m,2H),2.79(d,J=10.6Hz,2H),2.25-2.06(m,6H),1.98-1.89(m,2H),1.58-1.45(m,4H).

[0912] Example 50 Preparation of Compound 51

[0913] Step 1: Synthesis of compound 51

[0914] Compound 51A (180 mg, 0.3 mmol) and 2-hydroxy-1-sulfonamide (54 mg, 0.4 mmol) were dissolved in N,N-dimethylformamide (5 mL). Cuprous iodide (36 mg, 0.18 mmol), potassium phosphate (198 mg, 0.87 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (42 mg, 0.26 mmol) were added sequentially. The mixture was then stirred at 120°C for 2 hours under nitrogen. After LCMS showed completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (8 mL x 3). The combined organic phases were washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 51 (50 mg, yellow solid). MS (ESI): m / z 304.7 [M / 2+1] + . 1 H NMR (300MHz, DMSO-d6) δ (ppm) 10.65 (s, 1H), 10.05 (br.s, 1H), 8.51 (s, 1H), 7.70 (d, J = 8. 5Hz,1H),7.40(d,J=7.2Hz,1H),7.17(d,J=2.1Hz,1H),7.00(dd,J=8.5,2.0Hz,1H),4.95 (br.s,1H),4.44-4.31(m,4H),3.75(t,J=6.6Hz,2H),3.32(t,J=6.6Hz,2H),3.03–2.94( m,2H),2.80(d,J=10.5Hz,2H),2.31-2.22(m,2H),2.16–1.95(m,6H),1.66–1.47(m,4H).

[0915] Example 51 Preparation of Compound 52

[0916] Step 1: Synthesis of compound 51A

[0917] Compound 49A (456 mg, 1.5 mmol) was dissolved in dichloromethane (5 mL), and oxalyl chloride (468 mg, 3.8 mmol) was added dropwise under an ice bath, followed by stirring at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation, and the residue was dissolved in anhydrous tetrahydrofuran (5 mL). Compound 34D (400 mg, 1.5 mmol) and N,N-diisopropylethylamine (761 mg, 6.0 mmol) were added at room temperature, and the reaction solution was stirred at 25°C for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to obtain compound 51A (725 mg, yellow solid, 86.6% yield). MS (ESI): m / z 563.1 565.1 [M+1] +

[0918] Step 2: Synthesis of Compound 52

[0919] Compound 51A (180 mg, 0.3 mmol) and methanesulfonamide (42 mg, 0.4 mmol) were dissolved in N,N-dimethylformamide (5 mL). Cuprous iodide (36 mg, 0.18 mmol), potassium phosphate (198 mg, 0.87 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (42 mg, 0.26 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (8 mL x 3). The combined organic phases were washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 52 (60 mg, yellow solid). MS (ESI): m / z 289.5 [M / 2+1] + . 1 H NMR(300MHz,DMSO-d6)δ(ppm)10.64(s,1H),10.08(s,1H),8.51(s,1H),7.71 (d,J=8.5Hz,1H),7.40(d,J=7.2Hz,1H),7.15(d,J=2.1Hz,1H),7.01(dd,J=8 .5,2.0Hz,1H),4.43-4.32(m,4H),3.08(s,3H),2.99(dd,J=10.5,3.6Hz,2H) ,2.86–2.76(m,2H),2.30-2.21(m,2H),2.14-1.95(m,6H),1.65–1.45(m,4H).

[0920] Example 52 Preparation of Compound 53

[0921] Step 1: Synthesis of compound 53A

[0922] Compound 49A (438 mg, 1.42 mmol) was dissolved in dichloromethane (5 mL), and oxalyl chloride (450 mg, 3.55 mmol) was added dropwise under an ice bath. The mixture was then stirred at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation and then dissolved in anhydrous tetrahydrofuran (10 mL). A mixture of compound 23H (360 mg, 1.42 mmol) and N,N-diisopropylethylamine (731 mg, 5.68 mmol) were added sequentially at room temperature. The reaction solution was then stirred at 50°C for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to afford compound 53A (350 mg, yellow solid, yield: 45.2%). MS (ESI): m / z 546.1548.1[M+1] + .

[0923] Step 2: Synthesis of Compound 53

[0924] Compound 53A (150 mg, 0.27 mmol) and methanesulfonamide (31 mg, 0.32 mmol) were dissolved in N,N-dimethylformamide (4 mL). Cuprous iodide (5 mg, 0.03 mmol), potassium phosphate (116 mg, 0.54 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (8 mg, 0.05 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 53 (30 mg, off-white solid). MS (ESI): m / z 561.2 [M+1] + . 1H NMR (300MHz, DMSO-d6) δ (ppm) 10.92 (s, 1H), 10.09 (br.s, 1H), 9.04 (s, 1H), 8.50 (s, 1H), 7.74 (d, J = 8.5Hz, 1H), 7.17 (d, J = 2.0Hz, 1H), 7.06–6. 96(m,1H),4.39-4.32(m,4H),3.08(s,3H),3.02-2.96(m,2H),2.82(d,J =10.7Hz,2H),2.29-2.22(m,2H),2.20–1.94(m,6H),1.63-1.50(m,4H).

[0925] Example 53 Preparation of Compound 54

[0926] Step 1: Synthesis of compound 54

[0927] Compound 53A (150 mg, 0.27 mmol) and 2-hydroxy-1-sulfonamide (41 mg, 0.32 mmol) were dissolved in N,N-dimethylformamide (4 mL). Cuprous iodide (5 mg, 0.03 mmol), potassium phosphate (116 mg, 0.54 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (8 mg, 0.05 mmol) were added sequentially. The mixture was then stirred at 120°C for 2 hours under nitrogen. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 54 (30 mg, off-white solid). MS (ESI): m / z 591.2 [M+1] + . 1 H NMR(300MHz,DMSO-d6)δ(ppm)10.92(s,1H),10.06(br.s,1H),9.04(s,1H),8 .50(s,1H),7.73(d,J=8.5Hz,1H),7.19(d,J=2.0Hz,1H),7.01(dd,J=8.5,2.0 Hz,1H),4.95(br.s,1H),4.42-4.28(m,4H),3.75(t,J=6.5Hz,2H),3.32(t,J=6.5Hz,2H),3.03 –2.92(m,2H),2.82(d,J=10.6Hz,2H),2.29-2.21(m,2H),2.20–1.92(m,6H),1.66–1.46(m,4H).

[0928] Example 54 Preparation of Compound 55

[0929] Step 1: Synthesis of compound 55

[0930] Compound 55A (150 mg, 0.27 mmol) and 2-hydroxy-1-sulfonamide (40 mg, 0.32 mmol) were dissolved in N,N-dimethylformamide (4 mL). Cuprous iodide (4 mg, 0.03 mmol), potassium phosphate (114 mg, 0.54 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (8 mg, 0.05 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 55 (30 mg, off-white solid). MS (ESI): m / z 302.7 [M / 2+1] + . 1 H NMR(300MHz,DMSO-d6)δ(ppm)10.04(s,1H),9.94(br.s,1H),8.20(s,1H),7.78(s,1H),7 .61(d,J=8.4Hz,1H),7.07(d,J=2.0Hz,1H),6.93(dd,J=8.4,2.0Hz,1H),4.91(br.s,1H), 4.25-4.17(m,4H),4.11(s,3H),3.72(t,J=6.6Hz,2H),3.27(t,J=6.7Hz,2H),3.04–2.95 (m,2H),2.74(d,J=10.6Hz,2H),2.22-2.16(m,2H),2.09–1.89(m,6H),1.53-1.41(m,4H).

[0931] Example 55 Preparation of Compound 56

[0932] Step 1: Synthesis of compound 55A

[0933] Compound 49A (556 mg, 1.80 mmol) was dissolved in dichloromethane (10 mL). Oxalyl chloride (570 mg, 4.50 mmol) was added dropwise under an ice bath, and the mixture was stirred at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation and then dissolved in anhydrous tetrahydrofuran (10 mL). A mixture of compound 25G (480 mg, 1.80 mmol) and N,N-diisopropylethylamine (928 mg, 7.20 mmol) were added sequentially at room temperature, and the reaction solution was stirred at 50°C for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to afford compound 55A (350 mg, yellow solid, yield: 34.8%). MS (ESI): m / z 559.2561.2[M+1] + .

[0934] Step 2: Synthesis of Compound 56

[0935] Compound 55A (150 mg, 0.27 mmol) and methanesulfonamide (31 mg, 0.32 mmol) were dissolved in N,N-dimethylformamide (4 mL). Cuprous iodide (4 mg, 0.03 mmol), potassium phosphate (114 mg, 0.54 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (8 mg, 0.05 mmol) were added sequentially. The mixture was then stirred at 120°C for 2 hours under nitrogen. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 56 (30 mg, off-white solid). MS (ESI): m / z 287.6 [M / 2+1] + . 1 H NMR (300MHz, DMSO-d6) δ (ppm) 10.03 (s, 1H), 9.97 (br.s, 1H), 8.20 (s, 1H), 7.78 (s, 1H), 7.62 (d, J = 8.5Hz, 1H), 7.06 (d, J = 2.0Hz, 1H), 6.93 (dd, J = 8. 4,2.0Hz,1H),4.24-4.18(m,4H),4.11(s,3H),3.04-2.96(m,5H),2.75(d ,J=10.5Hz,2H),2.22-2.15(m,2H),2.07-1.89(m,6H),1.56–1.42(m,4H).

[0936] Example 56 Preparation of Compound 57

[0937] Step 1: Synthesis of Compound 57

[0938] Compound 23I (100 mg, 0.18 mmol) and methanesulfonamide (21 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cuprous iodide (4 mg, 0.02 mmol), potassium phosphate (78 mg, 0.36 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.36 mmol) were added sequentially. The mixture was then stirred at 120°C for 2 hours under nitrogen. After TLC indicated the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 57 (30 mg, off-white solid). MS (ESI): m / z 281.2 [M / 2+1] + . 1 H NMR (300MHz, DMSO-d6) δ (ppm) 13.28 (s, 1H), 10.29 (s, 1H), 8.95 (s, 1H), 8.49 (s, 1H), 8.10 (d, J = 8.7Hz, 1H), 7.29 (d, J = 2. 2Hz,1H),7.15(dd,J=8.6,2.1Hz,1H),4.43-4.32(m,4H),3.13(s,3H),3.06–2.93(m,4H),2.35–1.43(m,8H),0.41(s,4H).

[0939] Example 57 Preparation of Compound 58

[0940] Step 1: Synthesis of Compound 58

[0941] Compound 27H (200 mg, 0.37 mmol) and methanesulfonamide (42 mg, 0.44 mmol) were dissolved in N,N-dimethylformamide (4 mL). Cuprous iodide (7 mg, 0.04 mmol), potassium phosphate (156 mg, 0.74 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (10 mg, 0.07 mmol) were added sequentially. The mixture was then stirred at 120°C for 2 hours under nitrogen. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 58 (30 mg, off-white solid). MS (ESI): m / z 560.2 [M+1] + . 1 H NMR (300MHz, DMSO-d6) δ (ppm) 12.81 (s, 1H), 10.24 (s, 1H), 8.71 (d, J = 0.8Hz, 1H),8.53(s,1H),8.08(d,J=8.6Hz,1H),7.87(s,1H),7.26(d,J=2.2Hz,1H), 7.14(dd,J=8.6,2.1Hz,1H),4.03-3.92(m,4H),3.12(s,3H),3.03-2.94(m,4H),2.28–1.53(m,8H),0.40(s,4H).

[0942] Example 58 Preparation of Compound 59

[0943] Step 1: Synthesis of compound 59A

[0944] Compound 49A (525 mg, 1.70 mmol) was dissolved in dichloromethane (10 mL). Oxalyl chloride (540 mg, 4.25 mmol) was added dropwise under an ice bath, and the mixture was stirred at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation and then dissolved in anhydrous tetrahydrofuran (10 mL). A mixture of compound 27G (430 mg, 1.70 mmol) and N,N-diisopropylethylamine (877 mg, 6.80 mmol) were added sequentially at room temperature, and the reaction solution was stirred at 50°C for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with water (80 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 59A (450 mg, yellow solid, purity: 75.1%, yield: 36.5%). MS(ESI):m / z 273.1 273.9[M / 2+1] + .

[0945] Step 2: Synthesis of Compound 59

[0946] Compound 59A (200 mg, 0.37 mmol) and 2-hydroxy-1-sulfonamide (55 mg, 0.44 mmol) were dissolved in N,N-dimethylformamide (6 mL). Cuprous iodide (7 mg, 0.04 mmol), potassium phosphate (156 mg, 0.74 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (10 mg, 0.07 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 59 (30 mg, off-white solid). MS (ESI): m / z 590.0 [M+1] + . 1H NMR(300MHz,DMSO-d6)δ(ppm)10.45(s,1H),10.02(br.s,1H),8.77(s,1H),8.53(s,1H), 7.85(s,1H),7.69(d,J=8.5Hz,1H),7.15(d,J=2.1Hz,1H),6.99(dd,J=8.4,2.0Hz,1H),4. 94(br.s,1H),3.98-3.87(m,4H),3.75(t,J=6.6Hz,2H),3.31(t,J=6.6Hz,2H),3.04–2.94 (m,2H),2.79(d,J=10.6Hz,2H),2.28-2.20(m,2H),2.16–1.93(m,6H),1.64–1.47(m,4H).

[0947] Example 59 Preparation of Compound 60

[0948] Step 1: Synthesis of Compound 60

[0949] Compound 59A (200 mg, 0.37 mmol) and methanesulfonamide (27 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (6 mL). Cuprous iodide (7 mg, 0.04 mmol), potassium phosphate (156 mg, 0.74 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (10 mg, 0.07 mmol) were added sequentially. The mixture was then stirred at 120°C for 2 hours under nitrogen. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 60 (20 mg, off-white solid). MS (ESI): m / z 560.3 [M+1] + . 1H NMR(300MHz,DMSO-d6)δ(ppm)10.45(s,1H),10.05(br.s,1H),8.77(s,1H),8.5 3(s,1H),7.85(s,1H),7.70(d,J=8.4Hz,1H),7.14(d,J=2.1Hz,1H),7.00(dd,J= 8.5,2.0Hz,1H),3.98-3.88(m,4H),3.07(s,3H),2.99(dd,J=10.7,3.7Hz,2H),2 .80(d,J=10.6Hz,2H),2.28-2.21(m,2H),2.18–1.90(m,6H),1.66–1.44(m,4H).

[0950] Example 60 Preparation of Compound 61

[0951] Step 1: Synthesis of compound 61

[0952] Compound 24K (150 mg, 0.28 mmol) and methanesulfonamide (35 mg, 0.36 mmol) were dissolved in N,N-dimethylformamide (4 mL). Cuprous iodide (32 mg, 0.17 mmol), potassium phosphate (170 mg, 0.81 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (34 mg, 0.24 mmol) were added sequentially. The mixture was then stirred at 120°C for 2 hours under nitrogen. After TLC indicated the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (8 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 61 (30 mg, yellow solid). MS (ESI): m / z 561.2 [M+1] + . 1 H NMR (300MHz, DMSO-d6) δ (ppm) 13.08 (s, 1H), 10.27 (s, 1H), 9.37 (s, 1H), 8.79 (s, 1H), 8.09 (d, J = 8.6Hz, 1H), 7.28 (d, J = 2.2Hz, 1H), 7.15(dd,J=8.7,2.1Hz,1H),4.54-4.38(m,4H),3.13(s,3H),3.04-2.94(m,4H),2.27-2.06(m,5H),1.87-1.62(m,3H),0.41(s,4H).

[0953] Example 61 Preparation of Compound 62

[0954] Step 1: Synthesis of compound 62A

[0955] Compound 49A (800 mg, 2.6 mmol) was dissolved in dichloromethane (10 mL), and oxalyl chloride (821 mg, 6.5 mmol) was added dropwise under an ice bath, followed by stirring at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation and then dissolved in anhydrous tetrahydrofuran (10 mL). Compound 22E (652 mg, 2.6 mmol) and N,N-diisopropylethylamine (1.33 g, 10.4 mmol) were added at room temperature, and the mixture was stirred at 25°C for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to obtain compound 62A (980 mg, 1.8 mmol, yellow solid, 69% yield). MS (ESI): m / z 272.6 273.4 [M / 2+1] +

[0956] Step 2: Synthesis of Compound 62

[0957] Compound 62A (200 mg, 0.36 mmol) and 2-hydroxy-1-sulfonamide (60 mg, 0.43 mmol) were dissolved in N,N-dimethylformamide (4 mL). Cuprous iodide (42 mg, 0.22 mmol), potassium phosphate (226 mg, 1.01 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (44 mg, 0.31 mmol) were added sequentially. The mixture was then stirred at 120°C for 2 hours under nitrogen. After TLC indicated the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 62 (52.7 mg, yellow solid). MS (ESI): m / z 589.1 [M+1] + . 1H NMR (300MHz, DMSO-d6) δ (ppm) 11.32 (s, 1H), 10.37 (s, 1H), 10.01 (s, 1H), 8.09 (s, 1H), 7.72 (dd, J = 8 .4,1.4Hz,1H),7.46(t,J=2.8Hz,1H),7.15(d,J=2.2Hz,1H),6.99(dd,J=8.5,2.0Hz,1H),6.46(dd,J =3.0,1.6Hz,1H),4.94(br.s,1H),3.74(t,J=6.6Hz,2H),3.52-3.44(m,4H),3.31(t,J=6.7Hz,2H), 3.05–2.96(m,2H),2.79(d,J=10.5Hz,2H),2.26–2.08(m,6H),2.02-1.94(m,2H),1.59-1.44(m,4H).

[0958] Example 62 Preparation of Compound 63

[0959] Step 1: Synthesis of compound 63

[0960] Compound 62A (200 mg, 0.36 mmol) and methanesulfonamide (46 mg, 0.43 mmol) were dissolved in N,N-dimethylformamide (4 mL). Cuprous iodide (42 mg, 0.22 mmol), potassium phosphate (226 mg, 1.01 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (44 mg, 0.31 mmol) were added sequentially. The mixture was then stirred at 120°C for 2 hours under nitrogen. After TLC indicated the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 63 (61.3 mg, yellow solid). MS (ESI): m / z 559.2 [M+1] + . 1H NMR (300MHz, DMSO-d6) δ (ppm) 11.32 (s, 1H), 10.37 (s, 1H), 10.03 (s, 1H), 8.10 (d, J = 1. 8Hz,1H),7.73(d,J=8.5Hz,1H),7.46(t,J=2.8Hz,1H),7.14(d,J=2.1Hz,1H),6.99(dd, J=8.4,2.0Hz,1H),6.46(s,1H),3.52-3.48(m,4H),3.07(s,J=1.8Hz,3H),3.06–2.97(m ,2H),2.80(d,J=10.5Hz,2H),2.25-2.10(m,6H),2.03-1.93(m,2H),1.59-1.44(m,4H).

[0961] Example 63 Preparation of Compound 64

[0962] Step 1: Synthesis of compound 64A

[0963] Compound 49A (729 mg, 2.4 mmol) was dissolved in dichloromethane (10 mL), and oxalyl chloride (750 mg, 6 mmol) was added dropwise under an ice bath, followed by stirring at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation and then dissolved in anhydrous tetrahydrofuran (10 mL). Compound 24J (600 mg, 2.4 mmol) and N,N-diisopropylethylamine (1.2 g, 9.6 mmol) were added at room temperature, and the mixture was stirred at room temperature for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to obtain compound 64A (573 mg, yellow solid, 45.8% yield). MS (ESI): m / z 273.6 274.5 [M / 2+1] +

[0964] Step 2: Synthesis of Compound 64

[0965] Compound 64A (180 mg, 0.33 mmol) and 2-hydroxy-1-sulfonamide (54 mg, 0.43 mmol) were dissolved in N,N-dimethylformamide (4 mL). Cuprous iodide (376 mg, 0.20 mmol), potassium phosphate (203 mg, 0.96 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (40 mg, 0.28 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 64 (30.1 mg, yellow solid). MS (ESI): m / z 591.3 [M+1] + . 1 H NMR (300MHz, DMSO-d6) δ (ppm) 10.67 (s, 1H), 10.05 (br.s, 1H), 9.37 (d, J = 1.2Hz, 1H), 8.86 (d,J=1.1Hz,1H),7.68(d,J=8.4Hz,1H),7.16(d,J=2.2Hz,1H),6.99(d,J=8.5Hz,1H),4.95 (br.s,1H),4.50-4.31(m,4H),3.75(t,J=6.6Hz,2H),3.31(t,J=7.1Hz,2H),2.98(d,J=10. 5Hz,2H),2.80(d,J=10.5Hz,2H),2.28–2.06(m,6H),1.99-1.90(m,2H),1.65–1.44(m,4H).

[0966] Example 64 Preparation of Compound 65

[0967] Step 1: Synthesis of Compound 65

[0968] Compound 64A (180 mg, 0.33 mmol) and methanesulfonamide (41 mg, 0.43 mmol) were dissolved in N,N-dimethylformamide (4 mL). Cuprous iodide (376 mg, 0.20 mmol), potassium phosphate (203 mg, 0.96 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (40 mg, 0.28 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 65 (37.7 mg, yellow solid). MS (ESI): m / z 561.2 [M+1] + . 1 H NMR (300MHz, DMSO-d6) δ (ppm) 10.66 (s, 1H), 10.08 (br.s, 1H), 9.37 (d, J = 1.3Hz ,1H),8.86(d,J=1.4Hz,1H),7.70(d,J=8.5Hz,1H),7.14(d,J=2.1Hz,1H),7.00( dd,J=8.4,2.0Hz,1H),4.50-4.33(m,4H),3.07(s,3H),2.99(d,J=10.6Hz,2H),2 .81(d,J=10.6Hz,2H),2.27-2.06(m,6H),2.00-1.91(m,2H),1.65-1.44(m,4H).

[0969] Example 65 Preparation of Compound 66

[0970] Preparation method:

[0971] Step 1: Synthesis of compound 66B

[0972] Compound 66A (180 mg, 0.29 mmol) and methanesulfonamide (35 mg, 0.09 mmol) were dissolved in N,N-dimethylformamide (4 mL). Cuprous iodide (33 mg, 0.17 mmol), potassium phosphate (176 mg, 0.84 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (34 mg, 0.25 mmol) were added sequentially. The mixture was then stirred at 120°C for 2 hours under nitrogen. After TLC indicated the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to afford compound 66B (120 mg, yellow solid, 65% yield). MS (ESI): m / z 281.1 [M-THP / 2+1] +

[0973] Step 2: Synthesis of Compound 66

[0974] Compound 66B (120 mg, 0.19 mmol) was dissolved in ethyl acetate (3 mL) with hydrochloric acid and stirred at room temperature for 0.5 hours. After TLC indicated the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified by HPLC to give compound 66 (42.1 mg, white solid). MS (ESI): m / z 281.1 [M / 2+1] + . 1 H NMR(300MHz,DMSO-d6)δ(ppm)15.73(s,1H),10.47(s,1H),10.07(br.s,1H),7 .86(d,J=1.6Hz,1H),7.66(d,J=8.4Hz,1H),7.10(d,J=2.3Hz,1H),6.98(dd,J =8.4,2.1Hz,1H),4.42-4.27(m,4H),3.10–2.97(m,5H),2.79(d,J=10.6Hz,2H ),2.27-2.17(m,2H),2.14–2.00(m,4H),1.97-1.90(m,2H),1.61-1.43(m,4H).

[0975] Example 66 Preparation of Compound 67

[0976] Step 1: Synthesis of compound 66A

[0977] Compound 49A (457 mg, 1.5 mmol) and compound 28G (625 mg, 1.8 mmol) were dissolved in pyridine (10 mL). Phosphorus oxychloride (1.4 mg, 9 mmol) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 3 hours. After TLC indicated the reaction was complete, 1N hydrochloric acid solution was added to the reaction mixture under ice-cooling to adjust the pH to 6, and then the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to obtain compound 66A (360 mg, yellow solid, 38% yield). MS (ESI): m / z 273.6 274.3 [M-THP / 2+1] +

[0978] Step 2: Synthesis of Compound 67A

[0979] Compound 66A (180 mg, 0.29 mmol) and 2-hydroxy-1-sulfonamide (46 mg, 0.09 mmol) were dissolved in N,N-dimethylformamide (4 mL). Cuprous iodide (33 mg, 0.17 mmol), potassium phosphate (176 mg, 0.84 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (34 mg, 0.25 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to afford compound 67A (180 mg, yellow solid, 89.6% yield). MS (ESI): m / z 296.2 [M-THP / 2+1] +

[0980] Step 3: Synthesis of Compound 67

[0981] Compound 67A (180 mg, 0.26 mmol) was dissolved in ethanolic hydrochloric acid (3 mL) and stirred at room temperature for 0.5 hours. After TLC indicated the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified by HPLC to give compound 67 (47.5 mg, white solid). MS (ESI): m / z 296.2 [M / 2+1] + . 1H NMR(300MHz,DMSO-d6)δ(ppm)15.59(br.s,1H),10.48(s,1H),10.03(s,1H),7.86(s,1H ),7.65(d,J=8.3Hz,1H),7.12(s,1H),7.02–6.90(m,1H),4.95(br.s,1H),4.42-4.31(m ,4H),3.74(d,J=6.7Hz,2H),3.31(t,J=6.6Hz,2H),3.01(d,J=9.9Hz,2H),2.78(d,J=10 .5Hz,2H),2.29-2.18(m,2H),2.15-2.01(m,4H),1.98-1.89(m,2H),1.61–1.40(m,4H).

[0982] Example 67 Preparation of Compound 68

[0983] Step 1: Synthesis of compound 68A

[0984] Compound 28H (200 mg, 0.32 mmol) and methanesulfonamide (39 mg, 0.42 mmol) were dissolved in N,N-dimethylformamide (4 mL). Cuprous iodide (36 mg, 0.19 mmol), potassium phosphate (195 mg, 0.93 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (39 mg, 0.28 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 68A (144 mg, yellow solid, 68.7% yield). MS (ESI): m / z 281.2 [M-THP / 2+1] +

[0985] Step 2: Synthesis of Compound 68

[0986] Compound 68A (144 mg, 0.22 mmol) was dissolved in a hydrochloric acid and ethyl acetate solution (3 mL). The mixture was then stirred at room temperature for 0.5 hours. After TLC indicated the reaction was complete, the mixture was desolvated under reduced pressure and the residue was purified by HPLC to yield compound 68 (50.6 mg, white solid). MS (ESI): m / z 281.2 [M / 2+1] + . 1H NMR(300MHz,DMSO-d6)δ(ppm)15.60(br.s,1H),12.99(s,1H),10.27(br.s,1H),8.10(dd,J=8.7,1.4Hz,1H),7.85(d,J=1.4Hz,1H),7.26(d,J= 2.2Hz,1H),7.13(dd,J=8.7,2.0Hz,1H),4.49-4.32(m,4H),3.12(s,3H) ,3.05-2.94(m,4H),2.29-2.02(m,5H),1.91-1.55(m,3H),0.40(s,4H).

[0987] Example 68 Preparation of Compound 69

[0988] Step 1: Synthesis of compound 69A

[0989] Compound 49A (646 mg, 2.09 mmol) was dissolved in dichloromethane (10 mL). Oxalyl chloride (664 mg, 5.23 mmol) was added dropwise under an ice bath, and the mixture was stirred at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation and then dissolved in anhydrous tetrahydrofuran (10 mL). A mixture of compound 41C (780 mg, 2.09 mmol) and N,N-diisopropylethylamine (1.1 g, 8.36 mmol) were added sequentially at room temperature, and the reaction solution was stirred at 50°C for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with water (80 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 69A (800 mg, yellow solid, purity: 81.2%, yield: 46.7%). MS(ESI):m / z 332.9 334.2[M / 2+1] + .

[0990] Step 2: Synthesis of compound 69B

[0991] Compound 69A (200 mg, 0.30 mmol) and methanesulfonamide (34 mg, 0.36 mmol) were dissolved in N,N-dimethylformamide (6 mL). Cuprous iodide (6 mg, 0.03 mmol), potassium phosphate (128 mg, 0.60 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (9 mg, 0.06 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to yield compound 69B (100 mg, yellow oil, purity: 93.7%, yield: 45.9%). MS (ESI): m / z 340.7 [M / 2+1] + .

[0992] Step 3: Synthesis of Compound 69

[0993] Compound 69B (100 mg, 0.14 mmol) was dissolved in trifluoroacetic acid (2 mL), and trifluoromethanesulfonic acid (0.2 mL) was added dropwise under an ice bath, followed by stirring at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL), then adjusted to pH 8 with solid sodium bicarbonate, and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 69 (20 mg, off-white solid). MS (ESI): m / z 560.2 [M+1] + . 1 H NMR (300MHz, DMSO-d6) δ (ppm) 13.94 (s, 1H), 10.31-9.98 (m, 2H), 8.22 (s, 1H), 7.96 (s, 1H), 7.67 (d, J = 8.4Hz, 1H), 7.10 (d, J = 2.1Hz, 1H), 6.97 ( dd,J=8.4,1.9Hz,1H),4.32-3.79(m,4H),3.08-2.98(m,5H),2.79(d,J =10.5Hz,2H),2.27-2.19(m,2H),2.17-1.93(m,6H),1.58-1.45(m,4H).

[0994] Example 69 Preparation of Compound 70

[0995] Step 1: Synthesis of Compound 70

[0996] Compound 39E (100 mg, 0.18 mmol) and methanesulfonamide (21 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cuprous iodide (3 mg, 0.02 mmol), potassium phosphate (76 mg, 0.36 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 2 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by HPLC to yield compound 70 (8 mg, yellow solid). MS (ESI): m / z 286.6 [M / 2+1] + . 1 H NMR(300MHz,DMSO-d6)δ(ppm)13.09(s,1H),10.30(s,1H),8.93(d,J=1.8Hz,1H),8.69(d,J=1.8Hz,1H),8.22–8.06(m,2H),7 .27(d,J=2.1Hz,1H),7.20–7.05(m,1H),4.28-4.16(m,4H),3.13(s,3H),3.06-2.98(m,4H),2.33–1.56(m,8H),0.41(s,4H).

[0997] Example 70 Preparation of Compound 71

[0998] Step 1: Synthesis of compound 71A

[0999] Compound 69A (200 mg, 0.30 mmol) and 2-hydroxy-1-sulfonamide (45 mg, 0.36 mmol) were dissolved in N,N-dimethylformamide (6 mL). Cuprous iodide (6 mg, 0.03 mmol), potassium phosphate (128 mg, 0.60 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (9 mg, 0.06 mmol) were added sequentially. The mixture was then stirred at 120°C under nitrogen for 2 hours. After TLC indicated completion of the reaction, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified on a silica gel column to afford compound 71A (100 mg, yellow oil, purity: 88.5%, yield: 41.5%). MS (ESI): m / z 355.7 [M / 2+1] + .

[1000] Step 3: Synthesis of Compound 71

[1001] Compound 71A (100 mg, 0.14 mmol) was dissolved in trifluoroacetic acid (2 mL), and trifluoromethanesulfonic acid (0.2 mL) was added dropwise under an ice bath, followed by stirring at room temperature for 30 minutes. After TLC showed completion of the reaction, the reaction solution was diluted with water (20 mL), then adjusted to pH 8 with solid sodium bicarbonate, and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and desolventized under reduced pressure. The residue was purified by silica gel column chromatography to obtain the crude compound, which was then purified by preparative thin-layer chromatography to obtain compound 71 (30 mg, off-white solid). MS (ESI): m / z 590.3 [M+1] + . 1 H NMR(300MHz,DMSO-d6)δ(ppm)14.20-13.23(m,1H),10.51–9.92(m,2H),8.32 –7.79(m,2H),7.72-7.61(m,1H),7.11(s,1H),6.96(d,J=8.3Hz,1H),4.96(t ,J=5.7Hz,1H),4.35-4.19(m,2H),3.83-3.60(m,4H),3.31(t,J=5.7Hz,2H), 3.08-2.96(m,2H),2.82-2.73(m,2H),2.26–1.93(m,8H),1.61-1.44(m,4H).

[1002] Example 71 Preparation of Compound 72

[1003] Step 1: Synthesis of Compound 72A

[1004] Compound 49A (408 mg, 1.32 mmol) was dissolved in dichloromethane (5 mL), and oxalyl chloride (420 mg, 3.30 mmol) was added dropwise under an ice bath. The mixture was then stirred at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation and then dissolved in anhydrous tetrahydrofuran (10 mL). Compound 39D (350 mg, 1.32 mmol) and N,N-diisopropylethylamine (512 mg, 3.96 mmol) were added sequentially at room temperature. The reaction solution was then stirred at 50°C for 16 hours. After TLC indicated the reaction was complete, the reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by column chromatography to yield compound 72A (200 mg, brownish-red solid, yield: 27.2%).

[1005] MS(ESI):m / z 279.2 280.2[M / 2+1] + .

[1006] Step 2: Synthesis of Compound 72

[1007] Compound 72A (100 mg, 0.18 mmol) and methanesulfonamide (21 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (3 mL). Cuprous iodide (3 mg, 0.04 mmol), potassium phosphate (76 mg, 0.36 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.04 mmol) were added sequentially. The mixture was then stirred at 120°C for 2 hours under nitrogen. After TLC indicated completion of the reaction, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by preparative HPLC to yield compound 72 (8 mg, orange-yellow solid).

[1008] MS (ESI): m / z 286.6 [M / 2+1] + .

[1009] 1 H NMR (300MHz, DMSO-d6) δ (ppm) 10.65 (s, 1H), 10.07 (br.s, 1H), 8.93 (d, J = 1.8Hz, 1H), 8.69 (d, J = 1.8Hz, 1H), 8.17 (s, 1H), 7.65 (d, J = 8.3Hz, 1H), 7.0 9(s,1H),6.97(d,J=8.4Hz,1H),4.22-4.14(m,4H),3.08-2.99(m,5H),2. 85-2.77(m,2H),2.26-2.05(m,6H),1.97-1.86(m,2H),1.58-1.43(m,4H).

[1010] Example 72 Preparation of Compound 73

[1011] Compound 72A (200 mg, 0.36 mmol) and 2-hydroxyethane-1-sulfonamide (54 mg, 0.44 mmol) were dissolved in N,N-dimethylformamide (6 mL). Cuprous iodide (7 mg, 0.04 mmol), potassium phosphate (153 mg, 0.72 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (10 mg, 0.08 mmol) were added sequentially. The mixture was then stirred at 120°C for 2 hours under nitrogen. After TLC indicated completion of the reaction, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by preparative chromatography to yield compound 73 (55 mg, orange-yellow solid).

[1012] MS (ESI): m / z 301.7 [M / 2+1] + .

[1013] 1 H NMR (300MHz, DMSO-d6) δ (ppm) 10.64 (s, 1H), 10.03 (br.s, 1H), 8.93 (t, J = 1.5Hz, 1H), 8.68 (t ,J=1.6Hz,1H),8.17(s,1H),7.64(d,J=8.3Hz,1H),7.11(d,J=2.1Hz,1H),6.97(dd,J=8.4,1. 8Hz,1H),4.96(br.s,1H),4.24-4.11(m,4H),3.76(t,J=6.6Hz,2H),3.31(t,J=6.6Hz,2H),3. 07-2.98(m,2H),2.84-2.75(m,2H),2.25–2.06(m,6H),1.95-1.86(m,2H),1.57-1.44(m,4H).

[1014] Example 73 Preparation of Compound 74

[1015] Compound 8-E (200 mg, 0.37 mmol) and sodium methanesulfinate (56 mg, 0.56 mmol) were dissolved in dimethyl sulfoxide (5 mL). Sodium hydroxide (3 mg, 0.074 mmol), cuprous iodide (7 mg, 0.037 mmol), and L-proline (9 mg, 0.074 mmol) were added sequentially. The mixture was then stirred at 95°C for 16 hours under nitrogen. After LCMS indicated completion of the reaction, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography and then by preparative chromatography to afford compound 74 (5 mg, light yellow solid).

[1016] MS (ESI): m / z 273.0 [M / 2+1] + .

[1017] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 12.80 (br.s, 1H), 8.85 (s, 1H), 8.30 (d, J = 8.2Hz, 1H), 8.11 (d, J = 1.1Hz, 1H), 7.95 (d, J = 1.8Hz, 1H), 7.85 (dd, J = 8.2,1.7Hz,1H),7.57(d,J=1.0Hz,1H),4.48-4.39(m,4H),3.31(s,3H) ,3.14-3.08(m,4H),2.18–2.07(m,4H),1.78-1.66(m,4H),0.40(s,4H).

[1018] Example 74 Preparation of Compound 75

[1019] Step 1: Synthesis of compound 75B

[1020] Compound 75A (1 g, 3.98 mmol) was dissolved in methylpyrrolidone (10 mL), and compound 3A1 (1.77 g, 15.92 mmol) and potassium carbonate (4.42 g, 31.84 mmol) were added. The mixture was then stirred at 120°C under nitrogen for 16 hours. LCMS indicated the reaction was complete. The reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 75B (310 mg, yellow solid).

[1021] MS (ESI): m / z 328.0 [M+1] +.

[1022] Step 2: Synthesis of Compound 75C

[1023] Compound 75B (217.78 mg, 0.664 mmol) was dissolved in dichloromethane (5 mL), and oxalyl chloride (210.58 mg, 1.66 mmol) was added dropwise at 0°C. The mixture was stirred at room temperature for 30 minutes. TLC indicated the reaction was complete, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (3 mL). Compound 34D (180 mg, 0.664 mmol) and a solution of N,N-diisopropylethylamine in tetrahydrofuran (3 mL) were then added to the reaction mixture, and the mixture was stirred at 50°C for one hour. LCMS indicated the reaction was complete. The reaction mixture was diluted with water (15 mL) and extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 75C (101 mg, yellow solid).

[1024] Step 3: Synthesis of Compound 75

[1025] Compound 75C (119 mg, 0.205 mmol) was dissolved in anhydrous N-dimethylformamide (5 mL), and methylsulfonamide (38.4 mg, 0.404 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (5.83 mg, 0.041 mmol), cuprous iodide (3.89 mg, 0.0205 mmol), and anhydrous potassium phosphate (86.8 mg, 0.41 mmol) were added. The mixture was then stirred at 120°C under nitrogen for 4 hours. After LCMS showed completion of the reaction, the reaction solution was diluted with water (15 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by chromatography to afford compound 75 (71 mg, light yellow solid).

[1026] MS (ESI): m / z 298.6 [M / 2+1] + .

[1027] 1H NMR (400MHz, DMSO-d6) δ (ppm) 10.59 (s, 1H), 10.08 (s, 1H), 8.38 (s, 1H), 7.40 (d, J = 7.2Hz, 1H), 6.72–6.60 (m, 2H), 4.43 -4.29(m,4H),3.12-3.02(m,5H),2.74(d,J=10.4Hz,2H),2.19–1.98(m,6H),1.64(d,J=7.3Hz,2H),1.49–1.32(m,4H).

[1028] Example 75 Preparation of Compound 76

[1029] Step 1: Synthesis of compound 76C

[1030] A solution of compound 76A (9.2 g, 47.6 mmol) and compound 76B (11.3 g, 57.1 mmol) in anhydrous N,N-dimethylformamide (50 mL) was slowly added to a solution of potassium tert-butoxide (9.6 g, 85.7 mmol) in anhydrous N,N-dimethylformamide (40 mL) at -60°C, followed by stirring at -60°C under nitrogen for 0.5 hours. After TLC indicated completion of the reaction, the reaction was quenched with saturated sodium bicarbonate solution (50 mL) at -60°C and stirred for 0.5 hours. Subsequently, 3N hydrochloric acid solution (100 mL) was slowly added and stirred for 0.5 hours. The mixture was then warmed to room temperature and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and desolventized under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 76C (11.0 g, yellow oil).

[1031] MS (ESI): m / z 234.1[M+1] + .

[1032] Step 2: Synthesis of compound 76D

[1033] Compound 76C (700 mg, 3.0 mmol) was dissolved in a hydrochloric acid / ethyl acetate solution (10 mL) and stirred at 25° C. for 4 hours. After TLC showed the reaction was complete, the reaction solution was desolvated under reduced pressure to give crude compound 76D (500 mg, white solid).

[1034] MS (ESI): m / z 134.1[M+1] + .

[1035] Step 3: Synthesis of Compound 76E

[1036] Compound 76D (500 mg, 2.9 mmol) was dissolved in N-methyl-2-pyrrolidone (5 mL), and potassium carbonate (814 mg, 5.8 mmol) and compound 6D (827 mg, 3.5 mmol) were added. After the addition was complete, the mixture was stirred at 120°C in a sealed bottle for 24 hours. After TLC indicated the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was added to ice water (30 mL), followed by extraction with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and desolventized under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 76E (800 mg, 2.3 mmol, yellow oil).

[1037] MS (ESI): m / z 346.1[M+1] + .

[1038] Step 4: Synthesis of compound 76F

[1039] Compound 76E (800 mg, 2.3 mmol) was dissolved in methanol (8 mL) and water (8 mL), and lithium hydroxide monohydrate (486 mg, 11.5 mmol) was added, followed by stirring at room temperature for 5 hours. After TLC indicated completion of the reaction, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL). The aqueous phase was collected and acidified with 1N dilute hydrochloric acid, extracted with ethyl acetate (15 mL x 2), dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 76F (250 mg, yellow solid).

[1040] MS (ESI): m / z 332.0 [M+1] + .

[1041] Step 5: Synthesis of Compound 76G

[1042] Compound 76F (220 mg, 0.65 mmol) was dissolved in dichloromethane (3 mL), and oxalyl chloride (211 mg, 1.63 mmol) was added dropwise under ice-cooling, followed by stirring at room temperature for 30 minutes. After TLC indicated the reaction was complete, the reaction solution was dried by rotary evaporation and then dissolved in anhydrous tetrahydrofuran (3 mL). Compound 8-D (168 mg, 0.65 mmol) and N,N-diisopropylethylamine (342 mg, 2.6 mmol) were added under ice-cooling, and the reaction solution was stirred at 25°C for 1 hour. After TLC indicated the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The co...

Claims

1. A nitrogen-containing compound as represented by formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, in, R x is a 3-6 membered monocyclic cycloalkyl, a 5-6 membered monocyclic heterocycloalkyl, a 6-9 membered bridged heterocycloalkyl, a 7-9 membered spiro heterocycloalkyl, or one or more R x-1 substituted 5-6 membered monocyclic heterocycloalkyl, x-2 Substituted 6-9 membered bridged heterocyclic alkyl, one or more R x-3 substituted 7-9 membered spirocyclic heterocyclic alkyl or one or more R x-4 substituted 3-6 membered monocyclic cycloalkyl; the "5-6 membered monocyclic heterocycloalkyl", the "6-9 membered bridged heterocycloalkyl", the "7-9 membered spiro heterocycloalkyl", the "substituted one or more R x-1 substituted 5-6 membered monocyclic heterocycloalkyl" and the "substituted 5-6 membered monocyclic heterocycloalkyl" x-2 substituted 6-9 membered bridged heterocyclic alkyl" and said "substituted by one or more R x-3 In the "substituted 7-9 membered spirocyclic heterocycloalkyl", the heteroatoms are independently composed of 1 N atom and 0, 1 or 2 X atoms, and the X atoms are independently selected from 1 or 2 of N, O and S; the "5-6 membered monocyclic heterocycloalkyl", the "6-9 membered bridged heterocycloalkyl", the "7-9 membered spirocyclic heterocycloalkyl", the "substituted one or more R x-1 substituted 5-6 membered monocyclic heterocycloalkyl" and the "substituted 5-6 membered monocyclic heterocycloalkyl" x-2 substituted 6-9 membered bridged heterocyclic alkyl" and said" x-3 The substituted 7-9 membered spirocyclic heterocycloalkyl is connected to ring A via an N atom; Each R x-1 、R x-2 、R x-3 and R x-4 are independently halogen, R N-10k 、R N-101 、C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, -OR N-a , C substituted by one or more halogens 1-6 Alkoxy, CN, -NR N-a R N-a or oxo; R 1 -LR 1-1 ; L is *-NHSO2-, -NH-, *-NHC(O)-, -NHC(O)NH-, *-SO2NH- or -SO2-; * represents the end connected to ring A; R 1-1 C 1-6 Alkyl, 3-6 membered monocyclic cycloalkyl, 4-8 membered monocyclic heterocycloalkyl, a Substituted C 1-6 Alkyl or one or more R b Substituted 3-6 membered monocyclic cycloalkyl; in the 4-8 membered monocyclic heterocycloalkyl, the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; Each R a are independently hydroxy, halogen or -NH(R a-1 ); R a-1 C 1-6 alkyl; Each R b Each independently is C 1-6 Alkyl or C substituted by one or more hydroxyl groups 1-6 alkyl; G is C(R 10 ) or N; R 10 H, halogen, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, -OH, -OR N- 8a OR N-8b ; M is phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 9-10-membered heteroaryl, 6-membered heterocycloalkenyl, substituted by one or more R 2 substituted 6-membered heteroaryl, one or more R 3 substituted 9-10 membered heteroaryl, substituted by one or more R 4 substituted 6-membered heterocycloalkenyl, one or more R 5 Substituted phenyl, one or more R 5 substituted naphthyl or one or more R 6 substituted 5-membered heteroaryl; the "5-membered heteroaryl", "6-membered heteroaryl", "9-10-membered heteroaryl", "6-membered heterocycloalkenyl", "substituted by one or more R 2 substituted 6-membered heteroaryl", "substituted by one or more R 3 substituted 9-10 membered heteroaryl", "substituted by one or more R 4 substituted 6-membered heterocycloalkenyl" and "substituted by one or more R 6 In the "substituted 5-membered heteroaryl", the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; Each R 2 、R 3 、R 4 、R 5 and R 6 are independently oxo, halogen, R N-4a 、R N-4b 、C 1-6 Alkyl, substituted by one or more halogens Substituted C 1-6 Alkyl, cyano, C 1-6 Alkoxy, -OR N-6a or -YR N-13 ; R N-6a is a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; Y is -C 1-6 Alkyl-, -N(C 1-6 alkyl)-C 1-6 Alkyl-, -C(=O)NR N-a R N-a (C 1-6 Alkyl), -O-, -OC 1-6 Alkyl-, S, S=O, S(=O)2, -S(=O)(=NR N-13 )- or -S(=O)(=NH)-; R N-13 R N-13a or R N-13b ; Each R N-4a 、R N-8a 、R N-10k and R N-13a are independently selected from the group consisting of: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, which is substituted by 0, 1, 2 or 3 groups selected from the group consisting of halogen, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, -OR N-a , C substituted by one or more halogens 1-6 Alkoxy, CN, -C(=O)R N-b 、-C(=O)OR N-a 、-C(=O)NR N-a R N-a 、-C(=NR N-a )NR N-a R N-a 、-OC(=O)R N-b 、-OC(=O)NR N-a R N-a 、-OC 1-6 Alkyl NR N-a R N-a 、-OC 1-6 Alkyl OR N-a 、-SR N-a 、-S(=O)R N-b 、-S(=O)2R N-b 、-S(=O)2NR N-a R N-a 、-NR N-a R N-a 、-N(R N-a )C(=O)R N-b 、-N(R N-a )C(=O)OR N-b 、-N(R N-a )C(=O)NR N-a R N-a 、-N(R N-a )C(=NR N-a )NR N-a R N-a 、-N(R N-a )S(=O)2R N-b 、-N(R N-a )S(=O)2NR N-a R N-a 、-NR N-a C 1-6 Alkyl NR N-a R N-a 、-NR N-a C 1-6 Alkyl OR N-a 、-C 1-6 Alkyl NR N-a R N-a 、-C 1-6 Alkyl OR N-a 、-C 1-6 Alkyl N(R N-a )C(=O)R N-b 、-C 1-6 Alkyl OC(=O)R N-b 、-C 1-6 Alkyl C(=O)NR N-a R N-a 、-C 1-6 Alkyl C(=O)OR N-a 、R N-14 and oxo; Each R N-4b 、R N-8b 、R N-101 and R N-13b are independently selected from halogen, -OR N-a , C substituted by one or more halogens 1- 6 alkoxy and C substituted with 0, 1, 2, 3, 4 or 5 groups in CN 1-6 alkyl; Each R N-14 are independently selected from the group consisting of: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, which is substituted by 0, 1, 2 or 3 groups selected from the following: halogen, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, -OR N-a , C substituted by one or more halogens 1-6 Alkoxy, CN, -C(=O)R N- b 、-C(=O)OR N-a 、-C(=O)NR N-a R N-a 、-C(=NR N-a )NR N-a R N-a 、-OC(=O)R N-b 、-OC(=O)NR N-a R N-a 、-OC 1-6 Alkyl NR N-a R N-a 、-OC 1-6 Alkyl OR N-a 、-SR N-a 、-S(=O)R N-b 、-S(=O)2R N-b 、-S(=O)2NR N-a R N-a 、-NR N-a R N-a 、-N(R N-a )C(=O)R N-b 、-N(R N-a )C(=O)OR N-b 、-N(R N-a )C(=O)NR N-a R N-a 、-N(R N-a )C(=NR N- a )NR N-a R N-a 、-N(R N-a )S(=O)2R N-b 、-N(R N-a )S(=O)2NR N-a R N-a 、-NR N-a C 1-6 Alkyl NR N-a R N-a 、-NR N-a C 1-6 Alkyl OR N-a 、-C 1-6 Alkyl NR N-a R N-a 、-C 1-6 Alkyl OR N-a 、-C 1-6 Alkyl N(R N-a )C(=O)R N-b 、-C 1-6 Alkyl OC(=O)R N-b 、-C 1-6 Alkyl C(=O)NR N-a R N-a 、-C 1-6 Alkyl C(=O)OR N-a and oxo; Each R N-a are independently H or R N-b ; Each R N-b Each independently is C 1-6 alkyl, phenyl or benzyl, wherein the C 1-6 The alkyl group is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -OC(=O)C 1-6 Alkyl or -N(C 1-6 Alkyl)C 1-6 Alkyl; and the phenyl or benzyl is substituted by 0, 1, 2 or 3 substituents selected from the group consisting of halogen, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, -OH, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -OC(=O)C 1-6 Alkyl or -N(C 1-6 Alkyl)C 1-6 alkyl; W and X 2 is defined as follows: Solution 1: W is *-CONR W -;X 2 R W-1 ; * indicates the end connected to ring A; Solution 2: W is *-NR W CO-;X 2 R W-1 ; * indicates the end connected to ring A; Solution 3: W is *-C(=X 1 )NR W -;X 1 、X 2 and the C atoms therebetween together form a 6-membered heteroaryl group; in the 6-membered heteroaryl group, The heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; * represents the end connected to ring A; R W H, C 1-6 Alkyl or C substituted by one or more halogen 1-6 alkyl; R W-1 H, halogen, C 1-6 Alkyl or C substituted by one or more halogen 1-6 alkyl; Furthermore, the compound as shown in Formula I satisfies one, two or three of the following conditions: Condition 1: R x is a 6-9 membered bridged heterocyclic alkyl group or is replaced by one or more R x-2 substituted 6-9 membered bridged heterocycloalkyl; Condition 2: M is naphthyl, 5-membered heteroaryl, 9-10-membered heteroaryl, 6-membered heterocycloalkenyl, or one or more R 5 Substituted naphthyl, one or more R 6 substituted 5-membered heteroaryl, one or more R 3 9-10 membered heteroaryl substituted or one or more R 4 substituted 6-membered heterocycloalkenyl; Condition 3: W is *-C(=X 1 )NR W -;X 1 、X 2 and the intervening C atoms together form a 6-membered heteroaryl group.

2. A nitrogen-containing compound as represented by Formula II, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, in, R x is a 3-6 membered monocyclic cycloalkyl, a 5-6 membered monocyclic heterocycloalkyl, a 6-9 membered bridged heterocycloalkyl, a 7-9 membered spiro heterocycloalkyl, or one or more R x-1 substituted 5-6 membered monocyclic heterocycloalkyl, x-2 Substituted 6-9 membered bridged heterocyclic alkyl, one or more R x-3 substituted 7-9 membered spirocyclic heterocyclic alkyl or one or more R x-4 substituted 3-6 membered monocyclic cycloalkyl; the "5-6 membered monocyclic heterocycloalkyl", the "6-9 membered bridged heterocycloalkyl", the "7-9 membered spiro heterocycloalkyl", the "substituted one or more R x-1 substituted 5-6 membered monocyclic heterocycloalkyl" and the "substituted 5-6 membered monocyclic heterocycloalkyl" x-2 substituted 6-9 membered bridged heterocyclic alkyl" and said" x-3 In the "substituted 7-9 membered spirocyclic heterocycloalkyl", the heteroatoms are independently composed of 1 N atom and 0, 1 or 2 X atoms, and the X atoms are independently selected from 1 or 2 of N, O and S; the "5-6 membered monocyclic heterocycloalkyl", the "6-9 membered bridged heterocycloalkyl", the "7-9 membered spirocyclic heterocycloalkyl", the "substituted one or more R x-1 substituted 5-6 membered monocyclic heterocycloalkyl" and the "substituted 5-6 membered monocyclic heterocycloalkyl" x-2 substituted 6-9 membered bridged heterocyclic alkyl" and said" x-3 The substituted 7-9 membered spirocyclic heterocycloalkyl is connected to ring A via an N atom; Each R x-1 、R x-2 、R x-3 and R x-4 are independently halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C substituted by one or more halogen 1-6 Alkyl or C substituted by one or more halogen 1-6 alkoxy; R 1 -LR 1-1 ; L is *-NHSO2-, -NH-, *-NHC(O)-, -NHC(O)NH-, *-SO2NH- or -SO2-; * represents the end connected to ring A; R 1-1 C 1-6 Alkyl, 3-6 membered monocyclic cycloalkyl, 4-8 membered monocyclic heterocycloalkyl, a Substituted C 1-6 Alkyl or one or more R b Substituted 3-6 membered monocyclic cycloalkyl; in the 4-8 membered monocyclic heterocycloalkyl, the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; Each R a are independently hydroxy, halogen or -NH(R a-1 ); R a-1 C 1-6 alkyl; Each R b Each independently is C 1-6 Alkyl, C substituted by one or more hydroxyl groups 1-6 alkyl; B is phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 9-10-membered heteroaryl, 6-membered heterocycloalkenyl, substituted by one or more R 2 Pick substituted 6-membered heteroaryl, replaced by one or more R 3 substituted 9-10 membered heteroaryl, substituted by one or more R 4 substituted 6-membered heterocycloalkenyl, one or more R 5 Substituted phenyl, one or more R 5 substituted naphthyl or one or more R 6 substituted 5-membered heteroaryl; the "5-membered heteroaryl", "6-membered heteroaryl", "9-10-membered heteroaryl", "6-membered heterocycloalkenyl", "substituted by one or more R 2 substituted 6-membered heteroaryl", "substituted by one or more R 3 substituted 9-10 membered heteroaryl", "substituted by one or more R 4 substituted 6-membered heterocycloalkenyl" and "substituted by one or more R 6 In the "substituted 5-membered heteroaryl", the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; Each R 2 、R 3 、R 4 、R 5 、R 6 are independently halogen, cyano, oxo (=O), C 1-6 Alkyl or C substituted by one or more halogen 1-6 alkyl; U is a 3-10 membered cycloalkyl, a 4-10 membered heterocycloalkyl, a 6-10 membered aryl, a 5-10 membered heteroaryl, or a 6-10 membered aryl group. 2-1 Substituted 3-10 membered cycloalkyl, one or more R 2-2 substituted 4-10 membered heterocycloalkyl or one or more R 2-3 substituted 5-10 membered heteroaryl; the "5-10 membered heteroaryl", "4-10 membered heterocycloalkyl", "substituted by one or more R 2-2 substituted 4-10 membered heterocycloalkyl" and "substituted by one or more R 2-3 In the "substituted 5-10 membered heteroaryl", the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; Each R 2-1 、R 2-2 and R 2-3 are independently halogen, C 1-6 Alkyl, oxo, CN, hydroxy, 3-6 membered monocyclic cycloalkyl, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkoxy, 3-6 membered monocyclic cycloalkyl substituted by one or more halogens or C 1-6 alkoxy; W and X 2 is defined as follows: (1)W is *-CONR W -;X 2 R W-1 ; * indicates the end connected to ring A; (2)W is *-NR W CO-;X 2 R W-1 ; * indicates the end connected to ring A; (3)W is *-C(=X 1 )NR W -;X 1 、X 2 and the C atoms therebetween together form a 6-membered heteroaryl group; in the 6-membered heteroaryl group, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; * represents the end connected to ring A; R W H, C 1-6 Alkyl or C substituted by one or more halogen 1-6 alkyl; R W-1 H, halogen, C 1-6 Alkyl or C substituted by one or more halogen 1-6 alkyl; G is C(R 10 ) or N; R 10 H, halogen, C 1-6 Alkyl, hydroxy or C substituted by one or more halogen 1-6 alkyl; Furthermore, the compound represented by Formula II satisfies one, two or three of the following conditions: (1)R x is a 6-9 membered bridged heterocyclic alkyl group or is replaced by one or more R x-2 substituted 6-9 membered bridged heterocycloalkyl; (2) B is naphthyl, 5-membered heteroaryl, 9-10-membered heteroaryl, 6-membered heterocycloalkenyl, or one or more R 5 Substituted naphthyl, one or more R 6 substituted 5-membered heteroaryl, one or more R 3 9-10 membered heteroaryl substituted or one or more R 4 substituted 6-membered heterocycloalkenyl; (3)W is *-C(=X 1 )NR W -;X 1 、X 2 and the intervening C atoms together form a 6-membered heteroaryl group.

3. The nitrogen-containing compound of formula II according to claim 2, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its metabolite, its prodrug, its isotope-labeled derivative, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: The nitrogen-containing compound shown in Formula II is any of the following: Option 1: R x is a 6-9 membered bridged heterocycloalkyl, a 7-9 membered spiro heterocycloalkyl, or one or more R x-2 Substituted 6-9 membered bridged heterocycloalkyl; the "6-9 membered bridged heterocycloalkyl", the "7-9 membered spiro heterocycloalkyl" and the "substituted by one or more R x-2 In the "substituted 6-9 membered bridged heterocycloalkyl", the heteroatoms are independently composed of 1 N atom and 0, 1 or 2 X atoms, and the X atoms are independently selected from 1 or 2 of N, O and S; the "6-9 membered bridged heterocycloalkyl", the "7-9 membered spiro heterocycloalkyl" and the "substituted by one or more R x-2 The substituted 6-9 membered bridged heterocycloalkyl is connected to the ring A through the N atom; Each R x-2 Each independently is C 1-6 alkyl; R 1 -LR 1-1 ; L is *-NHSO2-; * represents the end connected to ring A; R 1-1 C 1-6 Alkyl, one or more R a Substituted C 1-6 Alkyl or one or more R b substituted 3-6 membered monocyclic cycloalkyl; Each R a are independently hydroxyl groups; Each R b Each independently is C 1-6 alkyl; B is a 5-membered heteroaryl, a 9-10-membered heteroaryl, or a 5-membered heteroaryl, 2 substituted 6-membered heteroaryl, one or more R 3 substituted 9-10 membered heteroaryl; the "5 membered heteroaryl", "9-10 membered heteroaryl", "substituted by one or more R 2 substituted 6-membered heteroaryl" and "substituted by one or more R 3 In the "substituted 9-10 membered heteroaryl", the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; Each R 2 Each independently is C 1-6 alkyl; Each R 3 are independently halogen, C 1-6 Alkyl or C substituted by one or more halogen 1-6 alkyl; U is a 3-10 membered cycloalkyl, a 4-10 membered heterocycloalkyl, 2-1 substituted 3-10 membered cycloalkyl or one or more R 2-2 substituted 4-10 membered heterocycloalkyl; said "4-10 membered heterocycloalkyl" or "substituted by one or more R 2-2 In the "substituted 4-10 membered heterocycloalkyl", the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; Each R 2-1 、R 2-2 and R 2-3 are each independently halogen; W and X 2 is defined as follows: (1)W is *-CONR W -;X 2 R W-1 ; * indicates the end connected to ring A; (2)W is *-C(=X 1 )NR W -;X 1 、X 2 and the C atoms therebetween together form a 6-membered heteroaryl group; in the 6-membered heteroaryl group, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; * represents the end connected to ring A; R W H; R W-1 is H; G is C(R 10 ) or N; R 10 is H; Furthermore, the compound represented by Formula II satisfies one, two or three of the following conditions: (1)R x is a 6-9 membered bridged heterocyclic alkyl group or is replaced by one or more R x-2 substituted 6-9 membered bridged heterocycloalkyl; (2) B is naphthyl, 5-membered heteroaryl, 9-10-membered heteroaryl, 6-membered heterocycloalkenyl, or one or more R 5 Substituted naphthyl, one or more R 6 substituted 5-membered heteroaryl, one or more R 3 9-10 membered heteroaryl substituted or one or more R 4 substituted 6-membered heterocycloalkenyl; (3)W is *-C(=X 1 )NR W -;X 1 、X 2 and the C atoms therebetween together form a 6-membered heteroaryl group; Option 2: R x is a 6-9 membered bridged heterocycloalkyl, a 7-9 membered spiro heterocycloalkyl, or one or more R x-2 Substituted 6-9 membered bridged heterocycloalkyl; the "6-9 membered bridged heterocycloalkyl", the "7-9 membered spiro heterocycloalkyl" and the "substituted by one or more R x-2 In the "substituted 6-9 membered bridged heterocycloalkyl", the heteroatoms are independently composed of 1 N atom and 0, 1 or 2 X atoms, and the X atoms are independently selected from 1 or 2 of N, O and S; the "6-9 membered bridged heterocycloalkyl", the "7-9 membered spiro heterocycloalkyl" and the "substituted by one or more R x-2 The substituted 6-9 membered bridged heterocycloalkyl is connected to the ring A through the N atom; Each R x-2 Each independently is C 1-6 alkyl; R 1 -LR 1-1 ; L is *-NHSO2-; * represents the end connected to ring A; R 1-1 C 1-6 Alkyl, one or more R a Substituted C 1-6 Alkyl or one or more R b substituted 3-6 membered monocyclic cycloalkyl; Each R a are independently hydroxyl groups; Each R b Each independently is C 1-6 alkyl; B is a 9-10 membered heteroaryl group, 2 substituted 6-membered heteroaryl, one or more R 3 substituted 9-10 membered heteroaryl; the "5 membered heteroaryl", "9-10 membered heteroaryl", "substituted by one or more R 2 substituted 6-membered heteroaryl" and "substituted by one or more R 3 In the "substituted 9-10 membered heteroaryl", the heteroatoms are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; when the 9-10 membered heteroaryl is a 9-membered heteroaryl and the number of heteroatoms is 2, the heteroatoms are independently selected from one or two of N or O; when the 9-10 membered heteroaryl is a 9-membered heteroaryl and the number of heteroatoms is 3, the heteroatom is N; when the 9-10 membered heteroaryl is a 10-membered heteroaryl and the heteroatom is N, and the number of heteroatoms is 2, the heteroatoms are located on different rings; When B is occupied by one or more R 2 When the 6-membered heteroaryl group is substituted, R x is an 8-9 membered bridged heterocycloalkyl group; in the "8-9 membered bridged heterocycloalkyl group", the heteroatoms are independently composed of 1 N atom and 0, 1 or 2 X atoms, and the X atoms are independently selected from 1 or 2 of N, O and S; the "8-9 membered bridged heterocycloalkyl group" is connected to ring A through the N atom; Each R 2 Each independently is C 1-6 alkyl; Each R 3 are independently halogen or C 1-6 alkyl; U is a 4-10 membered heterocycloalkyl group or is replaced by one or more R 2-2 substituted 4-10 membered heterocycloalkyl; said "4-10 membered heterocycloalkyl" or "substituted by one or more R 2-2 In the "substituted 4-10 membered heterocycloalkyl", the heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 2, 3 or 4; Each R 2-2 are each independently halogen; W is *-CONR W -;X 2 R W-1 ; * indicates the end connected to ring A; R W H; R W-1 is H; G is C(R 10 ) or N; R 10 is H; Furthermore, the compound as shown in Formula II satisfies one or two of the following conditions: (1)R x is a 6-9 membered bridged heterocyclic alkyl group or is replaced by one or more R x-2 substituted 6-9 membered bridged heterocycloalkyl; (2) B is a 9-10 membered heteroaryl group, supported by one or more R 3 substituted 9-10 membered heteroaryl; Option 3: R x is a 6-9 membered bridged heterocyclic alkyl group, x-2 substituted 6-9 membered bridged heterocycloalkyl or 7-9 membered spiro heterocycloalkyl; Each R x-2 Each independently is C 1-6 alkyl; R 1 -LR 1-1 ; L is *-NHSO2-; R 1-1 C 1-6 Alkyl, one or more R a Substituted C 1-6 Alkyl or one or more R b substituted 3-6 membered monocyclic cycloalkyl; R a is hydroxyl group; Each R b Each independently is C 1-6 alkyl; B is a 5-membered heteroaryl, a 9-10-membered heteroaryl, or a 5-membered heteroaryl, 2 substituted 6-membered heteroaryl or one or more R 3 substituted 9-10 membered heteroaryl; Each R 2 Each independently is C 1-6 alkyl; Each R 3 Each independently is C 1-6 alkyl; U is a 4-10 membered heterocycloalkyl group, 2-1 substituted 3-10 membered cycloalkyl or one or more R 2-2 substituted 4-10 membered heterocycloalkyl; Each R 2-1 are each independently halogen; Each R 2-2 are each independently halogen; W is *-CONH-; X 2 is H; Furthermore, the compound as shown in Formula II satisfies one or two of the following conditions: (1)R x is a 6-9 membered bridged heterocycloalkyl group; (2) B is a 5-membered heteroaryl, naphthyl, 9-10-membered heteroaryl, or one or more R 5 substituted naphthyl or one or more R 3 Substituted 9-10 membered heteroaryl.

4. The nitrogen-containing compound of formula II according to claim 2, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its metabolite, its prodrug, its isotope-labeled derivative, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: R x is a 6-9 membered bridged heterocyclic alkyl group, x-2 substituted 6-9 membered bridged heterocycloalkyl or 7-9 membered spiro heterocycloalkyl; Each R x-2 Each independently is C 1-6 alkyl; R 1 -LR 1-1 ; L is *-NHSO2-; R 1-1 C 1-6 Alkyl, one or more R a Substituted C 1-6 Alkyl or one or more R b substituted 3-6 membered monocyclic cycloalkyl; R a is hydroxyl group; Each R b Each independently is C 1-6 alkyl; B is naphthyl, 5-membered heteroaryl, 9-10-membered heteroaryl, or one or more R 5 Substituted naphthyl, one or more R 2 substituted 6-membered heteroaryl or one or more R 3 substituted 9-10 membered heteroaryl; Each R 2 Each independently is C 1-6 alkyl; Each R 3 Each independently is C 1-6 alkyl; U is a 4-10 membered heterocycloalkyl group, 2-1 substituted 3-10 membered cycloalkyl or one or more R 2-2 substituted 4-10 membered heterocycloalkyl; Each R 2-1 are each independently halogen; Each R 2-2 are each independently halogen; W is *-CONH-; X 2 is H; Furthermore, the compound as shown in Formula II satisfies one or two of the following conditions: (1)R x is a 6-9 membered bridged heterocycloalkyl group; (2) B is a 5-membered heteroaryl, naphthyl, 9-10-membered heteroaryl, or one or more R 5 substituted naphthyl or one or more R 3 Substituted 9-10 membered heteroaryl.

5. The nitrogen-containing compound of formula II according to claim 2, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its metabolite, its prodrug, its isotope-labeled derivative, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: It meets one or more of the following conditions: (1)R x is a 6-9 membered bridged heterocycloalkyl, a 7-9 membered spiro heterocycloalkyl, or one or more R x-2 substituted 6-9 membered bridged heterocyclic alkyl or one or more R x-3 substituted 7-9 membered spirocyclic heterocycloalkyl; (2) Each R x-1 、R x-2 、R x-3 and R x-4 are independently halogen, C 1-6 Alkyl or C substituted by one or more halogen 1-6 alkyl; (3) L is *-NHSO2-; (4)R 1-1 C 1-6 Alkyl, 3-6 membered monocyclic cycloalkyl, b substituted 3-6 membered monocyclic cycloalkyl or one or more R a Substituted C 1-6 alkyl; (5)R a is hydroxyl group; (6) Each R b Each independently is C 1-6 alkyl; (7) B is phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 9-10-membered heteroaryl, 6-membered heterocycloalkenyl, substituted by one or more R 5 Substituted naphthyl, one or more R 2 substituted 6-membered heteroaryl, one or more R 3 9-10 membered heteroaryl substituted or one or more R 4 substituted 6-membered heterocycloalkenyl; (8) Each R 2 、R 3 、R 4 、R 5 、R 6 are independently halogen, oxo or C 1-6 alkyl; (9) U is a 3-10 membered cycloalkyl, a 4-10 membered heterocycloalkyl, or one or more R 2-1 substituted 3-10 membered cycloalkyl or one or more R 2-2 substituted 4-10 membered heterocycloalkyl; (10) Each R 2-1 、R 2-2 and R 2-3 are independently halogen, C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy or C substituted by one or more halogen 1-6 alkyl; (11)G is C(R 10 ); (12)R 10 H, halogen, C 1-6 Alkyl or C substituted by one or more halogen 1-6 alkyl; (13)W is *-CONR W -;X 2 R W-1 ; R W-1 is H or halogen; R W For H.

6. The nitrogen-containing compound of formula II according to claim 2, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its metabolite, its prodrug, its isotope-labeled derivative, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: It meets one or more of the following conditions: (1)R x is a 6-9 membered bridged heterocycloalkyl, a 7-9 membered spiro heterocycloalkyl, or one or more R x-2 substituted 6-9 membered bridged heterocycloalkyl; Each R x-2 Each independently is C 1-6 alkyl; (2) Each R x-1 、R x-2 、R x-3 and R x-4 Each independently is C 1-6 alkyl; (3) L is *-NHSO2- or -NH-; (4) B is a 5-membered heteroaryl, a 9-10-membered heteroaryl, or one or more R 2 substituted 6-membered heteroaryl, one or more R 3 substituted 9-10 membered heteroaryl; Preferably, B is a 9-10 membered heteroaryl group, 3 substituted 9-10 membered heteroaryl; (5) When B is occupied by one or more R 2 When the 6-membered heteroaryl group is substituted, R x is an 8-9 membered bridged heterocycloalkyl group; (6) Each R 2 、R 3 、R 4 、R 5 、R 6 are independently halogen, C 1-6 Alkyl or C substituted by one or more halogen 1-6 alkyl; Each R 2 Each independently preferably is C 1-6 Alkyl; each R 3 are independently preferably halogen or C 1-6 alkyl; (7) U is a 4-10 membered heterocycloalkyl group or is replaced by one or more R 2-2 substituted 4-10 membered heterocycloalkyl; Each R 2-2 are each independently halogen; (8)G is C(R 10 ) or N; R 10 is H; (9)R W is H; (10)R W-1 For H.

7. The nitrogen-containing compound of formula II according to claim 2, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its metabolite, its prodrug, its isotope-labeled derivative, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: It meets one or more of the following conditions: (1) In B, the 9-10 membered heteroaryl group is a 9-membered heteroaryl group having 2 heteroatoms, and the heteroatoms are independently selected from one or two of N and O; Alternatively, in B, the 9-10 membered heteroaryl group is a 9-membered heteroaryl group, the number of heteroatoms is 3, and the heteroatom is N; Alternatively, in B, the 9-10 membered heteroaryl group is a 10 membered heteroaryl group, the heteroatom is N, the number of heteroatoms is 2, and the heteroatoms are located in different rings; (2) B is a 9-10 membered heteroaryl group, supported by one or more R 2 substituted 6-membered heteroaryl or one or more R 3 substituted 9-10 membered heteroaryl; Each R 2 Each independently is C 1-6 alkyl; Each R 3 are independently halogen or C 1-6 alkyl; (3) In U, the 4-10 membered heterocycloalkyl group is a 4-6 membered monocyclic heterocycloalkyl group, a 6-9 membered bridged heterocycloalkyl group or a 7-9 membered spirocyclic heterocycloalkyl group; (4)R x is a 6-9 membered bridged heterocyclic alkyl group or is replaced by one or more R x-2 substituted 6-9 membered bridged heterocycloalkyl; (5)R 1-1 In the C 1-6 The alkyl group is ethyl or isopropyl.

8. The nitrogen-containing compound of formula II according to claim 2, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its metabolite, its prodrug, its isotope-labeled derivative, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: It meets one or more of the following conditions: (1)R x For one or more R x-2 Substituted 6-9 membered bridged heterocycloalkyl, 6-9 membered bridged heterocycloalkyl or 7-9 membered spiro heterocycloalkyl; preferably 6-9 membered bridged heterocycloalkyl or 7-9 membered spiro heterocycloalkyl; (2) Each R x-1 、R x-2 、R x-3 and R x-4 are independently halogen or C 1-6 Alkyl; preferably C 1-3 Alkyl, F, Cl or Br; (3)R 1-1 C 1-3 Alkyl, one or more R a Substituted C 1-3 Alkyl or one or more R b substituted 3-6 membered monocyclic cycloalkyl; (4) B is a 5-membered heteroaryl, a 9-10-membered heteroaryl, or one or more R 2 substituted 6-membered heteroaryl or one or more R 3 substituted 9-10 membered heteroaryl; preferably 9-10 membered heteroaryl or substituted by one or more R 3 substituted 9-10 membered heteroaryl; (5) Each R 2 、R 3 、R 4 、R 5 、R 6 Each independently is C 1-3 alkyl; (6) U is a 4-9 membered heterocycloalkyl group, which is replaced by one or more R 2-1 substituted 3-8 membered cycloalkyl or one or more R 2-2 substituted 4-9 membered heterocycloalkyl; preferably 4-9 membered heterocycloalkyl or substituted by one or more R 2-2 substituted 4-9 membered heterocycloalkyl; (7) Each R 2-1 、R 2-2 and R 2-3 are independently halogen; preferably F, Cl or Br; (8)W is *-CONR W -;X 2 R W-1 ; R W-1 H; R W For H.

9. The nitrogen-containing compound of formula II according to claim 2, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its metabolite, its prodrug, its isotope-labeled derivative, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: It meets one or more of the following conditions: (1)R x is a 6-9 membered bridged heterocycloalkyl, a 7-9 membered spiro heterocycloalkyl, or one or more R x-2 substituted 6-9 membered bridged heterocyclic alkyl or one or more R x-3 substituted 7-9 membered spirocyclic heterocycloalkyl; Each R x-1 、R x-2 、R x-3 and R x-4 are independently halogen, C 1-6 Alkyl or C substituted by one or more halogen 1-6 Alkyl, preferably halogen or C 1-6 Alkyl, more preferably C 1-3 Alkyl, F, Cl or Br; (2)R 1-1 C 1-6 Alkyl, one or more R b substituted 3-6 membered monocyclic cycloalkyl or one or more R a Substituted C 1-6 alkyl; R a is hydroxyl group; Each R b Each independently is C 1-6 alkyl; (3) B is a 5-membered heteroaryl, a 9-10-membered heteroaryl, or one or more R 2 substituted 6-membered heteroaryl or one or more R 3 substituted 9-10 membered heteroaryl; Each R 2 、R 3 are independently halogen or C 1-6 alkyl; (4) U is a 3-10 membered cycloalkyl, a 4-10 membered heterocycloalkyl, or one or more R 2-1 substituted 3-10 membered cycloalkyl or one or more R 2-2 substituted 4-10 membered heterocycloalkyl; Each R 2-1 and R 2-2 are independently halogen, C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy or C substituted by one or more halogen 1-6 Alkyl, preferably F, Cl or Br; (5)G is C(R 10 );R 10 is H; (6) The compound of formula II satisfies one or two of the following conditions: (a) R x (b) B is a 5-membered heteroaryl, a 9-10-membered heteroaryl, a 6-membered heterocycloalkenyl, or a 6-membered heterocycloalkyl; 4 substituted 6-membered heterocycloalkenyl or one or more R 3 substituted 9-10 membered heteroaryl, preferably 9-10 membered heteroaryl or substituted by one or more R 3 Substituted 9-10 membered heteroaryl.

10. The nitrogen-containing compound of formula II according to claim 2, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its metabolite, its prodrug, its isotope-labeled derivative, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: The nitrogen-containing compound shown in Formula II is the following compound: Each V1 is independently C or N; V2 is N or CR 11 ; preferably N; D is a partially saturated or unsaturated 5-6 membered carbocyclic ring, or a partially saturated or unsaturated 5-6 membered heterocyclic ring, wherein the 5-6 membered carbocyclic ring or the 5-6 membered heterocyclic ring is optionally substituted by 0, 1, 2 or 3 R 11 Substitution; in the "5-6 membered heterocycle", the heteroatom is N, O, S, and the number of heteroatoms is independently 1, 2, 3 or 4; R 11 For hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C substituted by one or more halogen 1-6 alkyl.

11. The nitrogen-containing compound of formula II according to claim 2 or 10, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its metabolite, its prodrug, its isotope-labeled derivative, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: It meets one or more of the following conditions: (1) The “6-9 membered bridged heterocycloalkyl” is independently a 6-9 membered bridged heterocycloalkyl containing 1 or 2 heteroatoms, preferably any of the following fragments: More preferred (2) In a certain embodiment, the "9-10 membered heteroaryl" is independently any of the following fragments: Preferably connected to U by the left dotted line More preferably, it is connected to U by the left dotted line (3) The "4-10 membered heterocycloalkyl" are each independently a 4-6 membered monocyclic heterocycloalkyl, a 6-8 membered spirocyclic heterocycloalkyl or a 7-9 membered bridged heterocycloalkyl, preferably More preferred (4)R x For any of the following fragments: Preferably (5) In one embodiment, B is any of the following fragments (the left dashed line in the following fragments represents the bond to U): Preferably (6) U is any of the following fragments: Preferably 12. The nitrogen-containing compound of formula II according to claim 2 or 10, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its metabolite, its prodrug, its isotope-labeled derivative, its solvate, or its solvate of a pharmaceutically acceptable salt, wherein: It meets one or more of the following conditions: (1) The “5-6 membered monocyclic heterocycloalkyl” is independently a 5-6 membered heterocycloalkyl containing 1 or 2 heteroatoms; (2) The "6-9 membered bridged heterocycloalkyl" are each independently a 6-9 membered bridged heterocycloalkyl containing 1 or 2 heteroatoms; (3) The "7-9 membered spirocyclic heterocycloalkyl" are each independently a 7-9 membered spirocyclic heterocycloalkyl containing 1 or 2 heteroatoms; (4) The "halogen" is independently fluorine, chlorine, bromine or iodine; (5) The "C 1-6 "Alkyl" are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; (6) The "3-6 membered monocyclic cycloalkyl" are each independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (7) The "C 1-6 "Alkoxy" are each independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy; (8) The "4-8 membered monocyclic heterocycloalkyl" is a "4-8 membered monocyclic heterocycloalkyl" containing one O atom; (9) The 5-membered heteroaryl groups are each independently a 5-membered heteroaryl group wherein the heteroatom is one or two selected from N and S; (10) The “6-membered heteroaryl” is independently any of the following fragments: (11) The “9-10 membered heteroaryl” is independently any of the following fragments: (12) The “6-membered heterocycloalkenyl” is independently a 6-membered heterocycloalkenyl group having a nitrogen atom and one or two heteroatoms; (13) The "3-10 membered cycloalkyl" is a 3-6 membered monocyclic cycloalkyl or a 6-8 membered spirocyclic cycloalkyl; (14) The “4-10 membered heterocycloalkyl” is a 4-6 membered monocyclic heterocycloalkyl, a 6-8 membered spirocyclic heterocycloalkyl or a 7-9 membered bridged heterocycloalkyl; (15) The "6-10 membered aryl" is a phenyl group; (16) The “5-10 membered heteroaryl group” is a 5-6 membered heteroaryl group in which the heteroatom is nitrogen and the number of heteroatoms is 1 or 2; (17) When W is *-C(X 1 )NR W -;X 1 、X 2 When the carbon atoms therebetween form a 6-membered heteroaryl group, the heteroatom in the "6-membered heteroaryl group" is N, and the number of heteroatoms is 1 or 2.

13. The nitrogen-containing compound of formula II according to claim 2 or 10, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its metabolite, its prodrug, its isotope-labeled derivative, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: It meets one or more of the following conditions: (1) The "5-6 membered monocyclic heterocycloalkyl" are each independently (2) The "6-9 membered bridged heterocycloalkyl" are each independently (3) The "7-9 membered spirocyclic heterocycloalkyl" is independently any of the following fragments: (4) The "halogen" is fluorine; (5) The "C 1-6 "Alkyl" are each independently methyl or ethyl; (6) The "3-6 membered monocyclic cycloalkyl" is a cyclopropyl group; (7) The "C 1-6 "Alkoxy" are each independently methoxy or ethoxy; (8) The "4-8 membered monocyclic heterocycloalkyl" is (9) The “5-membered heteroaryl” is independently any of the following fragments: (10) The "6-membered heteroaryl" is independently connected to U by the left dotted line (11) The "9-10 membered heteroaryl" is independently connected to U by the left dotted line (12) The “6-membered heterocycloalkenyl” is independently any of the following fragments: (13) The "3-10 membered cycloalkyl" are independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, (14) The "4-10 membered heterocycloalkyl" are each independently a 4-6 membered monocyclic heterocycloalkyl, a 6-8 membered spirocyclic heterocycloalkyl or a 7-9 membered bridged heterocycloalkyl, preferably (15) The "5-10 membered heteroaryl" is 14. The nitrogen-containing compound of formula II according to claim 2 or 10, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its metabolite, its prodrug, its isotope-labeled derivative, its solvate, or its pharmaceutically acceptable salt solvate, characterized in that: It meets one or more of the following conditions: (1) The "6-9 membered bridged heterocycloalkyl" are each independently (2) The "7-9 membered spirocyclic heterocycloalkyl" is (3) The "5-membered heteroaryl" is For example, the one connected to U by the dotted line on the right (4) The "6-membered heteroaryl" is connected to U by the dotted line on the left (5) The "9-10 membered heteroaryl" is independently connected to U by the left dotted line (6) The "6-membered heterocycloalkenyl" is connected to U by the dotted line on the left (7) The "3-10 membered cycloalkyl" is (8) The "4-10 membered heterocycloalkyl" are each independently 15. The nitrogen-containing compound of formula II according to claim 2 or 10, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its metabolite, its prodrug, its isotope-labeled derivative, its solvate, or its solvate of a pharmaceutically acceptable salt, wherein: It meets one or more of the following conditions: (1)R x For any of the following fragments: (2) R1 is any of the following fragments: (3) B is any of the following fragments: (4) U is any of the following segments:

16. The nitrogen-containing compound of formula II according to claim 2 or 10, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its metabolite, its prodrug, its isotope-labeled derivative, its solvate, or its solvate of a pharmaceutically acceptable salt, wherein: It meets one or more of the following conditions: (1)R x for (2) R1 is (3)B is (4) U is 17. A nitrogen-containing compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that: The nitrogen-containing compound is any of the following compounds:

18. A pharmaceutical composition comprising: (1) the nitrogen-containing compound of formula I according to claim 1, the nitrogen-containing compound of formula II according to claim 2 or 10, the nitrogen-containing compound according to claim 17, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and (2) Pharmaceutically acceptable excipients.

19. Use of the nitrogen-containing compound of formula I according to claim 1, the nitrogen-containing compound of formula II according to claim 2 or 10, the nitrogen-containing compound according to claim 17, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a metabolite thereof, a prodrug thereof, an isotope-labeled derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof in the preparation of a KIF18A inhibitor.

20. Use of the nitrogen-containing compound of formula I according to claim 1, the nitrogen-containing compound of formula II according to claim 2 or 10, the nitrogen-containing compound according to claim 17, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, metabolites thereof, prodrugs thereof, isotope-labeled derivatives thereof, solvates thereof, or solvates of pharmaceutically acceptable salts thereof in the preparation of a medicament, wherein the medicament is used to treat a disease related to the mechanism of action of the KIF18A protein, such as cancer, or another example of a cancer related to the mechanism of action of the KIF18A protein, preferably, the cancer is ovarian cancer, colon cancer, or ductal breast cancer.

21. Use of the nitrogen-containing compound of formula I according to claim 1, the nitrogen-containing compound of formula II according to claim 2 or 10, the nitrogen-containing compound according to claim 17, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, metabolites thereof, prodrugs thereof, isotope-labeled derivatives thereof, solvates thereof, or solvates of pharmaceutically acceptable salts thereof in the preparation of a medicament, wherein the medicament is for treating cancer, preferably, the cancer is ovarian cancer, colon cancer, or ductal carcinoma of the breast.

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