USP1 inhibitor, and preparation method therefor and use thereof

Abstract

The present invention relates to a compound represented by formula (XI), or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, co-crystal, hydrate, solvate, metabolite, prodrug, and deuterated compound thereof. The present invention also relates to a pharmaceutical composition comprising the compound as an active ingredient, and a use of the compound or the pharmaceutical composition for treating and / or preventing diseases associated with USP1.

Description

USP1 inhibitors and their preparation and use Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a USP1 inhibitor, a preparation method and use thereof. Background Art

[0002] Ubiquitination is a common post-translational modification that can be deubiquitinated by deubiquitinating enzymes (DUBs) acting on ubiquitinated substrates to catalyze the removal of the ubiquitin moiety. Ubiquitin-specific proteases (USPs) comprise the largest family of DUBs, encompassing 58 members. USPs regulate a variety of important cellular functions in the tumor environment, including the cell cycle, DNA damage repair mechanisms, chromatin remodeling, and other signaling pathways.

[0003] USP1, a member of the USPs family, is one of the best-characterized DUBs. USP1 is highly expressed in various tumors and is associated with poor prognosis and metastasis in some tumors. USP1 can regulate two DNA damage repair pathways, namely translesion synthesis (TLS) and interstrand crosslink repair (ICL), by forming a complex with USP1-Associated Factor 1 (UAF1). This complex can also influence cell differentiation and cancer progression. In the TLS pathway, USP1 regulates the recruitment and conversion of high-fidelity and low-fidelity TLS polymerases by regulating the deubiquitination of proliferating cell nuclear antigen (PCNA). In the ICL repair pathway, USP1 targets sites of nuclear DNA damage by regulating the deubiquitination of FANCD2, where it colocalizes with BRCA1 and RAD51 and interacts with downstream FA proteins. Furthermore, USP1 can influence the ubiquitination of ID proteins (a family of inhibitors of DNA binding proteins), regulating cell proliferation and differentiation. USP1 inhibition leads to blockage of the FA repair pathway and increased error-prone repair in the TLS pathway, resulting in increased SSB repair errors, replication fork collapse or premature arrest, and the formation of DSBs during S phase replication.

[0004] Homologous recombination (HR) is an error-free repair pathway involved in repairing double-strand breaks (DSBs). When mutations in factors such as BRCA1 / 2 impair the HR repair pathway, DSBs generated after USP1 inhibition can only be repaired through error-prone pathways such as NHEJ and MMEJ. This can lead to abnormal mutations such as gene deletions or structural changes, preventing timely and correct repair, resulting in cell cycle arrest and apoptosis. Studies have confirmed that USP1 expression is higher in BRCA1-deficient tumors compared to wild-type tumors. Knocking out or inhibiting USP1 can lead to replication fork instability and reduced viability of BRCA1-deficient cells, indicating that inhibition of USP1 and HR pathway defects can form a synergistic lethal effect.

[0005] In summary, USP1 small molecule inhibitors are a potential therapy for treating HR pathway-deficient tumors and can provide a new therapeutic strategy for tumor treatment. Summary of the Invention

[0006] The present invention provides a compound of formula (XI), or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof:

[0007] wherein X1 is selected from N or CR2; X2 is selected from N or CR3; M is selected from C(R4)(R5);

[0008] R2 and R3 are each independently selected from H, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1- 6 alkoxy, C 3-6 Cycloalkyl, 4-10 membered heterocycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -SCH3, -SF5, -SeR k 、-Se(O)R k , phenyl, 5-membered or 6-membered heteroaryl, -C(O)R i 、-C(O)OR i 、-C(O)NR i R j The 4-10 membered heterocycloalkyl, 5-membered or 6-membered heteroaryl groups each independently contain 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-10 membered heterocycloalkyl, C 2-6 Alkenyl, C 2-6Alkynyl, phenyl, 5-membered or 6-membered heteroaryl are each independently unsubstituted or substituted by one or more R a replace;

[0009] R1 is selected from H, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 4-7 membered heterocycloalkyl are each independently unsubstituted or substituted by one or more R a replace;

[0010] R4 and R5 are each independently selected from H, deuterium, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy; or R4 and R5 are combined with the atoms to which they are attached to form C 3-6 Cycloalkyl;

[0011] Ring A is selected from C 6-10 Aryl or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl contains 1-3 heteroatoms selected from N, O and S, and the C 6-10 Aryl and 5-10 membered heteroaryl are each independently unsubstituted or substituted by one or more R b replace;

[0012] B is selected from C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group, C 3-10 Cycloalkyl or C 3-10 The cycloalkenyl group, the 5-10 membered heteroaryl group, the 4-10 membered heterocyclic group each independently contain 1-3 heteroatoms selected from N, O and S, the C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group, C 3-10 Cycloalkyl, C 3-10 Each cycloalkenyl group is independently unsubstituted or substituted with one or more R c replace;

[0013] Each R b and R c Each independently selected from the same or different halogen, cyano, hydroxyl, amino, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10Cycloalkyl, 4-7 membered heterocyclic group, -SeR k 、-C(O)NR i R j 、 The 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted by one or more R a replace;

[0014] Each R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 are each independently selected from hydrogen, deuterium, amino, C 1-6 Alkyl, C 3-10 Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the amino, C 1-6 Alkyl, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted by one or more R a replace;

[0015] or R 11 and R 12 Together with the P to which they are connected, they form a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O, S and P, and at least one heteroatom is P, and the 4-7 membered heterocyclic group is unsubstituted or substituted by one or more R a replace;

[0016] or R 17 and R 18 Together with the atoms to which they are attached, they form a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 2-3 heteroatoms selected from N, O and S, and at least two heteroatoms are N and S, and the 4-7 membered heterocyclic group is unsubstituted or substituted by one or more R a replace;

[0017] C is selected from -C(O)NR i R j 、C 1-6 Alkoxy, C 6-10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group, wherein the 5-10 membered heteroaryl and 4-10 membered heterocyclic group each independently contain 1-3 heteroatoms selected from N, O and S, and the C1-6 Alkoxy, C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group are each independently unsubstituted or substituted by one or more R d replace;

[0018] Each R d Each independently selected from the same or different phenyl, 5-membered or 6-membered heteroaryl, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl or 4-7 membered heterocyclic group, the 5-membered or 6-membered heteroaryl, 4-7 membered heterocyclic group each independently contains 1-3 heteroatoms selected from N, O and S, the phenyl, 5-membered or 6-membered heteroaryl, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted by one or more R a Substitution; or two adjacent substituents R on C d The 4-7 membered heterocyclic group or carbocyclic ring is combined with the atoms to which it is connected, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S; the 4-7 membered heterocyclic group or carbocyclic ring is unsubstituted or substituted by one or more R a replace;

[0019] or R c and R d The 4-10 membered heterocyclic group or carbocyclic ring is combined with the atoms to which it is attached, wherein the 4-10 membered heterocyclic group contains 1-4 heteroatoms selected from N, O and S; the 4-10 membered heterocyclic group or carbocyclic ring is unsubstituted or substituted by one or more R a replace;

[0020] Each R a Each independently selected from the same or different halogen, cyano, =O, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)NR i R j 、C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted by one or more R ereplace;

[0021] Each R e are independently selected from the same or different deuterium, halogen, cyano, =O, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted by one or more R f replace;

[0022] Each R f Each independently selected from the same or different halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S;

[0023] Each R i 、R j 、R k Each independently selected from the same or different hydrogen or C 1-6 alkyl.

[0024] The present invention provides a compound of formula (XI), or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof:

[0025] wherein X1 is selected from N or CR2; X2 is selected from N or CR3; M is selected from C(R4)(R5);

[0026] R2 and R3 are each independently selected from H, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1- 6 alkoxy, C 3-6 Cycloalkyl, 4-10 membered heterocycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -SCH3, -SF5, -SeR k , phenyl, 5-membered or 6-membered heteroaryl, -C(O)R i 、-C(O)OR i 、-C(O)NR i R jThe 4-10 membered heterocycloalkyl, 5-membered or 6-membered heteroaryl groups each independently contain 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-10 membered heterocycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, 5-membered or 6-membered heteroaryl are each independently unsubstituted or substituted by one or more R a replace;

[0027] R1 is selected from H, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 4-7 membered heterocycloalkyl are each independently unsubstituted or substituted by one or more R a replace;

[0028] R4 and R5 are each independently selected from H, deuterium, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy; or R4 and R5 are combined with the atoms to which they are attached to form C 3-6 Cycloalkyl;

[0029] Ring A is selected from C 6-10 Aryl or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl contains 1-3 heteroatoms selected from N, O and S, and the C 6-10 Aryl and 5-10 membered heteroaryl are each independently unsubstituted or substituted by one or more R b replace;

[0030] B is selected from C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group, C 3-10 Cycloalkyl or C 3-10 The cycloalkenyl group, the 5-10 membered heteroaryl group, the 4-10 membered heterocyclic group each independently contain 1-3 heteroatoms selected from N, O and S, the C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group, C 3-10 Cycloalkyl, C 3-10 Each cycloalkenyl group is independently unsubstituted or substituted with one or more Rc replace;

[0031] Each R b and R c Each independently selected from the same or different halogen, cyano, hydroxyl, amino, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 4-7 membered heterocyclic group, -SeR k 、-C(O)NR i R j 、 The 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted by one or more R a replace;

[0032] Each R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 are each independently selected from hydrogen, deuterium, amino, C 1-6 Alkyl, C 3-10 Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the amino, C 1-6 Alkyl, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted by one or more R a replace;

[0033] or R 11 and R 12 Together with the P to which they are connected, they form a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O, S and P, and at least one heteroatom is P, and the 4-7 membered heterocyclic group is unsubstituted or substituted by one or more R a replace;

[0034] or R 17 and R 18 Together with the atoms to which they are attached, they form a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 2-3 heteroatoms selected from N, O and S, and at least two heteroatoms are N and S, and the 4-7 membered heterocyclic group is unsubstituted or substituted by one or more R a replace;

[0035] C is selected from -C(O)NR i R j 、C 1-6 Alkoxy, C 6-10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group, wherein the 5-10 membered heteroaryl and 4-10 membered heterocyclic group each independently contain 1-3 heteroatoms selected from N, O and S, and the C 1-6 Alkoxy, C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group are each independently unsubstituted or substituted by one or more R d replace;

[0036] Each R d Each is independently selected from the same or different phenyl, 5-membered or 6-membered heteroaryl, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl or 4-7 membered heterocyclic group, the 5-membered or 6-membered heteroaryl, 4-7 membered heterocyclic group each independently contains 1-3 heteroatoms selected from N, O and S, the phenyl, 5-membered or 6-membered heteroaryl, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted by one or more R a Substitution; or two adjacent substituents R on C d The 4-7 membered heterocyclic group or carbocyclic ring is combined with the atoms to which it is connected, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S; the 4-7 membered heterocyclic group or carbocyclic ring is unsubstituted or substituted by one or more R a replace;

[0037] or R c and R d The 4-10 membered heterocyclic group or carbocyclic ring is combined with the atoms to which it is attached, wherein the 4-10 membered heterocyclic group contains 1-4 heteroatoms selected from N, O and S; the 4-10 membered heterocyclic group or carbocyclic ring is unsubstituted or substituted by one or more R a replace;

[0038] Each R a Each independently selected from the same or different halogen, cyano, =O, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)NR i R j 、C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted by one or more R e replace;

[0039] Each R e are independently selected from the same or different deuterium, halogen, cyano, =O, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted by one or more R f replace;

[0040] Each R f Each independently selected from the same or different halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S;

[0041] Each R i 、R j 、R k Each independently selected from the same or different hydrogen or C 1-6 alkyl.

[0042] The present invention provides a compound of formula (XI), or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof:

[0043] wherein X1 is selected from N or CR2; X2 is selected from N or CR3; M is selected from C(R4)(R5);

[0044] R2 and R3 are each independently selected from H, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1- 6 alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 2-6 Alkenyl or C 2-6Alkynyl, the 4-7 membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O and S, the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 2-6 Alkenyl, C 2-6 Each alkynyl group is independently unsubstituted or substituted with one or more R a replace;

[0045] R1 is selected from H, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 4-7 membered heterocycloalkyl are each independently unsubstituted or substituted by one or more R a replace;

[0046] R4 and R5 are each independently selected from H, deuterium, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy; or R4 and R5 are combined with the atoms to which they are attached to form C 3-6 Cycloalkyl;

[0047] Ring A is selected from C 6-10 Aryl or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl contains 1-3 heteroatoms selected from N, O and S, and the C 6-10 Aryl and 5-10 membered heteroaryl are each independently unsubstituted or substituted by one or more R b replace;

[0048] B is selected from C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group, C 3-10 Cycloalkyl or C 3-10 The cycloalkenyl group, the 5-10 membered heteroaryl group, the 4-10 membered heterocyclic group each independently contain 1-3 heteroatoms selected from N, O and S, the C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group, C 3-10 Cycloalkyl, C 3-10 Each cycloalkenyl group is independently unsubstituted or substituted with one or more R c replace;

[0049] Each R b and R c Each independently selected from the same or different halogen, cyano, hydroxyl, amino, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 4-7 membered heterocyclic group, -SeR k 、-C(O)NR i R j 、 The 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted by one or more R a replace;

[0050] R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 are each independently selected from hydrogen, deuterium, amino, C 1-6 Alkyl, C 3-10 Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the amino, C 1-6 Alkyl, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted by one or more R a replace;

[0051] or R 11 and R 12 Together with the P to which they are connected, they form a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O, S and P, and at least one heteroatom is P, and the 4-7 membered heterocyclic group is unsubstituted or substituted by one or more R a replace;

[0052] or R 17 and R 18 Together with the atoms to which they are attached, they form a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 2-3 heteroatoms selected from N, O and S, and at least two heteroatoms are N and S, and the 4-7 membered heterocyclic group is unsubstituted or substituted by one or more R a replace;

[0053] C is selected from -C(O)NR i Rj 、C 6-10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group, wherein the 5-10 membered heteroaryl and 4-10 membered heterocyclic group each independently contain 1-3 heteroatoms selected from N, O and S, and the C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group are each independently unsubstituted or substituted by one or more R d replace;

[0054] Each R d Each independently selected from the same or different halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted by one or more R a replace;

[0055] Each R a Each independently selected from the same or different halogen, cyano, =O, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)NR i R j 、C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted by one or more R e replace;

[0056] Each R e are independently selected from the same or different deuterium, halogen, cyano, =O, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted by one or more R f replace;

[0057] Each R f Each independently selected from the same or different halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S;

[0058] Each R i 、R j 、R k Each independently selected from the same or different hydrogen or C 1-6 alkyl.

[0059] In some embodiments, the above compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, X1 is selected from CR2, X2 is selected from N; R2 is selected from H, halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, 4-8 membered heterocycloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -SCH3, -SF5, -SeR k ,5-membered heteroaryl, -C(O)R i 、-C(O)OR i 、-C(O)NR i R j The 4-8 membered heterocycloalkyl and 5 membered heteroaryl groups each independently contain 1-2 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, 4-8 membered heterocycloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl and 5-membered heteroaryl are each independently unsubstituted or substituted by one or more R a Replacement; R 11 、R 12 、R 13 、R 14 、R 17 and R 18 Each R is independently selected from hydrogen, methyl or ethyl, i 、R j 、R kare each independently selected from the same or different hydrogen, methyl or ethyl.

[0060] In some embodiments, X1 is selected from CR2, X2 is selected from N; R2 is selected from H, F, Cl, Br, cyano, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, 4-8 membered heterocycloalkyl, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl, -SCH3, -SF5, -SeCH3, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, The 4-8 membered heterocycloalkyl contains 1-2 heteroatoms selected from N and O, and the hydroxyl, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, 4-8 membered heterocycloalkyl, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl are each independently unsubstituted or substituted by one or more R a replace.

[0061] In some embodiments, X1 is selected from CR2, X2 is selected from N; R2 is selected from H, F, Cl, cyano, hydroxy, amino, methyl, isopropyl, methoxy, ethoxy, 6-8 membered heterocycloalkyl, vinyl, propenyl, ethynyl, propynyl, -SCH3, -SF5, -SeCH3, imidazolyl, oxazolyl, The 6-8 membered heterocycloalkyl contains 1-2 heteroatoms selected from N and O, and the hydroxyl, amino, methyl, isopropyl, methoxy, ethoxy, 6-8 membered heterocycloalkyl, vinyl, propenyl, ethynyl, propynyl, imidazolyl, oxazolyl are each independently unsubstituted or substituted by one or more R a replace.

[0062] In some embodiments, X1 is selected from CR2, X2 is selected from N; R2 is selected from H, F, Cl, cyano, hydroxy, amino, methyl, isopropyl, methoxy, ethoxy, 6-7 membered heterocycloalkyl, vinyl, propenyl, ethynyl, propynyl, -SCH3, -SF5, -SeCH3, imidazolyl, oxazolyl, The 6-7 membered heterocycloalkyl contains 1-2 heteroatoms selected from N and O, and the hydroxyl, amino, methyl, isopropyl, methoxy, ethoxy, 6-7 membered heterocycloalkyl, ethynyl, and imidazolyl are each independently unsubstituted or substituted by one or more R a replace.

[0063] In some embodiments, each R aEach independently selected from the same or different halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 4-7 membered heterocyclic group, said 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, said 4-7 membered heterocyclic group is unsubstituted or replaced by one or more identical or different C 1-6 Alkyl substitution.

[0064] In some embodiments, each R a Each independently selected from the same or different halogen, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, the 4-7 membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O and S, the 4-7 membered heterocycloalkyl is unsubstituted or replaced by one or more identical or different C 1-4 Alkyl substitution.

[0065] In some embodiments, each R a Each independently selected from the same or different F, Cl, Br, hydroxyl, cyano, C 1-2 Alkyl, C 3-4 Alkyl, C 1-2 Fluorinated alkyl, C 3-4 Fluorinated alkyl, C 1-2 Alkoxy, C 3-4 Alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-7 membered heterocycloalkyl, the 4-7 membered heterocycloalkyl contains 1-2 heteroatoms selected from N, O and S, the 4-7 membered heterocycloalkyl is unsubstituted or replaced by one or more identical or different C 1-2 Alkyl or C 3-4 Alkyl substitution.

[0066] In some embodiments, each R a Each is independently selected from the same or different F, Cl, Br, hydroxy, cyano, methyl, ethyl, fluoromethyl, fluoroethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-6 membered heterocycloalkyl, the 5-6 membered heterocycloalkyl contains 1-2 heteroatoms selected from N and O, the 5-6 membered heterocycloalkyl is unsubstituted or substituted by one or more same or different methyl or ethyl groups.

[0067] In some embodiments, each R aEach is independently selected from the same or different F, Cl, hydroxy, cyano, methyl, fluoromethyl, fluoroethyl, methoxy, cyclopropyl, morpholinyl, N-methylpiperazinyl.

[0068] In some embodiments, X1 is selected from CR2, X2 is selected from N; R2 is selected from H, F, Cl, cyano, -SF5, Amino, methyl, methoxy, 6-7 membered heterocycloalkyl, ethenyl, propenyl, ethynyl, propynyl, imidazolyl, oxazolyl, wherein the 6-7 membered heterocycloalkyl contains 1-2 heteroatoms selected from N and O; the 6-7 membered heterocycloalkyl is unsubstituted or substituted by one or more identical or different methyl groups; the methyl is unsubstituted or substituted by one or more identical or different F, Cl, cyano, morpholinyl, methoxy or N-methylpiperazinyl; the methoxy is unsubstituted or substituted by one or more identical or different F or Cl; the amino is unsubstituted or substituted by one or more identical or different methyl or fluoroethyl groups; the ethynyl is unsubstituted or substituted by one fluoromethyl group; the isopropyl is unsubstituted or substituted by one or more hydroxy groups; the imidazolyl is unsubstituted or substituted by one or more methyl groups.

[0069] In some embodiments, X1 is CR2, X2 is N, and R2 is selected from H, F, Cl, cyano, amino, methyl, methoxy, -CF3, -CClF2, -OCHF2, -OCF3, -OCClF2, -SF5, vinyl, propenyl, ethynyl, propynyl,

[0070] In some embodiments, the above compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, X1 is selected from CR2, X2 is selected from N; R2 is selected from -Se(O)R k , R k Selected from C 1-6 alkyl.

[0071] In some embodiments, X1 is selected from CR2, X2 is selected from N; R2 is selected from -Se(O)R k , R k Selected from C 1-4 alkyl.

[0072] In some embodiments, X1 is selected from CR2, X2 is selected from N; R2 is selected from -Se(O)R k , R k Selected from C 1-2Alkyl, C 3-4 alkyl.

[0073] In some embodiments, X1 is selected from CR2, X2 is selected from N; R2 is selected from -Se(O)R k , R k Selected from methyl and ethyl.

[0074] In some embodiments, X1 is selected from CR2, X2 is selected from N; R2 is selected from -Se(O)R k , R k Selected from methyl.

[0075] In some specific embodiments, in the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof, X1 is selected from N, and X2 is selected from N.

[0076] In some specific embodiments, in the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof, X1 is selected from N, X2 is selected from CR3; and R3 is selected from H, methyl, F, Cl, Br, or cyano.

[0077] In some specific embodiments, in the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof, X1 is selected from CR2, and X2 is selected from N.

[0078] In some specific embodiments, in the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof, X1 is selected from CR2, and X2 is selected from CH.

[0079] In some specific embodiments, in the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof, X1 is selected from CR2, X2 is selected from CR3; and R3 is selected from H, methyl, F, Cl, Br, or cyano.

[0080] In some embodiments, the above compounds, or pharmaceutically acceptable salts, stereoisomers, tautomers, enantiomers, diastereomers, racemates, polymorphs, cocrystals, hydrates, solvates, metabolites, prodrugs, deuterated compounds thereof, R2 is selected from H, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 4-7 membered heterocycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, the 4-7 membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O and S, the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 4-7 membered heterocycloalkyl, C 2-6 Alkenyl, C 2-6 Each alkynyl group is independently unsubstituted or substituted with one or more R a replace.

[0081] In some embodiments, R2 is selected from H, halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, 4-7 membered heterocycloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, the 4-7 membered heterocycloalkyl contains 1-2 heteroatoms selected from N, O and S, the hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, 4-7 membered heterocycloalkyl, C 2-4 Alkenyl, C 2-4 Each alkynyl group is independently unsubstituted or substituted with one or more R a replace.

[0082] In some embodiments, R2 is selected from H, F, Cl, Br, cyano, hydroxyl, amino, C 1-2 Alkyl, C 3-4 Alkyl, C 1-2 Alkoxy, C 3-4 Alkoxy, 4-7 membered heterocycloalkyl, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl, the 4-7 membered heterocycloalkyl contains 1-2 heteroatoms selected from N, O and S, the hydroxyl, amino, C 1-2 Alkyl, C 3-4 Alkyl, C 1-2 Alkoxy, C 3-4 Alkoxy, 4-7 membered heterocycloalkyl, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl are each independently unsubstituted or substituted with one or more R a replace.

[0083] In some specific embodiments, R2 is selected from H, F, Cl, Br, cyano, hydroxyl, amino, methyl, ethyl, methoxy, ethoxy, 4-7 membered heterocycloalkyl, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl, the 4-7 membered heterocycloalkyl contains 1-2 heteroatoms selected from N and O, the hydroxyl, amino, methyl, ethyl, methoxy, ethoxy, 4-7 membered heterocycloalkyl, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl are each independently unsubstituted or replaced by one or more R a replace.

[0084] In some specific embodiments, R2 is selected from H, F, Cl, cyano, hydroxyl, amino, methyl, methoxy, ethoxy, 6-7 membered heterocycloalkyl, vinyl, propenyl, ethynyl, propynyl, the 6-7 membered heterocycloalkyl contains 1-2 heteroatoms selected from N and O, the hydroxyl, amino, methyl, methoxy, ethoxy, 6-7 membered heterocycloalkyl, vinyl, propenyl, ethynyl, propynyl are each independently unsubstituted or substituted by one or more R a replace.

[0085] In some specific embodiments, R2 is selected from H, F, Cl, cyano, hydroxy, amino, methyl, methoxy, ethoxy, 6-7 membered heterocycloalkyl, vinyl, propenyl, ethynyl, propynyl, the 6-7 membered heterocycloalkyl contains 1-2 heteroatoms selected from N and O, the hydroxy, amino, methyl, methoxy, ethoxy, 6-7 membered heterocycloalkyl is each independently unsubstituted or substituted by one or more R a replace.

[0086] In some embodiments, each R a are independently selected from the same or different halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 4-7 membered heterocyclic group, said 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, said 4-7 membered heterocyclic group is unsubstituted or replaced by one or more identical or different C 1-6 Alkyl substitution.

[0087] In some embodiments, each R a are independently selected from the same or different halogen, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 3-6Cycloalkyl, 4-7 membered heterocycloalkyl, the 4-7 membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O and S, the 4-7 membered heterocycloalkyl is unsubstituted or replaced by one or more identical or different C 1-4 Alkyl substitution.

[0088] In some embodiments, each R a Each independently selected from the same or different F, Cl, Br, cyano, C 1-2 Alkyl, C 3-4 Alkyl, C 1-2 Fluorinated alkyl, C 3-4 Fluorinated alkyl, C 1-2 Alkoxy, C 3-4 Alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-7 membered heterocycloalkyl, the 4-7 membered heterocycloalkyl contains 1-2 heteroatoms selected from N, O and S, the 4-7 membered heterocycloalkyl is unsubstituted or replaced by one or more identical or different C 1-2 Alkyl or C 3-4 Alkyl substitution.

[0089] In some embodiments, each R a Each is independently selected from the same or different F, Cl, Br, cyano, methyl, ethyl, fluoromethyl, fluoroethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-6 membered heterocycloalkyl, the 5-6 membered heterocycloalkyl contains 1-2 heteroatoms selected from N and O, the 5-6 membered heterocycloalkyl is unsubstituted or substituted by one or more same or different methyl or ethyl groups.

[0090] In some embodiments, each R a Each is independently selected from the same or different F, Cl, cyano, methyl, fluoroethyl, methoxy, cyclopropyl, morpholinyl, and N-methylpiperazinyl.

[0091] In some embodiments, R2 is selected from H, F, Cl, cyano, Amino, methyl, methoxy, 6-7 membered heterocycloalkyl, ethenyl, propenyl, ethynyl, propynyl, the 6-7 membered heterocycloalkyl contains 1-2 heteroatoms selected from N and O; the 6-7 membered heterocycloalkyl is unsubstituted or substituted by one or more identical or different methyl groups; the methyl is unsubstituted or substituted by one or more identical or different F, Cl, cyano, morpholinyl or N-methylpiperazinyl groups; the methoxy is unsubstituted or substituted by one or more identical or different F or Cl groups; the amino is unsubstituted or substituted by one or more identical or different methyl or fluoroethyl groups.

[0092] In some embodiments, R2 is selected from H, F, Cl, cyano, amino, methyl, methoxy, -CF3, -CClF2, -OCHF2, -OCF3, -OCClF2, vinyl, propenyl, ethynyl, propynyl,

[0093] In some embodiments, X1 is CR2, X2 is N, and R2 is selected from H, F, Cl, cyano, amino, methyl, methoxy, -CF3, -CClF2, -OCHF2, -OCF3, -OCClF2, vinyl, propenyl, ethynyl, propynyl,

[0094] In some embodiments, X1 is CR2, X2 is N, and R2 is selected from methyl.

[0095] In some embodiments, X1 is CR2, X2 is N, and R2 is selected from methoxy.

[0096] In some embodiments, the above compounds, or pharmaceutically acceptable salts, stereoisomers, tautomers, enantiomers, diastereomers, racemates, polymorphs, cocrystals, hydrates, solvates, metabolites, prodrugs, deuterated compounds thereof, R1 is selected from H, halogen, cyano, amino, C 1-4 Alkyl or C 1-4 Alkoxy, the amino, C 1-4 Each alkoxy group is independently unsubstituted or substituted with one or more R a replace.

[0097] In some embodiments, R1 is selected from H, Cl, cyano, amino, methyl or methoxy, wherein the amino and methoxy groups are each independently unsubstituted or replaced by one or more R a replace.

[0098] In some embodiments, each R a Each independently selected from the same or different C 1-4 Alkyl or C 5-6 alkyl.

[0099] In some embodiments, each R a are each independently selected from the same or different methyl groups.

[0100] In some embodiments, R1 is selected from H, Cl, methyl, cyano, methoxy, amino,

[0101] In some embodiments, R1 is selected from H.

[0102] In some embodiments, Selected from

[0103] In some embodiments, Selected from

[0104] In some embodiments, Selected from

[0105] In some embodiments, Selected from

[0106] In some embodiments, Selected from

[0107] In some embodiments, Selected from

[0108] In some embodiments, the above compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, M is selected from C(R4)(R5); R4 and R5 are each independently selected from H, deuterium, halogen, cyano, C 1-4 Alkyl or C 1-4 Alkoxy; or R4 and R5 are combined with the atoms to which they are attached to form C 3-6 Cycloalkyl.

[0109] In some embodiments, M is selected from C(R4)(R5); R4 and R5 are each independently selected from H, deuterium, F, cyano, methyl, or methoxy; or R4 and R5, combined with the atoms to which they are attached, form a cyclopropyl group.

[0110] In some embodiments, M is selected from C(R4)(R5); R4 and R5 are each independently selected from H, deuterium, C 1-4 Alkyl or C 5-6 alkyl.

[0111] In some embodiments, M is selected from C(R4)(R5); R4 and R5 are each independently selected from H, deuterium or methyl.

[0112] In some embodiments, M is selected from methylene,

[0113] In some embodiments, M is selected from methylene.

[0114] In some embodiments, the above compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof, Ring A is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heteroaryl and 5-membered heteroaryl, 5-membered heteroaryl and 6-membered heteroaryl, 6-membered heteroaryl and 6-membered heteroaryl. , phenyl and 5-membered heteroaryl or phenyl and 6-membered heteroaryl, the 5-membered heteroaryl and 6-membered heteroaryl each independently contain 1-3 heteroatoms selected from N, O and S, the phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heteroaryl and 5-membered heteroaryl, 5-membered heteroaryl and 6-membered heteroaryl, 6-membered heteroaryl and 6-membered heteroaryl, phenyl and 5-membered heteroaryl, phenyl and 6-membered heteroaryl each independently are unsubstituted or substituted by one or more R b replace.

[0115] In some embodiments, ring A is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl or phenyl-5-membered heteroaryl, wherein the 5-membered heteroaryl and 6-membered heteroaryl each independently contain 1-3 heteroatoms selected from N, O and S, and the phenyl, 5-membered heteroaryl, 6-membered heteroaryl and phenyl-5-membered heteroaryl are each independently unsubstituted or substituted with one or more R b replace.

[0116] In some embodiments, ring A is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl or phenyl-5-membered heteroaryl, wherein the 5-membered heteroaryl and 6-membered heteroaryl each independently contain 1-2 N heteroatoms, and the phenyl, 5-membered heteroaryl, 6-membered heteroaryl and phenyl-5-membered heteroaryl are each independently unsubstituted or substituted with one or more R b replace.

[0117] In some embodiments, ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, benzopyrazolyl or benzimidazolyl, wherein the phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, benzopyrazolyl, benzimidazolyl are each independently unsubstituted or substituted with one or more R b replace.

[0118] In some embodiments, ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl or benzopyrazolyl, wherein the phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl and benzopyrazolyl are each independently unsubstituted or substituted with one or more R b replace.

[0119] In some embodiments, Ring A is selected from

[0120] In some embodiments, Ring A is selected from

[0121] In some embodiments, each R b Each independently selected from the same or different halogen, amino, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 4-7 membered heterocyclic group, -SeR k 、-C(O)NR i R j 、 The 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the amino, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted by one or more R a Replacement; R i 、R j 、R k Each independently selected from H or C 1-4 Alkyl; R 11 、R 12 、R 13 、R 14 、R 17 and R 18 Each independently selected from H or C 1-4 alkyl.

[0122] In some embodiments, each R b Each independently selected from the same or different halogen, amino, SH, C 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Alkoxy, C 5-6 Alkoxy, C 3-8 Cycloalkyl, 4-7 membered heterocycloalkyl, -SeR k 、-C(O)NR i R j 、 The 4-7 membered heterocycloalkyl group contains 1-3 heteroatoms selected from N, O and S, and the amino, SH, C 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Alkoxy, C 5-6 Alkoxy, C 3-8 Cycloalkyl and 4-7 membered heterocycloalkyl are each independently unsubstituted or substituted by one or more R aReplacement; R i 、R j 、R k Each independently selected from H or C 1-4 Alkyl; R 11 、R 12 、R 13 、R 14 、R 17 and R 18 Each independently selected from H or C 1-4 alkyl.

[0123] In some embodiments, each R b Each independently selected from the same or different halogen, amino, SH, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, -SeR k 、-C(O)NR i R j 、 The 4-7 membered heterocycloalkyl group contains 1-2 heteroatoms selected from N, O and S, and the amino, SH, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 4-7 membered heterocycloalkyl are each independently unsubstituted or substituted by one or more R a Replacement; R i 、R j 、R k Each independently selected from H or C 1-4 Alkyl; R 11 、R 12 、R 13 、R 14 、R 17 and R 18 Each independently selected from H or C 1-4 alkyl.

[0124] In some embodiments, each R b each independently selected from the same or different F, Cl, Br, amino, SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-7 membered heterocycloalkyl, -SeR k 、-C(O)NR i R j 、 The 4-7 membered heterocycloalkyl contains one N heteroatom, and the amino, SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-7 membered heterocycloalkyl are each independently unsubstituted or substituted by one or more R a Replacement; R i 、R j 、R k are each independently selected from hydrogen, methyl, ethyl, n-propyl or isopropyl; R 11 、R 12 、R 13 、R 14 、R 17 and R 18 Each is independently selected from hydrogen, methyl, ethyl, n-propyl or isopropyl.

[0125] In some embodiments, each R b Each is independently selected from the same or different F, Cl, amino, SH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, azetidinyl, -SeR k 、-C(O)NR i R j 、 The amino, SH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, azetidinyl are each independently unsubstituted or substituted by one or more R a Replacement; R i 、R j 、R k are each independently selected from hydrogen, methyl or ethyl; R 11 、R 12 、R 13 、R 14 、R 17 and R 18 are each independently selected from hydrogen, methyl or ethyl.

[0126] In some embodiments, each R b Each is independently selected from the same or different F, Cl, amino, SH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, azetidinyl, -SeCH3, The amino, SH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, azetidinyl are each independently unsubstituted or substituted by one or more R a replace.

[0127] In some embodiments, each Ra Each independently selected from the same or different halogen, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy.

[0128] In some embodiments, each R a Each independently selected from the same or different halogen, hydroxyl, C 1-4 Alkyl or C 1-4 Alkoxy.

[0129] In some embodiments, each R a Each is independently selected from the same or different F, Cl, Br, hydroxy, methyl, ethyl, methoxy or ethoxy.

[0130] In some embodiments, each R a Each is independently selected from the same or different F, hydroxy, methyl or methoxy.

[0131] In some embodiments, each R b Each is independently selected from the same or different F, Cl, amino, methyl-substituted amino, -SCH3, methyl, fluoromethyl, methoxy, fluoromethoxy, fluorochloromethoxy, ethoxy, fluoroethoxy, hydroxy-substituted isopropyl, hydroxy-substituted cyclopropyl, methoxy-substituted ethoxy, isopropyl, isopropoxy, cyclopropyl, azetidinyl, -SeCH3,

[0132] In some embodiments, each R b Each is independently selected from the same or different methyl, methoxy, cyclopropyl, isopropyl, ethoxy, isopropoxy, -SCH3, -SeCH3, amino, F, Cl, -OCHF2, -OCClF2, -OCF3, -CF3,

[0133] In some embodiments, Ring A is selected from

[0134] In some embodiments, Ring A is selected from

[0135] In some embodiments, the above compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, B is selected from C2-4 Alkynyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4-7-membered heterocycloalkyl or C 3-8 Cycloalkyl, the 5-membered heteroaryl, 6-membered heteroaryl, 4-7-membered heterocycloalkyl each independently contains 1-3 heteroatoms selected from N, O and S, the C 2-4 Alkynyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4-7-membered heterocycloalkyl, C 3-8 The cycloalkyl groups are each independently unsubstituted or substituted with one or more halogen or C 1-4 Alkoxy substitution.

[0136] In some embodiments, B is selected from ethynyl, phenyl, pyridyl, pyrimidinyl, cyclohexyl, cubic alkyl, or piperidinyl, the phenyl, pyridinyl, pyrimidinyl, cyclohexyl, cubic alkyl, or piperidinyl are each independently unsubstituted or substituted with one or more identical or different F, Cl, Br, methoxy or ethoxy groups.

[0137] In some embodiments, B is selected from phenyl, pyridyl, pyrimidinyl, cyclohexyl, cubic alkyl, Piperidinyl, fluoropiperidinyl or ethynyl, wherein the phenyl group is unsubstituted or substituted by one or more identical or different F or methoxy groups.

[0138] In some embodiments, B is selected from C 2-4 Alkynyl, phenyl, 6-membered heteroaryl, 4-7-membered heterocycloalkyl or C 3-6 Cycloalkyl, the 6-membered heteroaryl, 4-7-membered heterocycloalkyl each independently contains 1-2 heteroatoms selected from N, the C 2-4 Alkynyl, phenyl, 6-membered heteroaryl, 4-7-membered heterocycloalkyl, C 3-6 The cycloalkyl groups are each independently unsubstituted or substituted with one or more halogen or C 1-4 Alkoxy substitution.

[0139] In some embodiments, B is selected from ethynyl, phenyl, pyridinyl, pyrimidinyl, cyclohexyl or piperidinyl, and each of the phenyl, pyridinyl, pyrimidinyl, cyclohexyl or piperidinyl groups is independently unsubstituted or substituted with one or more identical or different F, Cl, Br, methoxy or ethoxy groups.

[0140] In some embodiments, B is selected from phenyl, pyridyl, pyrimidinyl, cyclohexyl, piperidinyl, fluoropiperidinyl or ethynyl, wherein the phenyl is unsubstituted or substituted with one or more identical or different F or methoxy groups.

[0141] In some embodiments, B is selected from or ethynyl.

[0142] In some embodiments, B is selected from or ethynyl.

[0143] In some embodiments, B is selected from or ethynyl.

[0144] In some embodiments, B is selected from

[0145] In some embodiments, the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof, C is selected from -C(O)NR i R j 、C 6-10 Aryl or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl contains 1-3 heteroatoms selected from N, O and S, and the C 6-10 Aryl and 5-10 membered heteroaryl are each independently unsubstituted or substituted by one or more R d Replacement; R i 、R j are each independently selected from hydrogen, C 1-4 Alkyl or C 5-6 alkyl.

[0146] In some embodiments, C is selected from -C(O)NR i R j , phenyl, pyridyl, pyrimidinyl, 5-membered heteroaryl, the 5-membered heteroaryl contains 1-3 heteroatoms selected from N, O and S, the phenyl, pyridyl, pyrimidinyl, 5-membered heteroaryl are each independently unsubstituted or substituted by one or more R d Replacement; R i 、R j Each independently selected from H or C 1-4 alkyl.

[0147] In some embodiments, C is selected from -C(O)NR i R j , phenyl, pyridyl, pyrimidinyl, 5-membered heteroaryl, the 5-membered heteroaryl contains 1-2 heteroatoms selected from N, O and S, the phenyl, pyridyl, pyrimidinyl, 5-membered heteroaryl are each independently unsubstituted or substituted by one or more R d Replacement; R i 、R j Each is independently selected from hydrogen, methyl, ethyl, n-propyl or isopropyl.

[0148] In some embodiments, C is selected from -C(O)NR i R j , phenyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, said phenyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, each of which is independently unsubstituted or substituted by one or more R d Replacement; R i 、R j are each independently selected from hydrogen, methyl or ethyl.

[0149] In some embodiments, C is selected from -C(O)NHCH3, -C(O)N(CH3)2, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, and the pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl are each independently unsubstituted or substituted with one or more R d replace.

[0150] In some embodiments, C is selected from

[0151] In some embodiments, C is selected from

[0152] In some embodiments, each R d Each independently selected from the same or different phenyl, 6-membered heteroaryl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl, the 6 membered heteroaryl contains 1-2 N atoms, the 4-7 membered heterocycloalkyl contains 1 N heteroatom, the phenyl, 6 membered heteroaryl, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 4-7 membered heterocycloalkyl are each independently unsubstituted or substituted by one or more R a Substitution; or two adjacent substituents R on C d The 5-6 membered heterocyclic group is combined to form a 5-6 membered heterocyclic group containing 1-2 N heteroatoms.

[0153] In some embodiments, each R dEach is independently selected from the same or different pyridyl, F, Cl, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, cyclopropyl, cyclobutyl or azetidinyl, and the pyridyl, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, cyclopropyl, cyclobutyl, azetidinyl are each independently unsubstituted or substituted by one or more R a Substitution; or two adjacent substituents R on C d The 5-membered heterocyclic group contains one nitrogen heteroatom.

[0154] In some embodiments, each R d Each is independently selected from the same or different pyridyl, Cl, methyl, ethyl, isopropyl, methoxy, cyclopropyl or azetidinyl, wherein the methyl, ethyl, methoxy, azetidinyl is independently unsubstituted or substituted by one or more R a Substitution; or two adjacent substituents R on C d The 5-membered heterocyclic group contains one nitrogen heteroatom.

[0155] In some embodiments, each R d are independently selected from the same or different halogen, C 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Alkoxy, C 5-6 Alkoxy, C 3-8 Cycloalkyl or 4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl contains 1-2 heteroatoms selected from N, O and S, and the C 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Alkoxy, C 5-6 Alkoxy, C 3-8 Cycloalkyl and 4-7 membered heterocycloalkyl are each independently unsubstituted or substituted by one or more R a replace.

[0156] In some embodiments, each R d are independently selected from the same or different halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl contains 1 N heteroatom, the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 4-7 membered heterocycloalkyl are each independently unsubstituted or substituted by one or more R a replace.

[0157] In some embodiments, each Rd Each is independently selected from the same or different F, Cl, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl or azetidinyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, azetidinyl is independently unsubstituted or substituted by one or more R a replace.

[0158] In some embodiments, each R d Each is independently selected from the same or different Cl, methyl, ethyl, isopropyl, methoxy, cyclopropyl or azetidinyl, wherein the methyl, ethyl, methoxy, azetidinyl is independently unsubstituted or substituted by one or more R a replace.

[0159] In some embodiments, each R a are independently selected from the same or different halogen, =O or C 1-6 alkyl.

[0160] In some embodiments, each R a are independently selected from the same or different halogen, =O or C 1-4 alkyl.

[0161] In some embodiments, each R a Each is independently selected from the same or different F, Cl, Br, =O, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0162] In some embodiments, each R a are each independently selected from the same or different F, =0 or methyl.

[0163] In some embodiments, each R d Each is independently selected from the same or different pyridyl, Cl, fluoromethyl, ethyl, fluoroethyl, isopropyl, methoxy, fluoromethoxy, cyclopropyl, or two adjacent substituents R on C d The 5-membered heterocyclic group contains one nitrogen heteroatom.

[0164] In some embodiments, each R d Each independently selected from the same or different pyrimidinyl, methyl, isopropyl, -CF3, -CHF2, Cyclopropyl, methoxy, Cl, or -OCF3, or two adjacent substituents R on C d The 5-membered heterocyclic group contains one nitrogen heteroatom.

[0165] In some embodiments, each R d Each is independently selected from the same or different Cl, methyl, fluoromethyl, ethyl, fluoroethyl, isopropyl, methoxy, fluoromethoxy, cyclopropyl,

[0166] In some embodiments, each R d Each independently selected from the same or different methyl, isopropyl, -CF3, -CHF2, Cyclopropyl, methoxy, Cl, or -OCF3.

[0167] In some embodiments, C is selected from

[0168] In some embodiments, C is selected from

[0169] In some embodiments, C is selected from

[0170] In some embodiments, the above compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, B is phenyl, C is a 5-6 membered heteroaryl, B and C are separated by a substituent R c 、R d Combined to form a tricyclic ring; R c 、R d The combined monocyclic ring is unsubstituted or substituted with one or more R a substituted 4-10 membered heterocyclic group; wherein the 5-6 membered heteroaryl group and the 4-10 membered heterocyclic group each independently contain 1-3 heteroatoms selected from N, O and S; wherein C also has a substituent of C 1-4 Fluoroalkyl.

[0171] In some embodiments, B is phenyl, C is a 5-membered heteroaryl, and B and C are substituted by R c 、R d Combined to form a tricyclic ring; R c 、R d The combined monocyclic ring is unsubstituted or substituted with one or more R a substituted 4-8 membered heterocyclic group; wherein the 5-membered heteroaryl group and the 4-8 membered heterocyclic group each independently contain 1-3 heteroatoms selected from N, O and S; wherein C also has a substituent of C1-4 Fluoroalkyl.

[0172] In some embodiments, B is phenyl, C is a 5-membered heteroaryl, and B and C are substituted by R c 、R d Combined to form a tricyclic ring; R c 、R d The combined monocyclic ring is unsubstituted or substituted with one or more R a substituted 4-8 membered heterocyclic group; wherein the 5-membered heteroaryl group and the 4-8 membered heterocyclic group each independently contain 1-2 heteroatoms selected from N, O and S; wherein C also has a substituent of C 1-4 Fluoroalkyl.

[0173] In some embodiments, B is phenyl, C is a 5-membered heteroaryl, and B and C are substituted by R c 、R d Combined to form a tricyclic ring; R c 、R d The combined monocyclic ring is unsubstituted or substituted with one or more R a substituted 4-8 membered heterocyclic group; wherein the 5 membered heteroaryl group contains 1-2 N atoms, and the 4-8 membered heterocyclic group contains 1-2 heteroatoms selected from N and O; wherein C also has a substituent of C 1-2 Fluoroalkyl.

[0174] In some embodiments, B is phenyl, C is selected from pyrazolyl, imidazolyl, pyrrolyl, B and C are substituted by R c 、R d Combined to form a tricyclic ring; R c 、R d The combined monocyclic ring is unsubstituted or substituted with one or more R a A substituted 5-8 membered heterocyclic group; wherein the 5-8 membered heterocyclic group contains 1-2 heteroatoms selected from N and O; wherein C also has a substituent which is a fluoromethyl group.

[0175] In some embodiments, B is phenyl, C is selected from imidazolyl, B and C are substituted by R c 、R d Combined to form a tricyclic ring; R c 、R d The combined monocyclic ring is unsubstituted or substituted with one or more R a A substituted 6-7 membered heterocyclic group; wherein the 6-7 membered heterocyclic group contains 1-2 heteroatoms selected from N and O; wherein C also has a substituent group of -CF3.

[0176] In some embodiments, for B and C are connected by substituents Rc 、R d Combined to form a tricyclic ring; R c 、R d The combined monocyclic ring is unsubstituted or substituted with one or more R a A substituted 6-7 membered heterocyclic group; wherein the 6-7 membered heterocyclic group contains 1-2 heteroatoms selected from N and O, and at least one heteroatom is N.

[0177] In some embodiments, each R a Each independently selected from the same or different =O, C 1-6 alkyl.

[0178] In some embodiments, each R a Each independently selected from the same or different =O, C 1-2 Alkyl, C 3-4 alkyl.

[0179] In some embodiments, each R a Each is independently selected from the same or different =0, methyl, ethyl.

[0180] In some embodiments, each R a Each is independently selected from the same or different =O, methyl.

[0181] In some embodiments, Selected from

[0182] In some embodiments, Selected from

[0183] In a preferred technical solution of the present invention, the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof, has the structure shown in Formula XIa:

[0184] wherein R2 is as defined above.

[0185] The preferred technical solution of the present invention, the above-mentioned compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in Formula XIb:

[0186] Among them, R bDefined as shown above.

[0187] The preferred technical solution of the present invention, the above-mentioned compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in Formula XIc:

[0188] Among them, R b Defined as shown above.

[0189] In a preferred technical solution of the present invention, the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof, has the structure shown in Formula XId:

[0190] Among them, R d Defined as shown above.

[0191] In a preferred technical solution of the present invention, the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof, has the structure shown in Formula XIe:

[0192] Among them, R d Defined as shown above.

[0193] In a preferred technical solution of the present invention, the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof, has the structure shown in Formula XIf:

[0194] Among them, R d Defined as shown above.

[0195] The preferred technical solution of the present invention, the above-mentioned compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in Formula XIg:

[0196] Among them, R d Defined as shown above.

[0197] The preferred technical solution of the present invention, the above-mentioned compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in Formula XIh:

[0198] wherein R2 is as defined above.

[0199] In a preferred technical solution of the present invention, the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof, has the structure shown in Formula XIi:

[0200] Among them, R b Defined as shown above.

[0201] In a preferred technical solution of the present invention, the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof, has the structure shown in Formula XIj:

[0202] Among them, R b Defined as shown above.

[0203] The preferred technical solution of the present invention, the above-mentioned compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in Formula XIk:

[0204] Among them, R d Defined as shown above.

[0205] In a preferred technical solution of the present invention, the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof, has the structure shown in Formula XI1:

[0206] Among them, R d Defined as shown above.

[0207] The preferred technical solution of the present invention, the above-mentioned compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in Formula XIm:

[0208] Among them, R d Defined as shown above.

[0209] The preferred technical solution of the present invention is that the above-mentioned compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in Formula XIn:

[0210] Among them, R d Defined as shown above.

[0211] The preferred technical solution of the present invention, the above-mentioned compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in Formula XIq:

[0212] Among them, R d Defined as shown above.

[0213] The present invention also provides a compound represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof:

[0214] Wherein, X5 is selected from N or CR 20 ; R 20 Selected from H, F, Cl, Br or C 1-4 alkyl;

[0215] X6 is selected from N or CR 26 ; R 26 Selected from H, F, Cl, Br or C 1-4 alkoxy;

[0216] R 21 Selected from H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl, C 1-4 Deuterated alkyl, C1-4 Halogenated alkoxy, C 1-4 Deuterated alkoxy, C 3-6 Cycloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -SC 1-4 Alkyl, -Se-C 1-4 Alkyl, -C(O)-C 1-4 Alkyl, -Se(O)-C 1-4 Alkyl, 4-8 membered heterocycloalkyl, -C 2-4 Alkenylene-4-8 membered heterocycloalkyl; the 4-8 membered heterocycloalkyl each independently contains 1-2 heteroatoms selected from N, O and S; the 4-8 membered heterocycloalkyl each independently is unsubstituted or replaced by C 1- 4 alkyl substitution;

[0217] R 22 、R 23 Each independently selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, C 1-4 haloalkoxy;

[0218] R 24 、R 25 are each independently selected from H, deuterium, F, Cl, Br, methyl, ethyl; or R 24 、R 25 Combined with the atoms to which it is connected to form C 3-6 Cycloalkyl;

[0219] Ring D is selected from 5-membered heteroaryl, 6-membered heteroaryl, 9-membered heteroaryl, and 10-membered heteroaryl, wherein the 5-membered heteroaryl, 6-membered heteroaryl, 9-membered heteroaryl, and 10-membered heteroaryl each independently contain 1, 2, or 3 heteroatoms selected from N, O, and S; Ring D is unsubstituted or substituted by 1, 2, or more R m Replace, each R m Each independently selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl.

[0220] In some embodiments, Selected from

[0221] In some embodiments, Selected from

[0222] In some embodiments, Selected from

[0223] In some embodiments, R 21 Selected from H, F, Cl, Br, C 1-4 Alkyl, methoxy, ethoxy, isopropoxy, C 1-4 Hydroxyalkyl, fluoromethyl, fluoroethyl, deuterated methyl, deuterated ethyl, fluoromethoxy, fluoroethoxy, deuterated methoxy, deuterated ethoxy, C 3-6 Cycloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -SC 1-2 Alkyl, -Se-C 1-2 Alkyl, -C(O)-C 1-2 Alkyl, -Se(O)-C 1-2 Alkyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, -C 2-3 Alkenylene-5-6 membered heterocycloalkyl; the 5-6 membered heterocycloalkyl contains 1-2 heteroatoms selected from N and O; the 5-6 membered heterocycloalkyl is unsubstituted or substituted by methyl or ethyl.

[0224] In some embodiments, R 21 Selected from H, F, methyl, ethyl, isopropyl, tert-butyl, methoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, morpholinyl, -Se(O)CH3, -C(O)CH3, -SCH3, -SeCH3, -OCHF2, -OCH2CH2F,

[0225] In some embodiments, R 21 is selected from methyl or methoxy.

[0226] In some embodiments, R 22 、R 23 Each independently selected from C 1-2 Alkyl, C 3-4 Alkyl, C 1-2 Alkoxy, C 3-4 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, C 1-2 Halogenated alkoxy, C 3-4 Halogenated alkoxy.

[0227] In some embodiments, R 22 、R 23Each is independently selected from methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, fluoromethoxy, fluorochloromethoxy, fluoroethoxy, fluoroisopropoxy, and fluorotert-butoxy.

[0228] In some embodiments, Selected from

[0229] In some embodiments, Selected from

[0230] In some embodiments, ring D is selected from 5-membered heteroaryl and 6-membered heteroaryl, and the 5-membered heteroaryl and 6-membered heteroaryl each independently contain 1, 2 or 3 heteroatoms selected from N, O and S; ring D is unsubstituted or substituted by 1, 2 or more R m replace.

[0231] In some embodiments, ring D is selected from pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl; ring D is unsubstituted or substituted with one, two or more R m replace.

[0232] In some embodiments, ring D is selected from pyrazolyl, imidazolyl, pyridyl; ring D is unsubstituted or substituted with one, two or more R m replace.

[0233] In some embodiments, ring D is selected from Ring D is unsubstituted or substituted with one, two or more R m replace.

[0234] In some embodiments, each R m Each independently selected from C 1-4 Alkyl, C 1-2 Halogenated alkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl.

[0235] In some embodiments, each R m Each independently selected from C 1-4 Alkyl, fluoromethyl, fluoroethyl, deuterated methyl, deuterated ethyl, methoxy, ethoxy, C 3-6 Cycloalkyl.

[0236] In some embodiments, each R mEach is independently selected from methyl, ethyl, isopropyl, methoxy, cyclopropyl, -CF3, -CHF2, -CD3.

[0237] In some embodiments, ring D is selected from

[0238] The present invention also provides a compound represented by formula (II), or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof:

[0239] Among them, R 22 、R 23 Each is independently selected from methoxy, ethoxy, isopropoxy, cyclopropyloxy, cyclopropyl; Ring D is selected from R 27 Each is independently selected from -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -OCF3, -OCHF2; R 28 Each is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated butyl, cyclopropyl, and cyclobutyl.

[0240] The preferred technical solution of the present invention is the above-mentioned compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, wherein the compound is selected from the following structures:

[0241] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds discovered herein with the specified substituents with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.

[0242] The term "prodrug" refers to derivatives of the compounds with specific substituents discovered in the present invention, which themselves may have weak activity or even no activity, but after administration, they are converted into compounds with specific substituents discovered in the present invention under physiological conditions (for example, by metabolism, solvent decomposition or other means) and produce corresponding biological activity in the body.

[0243] The term "metabolite" refers to a product resulting from the in vivo metabolism of a compound identified herein as having a specific substituent. Metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized using assays as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention encompasses metabolites of the compound, including metabolites produced by contacting a compound of the invention with a mammal for a sufficient period of time.

[0244] The term "deuterated compound" refers to a compound of the present invention that includes at least one deuterium atom, specifically one or more hydrogen atoms in a compound of the present invention that can be replaced or substituted with a deuterium atom. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. Synthetic methods for incorporating isotopes into organic compounds are known in the art.

[0245] Preparation method:

[0246] The present invention also provides a method for preparing the compound. The preparation of the compound described in the general formula of the present invention can be completed by the following illustrative methods and examples, but these methods and examples should not be considered in any way to limit the scope of the present invention. The compound described in the present invention can also be synthesized by synthetic techniques known to those skilled in the art, or a combination of synthetic methods known in the art and the method described in the present invention. The product obtained by each step of the reaction is obtained using separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, etc. The starting materials and chemical reagents required for the synthesis can be conventionally synthesized according to the literature (such as provided by Scifinder) or purchased.

[0247] Step 1: The compound represented by Formula Ia-1 and the compound represented by Formula Id-1 are reacted by Negishi coupling to obtain the compound represented by Formula Ia-6;

[0248] Step 2: Suzuki coupling of the compound represented by Formula Ia-6 with the compound represented by Formula Ia-4 or the compound represented by Formula Ia-5 to obtain the compound represented by Formula XI;

[0249] Wherein, X1, X2, R1, R4, R5, ring A, B, and C are as defined above.

[0250] Pharmaceutical composition

[0251] The present invention also provides a pharmaceutical composition comprising a compound of Formula (XI), (XIa), (XIb), (XIc), (XId), (XIe), (XIf), (XIg), (XIh), (XIi), (XIj), (XIk), (XIl), (XIm), (XIn), (XIq), (I) or (II) or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, and optionally a pharmaceutically acceptable carrier and / or adjuvant and / or diluent.

[0252] Methods for preparing various pharmaceutical compositions containing a certain amount of active ingredient are known or will be apparent to those skilled in the art based on the disclosure of the present invention. As described in REMINGTON'S PHARMACEUTICAL SCIENCES, Martin, EW, ed., Mack Publishing Company, 19th ed. (1995), the method for preparing the pharmaceutical composition includes incorporating appropriate pharmaceutical excipients, carriers, diluents, etc.

[0253] Medical uses

[0254] In another aspect, the present invention also provides use of a compound of Formula (XI), (XIa), (XIb), (XIc), (XId), (XIe), (XIf), (XIg), (XIh), (XIi), (XIj), (XIk), (XIl), (XIm), (XIn), (XIq), (I) or (II) or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, or a pharmaceutical composition thereof in the preparation of a USP1 inhibitor.

[0255] In another aspect, the present invention also provides a compound of Formula (XI), (XIa), (XIb), (XIc), (XId), (XIe), (XIf), (XIg), (XIh), (XIi), (XIj), (XIk), (XIl), (XIm), (XIn), (XIq), (I) or (II) or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing and / or treating a disease mediated by USP1.

[0256] Preferably, the USP1-mediated disease is a tumor or cancer.

[0257] Preferably, the USP1-mediated disease refers to a USP1-mediated related disease with HR deficiency.

[0258] Preferably, the USP1-mediated disease refers to cancer or tumor with HR deficiency.

[0259] In another aspect, the present invention also provides a compound of Formula (XI), (XIa), (XIb), (XIc), (XId), (XIe), (XIf), (XIg), (XIh), (XIi), (XIj), (XIk), (XIl), (XIm), (XIn), (XIq), (I) or (II) or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, or the pharmaceutical composition thereof for the preparation of a medicament for the prevention and / or treatment of tumors or cancer.

[0260] Preferably, the tumor or cancer is associated with USP1 biological activity.

[0261] Preferably, the tumor or cancer is a tumor or cancer with HR deficiency associated with USP1 biological activity.

[0262] Preferably, the tumor or cancer is a cancer or tumor with HR deficiency.

[0263] In another aspect, the present invention also provides a compound of Formula (XI), (XIa), (XIb), (XIc), (XId), (XIe), (XIf), (XIg), (XIh), (XIi), (XIj), (XIk), (XIl), (XIm), (XIn), (XIq), (I) or (II) or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, or pharmaceutical composition thereof, for use in treating and / or preventing diseases mediated by USP1.

[0264] Preferably, the USP1-mediated disease is a tumor or cancer.

[0265] Preferably, the USP1-mediated disease refers to a USP1-mediated related disease with HR deficiency.

[0266] Preferably, the USP1-mediated disease refers to cancer or tumor with HR deficiency.

[0267] In another aspect, the present invention also provides a compound of Formula (XI), (XIa), (XIb), (XIc), (XId), (XIe), (XIf), (XIg), (XIh), (XIi), (XIj), (XIk), (XIl), (XIm), (XIn), (XIq), (I) or (II) or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, or pharmaceutical composition thereof, for use in treating and / or preventing tumors or cancer.

[0268] Preferably, the tumor or cancer is associated with USP1 biological activity.

[0269] Preferably, the tumor or cancer is a tumor or cancer with HR deficiency associated with USP1 biological activity.

[0270] Preferably, the tumor or cancer is a cancer or tumor with HR deficiency.

[0271] In another aspect, the present invention also provides a method for treating and / or preventing diseases mediated by USP1, comprising administering to a subject / individual in need thereof a therapeutically and / or prophylactically effective amount of a compound of Formula (XI), (XIa), (XIb), (XIc), (XId), (XIe), (XIf), (XIg), (XIh), (XIi), (XIj), (XIk), (XIl), (XIm), (XIn), (XIq), (I) or (II) or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, or pharmaceutical composition thereof.

[0272] Preferably, the USP1-mediated disease is a tumor or cancer.

[0273] Preferably, the USP1-mediated disease refers to a USP1-mediated related disease with HR deficiency.

[0274] Preferably, the USP1-mediated disease refers to cancer or tumor with HR deficiency.

[0275] In another aspect, the present invention also provides a method for preventing and / or treating tumors or cancer, comprising administering to a subject / individual in need thereof a therapeutically and / or prophylactically effective amount of a compound of Formula (XI), (XIa), (XIb), (XIc), (XId), (XIe), (XIf), (XIg), (XIh), (XIi), (XIj), (XIk), (XIl), (XIm), (XIn), (XIq), (I) or (II) or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, or pharmaceutical composition thereof.

[0276] Preferably, the tumor or cancer is associated with USP1 biological activity.

[0277] Preferably, the tumor or cancer is a tumor or cancer with HR deficiency associated with USP1 biological activity.

[0278] Preferably, the tumor or cancer is a cancer or tumor with HR deficiency.

[0279] As used herein, "treat" generally refers to obtaining a desired pharmacological and / or physiological effect. This effect can be prophylactic, in terms of completely or partially preventing a disease or its symptoms; and / or therapeutic, in terms of partially or completely stabilizing or curing a disease and / or causing side effects due to the disease. As used herein, "treat" encompasses any treatment of a disease in a patient, including: (a) preventing the onset of a disease or symptom in a patient who is susceptible to the disease or symptom but has not yet been diagnosed with the disease; (b) suppressing the symptoms of a disease, i.e., arresting its development; or (c) alleviating the symptoms of a disease, i.e., causing the disease or symptom to regress.

[0280] In the present invention, "subject / individual" refers to a vertebrate. In certain embodiments, a vertebrate refers to a mammal. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In certain embodiments, a mammal refers to a human.

[0281] In the present invention, an "effective amount" refers to an amount that is effective at the necessary dosage and time to achieve the desired therapeutic or preventive effect. The "therapeutically effective amount" of the substance / molecule of the present invention may vary according to factors such as the disease state, age, sex and weight of the individual and the ability of the substance / molecule to elicit the desired response in the individual. A therapeutically effective amount also encompasses an amount in which the therapeutically beneficial effects of the substance / molecule outweigh any toxic or deleterious consequences. A "prophylactically effective amount" refers to an amount that is effective at the necessary dosage and time to achieve the desired preventive effect. Typically, but not necessarily, a prophylactic dose is used in subjects before the onset of disease or in the early stages of the disease, so the prophylactic effective amount will be lower than the therapeutically effective amount. In the case of cancer, a therapeutically effective amount of a drug can reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slow down to a certain extent, preferably stop) cancer cell infiltration into surrounding organs; inhibit (i.e., slow down to a certain extent, preferably stop) tumor metastasis; inhibit tumor growth to a certain extent; and / or alleviate one or more symptoms associated with cancer to a certain extent.

[0282] Definition of terms:

[0283] According to the common practice in this field, The bonds used in the formulae herein to describe the points of attachment of the moiety or substituent to the parent core or structure.

[0284] A dash "-" that does not appear between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -CONH2 is attached through a carbon atom.

[0285] In the present invention, the term "optionally" means that it can be selected or not.

[0286] In the present invention, the term "substituted" means that an atom or a group of atoms formally replaces hydrogen and is connected to another group as a "substituent". Unless otherwise noted, the term "substituted" refers to any degree of substitution in the case where such substitution is allowed, such as monosubstituted, disubstituted, trisubstituted, tetrasubstituted or pentasubstituted. Independently select substituents, and substitution can be on any chemically accessible position. It should be understood that the substitution on the specified atom is subject to atomic valence restrictions. It should be understood that the substitution on the specified atom produces a chemically stable molecule.

[0287] In the present invention, the term "alkyl" used alone or in combination with other terms refers to a saturated hydrocarbon group that can be a straight chain or a branched chain. 1-10 "Alkyl" refers to an alkyl group having 1 to 10 carbon atoms. Alkyl formally corresponds to an alkane with one C-H bond replaced as the point of attachment of the alkyl group to the rest of the compound. In some embodiments, the alkyl group contains 1-10 carbon atoms, 1-8 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like.

[0288] In the present invention, the term "alkoxy" used alone or in combination with other terms refers to a group having the formula -O-alkyl, wherein the term "alkyl" is as defined above. 1-8 "Alkoxy" refers to an alkoxy group whose alkyl group has 1 to 8 carbon atoms. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, and the like. In some embodiments, the alkyl group has 1 to 8 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 3 carbon atoms.

[0289] In the present invention, the term "alkenyl" used alone or in combination with other terms refers to a straight or branched hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon double bonds. Alkenyl formally corresponds to an alkene in which one C—H bond is replaced as the point of attachment of the alkyl group to the rest of the compound. The term "C 2-8 "Alkenyl" refers to an alkenyl group having 2 to 8 carbons. Example alkenyl groups include, but are not limited to, ethenyl, propen-1-yl, propen-2-yl, and the like. In some embodiments, the alkenyl moiety contains 2 to 8 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 to 3 carbon atoms.

[0290] In the present invention, the term "alkynyl" used alone or in combination with other terms refers to a straight or branched hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon triple bonds. Alkynyl formally corresponds to an alkyne in which one C—H bond is replaced as the point of attachment of the alkyl group to the rest of the compound. The term "C 2-8 "Alkynyl" refers to an alkynyl group having 2 to 8 carbon atoms. Example alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 8 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 to 3 carbon atoms.

[0291] In the present invention, the term "halo" or "halogen" used alone or in combination with other terms refers to F, Cl, Br and I. In some embodiments, the term "halo" refers to a halogen atom selected from F, Cl or Br.

[0292] In the present invention, the term "haloalkyl" or "haloalkoxy" used alone or in combination with other terms refers to an alkyl or alkoxy group substituted with one or more halogens, wherein the terms "halogen", "alkyl" and "alkoxy" are as defined above. In some embodiments, the term "C 1-6 "Haloalkyl" is preferably fluorinated, for example, -CF3, -CHF2, -CH2F, -CH2CH2F, -CH2CHF2, -CH2CF3, etc. In some embodiments, the term "C 1-6 The "haloalkoxy" is preferably fluorinated, for example, -OCF3, -OCHF2, -OCH2F, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, etc.

[0293] In the present invention, the term "deuterated alkyl" used alone or in combination with other terms refers to an alkyl group substituted with one or more deuterium atoms, wherein the term "alkyl" is as defined above.

[0294] In the present invention, the term "hydroxyalkyl" used alone or in combination with other terms refers to an alkyl group substituted with one or more hydroxy groups, wherein the term "alkyl" is as defined above.

[0295] In the present invention, the term "heteroatom" used alone or in combination with other terms includes B, P, S, O and N.

[0296] In the present invention, the term "aryl" used alone or in combination with other terms refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (for example, having two fused rings). 6-10"Aryl" refers to an aromatic radical having 6 to 10 ring carbon atoms. Aryl radicals include, for example, phenyl, naphthyl, indanyl, indenyl, and the like. In some embodiments, an aryl radical has 6 carbon atoms. In some embodiments, an aryl radical has 10 carbon atoms. In some embodiments, an aryl radical is phenyl. In some embodiments, an aryl radical is naphthyl.

[0297] In the present invention, the term "heteroaryl" used alone or in combination with other terms refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from B, P, S, O, and N. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from S, O, and N. In some embodiments, any ring-forming N in the heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl group has 5 to 14 ring atoms, including carbon atoms and 1, 2, 3, or 4 heteroatom ring members independently selected from S, O, and N. In some embodiments, the heteroaryl group has 5 to 10 ring atoms, including carbon atoms and 1, 2, 3, or 4 heteroatom ring members independently selected from S, O, and N. In some embodiments, the heteroaryl group has 5 to 6 ring atoms and 1 or 2 heteroatom ring members independently selected from S, O, and N. In some embodiments, the heteroaryl group is a five-membered or six-membered heteroaryl ring. In other embodiments, the heteroaryl group is an eight-membered, nine-membered, or ten-membered fused bicyclic heteroaryl ring. Example heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, oxazolyl, oxazolyl, thiazolyl, imidazolyl, furyl, thienyl, quinolyl, isoquinolyl, naphthyridinyl (including 1,2-naphthyridine, 1,3-naphthyridine, 1,4-naphthyridine, 1,5-naphthyridine, 1,6-naphthyridine, 1,7-naphthyridine, 1,8-naphthyridine, 2,3-naphthyridine, and 2,6-naphthyridine), indolyl, benzothienyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, and the like.

[0298] In the present invention, the term "cycloalkyl" used alone or in combination with other terms refers to a fully saturated ring system (monocyclic, bicyclic or polycyclic), including cyclized alkyl groups. 3-8 Cycloalkyl" or "C 3- 14 "Cycloalkyl" refers to a cycloalkyl group having 3 to 8 or 3 to 14 ring member carbon atoms, respectively. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocyclic and bridged rings. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring member carbon atoms (C 3-14In some embodiments, the cycloalkyl group has 3 to 12 ring members, 3 to 10 ring members, 3 to 8 ring members, 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is C 3-8 Monocyclic cycloalkyl. Cycloalkyl also includes cycloalkylene. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, norpinyl, norcaryl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0299] In the present invention, "heterocyclyl" refers to a fully saturated or partially saturated (but not aromatic as a whole) monocyclic, biscyclic, spirocyclic, or bridged ring group. When the "heterocyclyl" is bicyclic or tricyclic, it may contain heteroatoms on any ring, or on both the bicyclic and tricyclic rings. "Heterocyclyl" includes "heterocycloalkyl," "heterocycloalkenyl," and "heterocycloalkynyl."

[0300] In the present invention, the term "heterocycloalkyl" used alone or in combination with other terms refers to a fully saturated ring system (monocycle, bicycle or polycycle) having at least one heteroatom ring member independently selected from B, P, N, S and O, and having 4 to 10 ring members, 4 to 7 ring members or 4 to 6 ring members. The term "heterocycloalkyl" includes monocyclic 4-, 5-, 6- and 7-membered heterocycloalkyls. Heterocycloalkyl can include monocyclic or bicyclic (e.g., having two fused or bridged rings, spiro rings) ring systems. In some embodiments, heterocycloalkyl is a monocyclic group having 1, 2 or 3 heteroatoms independently selected from N, S and O. Heterocycloalkyl can be connected via annular carbon atoms or annular heteroatoms. Examples of heterocycloalkyl groups include azetidinyl, azepanyl, N-morpholinyl, 3-oxa-9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tropanediyl.

[0301] As used herein, the term "cycloalkenyl" as used alone or in combination with other terms refers to a partially saturated, monocyclic, fused, spirocyclic, or bridged ring system containing at least one carbon-carbon double bond (not aromatic as a whole). When the cycloalkenyl group is bicyclic or tricyclic, the bicyclic or tricyclic rings as a whole do not form an aromatic ring. For example, one or two of the rings may be partially saturated or aromatic, and the remaining rings may be saturated or partially saturated.

[0302] In the present invention, when "phenyl and 5-membered heteroaryl" are connected to the main structure, they can be connected from the phenyl group or from the 5-membered heteroaryl group. Other similar compound names can be understood by referring to the above content.

[0303] In the present invention, it is preferred that the left connection point of B is connected to M, and the right connection point of B is connected to C.

[0304] It will be understood by those skilled in the art that when "-C(O)-" is used herein, this refers to the group When "-S(O)2-" is used, this refers to the group

[0305] Herein, unless otherwise expressly stated, the description “…are independently selected from” used throughout this document may mean that in different groups, the specific options expressed by the same or different symbols do not affect each other, or that in the same group, the specific options expressed by the same or different symbols do not affect each other.

[0306] Beneficial effects of the present invention:

[0307] The compound of the present invention has excellent USP1 inhibitory activity, and at the same time has the effects of longer half-life, higher exposure, good oral absorption performance, etc., and has achieved unexpected technical effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0308] Figure 1 Tumor volume of human breast cancer MDA-MB-436CDX model

[0309] Figure 2 Body weight of human breast cancer MDA-MB-436CDX model DETAILED DESCRIPTION

[0310] The present invention is further described below with reference to specific examples, but the protection scope of the present invention is not limited to these examples.

[0311] It should be understood that the terminology used herein is intended to describe specific embodiments and is not intended to be limiting. In addition, although any method, device, and material similar or equivalent to those described herein may be used for implementing or testing the present invention, preferred methods, devices, and materials are now described.

[0312] NMR measurements were performed using a Bruker ASCENA-400 nuclear magnetic spectrometer, reaction monitoring and MS measurements were performed using a Thermofisher ESQ (ESI) mass spectrometer, HPLC measurements were performed using a Thermo Fisher U3000 DAD high-pressure liquid chromatograph, reverse-phase and normal-phase purifications were performed using a Biotage Isera One model, and preparative liquid chromatography (prep-HPLC) was performed using an Agilent 1290 Infinity 2nd generation.

[0313] Abbreviated description

[0314] Intermediate I-1

[0315] Step 1: Synthesis of I-1-3

[0316] Dissolve I-1-1 (9.0 g, 44.4 mmol) and I-1-2 (6.8 g, 44.4 mmol) in hexafluoroisopropanol (70 mL). Add triethylamine (8.9 g, 87.9 mmol) dropwise at 0°C and stir at room temperature for 2 h. Concentrate under reduced pressure, and the residue is separated by silica gel column chromatography to obtain 9.2 g of compound I-1-3. MS m / z (ESI): 285.08 [M+H] + .

[0317] Step 2: Synthesis of I-1-4

[0318] I-1-3 (9.2 g, 32.4 mmol) was dissolved in THF (90 mL). DIBAL-H (1 M, 97.2 mL, 97.2 mmol) was added dropwise at 0°C. After addition, the mixture was stirred at 20°C for 2 h. Water was slowly added to quench the reaction. Saturated aqueous ammonium chloride (100 mL) and EA (150 mL) were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain 8.2 g of compound I-1-4. MS m / z (ESI): 257.08 [M+H] + .

[0319] Step 3: Synthesis of I-1-5

[0320] Dissolve I-1-4 (8.0 g, 31.22 mmol) and triphenylphosphine (12.28 g, 46.83 mmol) in acetonitrile (200 mL). Add carbon tetrabromide (15.53 g, 46.83 mmol) at 0°C and stir at room temperature for 3 hours. Concentrate the reaction mixture under reduced pressure to obtain a crude product, which is then separated by silica gel column chromatography to obtain 8.1 g of compound I-1-5. MS m / z (ESI): 319.00 [M+H] + .

[0321] Step 4: Synthesis of I-1

[0322] Under nitrogen, I-1-5 (8.1 g, 25.38 mmol), B2PIN2 (9.67 g, 38.07 mmol), potassium acetate (7.47 g, 76.14 mmol), and Pd(dppf)Cl2·CH2Cl2 (1.04 g, 1.27 mmol) were dissolved in dioxane (150 mL) and stirred at 100°C for 3 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography to obtain 5.6 g of compound I-1. MS m / z (ESI): 367.17 [M+H] + .

[0323] Intermediate I-2

[0324] Step 1: Synthesis of I-2-3

[0325] At room temperature, I-2-2 (9.9 g, 37.0 mmol) and sodium acetate (3.0 g, 37.0 mmol) were added to water, and the resulting mixture was stirred and heated at 100°C for 1 h. The reaction solution was cooled to room temperature and slowly added dropwise to a solution of I-2-1 (5.0 g, 30.5 mmol) in methanol (100 mL). Ammonia water (35 mL) was then added to the reaction solution, and the reaction was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure to remove the solvent, and the resulting residue was added to water (100 mL), extracted with ethyl acetate (3*100 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 5.0 g of compound I-2-3 was isolated by silica gel column chromatography. MS m / z (ESI): 271.06 [M+H] + .

[0326] Step 2: Synthesis of I-2-4

[0327] I-2-3 (3.0 g, 11.0 mmol) was dissolved in THF (30 mL), and sodium hydride (60%, 0.67 g, 17.0 mmol) was added portionwise at 0°C. The reaction mixture was stirred at 0°C for 0.5 h, followed by the addition of iodomethane (3.2 g, 22.0 mmol) and the mixture was slowly allowed to return to room temperature for 2 h. The reaction mixture was added to ice water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 3.0 g of compound I-2-4. MS m / z (ESI): 285.08 [M+H] + .

[0328] Step 3: Synthesis of I-2-5

[0329] I-2-4 (3.0 g, 11.0 mmol) was added to THF (60 mL), and lithium aluminum tetrahydride (1.3 g, 33.0 mmol) was added portionwise at 0°C. The resulting mixture was stirred at 0°C for 1 hour, then slowly returned to room temperature for 1 hour. Water (10 mL), 15% aqueous NaOH solution (10 mL), and water (30 mL) were added to the reaction solution at 0°C. The resulting mixture was stirred at room temperature for 1 hour and then filtered through celite. The filter cake was rinsed with dichloromethane. The resulting filtrates were combined and concentrated under reduced pressure to remove the solvent to obtain 3.0 g of compound I-2-5. MS m / z (ESI): 257.08 [M+H] + .

[0330] Step 4: Synthesis of I-2-6

[0331] Dissolve I-2-5 (2.0 g, 7.8 mmol) and triphenylphosphine (3.1 g, 11.7 mmol) in acetonitrile (40 mL). Add carbon tetrabromide (3.9 g, 11.7 mmol) at 0°C and stir at room temperature for 3 hours. Concentrate the reaction mixture under reduced pressure to obtain a crude product, which is then separated by silica gel column chromatography to obtain 1.5 g of compound I-2-6. MS m / z (ESI): 319.00 [M+H] + .

[0332] Step 5: Synthesis of I-2

[0333] Under nitrogen, I-2-6 (1.5 g, 4.7 mmol), B2PIN2 (1.8 g, 7.0 mmol), potassium acetate (1.4 g, 14.0 mmol), and Pd(dppf)Cl2·CH2Cl2 (190.0 mg, 0.2 mmol) were dissolved in dioxane (40 mL) and stirred at 100°C for 3 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then separated by silica gel column chromatography to obtain 880.0 mg of compound I-2. MS m / z (ESI): 367.17 [M+H] + .

[0334] Intermediate I-3

[0335] Step 1: Synthesis of I-3-2

[0336] At room temperature, I-2-2 (33.3 g, 123.5 mmol) and sodium acetate (10.1 g, 123.5 mmol) were added to water, and the resulting mixture was stirred and heated at 100°C for 1 h. The reaction solution was cooled to room temperature and slowly added dropwise to a solution of I-3-1 (15.0 g, 82.3 mmol) in methanol (200 mL). Ammonia water (70 mL) was then added to the reaction solution, and the reaction was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure to remove the solvent, and the resulting residue was added to water (200 mL), extracted with ethyl acetate (3*100 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography gave 11.0 g of compound I-3-2. MS m / z (ESI): 289.12 [M+H] + .

[0337] Step 2: Synthesis of I-3-3

[0338] I-3-2 (11.0 g, 38.2 mmol) was dissolved in DMF (200 mL), cooled to 0°C, and potassium carbonate (10.5 g, 76.4 mmol) was added under nitrogen. The mixture was stirred in an ice-water bath for 40 minutes. Methyl iodide (6.5 g, 45.8 mmol) was added at 0°C, and then stirred at room temperature for 2 hours. The reaction solution was slowly poured into ice water (500 mL), stirred for 2 minutes, and extracted with ethyl acetate (3*50 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 11.0 g of compound I-3-3. MS m / z (ESI): 303.07 [M+H] + .

[0339] Step 3: Synthesis of I-3-4

[0340] I-3-3 (11.0 g, 36.4 mmol) was dissolved in THF (100 mL) and methanol (50 mL). Sodium borohydride (2.8 g, 72.8 mmol) was added at 0°C. The reaction was allowed to warm to room temperature and stirred overnight. LC-MS monitored the completion of the reaction. The mixture was cooled to room temperature, filtered, concentrated, and purified by silica gel column chromatography to obtain 8.6 g of compound I-3-4. MS m / z (ESI): 275.12 [M+H] + .

[0341] Step 4: Synthesis of I-3-5

[0342] Dissolve I-3-4 (8.6 g, 31.4 mmol) and triphenylphosphine (12.3 g, 47.0 mmol) in acetonitrile (200 mL). Add carbon tetrabromide (15.6 g, 47.0 mmol) at 0°C and stir at room temperature for 3 hours. Concentrate the reaction mixture under reduced pressure to obtain a crude product, which is then separated by silica gel column chromatography to obtain 8.5 g of compound I-3-5. MS m / z (ESI): 336.99 [M+H] + .

[0343] Step 5: Synthesis of I-3

[0344] Under nitrogen, I-3-5 (8.5 g, 25.2 mmol), B2PIN2 (9.6 g, 37.8 mmol), potassium acetate (7.4 g, 75.6 mmol), and Pd(dppf)Cl2·CH2Cl2 (1.0 g, 1.3 mmol) were dissolved in dioxane (150 mL) and stirred at 100°C for 3 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography to obtain 5.2 g of compound I-3. MS m / z (ESI): 385.16 [M+H] + .

[0345] Intermediate I-4

[0346] Step 1: Synthesis of I-4-1

[0347] Under nitrogen protection, I-2-3 (3.0 g, 10.8 mmol) was dissolved in DMF (50 mL). Sodium hydride (0.5 g, 12.9 mmol) was added portionwise in an ice-water bath. After stirring for 1 hour in an ice-water bath, 2-iodopropane (2.8 g, 16.5 mmol) was added. The mixture was then stirred at 70°C for 4 hours. After the reaction solution cooled to room temperature, it was slowly poured into ice water and extracted with ethyl acetate (3*100 mL). The mixture was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by normal phase medium pressure preparative purification to obtain 3.1 g of compound I-4-1. MS m / z (ESI): 313.11 [M+H] + .

[0348] Step 2: Synthesis of I-4-2

[0349] Under nitrogen, I-4-1 (3.1 g, 9.9 mmol) was dissolved in THF (100 mL). DIBAL-H (39.7 mL, 59.6 mmol) was added dropwise at -78°C. After the addition, the mixture was stirred at room temperature for 2 hours. The reaction solution was slowly poured into ice water and the pH was adjusted to 5-6 with dilute hydrochloric acid (3N). The mixture was extracted with ethyl acetate (2 x 150 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by normal phase medium pressure preparative purification to obtain 2.2 g of compound I-4-2. MS m / z (ESI): 285.11 [M+H] + .

[0350] Step 3: Synthesis of I-4-3

[0351] Dissolve I-4-2 (2.0 g, 7.0 mmol) and triphenylphosphine (2.8 g, 10.5 mmol) in acetonitrile (100 mL). Add carbon tetrabromide (3.5 g, 10.5 mmol) under ice-water bath and stir at room temperature for 3 hours. Concentrate the reaction mixture under reduced pressure to obtain a crude product, which is then purified by normal phase medium pressure preparative chromatography to obtain 2.1 g of compound I-4-3. MS m / z (ESI): 347.03 [M+H] + .

[0352] Step 4: Synthesis of I-4

[0353] Under nitrogen, I-4-3 (500.0 mg, 1.4 mmol), B2PIN2 (731.3 mg, 2.9 mmol), potassium acetate (282.5 mg, 2.9 mmol), and Pd(dppf)Cl2·CH2Cl2 (52.7 mg, 0.07 mmol) were dissolved in dioxane (20 mL) and stirred at 100°C for 3 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography to obtain 400.0 mg of compound I-4. MS m / z (ESI): 395.29 [M+H] + .

[0354] Intermediate I-5

[0355] Step 1: Synthesis of I-5-2

[0356] I-2-2 (9.8 g, 36.3 mmol) and sodium acetate (4.9 g, 36.3 mmol) were dissolved in water (40 mL), and the resulting mixture was stirred at 100°C for 2 hours. After the reaction solution was cooled to room temperature, a solution of I-5-1 (5.0 g, 30.3 mmol) in methanol (120 mL) was added dropwise to the above mixture. Ammonia water (25 mL) was then added to the reaction solution, and stirring was continued at room temperature overnight. Saturated brine (150 mL) was added, and the mixture was extracted with ethyl acetate (2*100 mL), washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography to obtain 4.4 g of compound I-5-2. MS m / z (ESI): 272.06 [M+H] + .

[0357] Step 2: Synthesis of I-5-3

[0358] Dissolve I-5-2 (4.4 g, 16.2 mmol) in DMF (60 mL), add potassium carbonate (3.4 g, 24.3 mmol) and iodomethane (1.51 mL, 24.3 mmol), and stir at room temperature overnight. Add water (60 mL), extract with ethyl acetate (2*60 mL), wash three times with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 4.1 g of compound I-5-3. MS m / z (ESI): 286.07 [M+H] + .

[0359] Step 3: Synthesis of I-5-4

[0360] Dissolve I-5-3 (4.1 g, 14.4 mmol) in dioxane (50 mL) and THF (50 mL). Add lithium borohydride (0.94 g, 43.1 mmol) at room temperature and stir at 90°C for 3 hours. Cool to room temperature and slowly pour the reaction solution into ice water. Extract with ethyl acetate (2 x 50 mL), wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product is separated by silica gel column chromatography to obtain 2.77 g of compound I-5-4. MS m / z (ESI): 258.08 [M+H] + .

[0361] Step 4: Synthesis of I-5-5

[0362] Dissolve I-5-4 (2.77 g, 10.8 mmol) and triphenylphosphine (4.2 g, 16.2 mmol) in acetonitrile (100 mL), add carbon tetrabromide (5.4 g, 16.2 mmol), and stir at room temperature for 3 hours. Silica gel is added directly and the sample is stirred. Silica gel column chromatography is performed to obtain 2.4 g of compound I-5-5. MS m / z (ESI): 319.99 [M+H]+ .

[0363] Step 5: Synthesis of I-5-6

[0364] Dissolve I-5-5 (2.4 g, 7.5 mmol) and TMSCN (1.3 mL, 10.5 mmol) in acetonitrile (30 mL). Under nitrogen protection, add TBAF (9.8 mL, 9.8 mmol) in an ice bath and stir at room temperature for 2 hours. Add water (30 mL) and extract with ethyl acetate (2 x 50 mL). Wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product is separated by silica gel column chromatography to obtain 1.8 g of compound I-5-6. MS m / z (ESI): 267.08 [M+H] + .

[0365] Step 6: Synthesis of I-5

[0366] I-5-6 (1.8 g, 6.8 mmol) was dissolved in methanol (20 mL), and TMSCl (8.5 mL, 67.6 mmol) was added at room temperature. The mixture was stirred at 65°C for 4 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was diluted with water, adjusted to pH 7-8 with saturated sodium bicarbonate, extracted with ethyl acetate (2*20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography to obtain 1.5 g of compound I-5. MS m / z (ESI): 300.09 [M+H] + .

[0367] Intermediate I-6

[0368] Step 1: Synthesis of I-6-1

[0369] Under nitrogen, I-2-6 (21.0 g, 65.8 mmol) and TMSCN (16.1 mL, 92.2 mmol) were dissolved in acetonitrile (200 mL). TBAF (85.5 mL, 85.5 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Water (400 mL) was added, and the mixture was extracted with ethyl acetate (2 x 300 mL). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography to obtain 14.0 g of compound I-6-1. MS m / z (ESI): 266.08 [M+H] + .

[0370] Step 2: Synthesis of I-6

[0371] I-6-1 (14.0 g, 52.8 mmol) was dissolved in methanol (200 mL), and TMSCl (66 mL, 528.3 mmol) was added at room temperature. The mixture was stirred at 65°C for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water, adjusted to pH 7-8 with saturated sodium bicarbonate, extracted with ethyl acetate (2 x 300 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography to obtain 14.9 g of compound I-6. MS m / z (ESI): 299.09 [M+H] + .

[0372] Intermediate I-7

[0373] Step 1: Synthesis of I-7-1

[0374] I-3-2 (12.4 g, 43.0 mmol) was dissolved in DMF (100 mL), and cesium carbonate (70.1 g, 215.1 mmol) and isopropyl iodide (36.6 g, 215.1 mmol) were added. The mixture was stirred at 90°C overnight. The reaction solution was slowly poured into ice water (300 mL), stirred for 2 minutes, and extracted with ethyl acetate (3 x 200 mL). The organic phases were combined, washed with saturated brine (3 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 11.2 g of compound I-7-1. MS m / z (ESI): 331.20 [M+H] + .

[0375] Step 2: Synthesis of I-7-2

[0376] I-7-1 (11.2 g, 33.9 mmol) was dissolved in THF (20 mL) and 1,4-dioxane (40 mL), and lithium borohydride (2.2 g, 101.7 mmol) was added. Under nitrogen, the mixture was heated to 90°C and stirred for 2 hours. After cooling to room temperature, ice water (50 mL) was added to quench the mixture. Saturated brine (100 mL) was added, and the mixture was extracted with ethyl acetate (2 x 100 mL). The organic phases were combined, washed with saturated brine (2 x 60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 7.1 g of compound I-7-2. MS m / z (ESI): 303.19 [M+H] + .

[0377] Step 3: Synthesis of I-7-3

[0378] Dissolve I-7-2 (7.1 g, 23.5 mmol) and triphenylphosphine (9.2 g, 35.2 mmol) in acetonitrile (100 mL). Add carbon tetrabromide (11.7 g, 47.0 mmol) under ice-water bath and stir at room temperature for 3 hours. Concentrate under reduced pressure, and the crude product is separated by silica gel column chromatography to obtain 6.2 g of compound I-7-3. MS m / z (ESI): 365.11 [M+H] + .

[0379] Step 4: Synthesis of I-7

[0380] Under nitrogen protection, I-7-3 (400.0 mg, 1.10 mmol) was dissolved in dioxane (5 mL), and B2PIN2 (556.2 mg, 2.19 mmol), Pd(dppf)Cl2 (80.1 mg, 0.11 mmol) and potassium acetate (214.9 mg, 2.19 mmol) were added. The mixture was stirred at 100°C overnight. After the reaction was completed, 200 mL of water was added to the mixture, and the mixture was extracted with ethyl acetate (3*20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture. The mixture was separated and purified using a normal phase chromatography column to obtain 300.0 mg of compound I-7. MS m / z (ESI): 413.30 [M+H] + .

[0381] Intermediate I-8

[0382] Step 1: Synthesis of I-8-1

[0383] Under nitrogen, I-5-2 (2.2 g, 8.11 mmol) was dissolved in DMF (20 mL). Sodium hydride (1.0 g, 24.34 mmol) was added portionwise in an ice bath. After stirring in an ice bath for 1 hour, iodopropane (3.24 mL, 32.45 mmol) was added and stirred at 70°C for 4 hours. After the reaction solution cooled to room temperature, it was slowly poured into ice water and extracted with ethyl acetate (2 x 20 mL). The mixture was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2.3 g of crude compound I-8-1. MS m / z (ESI): 314.0 [M+H] + .

[0384] Step 2: Synthesis of I-8-2

[0385] I-8-1 (2.3 g, 7.34 mmol) was dissolved in a mixed solvent of dioxane (20 mL) and THF (20 mL). Lithium borohydride (0.5 g, 22.02 mmol) was added and stirred at 90°C for 2 hours. After cooling to room temperature, the reaction solution was slowly poured into ice water and extracted with ethyl acetate (2 x 20 mL). The mixture was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 565.0 mg of compound I-8-2. MS m / z (ESI): 286.2 [M+H] + .

[0386] Step 3: Synthesis of I-8-3

[0387] Dissolve I-8-2 (565.0 mg, 1.98 mmol) in acetonitrile (10 mL), add triphenylphosphine (779.2 mg, 2.97 mmol) and carbon tetrabromide (985.0 mg, 2.97 mmol), and stir at room temperature overnight. Silica gel was added directly to the mixture, and the mixture was purified by silica gel column chromatography to obtain 220.0 mg of compound I-8-3. MS m / z (ESI): 348.1 [M+H] + .

[0388] Step 4: Synthesis of I-8-4

[0389] Under nitrogen protection, I-8-3 (220.0 mg, 0.63 mmol) and TMSCN (0.11 mL, 0.88 mmol) were dissolved in acetonitrile (5 mL). TBAF (0.82 mL, 0.82 mmol) was added under ice-cooling and stirred at room temperature for 2 hours. Water (10 mL) was added and the mixture was extracted with ethyl acetate (2 x 10 mL). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 173.0 mg of compound I-8-4. MS m / z (ESI): 295.0 [M+H] + .

[0390] Step 5: Synthesis of I-8

[0391] I-8-4 (173.0 mg, 0.59 mmol) was dissolved in methanol (5 mL), and TMSCl (0.74 mL, 5.88 mmol) was added at room temperature. The mixture was stirred at 70°C for 4 hours. The reaction solution was concentrated under reduced pressure. Water (5 mL) was added to the resulting residue, and the pH was adjusted to 7-8 with sodium carbonate. The mixture was extracted with ethyl acetate (2*10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 152.0 mg of compound I-8. MS m / z (ESI): 328.0 [M+H] + .

[0392] Intermediate I-9

[0393] Step 1: Synthesis of I-9-3

[0394] Under nitrogen protection, I-9-1 (3.0 g, 35.19 mmol) and I-9-2 (5.0 g, 35.19 mmol) were dissolved in THF (100 mL) and methanol (100 mL), and sodium methoxide (14.08 mL, 5 M) was added. The mixture was stirred at 60°C overnight. After the reaction was completed, it was cooled in an ice-water bath. 2N dilute hydrochloric acid was added to the mixture to quench the reaction. The mixture was extracted with ethyl acetate (3*50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture. It was separated and purified by normal phase chromatography to obtain 4.0 g of compound I-9-3. MS m / z (ESI): 181.04 [M+H] + .

[0395] Step 2: Synthesis of I-9-4

[0396] Dissolve the hydrochloride salt of I-1-1 (3.7 g, 22.21 mmol) and I-9-3 (4.0 g, 22.21 mmol) in hexafluoroisopropanol (70 mL). Add sodium acetate (1.8 g, 22.21 mmol) dropwise at 0°C and stir at room temperature for 2 h. Concentrate under reduced pressure, and the residue is separated by silica gel column chromatography to obtain 4.0 g of compound I-9-4. MS m / z (ESI): 311.08 [M+H] + .

[0397] Step 3: Synthesis of I-9-5

[0398] I-9-4 (4.0 g, 12.89 mmol) was dissolved in THF (90 mL) and DIBAL-H (1 M, 19.3 mL, 19.33 mmol) was added dropwise at 0°C. After addition, the mixture was stirred at 20°C for 2 h. Water was slowly added to quench the reaction. Saturated aqueous ammonium chloride (100 mL) and EA (150 mL) were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain 3.0 g of compound I-9-5. MS m / z (ESI): 283.10 [M+H] + .

[0399] Step 4: Synthesis of I-9-6

[0400] Dissolve I-9-5 (3.0 g, 10.63 mmol) and triphenylphosphine (4.2 g, 15.94 mmol) in acetonitrile (200 mL). Add carbon tetrabromide (5.3 g, 15.94 mmol) at 0°C and stir at room temperature for 3 hours. Concentrate the reaction mixture under reduced pressure to obtain a crude product, which is then separated by silica gel column chromatography to obtain 3.0 g of compound I-9-6. MS m / z (ESI): 345.01 [M+H] + .

[0401] Step 5: Synthesis of I-9

[0402] Under nitrogen protection, I-9-6 (400.0 mg, 1.10 mmol) was dissolved in 5 mL of dioxane, and B2PIN2 (556.2 mg, 2.19 mmol), Pd(dppf)Cl2 (80.1 mg, 0.11 mmol), and potassium acetate (214.9 mg, 2.19 mmol) were added. The mixture was stirred at 100°C overnight. After the reaction was completed, water (200 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3*20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture. The mixture was separated and purified by normal phase chromatography to obtain 300.0 mg of compound I-9. MS m / z (ESI): 393.30 [M+H] + .

[0403] Intermediate I-10

[0404] Step 1: Synthesis of I-10-2

[0405] I-10-1 (20.0 g, 118.20 mmol) was dissolved in 37% aqueous hydrochloric acid (100 mL). A solution of sodium nitrite (8.2 g, 118.20 mmol) in water (40 mL) was added at 0°C. The mixture was stirred for 10 minutes after the addition was complete. Then, stannous chloride (112.1 g, 591.02 mmol) dissolved in 37% aqueous hydrochloric acid (100 mL) was added dropwise at 0°C. After the addition was complete, the mixture was heated to 25°C and stirred for 2 hours. The filter cake was filtered, washed with ethyl acetate (3 x 50 mL), and dried to obtain 24.0 g of compound I-10-2. MS m / z (ESI): 185.14 [M+H] + .

[0406] Step 2: Synthesis of I-10-3

[0407] I-10-2 (23.0 g, 124.86 mmol) and 1,1,1-trifluoro-2,4-pentanedione (15.15 mL, 124.86 mmol) were dissolved in hexafluoroisopropanol (150 mL). Triethylamine (34.62 mL, 249.73 mmol) dissolved in hexafluoroisopropanol (100 mL) was added dropwise at 0°C. After the addition, the temperature was raised to 25°C and stirred for 1 hour. Water (200 mL) was added, and the mixture was extracted with dichloromethane (200 mL). The mixture was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography to obtain 27.4 g of compound I-10-3. MS m / z (ESI): 303.12 [M+H] + .

[0408] Step 3: Synthesis of I-10-4

[0409] I-10-3 (26.4 g, 87.36 mmol) was dissolved in a mixed solvent of 1,4-dioxane (120 mL) and THF (30 mL). Lithium borohydride (5.7 g, 262.08 mmol) was added at room temperature and stirred at 90°C for 2 hours. After cooling to room temperature, the reaction solution was slowly poured into ice water and extracted with ethyl acetate (500 mL). The mixture was washed with saturated brine (500 mL) and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 23.0 g of compound I-10-4. MS m / z (ESI): 275.13 [M+H] + .

[0410] Step 4: Synthesis of I-10-5

[0411] Dissolve I-10-4 (23.0 g, 83.88 mmol) and triphenylphosphine (33.0 g, 125.82 mmol) in acetonitrile (200 mL), add carbon tetrabromide (33.4 g, 100.66 mmol), and stir at room temperature for 1 hour. The reaction solution is concentrated to obtain a crude product, which is purified by silica gel column chromatography to obtain 24.6 g of compound I-10-5. MS m / z (ESI): 339.10 [M+H] + .

[0412] Step 5: Synthesis of I-10

[0413] Under nitrogen, I-10-5 (6.0 g, 17.80 mmol) was dissolved in 1,4-dioxane (90 mL), and B2PIN2 (6.8 g, 26.70 mmol), Pd(dppf)Cl2 (0.7 g, 0.89 mmol), and potassium acetate (5.2 g, 53.4 mmol) were added. The mixture was stirred at 100°C for 2 hours. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 4.2 g of compound I-10. MS m / z (ESI): 385.22 [M+H] + .

[0414] Intermediate I-11

[0415] Step 1: Synthesis of I-11-1

[0416] I-3-2 (3.0 g, 10.41 mmol) was dissolved in DMF (50 mL). Potassium carbonate (2.9 g, 20.82 mmol) and deuterated iodomethane (2.3 g, 15.61 mmol) were added at room temperature and allowed to react for 2 h. The reaction solution was added to ice water (100 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3.0 g of compound I-11-1. MS m / z (ESI): 306.10 [M+H] + .

[0417] Step 2: Synthesis of I-11-2

[0418] I-11-1 (3.0 g, 9.83 mmol) was dissolved in THF (30 mL) and dioxane (30 mL). Lithium borohydride (0.6 g, 29.49 mmol) was added at room temperature. The temperature was raised to 80°C and stirred for 2 hours. LC-MS monitored the completion of the reaction. The mixture was cooled to room temperature and slowly poured into ice water. The mixture was extracted with ethyl acetate (2 x 50 mL), washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 2.0 g of compound I-11-2. MS m / z (ESI): 278.10 [M+H]. + .

[0419] Step 3: Synthesis of I-11-3

[0420] Dissolve I-11-2 (2.0 g, 7.22 mmol) and triphenylphosphine (2.8 g, 10.82 mmol) in acetonitrile (50 mL). Add carbon tetrabromide (3.6 g, 10.82 mmol) at 0°C and stir overnight at room temperature. Concentrate the reaction mixture under reduced pressure to obtain a crude product, which is then separated by silica gel column chromatography to obtain 2.0 g of compound I-11-3. MS m / z (ESI): 340.00 [M+H] + .

[0421] Step 4: Synthesis of I-11

[0422] Under nitrogen protection, I-11-3 (2.0 g, 5.88 mmol) was dissolved in dioxane (50 mL), and B2PIN2 (3.0 g, 11.76 mmol), Pd(dppf)Cl2 (0.4 g, 0.59 mmol), and potassium acetate (1.2 g, 11.76 mmol) were added. The mixture was stirred at 100°C overnight. After the reaction was completed, water (50 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (2*50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture. The mixture was separated and purified by normal phase chromatography to obtain 2.1 g of compound I-11. MS m / z (ESI): 388.20 [M+H] + .

[0423] Intermediate I-12

[0424] Step 1: Synthesis of I-12-b

[0425] I-12-a (1.0 g, 5.65 mmol) was dissolved in dichloromethane (20 mL), and m-chloroperbenzoic acid (1.0 g, 5.65 mmol) was added. The mixture was stirred at room temperature overnight. After the reaction was completed, water (100 mL) was added to the mixture, and the mixture was extracted with dichloromethane (3 x 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture. The mixture was separated and purified by normal phase chromatography to obtain 700.0 mg of compound I-12-b. MS m / z (ESI): 194.10 [M+H] + .

[0426] Step 2: Synthesis of I-12-c

[0427] I-12-b (700.0 mg, 3.63 mmol) was dissolved in toluene (20 mL), and phosphorus oxybromide (2078.6 mg, 7.25 mmol) was added. The mixture was stirred at 100°C overnight. After the reaction was completed, water (100 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3*20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture. The mixture was separated and purified by normal phase chromatography to obtain 300.0 mg of compound I-12-c. MS m / z (ESI): 256.08 [M+H] + .

[0428] Step 3: Synthesis of I-12-e

[0429] Under nitrogen, I-12-c (300.0 mg, 1.17 mmol) was dissolved in dioxane (10 mL), and water (2 mL), I-12-d (159.4 mg, 1.17 mmol), Pd(dppf)Cl2 (85.7 mg, 0.12 mmol), and potassium carbonate (323.9 mg, 2.34 mmol) were added. The mixture was stirred at 80°C overnight. After the reaction was completed, water (50 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3*20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a mixture that was separated and purified by normal phase chromatography to obtain 250.0 mg of compound I-12-e. MS m / z (ESI): 268.11 [M+H] + .

[0430] Step 4: Synthesis of I-12-f

[0431] I-12-e (250.0 mg, 0.94 mmol) was dissolved in carbon tetrachloride (20 mL). AIBN (153.6 mg, 0.94 mmol) and NBS (199.8 mg, 1.20 mmol) were added under nitrogen. The mixture was stirred at 80°C overnight. After the reaction was completed, water (100 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3*20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture. The mixture was separated and purified by normal phase chromatography to obtain 200.0 mg of compound I-12-f. MS m / z (ESI): 348.43 [M+H]. + .

[0432] Step 5: Synthesis of I-12

[0433] I-12-f (200.0 mg, 0.58 mmol) was dissolved in dioxane (10 mL). B2PIN2 (293.2 mg, 1.16 mmol), Pd(dppf)Cl2 (42.3 mg, 0.06 mmol), and potassium acetate (113.4 mg, 1.16 mmol) were added under nitrogen. The mixture was stirred at 100°C overnight. After the reaction was completed, water (200 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3*20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 180.0 mg of compound I-12. MS m / z (ESI): 394.21 [M+H] + .

[0434] Intermediate I-13

[0435] Step 1: Synthesis of I-13-c

[0436] I-13-a (2.0 g, 8.85 mmol) was dissolved in dioxane (50 mL). Under nitrogen, I-13-b (1.1 g, 8.85 mmol), Pd(dppf)Cl2 (600.3 mg, 0.88 mmol), and potassium acetate (2.4 g, 17.7 mmol) were added. The mixture was stirred at 100°C overnight. After the reaction was completed, water (200 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3*20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1.0 g of compound I-13-c. MS m / z (ESI): 162.08 [M+H] + .

[0437] Step 2: Synthesis of I-13-d

[0438] I-13-c (1.0 g, 6.21 mmol) was dissolved in dichloromethane (20 mL), and m-chloroperbenzoic acid (2.1 g, 12.42 mmol) was added. The mixture was stirred at room temperature overnight. After the reaction was completed, water (100 mL) was added to the mixture, and the mixture was extracted with dichloromethane (3 x 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture. The mixture was separated and purified by normal phase chromatography to obtain 800.0 mg of compound I-13-d. MS m / z (ESI): 178.12 [M+H] + .

[0439] Step 3: Synthesis of I-13-e

[0440] I-13-d (800.0 mg, 4.52 mmol) was dissolved in toluene (20 mL), and phosphorus oxybromide (2590.2 mg, 9.03 mmol) was added. The mixture was stirred at 100°C overnight. After the reaction was completed, water (100 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3*20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture. The mixture was separated and purified by normal phase chromatography to obtain 500.0 mg of compound I-13-e. MS m / z (ESI): 241.98 [M+H] + .

[0441] Step 4: Synthesis of I-13-f

[0442] Under nitrogen, I-13-e (500.0 mg, 2.08 mmol) was dissolved in dioxane (10 mL), and water (2 mL), I-12-d (283.3 mg, 2.08 mmol), Pd(dppf)Cl2 (76.2 mg, 0.10 mmol), and potassium carbonate (575.8 mg, 4.17 mmol) were added. The mixture was stirred at 80°C overnight. After the reaction was completed, water (50 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3*20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture that was separated and purified by normal phase chromatography to obtain 230.0 mg of compound I-13-f. MS m / z (ESI): 252.14 [M+H] + .

[0443] Step 5: Synthesis of I-13-g

[0444] I-13-f (230.0 mg, 0.92 mmol) was dissolved in carbon tetrachloride (20 mL). AIBN (150.3 mg, 0.92 mmol) and NBS (162.9 mg, 0.92 mmol) were added under nitrogen. The mixture was stirred at 80°C overnight. After the reaction was completed, water (100 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3*20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture. The mixture was separated and purified by normal phase chromatography to obtain 100.0 mg of compound I-13-g. MS m / z (ESI): 332.06 [M+H] + .

[0445] Step 6: Synthesis of I-13

[0446] I-13-g (100.0 mg, 0.30 mmol) was dissolved in dioxane (10 mL). B2PIN2 (153.8 mg, 0.61 mmol), Pd(dppf)Cl2 (22.2 mg, 0.03 mmol), and potassium acetate (59.4 mg, 0.61 mmol) were added under nitrogen. The mixture was stirred at 100°C overnight. After the reaction was completed, water (200 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3*20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 100.0 mg of compound I-13. MS m / z (ESI): 378.23 [M+H] + .

[0447] Intermediate I-14

[0448] Step 1: Synthesis of I-14-2

[0449] Referring to the synthesis of I-4-1, I-2-3 (1.0 g, 3.70 mmol) was replaced with I-14-1 (0.9 g, 7.40 mmol) using 2-iodopropane. The reaction was allowed to proceed at room temperature for 2 h. Following the same post-treatment, the product was concentrated under reduced pressure to yield 600.0 mg of compound I-14-2. MS m / z (ESI): 311.28 [M+H] + .

[0450] Step 2: Synthesis of I-14-3

[0451] Referring to the synthesis of I-1-4, I-1-3 was replaced with I-14-2 (600.0 mg, 1.93 mmol) to obtain 400.0 mg of compound I-14-3. MS m / z (ESI): 283.10 [M+H] + .

[0452] Step 3: Synthesis of I-14-4

[0453] Referring to the synthesis of I-1-5, I-1-4 was replaced with I-14-3 (400.0 mg, 1.42 mmol) to obtain 400.0 mg of compound I-14-4. MS m / z (ESI): 345.01 [M+H] + .

[0454] Step 4: Synthesis of I-14

[0455] Referring to the synthesis of I-7, I-7-3 was replaced with I-14-4 (400.0 mg, 1.16 mmol) to obtain 300.0 mg of compound I-14. MS m / z (ESI): 393.30 [M+H]+ .

[0456] Intermediate I-15

[0457] Step 1: Preparation of I-15-1

[0458] Referring to the synthesis of I-11-1, I-3-2 was replaced with I-2-3 (1.0 g, 3.70 mmol) to obtain 1.1 g of compound I-15-1. MS m / z (ESI): 288.20 [M+H] + .

[0459] Step 2: Synthesis of I-15-2

[0460] Referring to the synthesis of I-11-2, I-11-1 was replaced with I-15-1 (1.0 g, 3.48 mmol) to obtain 600.0 mg of compound I-15-2. MS m / z (ESI): 260.12 [M+H] + .

[0461] Step 3: Synthesis of I-15-3

[0462] Referring to the synthesis of I-1-5, I-1-4 was replaced with I-15-2 (600.0 mg, 2.31 mmol) to obtain 600.0 mg of compound I-15-3. MS m / z (ESI): 322.21 [M+H] + .

[0463] Step 4: Synthesis of I-15

[0464] Referring to the synthesis of I-7, I-7-3 was replaced with I-15-3 (600.0 mg, 1.86 mmol) to obtain 500.0 mg of compound I-15. MS m / z (ESI): 370.43 [M+H] + .

[0465] Intermediate I-16

[0466] Step 1: Synthesis of I-16-2

[0467] I-16-1 (24.0 g, 104.8 mmol) was dissolved in DMF (200 mL), potassium carbonate (29.0 g, 209.6 mmol) and iodomethane (9.8 mL, 157.21 mmol) were added, and the mixture was reacted at room temperature for 3 hours. The reaction solution was added to water (1000 mL) and extracted with ethyl acetate (3*300 mL). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography gave 22.5 g of compound I-16-2. MS m / z (ESI): 242.96 [M+H] + .

[0468] Step 2: Synthesis of I-16-3

[0469] At room temperature, I-2-2 (37.5 g, 138.83 mmol) and sodium acetate (12.8 g, 138.83 mmol) were added to water (200 mL), and the resulting mixture was stirred and heated at 100°C for 1 h. The reaction solution was cooled to room temperature and slowly added dropwise to a solution of I-16-2 (22.5 g, 92.55 mmol) in methanol (200 mL). Ammonia water (200 mL) was then added to the reaction solution, and the mixture was stirred and heated to 90°C for 2 h. The resulting mixture was concentrated under reduced pressure to remove the solvent, and the resulting residue was added to water (300 mL), extracted with ethyl acetate (3*100 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography gave 8.7 g of compound I-16-3. MS m / z (ESI): 348.97 [M+H] + .

[0470] Step 3: Synthesis of I-16-4

[0471] I-16-3 (8.6 g, 24.63 mmol) was dissolved in DMF (100 mL), potassium carbonate (6.8 g, 49.27 mmol) and benzyl bromide (6.3 g, 36.95 mmol) were added, and the mixture was allowed to react at room temperature for 4 h. The reaction solution was added to ice water (500 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography afforded 8.3 g of compound I-16-4. MS m / z (ESI): 439.02 [M+H] + .

[0472] Step 4: Synthesis of I-16-5

[0473] Under nitrogen, I-16-4 (3.3 g, 7.51 mmol) was dissolved in triethylamine (30 mL), and but-3-yn-2-ol (2.87 g, 22.54 mmol, 55% in water), Pd(PPh3)2Cl2 (1.05 g, 1.5 mmol), and cuprous iodide (572 mg, 3.0 mmol) were added. The mixture was stirred at 80°C for 12 hours. The reaction solution was added to water (50 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography afforded 2.4 g of compound I-16-5. MS m / z (ESI): 429.13 [M+H]. + .

[0474] Step 5: Synthesis of I-16-6

[0475] Dissolve I-16-5 (2.4 g, 5.6 mmol) in methanol (30 mL), add palladium carbon (500.0 mg) and palladium hydroxide (500.0 mg), replace with hydrogen, heat to 50°C and react for 12 hours, filter through celite, and concentrate the filtrate to dryness to obtain 2.4 g of crude compound I-16-6. MS m / z (ESI): 433.17 [M+H] + .

[0476] Step 6: Synthesis of I-16-7

[0477] Dissolve I-16-6 (2.4 g, 5.6 mmol) in THF (30 mL), add palladium carbon (500.0 mg) and palladium hydroxide (500.0 mg), replace with hydrogen, heat to 50°C and react for 12 hours, filter through celite, and concentrate the filtrate to dryness to obtain 1.3 g of crude compound I-16-7. MS m / z (ESI): 343.12 [M+H] + .

[0478] Step 7: Synthesis of I-16-8

[0479] Under nitrogen, I-16-7 (1.2 g, 3.5 mmol) was dissolved in THF (10 mL), triphenylphosphine (3.68 g, 14.02 mmol) was added, the temperature was lowered to 0°C, diethyl azodicarboxylate (12.44 g, 14.02 mmol) was added dropwise, and the mixture was naturally warmed to room temperature and reacted for 12 hours. The reaction solution was added to water (30 mL) and extracted with ethyl acetate (3*10 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography gave 1.08 g of compound I-16-8. MS m / z (ESI): 325.11 [M+H] + .

[0480] Step 8: Synthesis of I-16-9

[0481] Under nitrogen, I-16-8 (1.03 g, 3.18 mmol) was dissolved in THF (10 mL), cooled to 0°C, and lithium aluminum hydride (362.5 mg, 9.54 mmol) was added. The mixture was allowed to warm to room temperature and react for 1 hour. The reaction solution was added to water (50 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography gave 580.0 mg of compound I-16-9. MS m / z (ESI): 297.11 [M+H] + .

[0482] Step 9: Synthesis of I-16-10

[0483] Under nitrogen, I-16-9 (530.0 mg, 1.79 mmol) and triphenylphosphine (938.4 mg, 3.58 mmol) were dissolved in acetonitrile (5 mL). Carbon tetrabromide (1186.3 mg, 3.58 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by normal phase medium pressure preparative purification to obtain 430.0 mg of compound I-16-10. MS m / z (ESI): 359.03 [M+H] + .

[0484] Step 10: Synthesis of I-16

[0485] Under nitrogen, I-16-10 (430.0 mg, 1.2 mmol), B2PIN2 (457.6 mg, 1.8 mmol), potassium acetate (235.2 mg, 2.4 mmol), and Pd(dppf)Cl2 (175.4 mg, 0.24 mmol) were dissolved in dioxane (5 mL). The mixture was heated from room temperature to 80°C and stirred for 2 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography to obtain 300.0 mg of compound I-16. MS m / z (ESI): 407.2 [M+H] + .

[0486] Intermediate I-17

[0487] Step 1: Synthesis of I-17-2

[0488] Under nitrogen protection, I-16-4 (4.0 g, 9.11 mmol), I-17-1 (7.65 g, 45.55 mmol), Pd(PPh3)4 (1.05 g, 0.91 mmol), and sodium carbonate (1.93 g, 18.21 mmol) were dissolved in a mixed solution of dioxane (50 mL) and water (10 mL). The mixture was stirred at 85°C for 6 hours. The reaction solution was added to water (100 mL) and extracted with ethyl acetate (3*50 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 3.2 g of compound I-17-2 was obtained by purification by silica gel column chromatography. MS m / z (ESI): 401.14 [M+H] + .

[0489] Step 2: Synthesis of I-17-3

[0490] Compound I-17-2 (3.0 g, 7.49 mmol) was dissolved in THF (50 mL), replaced with nitrogen, cooled to 0°C, and borane-tetrahydrofuran complex (22.5 mL, 22.47 mmol) was added dropwise. The temperature was naturally raised to room temperature and reacted for 3 hours. Then, hydrogen peroxide (20 mL) was slowly added under an ice-water bath and reacted at room temperature for 1 hour. The reaction solution was added to water (100 mL) and extracted with ethyl acetate (3*50 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography gave 1.45 g of compound I-17-3. MS m / z (ESI): 419.15 [M+H] + .

[0491] Step 3: Synthesis of I-17-4

[0492] I-17-3 (1.35 g, 3.23 mmol) was dissolved in methanol (20 mL), palladium carbon (100.0 mg) was added, and the atmosphere was replaced with hydrogen. The mixture was reacted at room temperature for 2 hours, filtered through celite, and the filtrate was concentrated to dryness to obtain 0.9 g of crude compound I-17-4. MS m / z (ESI): 329.1 [M+H] + .

[0493] Step 4: Synthesis of I-17-5

[0494] Referring to the synthesis of I-16-8, I-16-7 was replaced with I-17-4 (0.8 g, 2.44 mmol) to obtain 0.7 g of compound I-17-5. MS m / z (ESI): 311.09 [M+H] + .

[0495] Step 5: Synthesis of I-17-6

[0496] Under nitrogen, I-17-5 (700.0 mg, 2.25 mmol) was dissolved in THF (10 mL), cooled to 0°C, and lithium borohydride (124.0 mg, 5.64 mmol) was added. The mixture was allowed to warm to room temperature and react for 1 hour. The reaction solution was added to water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography afforded 360.0 mg of compound I-17-6. MS m / z (ESI): 283.1 [M+H] + .

[0497] Step 6: Synthesis of I-17-7

[0498] Referring to the synthesis of I-16-10, I-16-9 was replaced with I-17-6 (360.0 mg, 1.28 mmol) and stirred at room temperature for 6 hours. After the same post-treatment, 300.0 mg of compound I-17-7 was obtained. MS m / z (ESI): 345.01 [M+H] + .

[0499] Step 7: Synthesis of I-17

[0500] Referring to the synthesis of I-16, I-16-10 was replaced with I-17-7 (300.0 mg, 0.87 mmol) to obtain 260.0 mg of compound I-17. MS m / z (ESI): 393.19 [M+H] + .

[0501] Intermediate I-18

[0502] Step 1: Synthesis of I-18-2

[0503] Under nitrogen, I-18-1 (10.0 g, 50.18 mmol) and TMSCF3 (11.13 mL, 75.26 mmol) were dissolved in THF (100 mL). After stirring in an ice-water bath for 10 minutes, TBAF (15.05 mL, 15.05 mmol) was slowly added and stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride was added to quench the mixture, and the mixture was extracted with ethyl acetate (2*100 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography to obtain 15.7 g of compound I-18-2. MS m / z (ESI): 214.15 [M-56+H] + .

[0504] Step 2: Synthesis of I-18-3

[0505] I-18-2 (15.7 g, 58.3 mmol) was dissolved in DCM (20 mL), and HCl / 1,4-dioxane (62.01 mL, 4 N) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and dried to obtain 10.7 g of compound I-18-3 hydrochloride. MS m / z (ESI): 170.12 [M+H] + .

[0506] Step 3: Synthesis of I-18-5

[0507] I-18-3 (10.7 g, 52.05 mmol) and I-18-4 (9.7 g, 53.83 mmol) were dissolved in DMF (120 mL), and HATU (24.6 g, 64.59 mmol) was added. After stirring at room temperature for 5 minutes, DIEA (37.49 mL, 215.32 mmol) was added and stirred at room temperature for 1 hour. Water (300 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (2 x 200 mL). The organic phases were combined, washed with saturated brine (2 x 200 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography to obtain 16.3 g of compound I-18-5. MS m / z (ESI): 332.12 [M+H] + .

[0508] Step 4: Synthesis of I-18-6

[0509] Under nitrogen, I-18-5 (15.0 g, 45.28 mmol) was dissolved in DCM (150 mL). Dess-Martin oxidant (25.0 g, 58.86 mmol) was added under ice-water bath, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium thiosulfate solution (150 mL) was added and stirred for 20 minutes, followed by saturated aqueous sodium bicarbonate solution (150 mL) and stirred for 10 minutes. The mixture was separated, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography to obtain 14.5 g of compound I-18-6. MS m / z (ESI): 330.11 [M+H] + .

[0510] Step 5: Synthesis of I-18-7

[0511] I-18-6 (7.0 g, 21.26 mmol) and ammonium trifluoroacetate (4.35 mL, 46.16 mmol) were added to a reaction flask, heated to 130°C, and stirred for 1.5 hours. The mixture was cooled to room temperature, quenched with water (30 mL), and extracted with ethyl acetate (2 x 50 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography to obtain 6.0 g of compound I-18-7. MS m / z (ESI): 311.13 [M+H] + .

[0512] Step 6: Synthesis of I-18-8

[0513] Referring to the synthesis of I-7-2, I-7-1 was replaced with I-18-7 (6.0 g, 19.34 mmol) to obtain 4.88 g of compound I-18-8. MS m / z (ESI): 283.13 [M+H] + .

[0514] Step 7: Synthesis of I-18-9

[0515] Under nitrogen, I-18-8 (4.88 g, 17.27 mmol) was dissolved in DCM (50 mL). Phosphorus tribromide (4.67 g, 17.27 mmol) was added under an ice-water bath and the mixture was allowed to stand overnight at room temperature. Saturated sodium bicarbonate aqueous solution was added to adjust the pH to 9. The mixture was separated, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography to obtain 4.47 g of compound I-18-9. MS m / z (ESI): 345.20 [M+H] + .

[0516] Step 8: Synthesis of I-18-10

[0517] Referring to the synthesis of I-5-6, I-5-5 was replaced with I-18-9 (2.4 g, 9.99 mmol) to obtain 2.7 g of compound I-18-10. MS m / z (ESI): 292.20 [M+H] + .

[0518] Step 9: Synthesis of I-18

[0519] Referring to the synthesis of I-5, I-5-6 was replaced with I-18-10 (2.7 g, 9.27 mmol) and stirred at 70°C overnight. The same post-treatment was performed to obtain 2.6 g of compound I-18. MS m / z (ESI): 325.14 [M+H] + .

[0520] Intermediate I-19

[0521] Step 1: Synthesis of I-19-1

[0522] Under nitrogen, I-3-5 (8.0 g, 23.73 mmol) and TMSCN (3.7 g, 33.22 mmol) were dissolved in acetonitrile (150 mL). TBAF in THF (30.85 mL, 1 M) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (2 x 100 mL). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 4.1 g of compound I-19-1. MS m / z (ESI): 284.1 [M+H] + .

[0523] Step 2: Synthesis of I-19

[0524] Referring to the synthesis of I-5, I-5-6 was replaced with I-19-1 (4.1 g, 14.48 mmol) and stirred at 65°C overnight. The same post-treatment was performed to obtain 3.8 g of compound I-19. MS m / z (ESI): 317.1 [M+H] + .

[0525] Intermediate I-20

[0526] Step 1: Synthesis of I-20-1

[0527] Referring to the synthesis of I-5-6, I-5-5 was replaced with I-4-3 (1.1 g, 3.2 mmol) to obtain 826.0 mg of compound I-20-1. MS m / z (ESI): 294.00 [M+H] + .

[0528] Step 2: Synthesis of I-20

[0529] Referring to the synthesis of I-5, I-5-6 was replaced with I-20-1 (826.0 mg, 2.8 mmol) and stirred at 70°C for 4 hours. The same post-treatment was performed to obtain 803.0 mg of compound I-20. MS m / z (ESI): 327.20 [M+H] + .

[0530] Intermediate I-21

[0531] Step 1: Synthesis of I-21-1

[0532] Referring to the synthesis of I-5-6, I-5-5 was replaced with I-15-3 (840.0 mg, 2.6 mmol) to obtain 658.0 mg of compound I-21-1. MS m / z (ESI): 269.00 [M+H] + .

[0533] Step 1: Synthesis of I-21

[0534] Referring to the synthesis of I-5, I-5-6 was replaced with I-21-1 (658.0 mg, 2.5 mmol) and stirred at 70°C for 4 hours. The same post-treatment was performed to obtain 573.0 mg of compound I-21. MS m / z (ESI): 302.00 [M+H] + .

[0535] Intermediate I-22

[0536] Step 1: Synthesis of I-22-b

[0537] Referring to the synthesis of I-12-b, I-12-a was replaced with I-22-a (1.3 g, 8.17 mmol) to obtain 1.2 g of compound I-22-b. MS m / z (ESI): 176.09 [M+H] + .

[0538] Step 2: Synthesis of I-22-c

[0539] Referring to the synthesis of I-12-c, I-12-b was replaced with I-22-b (1.2 g, 6.85 mmol), and phosphorus oxybromide was replaced with phosphorus oxychloride (2.1 g, 13.71 mmol) to obtain 800.0 mg of compound I-22-c. MS m / z (ESI): 194.09 [M+H] + .

[0540] Step 3: Synthesis of I-22-d

[0541] Referring to the synthesis of I-12-e, I-12-d (674.44 mg, 4.96 mmol), I-12-c was replaced with I-22-c (800.0 mg, 4.13 mmol) to obtain 700.0 mg of compound I-22-d. MS m / z (ESI): 250.20 [M+H] + .

[0542] Step 4: Synthesis of I-22-e

[0543] Referring to the synthesis of I-12-f, I-12-e was replaced with I-22-d (700.0 mg, 2.81 mmol) to obtain 750.0 mg of compound I-22-e. MS m / z (ESI): 329.87 [M+H] + .

[0544] Step 5: Synthesis of I-22

[0545] Referring to the synthesis of I-7, I-7-3 was replaced with I-22-e (750.0 mg, 2.29 mmol) to obtain 700.0 mg of compound I-22. MS m / z (ESI): 376.34 [M+H] + .

[0546] Intermediate I-23

[0547] Step 1: Synthesis of I-23-1

[0548] Referring to the synthesis of I-5-6, I-5-5 was replaced with I-9-6 (5.0 g, 14.5 mmol). After the same post-treatment, the filtrate was concentrated under reduced pressure to obtain 5.1 g of crude compound I-23-1. MS m / z (ESI): 292.10 [M+H] + .

[0549] Step 2: Synthesis of I-23

[0550] Referring to the synthesis of I-5, I-5-6 was replaced with I-23-1 (5.1 g, 14.0 mmol) and stirred at 70°C for 4 hours. The same post-treatment was performed to obtain 4.2 g of compound I-23. MS m / z (ESI): 325.20 [M+H] + .

[0551] Intermediate I-24

[0552] Step 1: Synthesis of I-24-2

[0553] At room temperature, I-24-1 (5.0 g, 33.6 mmol) and sodium acetate (3.0 g, 36.9 mmol) were added to water, and the resulting mixture was stirred and heated at 100°C for 1 hour. The reaction solution was cooled to room temperature and slowly added dropwise to a solution of I-2-2 (9.9 g, 36.9 mmol) dissolved in methanol (50 mL). Ammonia water (25 mL) was then added to the reaction solution, and the reaction was stirred at room temperature for 16 hours. The resulting mixture was concentrated under reduced pressure to remove the solvent, and the resulting residue was added to water (50 mL), extracted with ethyl acetate (3*30 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 5.0 g of compound I-24-2 was isolated by silica gel column chromatography. MS m / z (ESI): 256.04 [M+H] + .

[0554] Step 2: Synthesis of I-24-3

[0555] I-24-2 (5.0 g, 19.6 mmol) was dissolved in DMF (50 mL) and potassium carbonate (8.1 g, 58.8 mmol) was added. The reaction mixture was stirred at 20°C for 0.5 h, followed by the addition of iodomethane (8.4 g, 58.8 mmol) and stirring for 2 h. The reaction mixture was added to water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 4.0 g of compound I-24-3. MS m / z (ESI): 270.06 [M+H] + .

[0556] Step 3: Synthesis of I-24

[0557] Referring to the synthesis of I-2-5, I-2-4 was replaced with I-24-3 (4.0 g, 14.8 mmol). The resulting mixture was stirred at 0°C for 1 hour, then slowly returned to room temperature for 8 hours. Similar post-treatment was performed to obtain 3.0 g of compound I-24. MS m / z (ESI): 274.09 [M+H] + .

[0558] Intermediate I-25

[0559] Step 1: Synthesis of I-25-1

[0560] Referring to the synthesis of I-5-6, I-5-5 was replaced with I-10-5 (7.5 g, 22.3 mmol) to obtain 5.0 g of compound I-25-1. MS m / z (ESI): 284.12 [M+H] + .

[0561] Step 2: Synthesis of I-25

[0562] Referring to the synthesis of I-5, I-5-6 was replaced with I-25-1 (5.0 g, 17.7 mmol) and stirred at 70°C overnight. The same post-treatment was performed to obtain 5.1 g of compound I-25. MS m / z (ESI): 317.08 [M+H] + .

[0563] Example 1 Preparation of Compound 1

[0564] Step 1: Synthesis of compound 1-b

[0565] Under nitrogen, zinc powder (983.8 mg, 15.0 mmol) and iodine (95.4 mg, 0.4 mmol) were dissolved in DMF (5 mL), and the mixture was stirred at 30 ° C for 10 minutes. TMSCl (40.8 mg, 0.4 mmol) was added, and the mixture was stirred at 45 ° C for 30 minutes. I-2-6 (400.0 mg, 1.3 mmol) was added, and the mixture was stirred at 45 ° C for 1 hour. 1-a (224.4 mg, 1.3 mmol) and Pd (PPh3) 4 (144.9 mg, 0.13 mmol) were added, and the mixture was stirred at 60 ° C for 2 hours. After completion of the reaction, water (200 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3 * 50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a mixture that was separated and purified by normal phase chromatography to give 30.0 mg of compound 1-b. MS m / z(ESI):383.13[M+H] + .

[0566] Step 2: Synthesis of compound 1

[0567] Under nitrogen protection, 1-b (30.0 mg, 0.08 mmol) was dissolved in dioxane (2 mL), water (0.5 mL) was added, 1-c (30.4 mg, 0.16 mmol), Pd(dppf)Cl2 (5.7 mg, 0.01 mmol) and potassium carbonate (21.7 mg, 0.16 mmol) were added, and the mixture was stirred at 100 ° C overnight. After completion of the reaction, water (50 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3*20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a mixture that was separated and purified by reverse phase chromatography to give 1.8 mg of compound 1 (4'-cyclopropyl-5,6'-dimethoxy-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2,5'-bipyrimidine). MS m / z(ESI):497.23[M+H] + .

[0568] 1 H NMR (400MHz, DMSO-d6) δ8.68(s,1H),8.66(s,1H),7.92(s,1H),7.65(d,J=8.2Hz,2H),7.42(d,J=8.2Hz,2H), 4.22(s,2H),4.02(s,3H),3.86(s,3H),3.77(s,3H),1.75-1.55(m,1H),1.09-0.94(m,2H),0.94-0.80(m,2H).

[0569] Example 2 Preparation of Compound 2

[0570] Step 1: Synthesis of compound 2-a

[0571] Under nitrogen, 1-a (100.0 mg, 0.56 mmol) was dissolved in toluene (6 mL), and water (1.5 mL) was added. I-3 (429.0 mg, 1.12 mmol), Pd(PPh3)2Cl2 (39.0 mg, 0.01 mmol), and potassium phosphate (338.0 mg, 1.68 mmol) were also added, and the mixture was stirred at 100°C overnight. After the reaction was completed, water (30 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (2 x 50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by normal phase chromatography to obtain 80.0 mg of compound 2-a. MS m / z (ESI): 401.12 [M+H] + .

[0572] Step 2: Synthesis of compound 2

[0573] Under nitrogen, 2-a (60.0 mg, 0.15 mmol) and 2-b (199.0 mg, 0.75 mmol) were dissolved in dioxane (10 mL). Water (2 mL) was added, along with Pd(dppf)Cl2 (16 mg, 0.02 mmol) and potassium carbonate (41.0 mg, 0.30 mmol). The mixture was stirred at 100°C overnight. After the reaction was complete, water (20 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (2 x 30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture. The mixture was separated and purified by reverse phase chromatography and lyophilized to obtain 21.0 mg of compound 2. MS m / z (ESI): 505.16 [M+H]. + .

[0574] 1H NMR (400MHz, DMSO-d6) δ8.64(s,1H),8.60(s,1H),8.00(d,J=1.2Hz,1H),7.55(t,J=8.0H z,1H),7.34-7.25(m,2H),4.23(s,2H),4.02(s,3H),3.89(s,6H),3.61(d,J=1.6Hz,3H).

[0575] Example 3 Preparation of Compound 3

[0576] Step 1: Synthesis of compound 3-b

[0577] Dissolve 3-a (6.0 g, 36.8 mmol) and I-19 (3.1 g, 9.9 mmol) in THF (100 mL). Under nitrogen, add KHMDS in tetrahydrofuran (18.4 mL, 1 M) dropwise in an ice bath and stir at room temperature for 2 hours. Pour the reaction mixture into ice water, extract with ethyl acetate (2 x 50 mL), wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain 4.3 g of compound 3-b. MS m / z (ESI): 443.08 [M+H] + .

[0578] Step 2: Synthesis of compound 3-c

[0579] Dissolve 3-b (4.3 g, 9.7 mmol) in acetic acid (8 mL, 139.8 mmol) and add concentrated hydrochloric acid (4 mL). Stir in a sealed tube at 90°C for 1.5 hours. Pour the reaction mixture into ice water. Adjust the pH to 7-8 with saturated sodium bicarbonate solution. Extract with ethyl acetate (2 x 50 mL), wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under pressure to obtain the crude product. The crude product is purified by silica gel column chromatography to obtain 1.85 g of compound 3-c. MS m / z (ESI): 385.08 [M+H] + .

[0580] Step 3: Synthesis of compound 3

[0581] Under nitrogen protection, 3-c (1.7 g, 4.4 mmol), 1-c (1.7 g, 8.8 mmol), XPhos (0.8 g, 1.8 mmol), XPhos-Pd G2 (0.7 g, 0.9 mmol), potassium phosphate (3.1 g, 13.3 mmol), dioxane (24 mL), and water (6 mL) were added to a reaction flask and stirred at 95°C overnight. The mixture was extracted with ethyl acetate (2*20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was first purified by silica gel column chromatography and then purified by reverse phase medium pressure preparative purification and lyophilized to obtain 1.6 g of compound 3. MS m / z (ESI): 499.20 [M+H] + .

[0582] 1 H NMR (400MHz, DMSO-d6) δ8.72(s,1H),8.66(s,1H),7.98(s,1H),7.53(t,J=7.8Hz,1H),7.33(d,J=11.4Hz,1H),7.27(d,J= 7.8Hz,1H),4.29(s,2H),3.85(s,3H),3.58(s,3H),2.36(s,3H),1.71-1.61(m,1H),1.07-0.99(m,2H),0.92-0.81(m,2H).

[0583] Example 4 Preparation of Compound 4

[0584] Step 1: Synthesis of compound 4

[0585] Under nitrogen protection, 2-a (1.7 g, 4.2 mmol), 1-c (1.6 g, 8.5 mmol), XPhos-Pd G2 (0.7 g, 0.85 mmol), XPhos (0.8 g, 1.7 mmol), potassium phosphate (2.9 g, 12.7 mmol), dioxane (50 mL), and water (10 mL) were added to a reaction flask, stirred at 95 ° C overnight, extracted with ethyl acetate (2*50 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was first purified by silica gel column chromatography and then purified by reverse phase medium pressure preparative purification and lyophilized to obtain 1.05 g of compound 4 (4'-cyclopropyl-4-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5,6'-dimethoxy-2,5'-bipyrimidine). MS m / z(ESI):515.17[M+H] + .

[0586] 1H NMR (400MHz, DMSO-d6) δ8.68(s,1H),8.65(s,1H),7.98(d,J=1.0Hz,1H),7.52(t,J=7.8Hz,1H),7.31(d,J=11.4Hz,1H),7.26(dd,J=7. 8,1.4Hz,1H),4.25(s,2H),4.02(s,3H),3.84(s,3H),3.58(d,J=1.2Hz,3H),1.70-1.60(m,1H),1.06-0.99(m,2H),0.89-0.81(m,2H).

[0587] Example 5 Preparation of Compound 5

[0588] Step 1: Synthesis of compound 5-a

[0589] Under nitrogen, zinc powder (983.8 mg, 15.4 mmol) and iodine (95.4 mg, 0.38 mmol) were dissolved in DMF (5 mL), and the mixture was stirred at 30 ° C for 10 minutes. TMSCl (40.8 mg, 0.4 mmol) was added, and the mixture was stirred at 45 ° C for 30 minutes. I-1-5 (400.0 mg, 1.3 mmol) was added, and the mixture was stirred at 45 ° C for 1 hour. 3-a (204.3 mg, 1.3 mmol) and Pd (PPh3) 4 (144.9 mg, 0.13 mmol) were added, and the mixture was stirred at 60 ° C overnight. After completion of the reaction, water (200 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3 * 50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a mixture that was separated and purified by normal phase chromatography to give 50.0 mg of compound 5-a. MS m / z(ESI):367.12[M+H] + .

[0590] Step 2: Synthesis of compound 5

[0591] Under nitrogen, 5-a (50.0 mg, 0.14 mmol), 1-c (52.9 mg, 0.3 mmol), potassium carbonate (39.8 mg, 0.3 mmol), and Pd(dppf)Cl2 (10.5 mg, 0.01 mmol) were dissolved in dioxane (4 mL) and water (1 mL). The mixture was heated and stirred at 100°C for 4 h. The reaction was monitored by LC-MS. The mixture was cooled to room temperature, filtered, concentrated, and purified by reverse phase medium pressure preparative purification. The mixture was then lyophilized under vacuum to obtain 20.0 mg of compound 5. MS m / z (ESI): 481.21 [M+H] + .

[0592] 1 H NMR (400MHz, DMSO-d6) δ8.73(s,1H),8.68(s,1H),7.53(d,J=8.4Hz,2H),7.47(d,J=8.4Hz,2H),6.76(s,1H), 4.30(s,2H),3.87(s,3H),2.37(s,3H),2.34(s,3H),1.73-1.57(m,1H),1.11-0.99(m,2H),0.95-0.83(m,2H).

[0593] Example 6 Preparation of Compound 6

[0594] Step 1: Synthesis of compound 6-b

[0595] Under nitrogen, I-3 (400.0 mg, 1.0 mmol), 6-a (155.1 mg, 1.0 mmol), potassium phosphate (442.1 mg, 2.1 mmol), and Pd(PPh3)2Cl2 (73.1 mg, 0.1 mmol) were dissolved in toluene (8 mL) and water (2 mL). The mixture was heated and stirred at 100°C overnight. LC-MS monitored the completion of the reaction. The mixture was cooled to room temperature, filtered, and concentrated. The mixture was purified by reverse phase medium pressure preparative purification and concentrated under reduced pressure to obtain 80.0 mg of compound 6-b. MS m / z (ESI): 371.24 [M+H]. + .

[0596] Step 2: Synthesis of compound 6

[0597] Under nitrogen, 6-b (60.0 mg, 0.16 mmol), 1-c (62.8 mg, 0.32 mmol), potassium carbonate (44.7 mg, 0.32 mmol), and Pd(dppf)Cl2 (10.5 mg, 0.01 mmol) were dissolved in dioxane (4 mL) and water (1 mL). The mixture was heated and stirred at 100°C for 4 h. The reaction was monitored by LC-MS. The mixture was cooled to room temperature, filtered, concentrated, and purified by reverse phase medium pressure preparative purification. The mixture was then lyophilized in vacuo to afford 1.0 mg of compound 6. MS m / z (ESI): 485.23 [M+H]. + .

[0598] Example 7 Preparation of Compound 7

[0599] Step 1: Synthesis of compound 7-a

[0600] Under nitrogen, zinc powder (983.8 mg, 15.4 mmol) and iodine (95.4 mg, 0.38 mmol) were dissolved in DMF (5 mL), and the mixture was stirred at 30 ° C for 10 minutes. TMSCl (40.8 mg, 0.38 mmol) was added, and the mixture was stirred at 45 ° C for 30 minutes. I-2-6 (400.0 mg, 1.25 mmol) was added, and the mixture was stirred at 45 ° C for 1 hour. 3-a (204.3 mg, 1.25 mmol) and Pd (PPh3) 4 (144.9 mg, 0.13 mmol) were added, and the mixture was stirred at 60 ° C overnight. After completion of the reaction, water (200 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3 * 50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a mixture that was separated and purified by normal phase chromatography to give 80.0 mg of compound 7-a. MS m / z(ESI):367.12[M+H] + .

[0601] Step 2: Synthesis of compound 7

[0602] Under nitrogen, 7-a (80.0 mg, 0.12 mmol), 1-c (33.5 mg, 0.17 mmol), potassium carbonate (35.8 mg, 0.24 mmol), and Pd(dppf)Cl2 (10.5 mg, 0.01 mmol) were dissolved in dioxane (4 mL) and water (1 mL). The mixture was heated and stirred at 100°C for 4 h. The reaction was monitored by LC-MS. The mixture was cooled to room temperature, filtered, concentrated, and purified by reverse phase medium pressure preparative purification. The mixture was then lyophilized in vacuo to afford 5.0 mg of compound 7. MS m / z (ESI): 481.20 [M+H] + .

[0603] 1 H NMR (400MHz, DMSO-d6) δ8.73(s,1H),8.69(s,1H),7.93(d,J=1.0Hz,1H),7.68(d,J=8.2Hz,2H),7.43(d,J=8.4Hz, 2H),4.28(s,2H),3.88(s,3H),3.79(s,3H),2.36(s,3H),1.74-1.52(m,1H),1.13-1.02(m,2H),0.96-0.85(m,2H).

[0604] Example 8 Preparation of Compound 8

[0605] Step 1: Synthesis of compound 8-a

[0606] Dissolve 1-a (1.0 g, 6.1 mmol) and I-5 (500.0 mg, 1.7 mmol) in THF (20 mL). Under nitrogen, add KHMDS (3.4 mL, 1 M) dropwise in an ice bath and stir at room temperature for 2 hours. Pour the reaction mixture into ice water, extract with ethyl acetate (2 x 20 mL), wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product is separated and purified by normal phase chromatography to obtain 333.0 mg of compound 8-a. MS m / z (ESI): 442.08 [M+H] + .

[0607] Step 2: Synthesis of compound 8-b

[0608] Dissolve 8-a (333.0 mg, 0.75 mmol) in acetic acid (6 mL), add concentrated hydrochloric acid (2 mL), and stir at 90°C in a sealed tube for 1 hour. Cool to room temperature, pour the reaction mixture into ice water, and adjust the pH to 7-8 with saturated sodium carbonate. Extract with ethyl acetate (2 x 20 mL), wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product is separated and purified by normal phase column chromatography to obtain 214.0 mg of compound 8-b. MS m / z (ESI): 384.08 [M+H] + .

[0609] Step 3: Synthesis of compound 8

[0610] Under nitrogen, 8-b (214.0 mg, 0.56 mmol), 1-c (216.3 mg, 1.12 mmol), XPhos-Pd G2 (87.6 mg, 0.11 mmol), XPhos (106.3 mg, 0.22 mmol), potassium phosphate (340.1 mg, 1.67 mmol), dioxane (6 mL), and water (1.5 mL) were added to a reaction flask and stirred at 95°C overnight. The mixture was extracted with ethyl acetate (2*10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was first separated by normal phase column chromatography and then purified by reverse phase medium pressure preparative purification and lyophilized to obtain 181.0 mg of compound 8. MS m / z (ESI): 498.18 [M+H] + .

[0611] 1H NMR (400MHz, DMSO-d6) δ8.68(s,1H),8.63(s,1H),8.60(d,J=1.8Hz,1H),8.04-7.93(m,2H),7.80(dd,J=8.2,2.2Hz ,1H),4.24(s,2H),4.06(s,3H),4.02(s,3H),3.83(s,3H),1.67-1.59(m,1H),1.04-0.98(m,2H),0.89-0.88(m,2H).

[0612] Example 9 Preparation of Compound 9

[0613] Step 1: Synthesis of compound 9-a

[0614] Under nitrogen, I-4 (400.0 mg, 1.0 mmol), 1-a (181.6 mg, 1.0 mmol), potassium phosphate (430.8 mg, 2.0 mmol), and Pd(PPh3)2Cl2 (71.2 mg, 0.1 mmol) were dissolved in toluene (10 mL) and water (2 mL). The mixture was heated and stirred at 100°C overnight. The reaction was monitored by LC-MS. The mixture was cooled to room temperature, filtered, concentrated, and purified by reverse phase medium pressure preparative purification and lyophilized to obtain 200.0 mg of compound 9-a. MS m / z (ESI): 411.21 [M+H]. + .

[0615] Step 2: Synthesis of compound 9

[0616] Under nitrogen, 9-a (200.0 mg, 0.49 mmol), 1-c (94.4 mg, 0.49 mmol), potassium carbonate (134.6 mg, 0.97 mmol), and Pd(dppf)Cl2 (35.6 mg, 0.05 mmol) were dissolved in dioxane (4 mL) and water (1 mL). The mixture was heated and stirred at 100°C for 4 h. The reaction was monitored by LC-MS. The mixture was cooled to room temperature, filtered, and concentrated. The mixture was purified by reverse phase medium pressure preparative method and lyophilized in vacuo to obtain 1.0 mg of compound 9 (4'-cyclopropyl-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5,6'-dimethoxy-2,5'-bipyrimidine). MS m / z (ESI): 525.38 [M+H] + .

[0617] 1H NMR (400MHz, DMSO-d6) δ8.69(s,1H),8.67(s,1H),8.16(d,J=1.2Hz,1H),7.50(d,J=8.2Hz,2H),7.44(d,J=8.2Hz,2H),4.56-4.3 7(m,1H),4.23(s,2H),4.03(s,3H),3.86(s,3H),1.71-1.57(m,1H),1.41(d,J=6.6Hz,6H),1.11-0.98(m,2H),0.91-0.81(m,2H).

[0618] Example 10 Preparation of Compound 10

[0619] Step 1: Synthesis of compound 10-b

[0620] 10-a (3.0 g, 18.2 mmol) was dissolved in DCM (30 mL), and 2-(trimethylsilyl)ethoxymethyl chloride (4.8 mL, 27.3 mmol) and N,N-diisopropylethylamine (9.7 mL, 54.6 mmol) were added. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was poured into water and extracted with dichloromethane (2 x 100 mL). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by normal phase chromatography to obtain 4.8 g of compound 10-b. MS m / z (ESI): 295.04 [M+H] + .

[0621] Step 2: Synthesis of compound 10-c

[0622] Dissolve 10-b (4.8 g, 16.3 mmol) and I-6 (7.3 g, 24.4 mmol) in dry THF (50 mL). Under nitrogen, add a 1 M solution of KHMDS in tetrahydrofuran (25 mL) dropwise in an ice bath and stir at room temperature for 1 hour. Pour the reaction mixture into ice water and extract with ethyl acetate (2 x 100 mL). Wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product is separated and purified by normal phase chromatography to obtain 6.7 g of compound 10-c. MS m / z (ESI): 557.15 [M+H] + .

[0623] Step 3: Synthesis of compound 10-d

[0624] Dissolve 10-c (6.7 g, 12.1 mmol) in acetic acid (9 mL) and add concentrated hydrochloric acid (3 mL). Stir in a sealed tube at 80°C for 1 hour. Cool to room temperature, pour the reaction mixture into ice water, and adjust the pH to 7-8 with saturated sodium carbonate solution. Extract with ethyl acetate (2 x 100 mL), wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product is separated and purified by normal phase column chromatography to obtain 3.9 g of compound 10-d. MS m / z (ESI): 369.07 [M+H] + .

[0625] Step 4: Synthesis of compound 10-e

[0626] Under nitrogen, 10-d (2.0 g, 5.4 mmol), 1-c (1.2 g, 6.0 mmol), potassium phosphate (3.5 g, 16.3 mmol), XPhos (1 g, 2.2 mmol), XPhos-Pd G2 (0.9 g, 1.1 mmol), water (5 mL), and dioxane (25 mL) were added to a reaction flask. The mixture was stirred at 95°C overnight and extracted with ethyl acetate (2 x 50 mL). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by normal phase chromatography to obtain 1.9 g of compound 10-e. MS m / z (ESI): 483.17 [M+H] + .

[0627] Step 5: Synthesis of compound 10

[0628] 10-e (150.0 mg, 0.3 mmol) and potassium hydroxide (210.0 mg, 3.7 mmol) were dissolved in a mixture of acetonitrile (2 mL) and water (2 mL). 10-f (141.0 mg, 0.5 mmol) was added dropwise and allowed to react at room temperature for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate (2 x 100 mL). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by medium pressure preparative method to obtain 23.6 mg of compound 10. MS m / z (ESI): 533.16 [M+H] + .

[0629] 1H NMR (400MHz, DMSO-d6) δ8.87(s,1H),8.70(s,1H),7.93(d,J=1.6Hz,1H),7.69(d,J=8.4Hz,2H),7.49(t,J=72.0Hz,1H), 7.45(d,J=8.4Hz,2H),4.31(s,2H),3.88(s,3H),3.78(s,3H),1.70-1.61(m,1H),1.10-1.03(m,2H),0.93-0.85(m,2H).

[0630] Example 11 Preparation of Compound 11

[0631] Step 1: Synthesis of compound 11-b

[0632] Dissolve 11-a (2.5 g, 9.1 mmol) in dry THF (45 mL). Under nitrogen, slowly add a solution of n-butyllithium in n-hexane (5.7 mL, 9.2 mmol, 1.6 M) dropwise at -78°C and stir at -78°C for 1 hour. Add a diluted solution of dimethyldiselenane (2.2 mL, 22.7 mmol) in tetrahydrofuran (5 mL) dropwise, stir at -78°C for 40 minutes, then naturally warm to room temperature and stir for 2 hours. Quench with water, extract with ethyl acetate (2 x 50 mL), wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product, which is then separated and purified by normal phase chromatography to obtain 242.0 mg of compound 11-b. MS m / z (ESI): 243.0 [M+H] + .

[0633] Step 2: Synthesis of compound 11-c

[0634] Dissolve 11-b (100.0 mg, 0.4 mmol) and I-6 (123.3 mg, 0.4 mmol) in dry THF (4 mL). Under nitrogen, add a solution of KHMDS in tetrahydrofuran (433.9 μL, 1 M) dropwise in an ice bath and stir at room temperature for 1 hour. Pour the reaction mixture into ice water, extract with ethyl acetate (2 x 10 mL), wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product is separated and purified by normal phase chromatography to obtain 81.0 mg of compound 11-c. MS m / z (ESI): 505.11 [M+H] + .

[0635] Step 3: Synthesis of compound 11-d

[0636] Dissolve 11-c (81.0 mg, 0.16 mmol) in acetic acid (1.5 mL), add concentrated hydrochloric acid (0.5 mL), and stir at 80°C in a sealed tube for 1 hour. Cool to room temperature, pour the reaction mixture into ice water, and adjust the pH to 7-8 with saturated sodium carbonate. Extract with ethyl acetate (2 x 10 mL), wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product is separated and purified by normal phase column chromatography to obtain 21.0 mg of compound 11-d. MS m / z (ESI): 447.00 [M+H] + .

[0637] Step 4: Synthesis of compound 11

[0638] Under nitrogen, 11-d (21.0 mg, 0.05 mmol), 1-c (18.3 mg, 0.09 mmol), potassium phosphate (32.6 mg, 0.14 mmol), XPhos (9.0 mg, 0.02 mmol), XPhos-Pd G2 (7.4 mg, 0.01 mmol), water (0.5 mL), and dioxane (2 mL) were added to a reaction flask and stirred at 95°C overnight. The mixture was extracted with ethyl acetate (2*10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by medium pressure preparative method to obtain 7.0 mg of compound 11. MS m / z (ESI): 561.11 [M+H] + .

[0639] 1 H NMR (400MHz, DMSO-d6) δ8.86(s,1H),8.67(s,1H),7.91(d,J=1.1Hz,1H),7.65(d,J=8.3Hz,2H),7.41(d,J=8.3Hz, 2H),4.27(s,2H),3.86(s,3H),3.76(s,3H),2.49(s,3H),1.74-1.63(m,1H),1.08-1.00(m,2H),0.93-0.84(m,2H).

[0640] Example 12 Preparation of Compound 12

[0641] Step 1: Synthesis of compound 12-b

[0642] Under nitrogen, I-12 (180.0 mg, 0.46 mmol), 1-a (81.9 mg, 0.46 mmol), potassium phosphate (194.4 mg, 0.92 mmol), and Pd(PPh3)2Cl2 (32.1 mg, 0.05 mmol) were dissolved in toluene (5 mL) and water (1 mL) and stirred at 100°C overnight. The mixture was extracted with ethyl acetate (3 x 20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was separated and purified by normal phase chromatography to obtain 30.0 mg of compound 12-b. MS m / z (ESI): 410.12 [M+H] + .

[0643] Step 2: Synthesis of compound 12

[0644] Under nitrogen, 12-b (30.0 mg, 0.07 mmol) was dissolved in dioxane (5 mL), and water (1 mL), 1-c (14.2 mg, 0.07 mmol), Pd(dppf)Cl2 (5.4 mg, 0.01 mmol), and potassium carbonate (20.2 mg, 0.14 mmol) were added. The mixture was stirred at 100°C overnight. After the reaction was completed, water (50 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3*20 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was purified by medium pressure preparative method to give 6.0 mg of compound 12. MS m / z (ESI): 524.21 [M+H] + .

[0645] 1 H NMR (400MHz, DMSO-d6) δ8.68(s,1H),8.67(s,1H),7.87(d,J=8.6Hz,1H),7.80(d,J=8.2Hz,2H),7.76(d,J=8.6Hz,1H),7.40(d ,J=8.3Hz,2H),4.21(s,2H),4.04(s,3H),3.94(s,3H),3.86(s,3H),1.71-1.57(m,1H),1.08-0.99(m,2H),0.92-0.84(m,2H).

[0646] Example 13 Preparation of Compound 13

[0647] Step 1: Synthesis of compound 13-a

[0648] Under nitrogen, I-13 (50.0 mg, 0.13 mmol), 1-a (47.5 mg, 0.27 mmol), potassium phosphate (56.3 mg, 0.27 mmol), and Pd(PPh3)2Cl2 (4.7 mg, 0.01 mmol) were dissolved in toluene (5 mL) and water (1 mL) and stirred at 100°C overnight. The mixture was extracted with ethyl acetate (3 x 20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by normal phase chromatography to obtain 20.0 mg of compound 13-a. MS m / z (ESI): 394.12 [M+H] + .

[0649] Step 2: Synthesis of compound 13

[0650] Under nitrogen, 13-a (20.0 mg, 0.05 mmol) was dissolved in dioxane (5 mL), and water (1 mL), 1-c (9.9 mg, 0.05 mmol), Pd(dppf)Cl2 (3.7 mg, 0.01 mmol), and potassium carbonate (14.0 mg, 0.10 mmol) were added. The mixture was stirred at 100°C overnight. After the reaction was completed, water (50 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3*20 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was purified by medium pressure preparative method to obtain 2.0 mg of compound 13. MS m / z (ESI): 508.21 [M+H] + .

[0651] 1 H NMR (400MHz, DMSO-d6) δ8.68(s,1H),8.67(s,1H),8.02(d,J=7.9Hz,1H),7.79(d,J=7.9Hz,1H),7.52(d,J=8.1Hz,2H),7.42(d ,J=8.1Hz,2H),4.23(s,2H),4.04(s,3H),3.86(s,3H),2.42(s,3H),1.82-1.53(m,1H),1.08-0.98(m,2H),0.93-0.79(m,2H).

[0652] Example 14 Preparation of Compound 14

[0653] Step 1: Synthesis of compound 14-a

[0654] Under nitrogen, I-10 (1.29 g, 3.35 mmol) was dissolved in toluene (10 mL) and water (2.5 mL). 1-a (300.0 mg, 1.68 mmol), Pd(PPh3)2Cl2 (118.0 mg, 0.17 mmol), and potassium phosphate (1.02 g, 5.03 mmol) were added, and the mixture was stirred at 100°C overnight. The reaction solution was cooled to room temperature, saturated brine (20 mL) was added, and extraction was performed with ethyl acetate (2 x 20 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography to obtain 220.0 mg of compound 14-a. MS m / z (ESI): 401.17 [M+H] + .

[0655] Step 2: Synthesis of compound 14

[0656] Under nitrogen, 14-a (120.0 mg, 0.30 mmol) was dissolved in 1,4-dioxane (10 mL) and water (2 mL), and the mixture was stirred at 95°C overnight with 1-c (116.0 mg, 0.60 mmol), XPhos (57.0 mg, 0.12 mmol), XPhos-Pd G2 (47.0 mg, 0.06 mmol), and potassium phosphate (207.0 mg, 0.90 mmol). The reaction mixture was cooled to room temperature and concentrated to obtain the crude product, which was purified by medium pressure preparative purification and lyophilized to obtain 50.0 mg of compound 14. MS m / z (ESI): 515.16 [M+H] + .

[0657] 1 H NMR (400MHz, DMSO-d6) δ8.71(s,1H),8.67(s,1H),7.58(t,J=8.0Hz,1H),7.44(dd,J=11.6,2.0Hz,1H),7.32(dd,J=8.0,2.0Hz, 1H),6.79(s,1H),4.29(s,2H),4.04(s,3H),3.86(s,3H),2.20(s,3H),1.71-1.65(m,1H),1.06-1.02(m,2H),0.90-0.85(m,2H).

[0658] Example 15 Preparation of Compound 15

[0659] Step 1: Synthesis of compound 15-a

[0660] I-1-5 (4.4 g, 13.79 mmol) and TMSCN (2.4 mL, 19.30 mmol) were dissolved in acetonitrile (60 mL) under nitrogen protection. TBAF solution (17.9 mL, 17.93 mmol) was added under ice-cooling and stirred at room temperature for 2 hours. Water (50 mL) was added and the mixture was extracted with ethyl acetate (2 x 50 mL). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 8.1 g of crude compound 15-a. MS m / z (ESI): 266.10 [M+H] + .

[0661] Step 2: Synthesis of compound 15-b

[0662] 15-a (7.1 g, 12.05 mmol) was dissolved in methanol (100 mL), and TMSCl (22.8 mL, 180.7 mmol) was added. The mixture was stirred at 70°C for 4 hours and concentrated under reduced pressure. Ice water was added to the residue, and the pH was adjusted to 8 with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (2 x 50 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by normal phase chromatography to obtain 3.5 g of compound 15-b. MS m / z (ESI): 299.10 [M+H] + .

[0663] Step 3: Synthesis of compound 15-c

[0664] Dissolve 11-b (0.2 g, 0.83 mmol) and 15-b (246.5 mg, 0.83 mmol) in THF (5 mL). Under nitrogen, add KHMDS (0.9 mL, 1 M) dropwise in an ice bath and stir at room temperature for 2 hours. Pour the reaction mixture into ice water, extract with ethyl acetate (2 x 10 mL), wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. This crude product is separated and purified by normal phase chromatography to obtain 139.0 mg of compound 15-c. MS m / z (ESI): 505.00 [M+H] + .

[0665] Step 4: Synthesis of compound 15-d

[0666] Dissolve 15-c (139.0 mg, 0.14 mmol) in acetic acid (3 mL) and add concentrated hydrochloric acid (1 mL). Stir in a sealed tube at 80°C for 1 hour. Cool to room temperature, pour the reaction mixture into ice water, adjust the pH to 8 with saturated sodium carbonate, extract with ethyl acetate (2 x 5 mL), wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product is separated and purified by normal phase chromatography to obtain 31.0 mg of compound 15-d. MS m / z (ESI): 446.70 [M+H]+ .

[0667] Step 5: Synthesis of compound 15

[0668] Under nitrogen, 15-d (31.0 mg, 0.07 mmol), 1-c (27.0 mg, 0.14 mmol), potassium phosphate (48.1 mg, 0.21 mmol), XPhos (13.3 mg, 0.03 mmol), XPhos-Pd G2 (10.9 mg, 0.01 mmol), dioxane (2 mL), and water (0.5 mL) were added to a reaction flask and stirred at 95°C for 2 hours. The reaction solution was first separated and purified by normal phase column chromatography and then by medium pressure preparative purification to obtain 12.1 mg of compound 15. MS m / z (ESI): 561.00 [M+H] + .

[0669] 1 H NMR (400MHz, DMSO-d6) δ8.87(s,1H),8.67(s,1H),7.51(d,J=8.5Hz,2H),7.45(d,J=8.5Hz,2H),6.74(s,1H), 4.29(s,2H),3.86(s,3H),2.50(s,3H),2.32(s,3H),1.72-1.62(m,1H),1.07-0.98(m,2H),0.92-0.84(m,2H).

[0670] Example 16 Preparation of Compound 16

[0671] Step 1: Synthesis of compound 16-b

[0672] Under nitrogen, 16-a (1.0 g, 6.19 mmol) was dissolved in dry THF (5 mL). A solution of n-butyllithium in n-hexane (4.06 mL, 6.50 mmol, 1.6 M) was slowly added dropwise at -78°C and stirred at -78°C for 1 hour. Tributyltin chloride (1.76 mL, 6.50 mmol) was then added dropwise. After stirring at -78°C for half an hour, the mixture was warmed to room temperature and stirred overnight. The crude reaction mixture was purified by normal phase chromatography to yield 1.7 g of compound 16-b. MS m / z (ESI): 452.12 [M+H]. + .

[0673] Step 2: Synthesis of compound 16-c

[0674] Under nitrogen, 16-b (400.0 mg, 0.89 mmol), I-7-3 (324.2 mg, 0.89 mmol), and Pd(PPh3)2Cl2 (63.1 mg, 0.09 mmol) were dissolved in N-methylpyrrolidone (5 mL) and heated with stirring at 100°C overnight. The reaction solution was diluted with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL). The organic phase was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 11.0 mg of compound 16-c. MS m / z (ESI): 446.1 [M+H] + .

[0675] Step 3: Synthesis of compound 16

[0676] Under nitrogen, 16-c (11.0 mg, 0.02 mmol), 1-c (9.6 mg, 0.05 mmol), potassium phosphate (17.0 mg, 0.07 mmol), XPhos (4.7 mg, 0.01 mmol), XPhos-Pd G2 (3.9 mg), water (0.5 mL), and dioxane (5 mL) were added to a reaction flask and stirred at 100°C overnight. The filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by medium pressure preparative purification to obtain 4.5 mg of compound 16. MS m / z (ESI): 560.2 [M+H] + .

[0677] 1 H NMR (400MHz, DMSO-d6) δ8.70(s,1H),8.47(s,1H),8.26-8.22(m,1H),7.51(t,J=8.0Hz,1H),7.28-7.17(m,2H),4.19-4 .10(m,3H),4.06(s,3H),3.86(s,3H),1.76-1.67(m,1H),1.37(d,J=6.4Hz,6H),1.15-1.08(m,1H),1.05-0.83(m,3H).

[0678] Example 17 Preparation of Compound 17

[0679] Step 1: Synthesis of compound 17-b

[0680] Under nitrogen, 17-a (1.6 g, 10.99 mmol) was dissolved in dry THF (10 mL). A solution of lithium diisopropylamide (7.14 mL, 14.29 mmol) was slowly added dropwise at -78°C, and the mixture was stirred at -78°C for 1 hour. A diluted solution of iodine (3067.9 mg, 12.09 mmol) in tetrahydrofuran (10 mL) was then added dropwise, and the mixture was stirred at -78°C for 1 hour. The mixture was quenched with water (5 mL), ethyl acetate (100 mL) was added, and the mixture was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by normal phase chromatography to obtain 2.07 g of compound 17-b. MS m / z (ESI): 272.0 [M+H] + .

[0681] Step 2: Synthesis of compound 17-c

[0682] Under nitrogen, 17-b (70.0 mg, 0.26 mmol), I-3 (99.1 mg, 0.26 mmol), potassium phosphate (178.1 mg, 0.77 mmol), and Pd(PPh3)2Cl2 (18.1 mg, 0.03 mmol) were dissolved in toluene (15 mL) and water (3 mL) and heated with stirring at 100°C overnight. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by normal phase medium pressure preparative chromatography to obtain 3.0 mg of compound 17-c. MS m / z (ESI): 402.14 [M+H] + .

[0683] Step 3: Synthesis of compound 17

[0684] Under nitrogen, 17-c (3.0 mg, 0.01 mmol), 1-c (2.9 mg, 0.01 mmol), potassium phosphate (5.2 mg, 0.02 mmol), XPhos (1.4 mg), XPhos-Pd G2 (1.2 mg), water (0.2 mL), and dioxane (2 mL) were added to a reaction flask and stirred at 100°C overnight. The filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by medium pressure preparative purification to obtain 2.0 mg of compound 17. MS m / z (ESI): 516.22 [M+H] + .

[0685] 1H NMR (400MHz, DMSO-d6) δ8.71(s,1H),8.46(s,1H),8.02-7.98(m,1H),7.58(t,J=8.0Hz,1H),7.23(d,J=11.2Hz,1H),7.16(dd,J=8.0 ,1.6Hz,1H),4.26(s,2H),3.89(s,3H),3.61(d,J=1.6Hz,3H),2.38(s,3H),1.77-1.70(m,1H),1.17-1.11(m,1H),1.05-0.87(m,3H).

[0686] Example 18 Preparation of Compound 18

[0687] Step 1: Synthesis of compound 18-a

[0688] I-7-3 (2.0 g, 5.48 mmol) was dissolved in acetonitrile (40 mL), and TMSCN (0.76 g, 7.67 mmol) was added. Under nitrogen protection, the temperature was lowered to 0°C, and TBAF solution (7.12 mL, 7.12 mmol) was added dropwise. After the addition was complete, the temperature was naturally raised to room temperature and the reaction was allowed to react for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate (2*50 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by normal phase chromatography to obtain 1.6 g of compound 18-a. MS m / z (ESI): 312.1 [M+H] + .

[0689] Step 2: Synthesis of compound 18-b

[0690] 18-a (1.6 g, 5.14 mmol) was dissolved in methanol (20 mL), and TMSCl (6.5 mL, 51.4 mmol) was added at room temperature. The mixture was stirred at 70°C for 6 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was diluted with water, adjusted to pH 7-8 with saturated sodium bicarbonate, extracted with ethyl acetate (2 x 50 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain 1.62 g of compound 18-b. MS m / z (ESI): 345.11 [M+H] + .

[0691] Step 3: Synthesis of compound 18-c

[0692] 18-b (300.0 mg, 0.87 mmol) was dissolved in dry THF (10 mL). Under nitrogen protection, a solution of KHMDS in tetrahydrofuran (1.3 mL, 1.31 mmol) was added dropwise in an ice bath. The mixture was allowed to react for 10 minutes in an ice bath, followed by a solution of 1-a (187.2 mg, 1.05 mmol) in tetrahydrofuran (1 mL). The mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water and extracted with ethyl acetate (2 x 20 mL). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by normal phase chromatography to obtain 210.0 mg of compound 18-c. MS m / z (ESI): 487.11 [M+H]. + .

[0693] Step 4: Synthesis of compound 18-d

[0694] Dissolve 18-c (220.0 mg, 0.45 mmol) in acetic acid (3 mL) and add concentrated hydrochloric acid (1 mL). Stir in a sealed tube at 80°C for 0.5 hours. Cool to room temperature, pour the reaction mixture into ice water, and adjust the pH to 7-8 with saturated sodium carbonate. Extract with ethyl acetate (2 x 10 mL), wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product is separated and purified by normal phase chromatography to obtain 180.0 mg of compound 18-d. MS m / z (ESI): 429.1 [M+H] + .

[0695] Step 5: Synthesis of compound 18

[0696] Under nitrogen, 18-d (180.0 mg, 0.42 mmol), 1-c (122.1 mg, 0.63 mmol), potassium phosphate (178.1 mg, 0.84 mmol), XPhos (81.1 mg, 0.17 mmol), XPhos-Pd G2 (70.1 mg, 0.09 mmol), water (1 mL), and dioxane (5 mL) were added to a reaction flask and stirred at 95°C overnight. The mixture was extracted with ethyl acetate (2 x 10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by medium pressure preparative method to obtain 108.0 mg of compound 18. MS m / z (ESI): 543.21 [M+H] + .

[0697] 1H NMR (400MHz, DMSO-d6) δ8.71(s,1H),8.67(s,1H),8.24(d,J=1.2Hz,1H),7.50(t,J=8.0Hz,1H),7.36-7.31(m,1H),7.31-7.25(m,1H),4. 27(s,2H),4.18-4.10(m,1H),4.04(s,3H),3.86(s,3H),1.71-1.63(m,1H),1.37(d,J=6.4Hz,6H),1.08-1.01(m,2H),0.91-0.83(m,2H).

[0698] Example 19 Preparation of Compound 19

[0699] Step 1: Synthesis of compound 19

[0700] 10-e (100.0 mg, 0.21 mmol) was dissolved in acetonitrile (2 mL), and 19-a (72.2 mg, 0.42 mmol) and cesium carbonate (135.0 mg, 0.42 mmol) were added. The mixture was heated to 50°C for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate (2*10 mL). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by medium pressure preparative method to obtain 11.28 mg of compound 19. MS m / z (ESI): 529.19 [M+H] + .

[0701] 1 H NMR(400MHz, DMSO-d6)δ8.70(s,1H),8.68(s,1H),7.93(d,J=1.2Hz,1H),7.69-7.61(m,2H),7.49-7.42(m,2H),4.95-4.89(m,1H),4.83-4.77( m,1H),4.61-4.55(m,1H),4.53-4.47(m,1H),4.24(s,2H),3.86(s,3H) ,3.78(s,3H),1.68-1.59(m,1H),1.10-1.01(m,2H),0.92-0.83(m,2H).

[0702] Example 20 Preparation of Compound 20

[0703] Step 1: Synthesis of compound 20-a

[0704] Under nitrogen, I-1 (200.0 mg, 0.55 mmol), 1-a (97.8 mg, 0.55 mmol), potassium phosphate (231.9 mg, 1.09 mmol), and Pd(PPh3)2Cl2 (38.3 mg, 0.05 mmol) were dissolved in toluene (5 mL) and water (1 mL) and stirred at 100°C overnight. The mixture was extracted with ethyl acetate (3 x 20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by normal phase chromatography to obtain 20.0 mg of compound 20-a. MS m / z (ESI): 383.13 [M+H] + .

[0705] Step 2: Synthesis of compound 20

[0706] Under nitrogen, 20-a (20.0 mg, 0.05 mmol) was dissolved in dioxane (5 mL), and water (1 mL), 1-c (10.1 mg, 0.05 mmol), Pd(dppf)Cl2 (3.8 mg, 0.01 mmol), and potassium carbonate (14.4 mg, 0.10 mmol) were added. The mixture was stirred at 100°C overnight. After the reaction was completed, water (50 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3*20 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was purified by medium pressure preparative method to obtain 2.5 mg of compound 20. MS m / z (ESI): 497.19 [M+H] + .

[0707] 1 H NMR (400MHz, DMSO-d6) δ8.69(s,1H),8.66(s,1H),7.51(d,J=8.6Hz,2H),7.46(d,J=8.5Hz,2H),6.75(s,1H), 4.24(s,2H),4.03(s,3H),3.86(s,3H),2.33(s,3H),1.71-1.57(m,1H),1.10-0.94(m,2H),0.91-0.82(m,2H).

[0708] Example 21 Preparation of Compound 21

[0709] Step 1: Synthesis of compound 21-a

[0710] Under nitrogen, I-9 (400.0 mg, 1.02 mmol), 1-a (182.6 mg, 1.02 mmol), potassium phosphate (459.9 mg, 2.04 mmol), and Pd(PPh3)2Cl2 (76.3 mg, 0.11 mmol) were dissolved in toluene (10 mL) and water (2 mL) and stirred at 100°C overnight. The mixture was extracted with ethyl acetate (3 x 20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by normal phase chromatography to obtain 100.0 mg of compound 21-a. MS m / z (ESI): 408.93 [M+H] + .

[0711] Step 2: Synthesis of compound 21

[0712] Under nitrogen, 21-a (50.0 mg, 0.12 mmol) was dissolved in dioxane (5 mL), and water (1 mL), 1-c (23.7 mg, 0.12 mmol), Pd(dppf)Cl2 (8.9 mg, 0.01 mmol), and potassium carbonate (33.8 mg, 0.24 mmol) were added. The mixture was stirred at 100°C overnight. After the reaction was completed, water (50 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3*20 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was purified by medium pressure preparative method to obtain 20.0 mg of compound 21. MS m / z (ESI): 522.91 [M+H] + .

[0713] 1 H NMR (400MHz, DMSO-d6) δ8.70(s,1H),8.67(s,1H),7.59(d,J=8.4Hz,2H),7.48(d,J=8.4Hz,2H),6.63(s,1H),4.25(s,2H),4.04 (s,3H),3.86(d,J=4.8Hz,3H),1.93-1.75(m,1H),1.77-1.55(m,1H),1.08-1.01(m,2H),1.01-0.93(m,2H),0.91-0.76(m,4H).

[0714] Example 22 Preparation of Compound 22

[0715] Step 1: Synthesis of compound 22

[0716] Compound 19 (30.0 mg, 0.06 mmol) was dissolved in diethylaminosulfur trifluoride (1 mL) and reacted at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate (2 x 10 mL). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by medium pressure preparative method to obtain 4.81 mg of compound 22. MS m / z (ESI): 565.17 [M+H] + .

[0717] 1 H NMR (400MHz, DMSO-d6) δ9.01(s,1H),8.71(s,1H),7.99(s,1H),7.89(d,J=8.0Hz,2H),7.72(d,J=8.0Hz,2H),4.84- 4.64(m,2H),4.61-4.48(m,2H),3.89(s,3H),3.82(s,3H),1.74-1.64(m,1H),1.12-1.05(m,2H),1.00-0.89(m,2H).

[0718] Example 23 Preparation of Compound 23

[0719] Step 1: Synthesis of compound 23-b

[0720] I-2-2 (79.7 g, 295.57 mmol) and sodium acetate trihydrate (40.2 g, 295.57 mmol) were dissolved in water (400 mL), and the resulting mixture was stirred at 100°C for 2 hours. The reaction solution was cooled to room temperature, and a solution of 23-a (50.0 g, 246.31 mmol) in methanol (400 mL) was added dropwise to the above mixture. Ammonia water (250 mL) was then added to the reaction solution, and stirring was continued at room temperature overnight. Saturated brine (200 mL) was added, and the mixture was extracted with ethyl acetate (2*400 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by normal phase column chromatography to obtain 68.0 g of compound 23-b. MS m / z (ESI): 309.10 [M+H] + .

[0721] Step 2: Synthesis of compound 23-c

[0722] 23-b (9.7 g, 31.38 mmol), deuterated iodomethane (2.93 mL, 47.07 mmol), potassium carbonate (6.5 g, 47.07 mmol), and DMF (150 mL) were added to a reaction flask and stirred at room temperature for 2 hours. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (2 x 100 mL). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by normal phase chromatography to obtain 6.3 g of compound 23-c. MS m / z (ESI): 325.90 [M+H] + .

[0723] Step 3: Synthesis of compound 23-e

[0724] Under nitrogen, 23-c (2.2 g, 6.75 mmol), 23-d (1.6 g, 8.10 mmol), Pd(dppf)Cl2·CH2Cl2 (0.6 g, 0.67 mmol), potassium fluoride (1.2 g, 20.24 mmol), dimethyl sulfoxide (40 mL), and water (20 mL) were added to a reaction flask and stirred at 130°C overnight. The mixture was diluted with water and extracted with ethyl acetate (2 x 60 mL). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by normal phase chromatography to obtain 863.0 mg of compound 23-e. MS m / z (ESI): 287.14 [M+H] + .

[0725] Step 4: Synthesis of compound 23-f

[0726] 23-e (863.0 mg, 3.02 mmol) was dissolved in methanol (10 mL), and trimethylolmethane (TMSCl) (5.7 mL, 45.23 mmol) was added. The mixture was stirred at 70°C for 4 hours and concentrated under reduced pressure. Ice water was added to the residue, and the pH was adjusted to 8 with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (2 x 60 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by normal phase chromatography to obtain 562.0 mg of compound 23-f. MS m / z (ESI): 320.03 [M+H]. + .

[0727] Step 5: Synthesis of compound 23-g

[0728] Dissolve 1-a (1.0 g, 6.13 mmol) and 23-f (561.9 mg, 1.76 mmol) in THF (20 mL). Under nitrogen, add KHMDS (2.9 mL, 1 M) dropwise in an ice bath and stir at room temperature for 1 hour. Pour the reaction mixture into ice water and extract with ethyl acetate (2 x 15 mL). Wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. This crude product is separated and purified by normal phase chromatography to obtain 688.0 mg of compound 23-g. MS m / z (ESI): 461.89 [M+H] + .

[0729] Step 6: Synthesis of compound 23-h

[0730] 23-g (688.0 mg, 1.49 mmol), concentrated hydrochloric acid (4 mL), and acetic acid (12 mL) were added to a sealed tube. Stir at 80°C for 1.5 hours, then cooled to room temperature. The reaction mixture was poured into ice water and adjusted to pH 8 with saturated sodium carbonate. Extraction was performed with ethyl acetate (2 x 10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was then separated and purified by normal phase chromatography to yield 537.0 mg of compound 23-h. MS m / z (ESI): 403.90 [M+H] + .

[0731] Step 7: Synthesis of compound 23

[0732] Under nitrogen, compound 23-h (537.0 mg, 1.33 mmol), 1-c (516.0 mg, 2.66 mmol), potassium phosphate (918.8 mg, 3.99 mmol), XPhos (253.6 mg, 0.53 mmol), XPhos-Pd G2 (209.0 mg, 0.27 mmol), dioxane (12 mL), and water (3 mL) were added to a reaction flask and stirred at 95°C for 1.5 hours. The mixture was extracted with ethyl acetate (2 x 10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was first separated and purified by normal phase column chromatography, then purified by medium pressure preparative purification, and lyophilized to obtain 336.0 mg of compound 23. MS m / z (ESI): 517.97 [M+H] + .

[0733] 1H NMR (400MHz, DMSO-d6) δ8.69(s,1H),8.65(s,1H),7.99-7.95(m,1H),7.52(t,J=7.8Hz,1H),7.33-7.27(m,1H),7. 27-7.22(m,1H),4.25(s,2H),4.02(s,3H),3.84(s,3H),1.70-1.60(m,1H),1.07-0.99(m,2H),0.90-0.81(m,2H).

[0734] Example 24 Preparation of Compound 24

[0735] Step 1: Synthesis of compound 24-a

[0736] Dissolve 11-b (300.0 mg, 1.24 mmol) and I-19 (392.1 mg, 1.24 mmol) in THF (8 mL). Under nitrogen, add KHMDS (1.3 mL, 1 M) dropwise in an ice bath. Stir at room temperature for 1 hour. Pour the reaction mixture into ice water, extract with ethyl acetate (2 x 15 mL), wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product is separated and purified by normal phase chromatography to obtain 298.0 mg of compound 24-a. MS m / z (ESI): 522.90 [M+H] + .

[0737] Step 4: Synthesis of compound 24-b

[0738] 24-a (298.0 mg, 0.57 mmol) was dissolved in acetic acid (6 mL), and concentrated hydrochloric acid (2 mL) was added. The mixture was stirred at 80°C in a sealed tube for 1 hour. After cooling to room temperature, the reaction mixture was poured into ice water and adjusted to pH 8 with saturated sodium carbonate. The mixture was extracted with ethyl acetate (2 x 10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by normal phase chromatography to obtain 85.0 mg of compound 24-b. MS m / z (ESI): 465.00 [M+H] + .

[0739] Step 5: Synthesis of compound 24

[0740] Under nitrogen, 24-b (75.0 mg, 0.16 mmol), 1-c (62.8 mg, 0.32 mmol), potassium phosphate (111.7 mg, 0.49 mmol), XPhos (30.8 mg, 0.06 mmol), XPhos-Pd G2 (25.4 mg, 0.03 mmol), water (1 mL), and dioxane (4 mL) were added to a reaction flask and stirred at 95°C overnight. The mixture was extracted with ethyl acetate (2*10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was first separated and purified by normal phase column chromatography and then purified by medium pressure preparative purification to obtain 35.0 mg of compound 24. MS m / z (ESI): 579.20 [M+H] + .

[0741] 1 H NMR (400MHz, DMSO-d6) δ8.88(s,1H),8.67(s,1H),7.98(d,J=0.9Hz,1H),7.53(t,J=7.8Hz,1H),7.35-7.30(m,1H),7.30-7.22( m,1H),4.30(s,2H),3.85(s,3H),3.58(d,J=0.9Hz,3H),2.50(s,3H),1.77-1.65(m,1H),1.07-1.00(m,2H),0.91-0.84(m,2H).

[0742] Example 25 Preparation of Compound 25

[0743] Step 1: Synthesis of compound 25

[0744] Compound 11 (5.5 mg, 0.01 mmol) was dissolved in dichloromethane (1 mL). m-Chloroperbenzoic acid (1.7 mg, 0.01 mmol) was added under ice-cooling and stirred for 30 minutes. The reaction mixture was purified by reverse phase medium pressure preparative purification and lyophilized to obtain 2.8 mg of compound 25. MS m / z (ESI): 577.14 [M+H] + .

[0745] 1H NMR (400MHz, DMSO-d6) δ9.26(s,1H),8.72(s,1H),7.94(s,1H),7.70(d,J=8.2Hz,2H),7.44(d,J=8.2Hz,2H),4.47 (d,J=6.0Hz,2H),3.89(s,3H),3.79(s,3H),2.62(s,3H),1.74-1.61(m,1H),1.09-1.01(m,2H),0.94-0.83(m,2H).

[0746] Example 26 Preparation of Compound 26

[0747] Step 1: Synthesis of compound 26

[0748] Compound 15 (6.0 mg, 0.01 mmol) was dissolved in dichloromethane (1.5 mL). m-Chloroperbenzoic acid (1.9 mg, 0.01 mmol) was added under ice-cooling and stirred for 30 minutes. The reaction mixture was purified by reverse phase medium pressure preparative purification and lyophilized to obtain 2.6 mg of compound 26. MS m / z (ESI): 577.10 [M+H] + .

[0749] 1 H NMR(400MHz, CDCl3)δ9.42(s,1H),8.68(s,1H),7.48-7.39(m,4H),6.47(s,1H),4.40(s,2H),3.96 (s,3H),2.56-2.48(m,3H),2.35(s,3H),1.71-1.64(m,1H),1.29-1.23(m,2H),0.97-0.87(m,2H).

[0750] Example 27 Preparation of Compound 27

[0751] Step 1: Synthesis of compound 27

[0752] Compound 24 (22.0 mg, 0.04 mmol) was dissolved in dichloromethane (2 mL). m-Chloroperbenzoic acid (6.6 mg, 0.04 mmol) was added under ice-cooling and stirred for 30 minutes. The reaction mixture was purified by reverse phase medium pressure preparative purification and lyophilized to obtain 10.7 mg of compound 27. MS m / z (ESI): 595.16 [M+H] + .

[0753] 1H NMR (400MHz, DMSO-d6) δ9.24(s,1H),8.69(s,1H),7.99(s,1H),7.56(t,J=7.8Hz,1H),7.38(d,J=11.3Hz,1H),7.29(d,J=7.9H z,1H),4.49(d,J=2.4Hz,2H),3.86(s,3H),3.58(s,3H),2.71(s,3H),1.72-1.63(m,1H),1.10-0.98(m,2H),0.93-0.78(m,2H).

[0754] Example 28 Preparation of Compound 28

[0755] Step 1: Synthesis of compound 28-b

[0756] Referring to the synthesis of 2-a, I-3 (1.38 g, 3.59 mmol) was replaced with 28-a (300.0 mg, 1.80 mmol) to obtain 100.0 mg of compound 28-b. MS m / z (ESI): 389.07 [M+H] + .

[0757] Step 2: Synthesis of compound 28

[0758] Under nitrogen, 28-b (90.0 mg, 0.23 mmol) was dissolved in a mixture of 1,4-dioxane (10 mL) and water (2 mL). 1-c (89.8 mg, 0.46 mmol), Pd(dppf)Cl2 (16.9 mg, 0.02 mmol), and potassium carbonate (64.0 mg, 0.46 mmol) were added, and the mixture was stirred at 100°C overnight. The reaction mixture was cooled to room temperature and concentrated to obtain the crude product, which was purified by medium pressure preparative method and lyophilized to obtain 38.0 mg of compound 28. MS m / z (ESI): 503.18 [M+H] + .

[0759] 1 H NMR (400MHz, DMSO-d6) δ9.01(d,J=1.8Hz,1H),8.70(s,1H),8.01(s,1H),7.58(t,J=8.0Hz,1H),7.39(d,J=11.2Hz,1H),7.35-7 .28(m,1H),4.40(d,J=2.0Hz,2H),3.87(s,3H),3.61(d,J=1.6Hz,3H),1.71-1.66(m,1H),1.08-1.04(m,2H),0.91-0.87(m,2H).

[0760] Example 29 Preparation of Compound 29

[0761] Step 1: Synthesis of compound 29-a

[0762] Referring to the synthesis of 2-a, I-3 was replaced by I-10 (4.24 g, 11.04 mmol), and 1-a was replaced by 3-a (900.0 mg, 5.52 mmol) to obtain 1.10 g of compound 29-a. MS m / z (ESI): 384.94 [M+H] + .

[0763] Step 2: Synthesis of compound 29

[0764] Referring to the synthesis of compound 14, 1-c (100.8 mg, 0.52 mmol) was used to replace 14-a with 29-a (100.0 mg, 0.26 mmol) to obtain 25.0 mg of compound 29. MS m / z (ESI): 499.19 [M+H] + .

[0765] 1 H NMR (400MHz, DMSO-d6) δ8.75(s,1H),8.68(s,1H),7.60(t,J=8.4Hz,1H),7.46(dd,J=11.6,2.0Hz,1H),7.33(dd,J=8.4,2.0Hz, 1H),6.79(s,1H),4.34(s,2H),3.86(s,3H),2.39(s,3H),2.21(s,3H),1.73-1.64(m,1H),1.07-1.03(m,2H),0.91-0.86(m,2H).

[0766] Example 30 Preparation of Compound 30

[0767] Step 1: Synthesis of compound 30

[0768] Referring to the synthesis of compound 3, 3-c (886.0 mg, 2.3 mmol), 1-c was replaced with 2-b (1225.4 mg, 4.6 mmol) to obtain 245.0 mg of compound 30. MS m / z (ESI): 489.20 [M+H] + .

[0769] 1H NMR (400MHz, DMSO-d6) δ8.65(s,1H),8.60(s,1H),7.98(s,1H),7.54(t,J=7.8Hz,1H),7.31( d,J=11.5Hz,1H),7.27(d,J=8.0Hz,1H),4.25(s,2H),3.87(s,6H),3.59(s,3H),2.32(s,3H).

[0770] Example 31 Preparation of Compound 31

[0771] Step 1: Synthesis of compound 31-a

[0772] Under nitrogen, 40-b (155.0 mg, 0.3 mmol), trimethylsilylacetylene (88.2 μL, 0.6 mmol), Pd(PPh3)2Cl2 (43.8 mg, 0.06 mmol), cuprous iodide (9.9 mg, 0.03 mmol), triethylamine (86.5 μL, 0.6 mmol), and 2-methyltetrahydrofuran (6 mL) were added to a reaction flask and stirred at 55°C overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by normal phase chromatography to afford 76.0 mg of compound 31-a. MS m / z (ESI): 467.10 [M+H] + .

[0773] Step 2: Synthesis of compound 31

[0774] Referring to the synthesis of compound 3, 1-c (39.9 mg, 0.2 mmol) was replaced with 31-a (48.0 mg, 0.1 mmol) and stirred at 80°C for 2 hours. The same post-treatment was performed to obtain 7.2 mg of compound 31. MS m / z (ESI): 509.20 [M+H] + .

[0775] 1 H NMR (400MHz, CDCl3) δ8.92(s,1H),8.65(s,1H),7.57-7.49(m,1H),7.36-7.28(m,2H),7.27-7.22(m,1H),4.41(s ,2H),3.94(s,3H),3.64(s,1H),3.63(d,J=2.3Hz,3H),1.70-1.63(m,1H),1.25-1.20(m,2H),0.93-0.87(m,2H).

[0776] Example 32 Preparation of Compound 32

[0777] Step 1: Synthesis of compound 32-a

[0778] Referring to the synthesis of 18-c, 18-b (500.0 mg, 1.45 mmol) was prepared by replacing 1-a with 3-a (710.1 mg, 4.36 mmol) to obtain 600.0 mg of compound 32-a. MS m / z (ESI): 471.11 [M+H] + .

[0779] Step 2: Synthesis of compound 32-b

[0780] Referring to the synthesis of 3-c, 3-b was replaced with 32-a (480.0 mg, 1.02 mmol) and stirred at 80°C in a sealed tube for 0.5 h. Similar post-treatment yielded 320.0 mg of compound 32-b. MS m / z (ESI): 413.11 [M+H] + .

[0781] Step 3: Synthesis of compound 32

[0782] Referring to the synthesis of compound 4, 1-c (90.2 mg, 0.47 mmol) was prepared by replacing 2-a with 32-b (160.0 mg, 0.39 mmol). The mixture was stirred at 80°C for 3 hours. Similar post-treatments were performed to obtain a crude product, which was then purified by normal phase chromatography and then by reverse phase chromatography to yield 69.0 mg of compound 32. MS m / z (ESI): 527.21 [M+H] + .

[0783] 1 H NMR (400MHz, DMSO-d6) δ8.75(s,1H),8.69(s,1H),8.26-8.22(m,1H),7.55-7.48(m,1H),7.37-7.32(m,1H),7.32-7.26(m,1H),4.32( s,2H),4.20-4.09(m,1H),3.87(s,3H),2.39(s,3H),1.72-1.62(m,1H),1.37(d,J=6.4Hz,6H),1.08-1.02(m,2H),0.92-0.84(m,2H).

[0784] Example 33 Preparation of Compound 33

[0785] Step 1: Synthesis of compound 33-a

[0786] Referring to the synthesis of 3-b, 3-a was replaced with 11-b (67.4 mg, 0.28 mmol) and I-19 was replaced with I-8 (76.0 mg, 0.23 mmol) to obtain 40.0 mg of compound 33-a. MS m / z (ESI): 534.00 [M+H] + .

[0787] Step 2: Synthesis of compound 33-b

[0788] Referring to the synthesis of 3-c, 3-b was replaced with 33-a (40.0 mg, 0.08 mmol) and stirred at 80°C for 1 hour. Similar post-treatment yielded 15.0 mg of compound 33-b. MS m / z (ESI): 476.00 [M+H] + .

[0789] Step 3: Synthesis of compound 33

[0790] Referring to the synthesis of compound 3, 1-c (12.3 mg, 0.06 mmol) was substituted with 33-b (15.0 mg, 0.03 mmol). Similar post-treatments were performed to obtain a crude product, which was first purified by normal phase chromatography, then by medium pressure preparative purification, and lyophilized to yield 4.5 mg of compound 33. MS m / z (ESI): 590.10 [M+H] + .

[0791] 1 H NMR (400MHz, CDCl3) δ8.77(s,1H),8.65(s,1H),8.63(d,J=1.7Hz,1H),8.10(d,J=8.2Hz,1H),7.77(dd,J=8.2,2.3Hz,1H),7.46(d,J=1.0Hz,1 H),5.93-5.81(m,1H),4.33(s,2H),3.95(s,3H),2.42(s,3H),1.72-1. 63(m,1H),1.48(d,J=6.7Hz,6H),1.24-1.19(m,2H),0.92-0.86(m,2H).

[0792] Example 34 Preparation of Compound 34

[0793] Step 1: Synthesis of compound 34-b

[0794] Referring to the synthesis of 3-b, I-19 (99.2 mg, 0.3 mmol) was used to replace 3-a with 34-a (200.0 mg, 1.0 mmol) to obtain 73.0 mg of compound 34-b. MS m / z (ESI): 470.12 [M+H]+ .

[0795] Step 2: Synthesis of compound 34-c

[0796] Referring to the synthesis of 3-c, 3-b was replaced with 34-b (73.0 mg, 0.2 mmol) and stirred at 80°C for 1 hour. Similar post-treatment was performed to obtain 15.0 mg of compound 34-c. MS m / z (ESI): 413.09 [M+H] + .

[0797] Step 3: Synthesis of compound 34

[0798] Referring to the synthesis of compound 3, 1-c (14.1 mg, 0.1 mmol) was replaced with 34-c (15.0 mg, 0.04 mmol) and stirred at 100°C overnight. The crude product was purified by reverse phase chromatography to yield 7.21 mg of compound 34. MS m / z (ESI): 526.97 [M+H] + .

[0799] 1 H NMR (400MHz, DMSO-d6) δ8.93(s,1H),8.69(s,1H),8.00(d,J=7.8Hz,1H),7.55(t,J=7.8Hz,1H),7.38-7.24(m,2H),4.39(s,2H),3.8 8(s,3H),3.60(d,J=1.3Hz,3H),3.45-3.24(m,1H),1.72-1.64(m,1H),1.27(d,J=6.9Hz,6H),1.09-1.04(m,2H),0.92-0.89(m,2H).

[0800] Example 35 Preparation of Compound 35

[0801] Step 1: Synthesis of compound 35-b

[0802] Referring to the synthesis of 3-b, I-19 (215.5 mg, 0.7 mmol) was prepared by replacing 3-a with 35-a (400.0 mg, 2.3 mmol) to obtain 144.0 mg of compound 35-b. MS m / z (ESI): 456.88 [M+H] + .

[0803] Step 2: Synthesis of compound 35-c

[0804] Referring to the synthesis of 3-c, 3-b was replaced with 35-b (144.0 mg, 0.3 mmol) and stirred at 80°C for 1 hour. The same post-treatment was performed to obtain 61.0 mg of compound 35-c. MS m / z (ESI): 399.09 [M+H] + .

[0805] Step 3: Synthesis of compound 35

[0806] Referring to the synthesis of compound 3, 1-c (59.5 mg, 0.3 mmol) was replaced with 35-c (61.0 mg, 0.2 mmol) and stirred at 100°C overnight. The crude product was purified by reverse phase chromatography to afford 18.51 mg of compound 35. MS m / z (ESI): 513.12 [M+H] + .

[0807] 1 H NMR (400MHz, DMSO-d6) δ8.80(s,1H),8.69(s,1H),8.00(d,J=1.0Hz1H),7.56(t,J=7.8Hz,1H),7.40-7.26(m,2H),4.35(s,2H),3.88( s,3H),3.60(d,J=1.2Hz,3H),2.80(q,J=7.5Hz,2H),1.71-1.68(m,1H),1.23(t,J=7.5Hz,3H),1.08-1.02(m,2H),0.91-0.88(m,2H).

[0808] Example 36 Preparation of Compound 36

[0809] Step 1: Synthesis of compound 36-b

[0810] Referring to the synthesis of 3-b, I-19 (324.2 mg, 1.03 mmol) was prepared by replacing 3-a with 36-a (200.0 mg, 1.03 mmol) and stirring at room temperature for 1 hour. Similar post-treatment was performed to obtain 310.0 mg of compound 36-b. MS m / z (ESI): 475.10 [M+H] + .

[0811] Step 2: Synthesis of compound 36-c

[0812] Referring to the synthesis of 3-c, 3-b was replaced with 36-b (310.0 mg, 0.65 mmol) and stirred at 80°C in a sealed tube for 1 hour. Similar post-treatment yielded 138.0 mg of compound 36-c. MS m / z (ESI): 417.10 [M+H] + .

[0813] Step 3: Synthesis of compound 36

[0814] Referring to the synthesis of compound 4, 1-c (125.7 mg, 0.65 mmol) was used to replace 2-a with 36-c (135.0 mg, 0.32 mmol). Similar post-treatments were performed to obtain a crude product, which was purified by medium-pressure preparative purification and lyophilized to yield 10.0 mg of compound 36. MS m / z (ESI): 531.20 [M+H] + .

[0815] 1 H NMR (400MHz, DMSO-d6) δ8.82(s,1H),8.69(s,1H),8.00(d,J=1.2Hz,1H),7.56(t,J=8.0Hz,1H),7.35(d,J=11.2Hz,1H),7.29(dd,J=8. 0,1.6Hz,1H),4.31(s,2H),3.88(s,3H),3.60(d,J=1.6Hz,3H),2.67(s,3H),1.75-1.70(m,1H),1.08-1.05(m,2H),0.93-0.88(m,2H).

[0816] Example 37 Preparation of Compound 37

[0817] Step 1: Synthesis of compound 37-b

[0818] Under nitrogen, 40-b (600.0 mg, 1.21 mmol) was dissolved in dioxane (10 mL), and 37-a (523.7 mg, 1.45 mmol) and Pd(PPh3)2Cl2 (169.6 mg, 0.24 mmol) were added. The mixture was stirred at 80°C for 12 hours. After the reaction was complete, water (20 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a mixture that was separated and purified by normal phase chromatography to afford 380.0 mg of compound 37-b. MS m / z (ESI): 441.1 [M+H]. + .

[0819] Step 2: Synthesis of compound 37-c

[0820] Referring to the synthesis of compound 4, 1-c (308.1 mg, 1.59 mmol) was prepared by replacing 2-a with 37-b (350.0 mg, 0.79 mmol). The mixture was stirred at 80°C for 3 hours. Similar post-treatment was performed to obtain a crude product, which was then separated and purified by normal phase chromatography to yield 380.0 mg of compound 37-c. MS m / z (ESI): 555.21 [M+H] + .

[0821] Step 3: Synthesis of compound 37

[0822] 37-c (100.0 mg, 0.18 mmol) was dissolved in THF (10 mL), and 2N HCl (2 mL) was added. The reaction was allowed to react at room temperature for 1 hour. After completion of the reaction, sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (3*20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture. The mixture was separated and purified using a normal phase column chromatography, and then purified by medium pressure preparative purification to obtain 23.3 mg of compound 37. MS m / z (ESI): 527.17 [M+H] + .

[0823] 1 H NMR(400MHz,DMSO-d6)δ9.46(s,1H),8.72(s,1H),8.01-7.95(m,1H),7.57-7.48(m,1H),7.35-7.31(m,1H),7.31-7.25 (m,1H),4.51(s,2H),3.88(s,3H),3.60(s,3H),2.73(s,3H),1.75-1.66(m,1H),1.10-1.05(m,2H),0.92-0.85(m,2H).

[0824] Example 38 Preparation of Compound 38

[0825] Step 1: Synthesis of compound 38-b

[0826] Under nitrogen, 38-a (15.0 g, 104.2 mmol), ethyl formate (23.0 g, 312.5 mmol), TiCl4 (29.7 g, 156.3 mmol), and TEA (25.3 g, 250.0 mmol) were dissolved in DCM (5 mL) and stirred at room temperature overnight. After the reaction, water (20 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a mixture that was separated and purified by normal phase chromatography to yield 12.0 g of compound 38-b. MS m / z (ESI): 173.11 [M+H]. + .

[0827] Step 2: Synthesis of compound 38-c

[0828] Under nitrogen, 38-b (12.0 g, 69.8 mmol) and thiourea (15.9 g, 209.3 mmol) were dissolved in H2O (150 mL) and stirred at 100°C overnight. After completion of the reaction, dilute hydrochloric acid was added to the mixture to adjust the pH to 2. The mixture was extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a mixture that was separated and purified by normal phase chromatography to afford 1.8 g of compound 38-c. MS m / z (ESI): 185.07 [M+H]. + .

[0829] Step 3: Synthesis of compound 38-d

[0830] Under nitrogen, compound 38-c (1.8 g, 9.8 mmol) and chloroacetic acid (2.8 g, 29.3 mmol) were dissolved in HCl (6N, 20 mL). The mixture was stirred at 100°C overnight. After completion of the reaction, saturated sodium bicarbonate solution was added to the mixture to adjust the pH to 8. The mixture was extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture. The mixture was separated and purified by normal phase chromatography to obtain 150.0 mg of compound 38-d. MS m / z (ESI): 169.09 [M+H]. + .

[0831] Step 4: Synthesis of compound 38-e

[0832] Under nitrogen, 38-d (150.0 mg, 0.9 mmol), phosphorus oxychloride (409.8 mg, 2.7 mmol), and DIEA (345.5 mg, 2.7 mmol) were dissolved in toluene (10 mL). The mixture was stirred at 120°C overnight. After the reaction was complete, sodium bicarbonate solution was added to the mixture to adjust the pH to 8. The mixture was extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a mixture that was separated and purified by normal phase chromatography to afford 98.0 mg of compound 38-e. MS m / z (ESI): 205.02 [M+H]. + .

[0833] Step 5: Synthesis of compound 38-f

[0834] Referring to the synthesis of 3-b, I-19 (45.5 mg, 0.1 mmol) was prepared by replacing 3-a with 38-e (98.0 mg, 0.5 mmol) to obtain 68.0 mg of compound 38-f. MS m / z (ESI): 485.13 [M+H] + .

[0835] Step 6: Synthesis of compound 38-g

[0836] Referring to the synthesis of 3-c, 3-b was replaced with 38-f (68.0 mg, 0.1 mmol), and the mixture was stirred at 80°C for 1 hour. Similar post-treatment yielded 23.0 mg of compound 38-g. MS m / z (ESI): 427.12 [M+H] + .

[0837] Step 7: Synthesis of compound 38

[0838] Referring to the synthesis of compound 3, 1-c (19.9 mg, 0.1 mmol) was replaced with 38-g (23.0 mg, 0.1 mmol) and stirred at 100°C overnight. The crude product was purified by reverse phase chromatography to give 6.6 mg of compound 38. MS m / z (ESI): 541.23 [M+H] + .

[0839] 1H NMR (400MHz, DMSO-d6) δ8.97(s,1H),8.67(s,1H),8.00(d,J=1.1Hz1H),7.53(t,J=7.9Hz,1H),7.25(d,J=11.5Hz,1H),7.19(d,J=8 .0Hz,1H),4.57(s,2H),3.86(s,3H),3.60(d,J=1.2Hz,3H),1.71-1.66(s,1H),1.50(s,9H),1.08-1.02(m,2H),0.88-0.82(m,2H).

[0840] Example 39 Preparation of Compound 39

[0841] Step 1: Synthesis of compound 39-a

[0842] Referring to the synthesis of 3-b, replace I-19 with I-20 (400.0 mg, 1.2 mmol) and 3-a with 11-b (296.7 mg, 1.2 mmol). Stir at room temperature for 1 hour. Following the same post-treatment, 244.0 mg of compound 39-a was obtained. MS m / z (ESI): 532.90 [M+H] + .

[0843] Step 2: Synthesis of compound 39-b

[0844] Referring to the synthesis of 3-c, 3-b was replaced with 39-a (244.0 mg, 0.46 mmol) and stirred at 80°C for 1 hour. Similar post-treatment was performed to obtain 94.0 mg of compound 39-b. MS m / z (ESI): 475.00 [M+H] + .

[0845] Step 3: Synthesis of compound 39

[0846] Referring to the synthesis of compound 3, 1-c (77.0 mg, 0.4 mmol) was substituted with 39-b (94.0 mg, 0.2 mmol). Similar post-treatment was performed to obtain a crude product, which was purified by medium pressure preparative purification and lyophilized to yield 31.4 mg of compound 39. MS m / z (ESI): 588.60 [M+H] + .

[0847] 1H NMR (400MHz, DMSO-d6) δ8.87(s,1H),8.67(s,1H),8.15(d,J=1.0Hz,1H),7.50(d,J=8.2Hz,2H),7.42(d,J=8.2Hz,2H),4.48-4.4 0(m,1H),4.28(s,2H),3.86(s,3H),2.50(s,3H),1.72-1.62(m,1H),1.39(d,J=6.6Hz,6H),1.07-1.00(m,2H),0.93-0.82(m,2H).

[0848] Example 40 Preparation of Compound 40

[0849] Step 1: Synthesis of compound 40-a

[0850] Referring to the synthesis of 3-b, I-19 (103.8 mg, 0.3 mmol) was prepared by replacing 3-a with 11-a (300.0 mg, 1.1 mmol) to obtain 180.0 mg of compound 40-a. MS m / z (ESI): 553.97 [M+H] + .

[0851] Step 2: Synthesis of compound 40-b

[0852] Referring to the synthesis of 3-c, 3-b was replaced with 40-a (180.0 mg, 0.3 mmol) and the mixture was stirred at 80°C for 1 hour in a sealed tube. Similar post-treatment was performed to obtain 100.0 mg of compound 40-b. MS m / z (ESI): 496.96 [M+H] + .

[0853] Step 3: Synthesis of compound 40-d

[0854] Under nitrogen, 40-b (100.0 mg, 0.2 mmol), 40-c (51.9 mg, 0.6 mmol), Pd(dppf)Cl2 (14.7 mg, 0.02 mmol), and potassium carbonate (83.5 mg, 0.6 mmol) were dissolved in dioxane (3 mL) and water (0.6 mL). The mixture was stirred at 100°C overnight. After completion of the reaction, the mixture was extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a mixture that was separated and purified by normal phase chromatography to afford 37.0 mg of compound 40-d. MS m / z (ESI): 411.09 [M+H]. + .

[0855] Step 4: Synthesis of compound 40

[0856] Referring to the synthesis of compound 3, 1-c (35.0 mg, 0.2 mmol) was replaced with 40-d (37.0 mg, 0.1 mmol), and the mixture was stirred at 100°C overnight. Similar post-treatments were performed to obtain a crude product, which was then separated and purified by reverse-phase chromatography to yield 16.99 mg of compound 40. MS m / z (ESI): 525.19 [M+H] + .

[0857] 1 H NMR (400MHz, DMSO-d6) δ8.68(s,1H),8.58(s,1H),8.00(d,J=1.0Hz1H),7.55(t,J=7.8Hz,1H),7.37(d,J=11.4Hz,1H),7.31(dd,J=7.9Hz, 1.3Hz,1H),4.46(s,2H),3.86(s,3H),3.60(d,J=1.2Hz,3H),2.14-2.07(m,1H),1.71-1.63(m,1H),1.07-1.02(m,4H),0.86-0.84(m,4H).

[0858] Example 41 Preparation of Compound 41

[0859] Step 1: Synthesis of compound 41-a

[0860] Referring to the synthesis of 3-b, I-19 was replaced by I-6 (163.1 mg, 0.5 mmol), and 3-a was replaced by 11-a (500.0 mg, 1.8 mmol) to obtain 263.0 mg of compound 41-a. MS m / z (ESI): 536.97 [M+H] + .

[0861] Step 2: Synthesis of compound 41-b

[0862] Referring to the synthesis of 3-c, 3-b was replaced with 41-a (263.0 mg, 0.5 mmol) and the mixture was stirred at 80°C for 1 hour in a sealed tube. Similar post-treatment was performed to obtain 67.0 mg of compound 41-b. MS m / z (ESI): 478.97 [M+H] + .

[0863] Step 3: Synthesis of compound 41-d

[0864] Under nitrogen, 41-b (67.0 mg, 0.1 mmol) was dissolved in THF (5 mL), and 41-c (59.5 mg, 0.3 mmol) and Pd(PPh3)2Cl2 (9.8 mg, 0.01 mmol) were added. The mixture was stirred at 65°C overnight. After the reaction was completed, water (10 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture that was separated and purified by normal phase chromatography to obtain 39.0 mg of compound 41-d. MS m / z (ESI): 379.09 [M+H]. + .

[0865] Step 4: Synthesis of compound 41

[0866] Referring to the synthesis of compound 3, 1-c (40.0 mg, 0.2 mmol) was replaced with 41-d (39.0 mg, 0.1 mmol), and the mixture was stirred at 100°C overnight. Similar post-treatments were performed to obtain a crude product, which was then separated and purified by reverse-phase chromatography to yield 14.78 mg of compound 41. MS m / z (ESI): 493.10 [M+H] + .

[0867] 1 H NMR (400MHz, DMSO-d6) δ9.10(s,1H),8.70(s,1H),7.92(d,J=1.0Hz1H),7.66(d,J=8.2Hz,2H),7.42(d,J=8.2Hz,2H),7.15(dd,J=17.5Hz,11.3Hz,1 H),6.05(d,J=17.5Hz,1H),5.59(d,J=11.6Hz,1H),4.36(s,2H),3.88(s,3 H),3.77(s,3H),1.73-1.59(m,1H),1.10-1.02(m,2H),0.93-0.90(m,2H).

[0868] Example 42 Preparation of Compound 42

[0869] Step 1: Synthesis of compound 42

[0870] Under nitrogen, compound 37 (60.0 mg, 0.11 mmol) was dissolved in THF (2 mL), cooled to -78°C, and methylmagnesium bromide (0.38 mL, 1.14 mmol) was added. The mixture was allowed to warm to room temperature and react for 1 hour. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture. The mixture was separated and purified using a normal phase column chromatography and then purified by medium pressure preparative purification to obtain 5.03 mg of compound 42. MS m / z (ESI): 543.21 [M+H]. + .

[0871] 1 H NMR (400MHz, DMSO-d6) δ8.96(s,1H),8.67(s,1H),8.00(d,J=1.2Hz,1H),7.51(t,J=8.0Hz,1H),7.33-7.21(m,2H),5.5 6(s,1H),4.69(s,2H),3.86(s,3H),3.60(s,3H),1.65(s,6H),1.63-1.58(m,1H),1.05-1.00(m,2H),0.86-0.81(m,2H).

[0872] Example 43 Preparation of Compound 43

[0873] Step 1: Synthesis of compound 43-a

[0874] Referring to the synthesis of 3-b, I-19 was replaced by I-8 (548.5 mg, 1.7 mmol) and 3-a was replaced by 1-a (1.0 g, 5.6 mmol) to obtain 434.0 mg of compound 43-a. MS m / z (ESI): 469.90 [M+H] + .

[0875] Step 2: Synthesis of compound 43-b

[0876] Referring to the synthesis of 3-c, 3-b was replaced with 43-a (434.0 mg, 0.92 mmol) and the reaction was carried out at 80°C for 1 hour. Similar post-treatment was performed to obtain 358.0 mg of compound 43-b. MS m / z (ESI): 412.00 [M+H] + .

[0877] Step 3: Synthesis of compound 43

[0878] Referring to the synthesis of compound 3, 1-c (141.3 mg, 0.73 mmol) was replaced with 43-b (150.0 mg, 0.36 mmol) to obtain 71.1 mg of compound 43. MS m / z (ESI): 526.20 [M+H] + .

[0879] 1 H NMR (400MHz, DMSO-d6) δ8.68(s,1H),8.63(s,1H),8.6-8.58(m,1H),8.20(s,1H),7.97(d,J=8.2Hz,1H),7.81(dd,J=8.2,2.0Hz,1H),5.75-5. 66(m,1H),4.22(d,J=12.3Hz,2H),4.03(s,3H),3.83(s,3H),1.67-1.5 7(m,1H),1.44(d,J=6.7Hz,6H),1.05-0.96(m,2H),0.88-0.79(m,2H).

[0880] Example 44 Preparation of Compound 44

[0881] Step 1: Synthesis of compound 44-a

[0882] Under nitrogen, I-16 (80.0 mg, 0.2 mmol) and 1-a (52.9 mg, 0.3 mmol) were dissolved in dioxane (2 mL). Water (0.4 mL), Pd(dppf)Cl2 (28.8 mg, 0.04 mmol), and sodium carbonate (41.7 mg, 0.39 mmol) were added, and the mixture was stirred at 80°C for 4 hours. After the reaction was completed, water (10 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (2 x 10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture that was separated and purified by normal phase chromatography to obtain 30.0 mg of compound 44-a. MS m / z (ESI): 423.11 [M+H]. + .

[0883] Step 2: Synthesis of compound 44

[0884] Referring to the synthesis of compound 4, 1-c (27.5 mg, 0.14 mmol) was used to replace 2-a with 44-a (30.0 mg, 0.07 mmol). The mixture was stirred at 80°C for 3 hours. Similar post-treatment was performed to obtain 7.15 mg of compound 44. MS m / z (ESI): 537.21 [M+H] + .

[0885] 1 H NMR(400MHz,DMSO-d6)δ8.69(s,1H),8.67(s,1H),7.96(d,J=1.2Hz,1H),7.63-7 .58(m,1H),7.31-7.24(m,2H),4.19(s,2H),4.11-4.04(m,1H),4.03(s,3H),3.86 (s,3H),2.75-2.66(m,1H),2.51-2.44(m,1H),2.37-2.25(m,1H),2.09-1.98(m, 1H),1.68-1.60(m,1H),1.51-1.42(m,3H),1.09-1.02(m,2H),0.90-0.82(m,2H).

[0886] Example 45 Preparation of Compound 45

[0887] Step 1: Synthesis of compound 45-a

[0888] Referring to the synthesis of 3-b, I-19 was replaced by I-21 (149.4 mg, 0.50 mmol), and 3-a was replaced by 11-b (200.0 mg, 0.83 mmol) to obtain 74.0 mg of compound 45-a. MS m / z (ESI): 507.80 [M+H] + .

[0889] Step 2: Synthesis of compound 45-b

[0890] Referring to the synthesis of 3-c, 3-b was replaced with 45-a (74.0 mg, 0.15 mmol) and stirred at 80°C for 1 hour. Similar post-treatment yielded 20.0 mg of compound 45-b. MS m / z (ESI): 450.00 [M+H] + .

[0891] Step 3: Synthesis of compound 45

[0892] Referring to the synthesis of compound 3, 1-c (17.3 mg, 0.09 mmol) was replaced with 45-b (20.0 mg, 0.04 mmol) to obtain 5.6 mg of compound 45. MS m / z (ESI): 564.20 [M+H] + .

[0893] 1H NMR (400MHz, DMSO-d6) δ8.86(s,1H),8.67(s,1H),7.91(d,J=1.2Hz,1H),7.66(d,J=8.2Hz,2H),7.41(d,J=8 .3Hz,2H),4.27(s,2H),3.86(s,3H),2.49(s,3H),1.73-1.62(m,1H),1.08-1.00(m,2H),0.93-0.84(m,2H).

[0894] Example 46 Preparation of Compound 46

[0895] Step 1: Synthesis of compound 46-a

[0896] Under nitrogen, 40-b (60.0 mg, 0.12 mmol), tributylpropynylstannane (0.06 mL, 0.18 mmol), Pd(PPh3)2Cl2 (8.5 mg, 0.01 mmol), and toluene (2 mL) were added to a reaction flask and stirred at 100°C for 2 hours. The reaction solution was directly purified by normal phase medium pressure preparative chromatography to obtain 38.0 mg of compound 46-a. MS m / z (ESI): 409.10 [M+H] + .

[0897] Step 2: Synthesis of compound 46

[0898] Referring to the synthesis of compound 3, 1-c (36.1 mg, 0.19 mmol) was replaced with 46-a (38.0 mg, 0.09 mmol) and stirred at 95°C for 2 hours. Similar post-treatment yielded 13.5 mg of compound 46. MS m / z (ESI): 523.20 [M+H] + .

[0899] 1 H NMR (400MHz, DMSO-d6) δ8.93(s,1H),8.68(s,1H),8.00-7.96(m,1H),7.55(t,J=7.8Hz,1H),7.38-7.31(m,1H),7.31-7.26(m ,1H),4.40(s,2H),3.85(s,3H),3.59(d,J=1.1Hz,3H),2.22(s,3H),1.73-1.63(m,1H),1.08-0.99(m,2H),0.92-0.82(m,2H).

[0900] Example 47 Preparation of Compound 47

[0901] Step 1: Synthesis of compound 47-a

[0902] Referring to the synthesis of 44-a, 1-a (54.8 mg, 0.31 mmol) was replaced with I-17 (80.0 mg, 0.2 mmol) to obtain 30.0 mg of compound 47-a. MS m / z (ESI): 409.1 [M+H] + .

[0903] Step 2: Synthesis of compound 47

[0904] Referring to the synthesis of compound 4, 1-c (28.5 mg, 0.15 mmol) was used to replace 2-a with 47-a (30.0 mg, 0.07 mmol). The mixture was stirred at 80°C for 3 hours. Similar post-treatment was performed to obtain 9.11 mg of compound 47. MS m / z (ESI): 523.2 [M+H] + .

[0905] 1 H NMR (400MHz, DMSO-d6) δ8.69(s,1H),8.67(s,1H),7.97(d,J=1.2Hz,1H),7.66-7.59(m,1H),7.31-7.26(m,2H),4.19(s,2H),4.03(s,3H) ,4.00(t,J=6.8Hz,2H),3.86(s,3H),2.66(t,J=6.8Hz,2H),2.30-2.21(m,2H),1.70-1.60(m,1H),1.08-1.02(m,2H),0.90-0.82(m,2H).

[0906] Example 48 Preparation of Compound 48

[0907] Step 1: Synthesis of compound 48-a

[0908] Referring to the synthesis of 3-b, I-19 was replaced with I-23 (268.0 mg, 0.83 mmol), and 3-a was replaced with 11-b (200.0 mg, 0.83 mmol) to obtain 193.0 mg of compound 48-a. MS m / z (ESI): 531.20 [M+H] + .

[0909] Step 2: Synthesis of compound 48-b

[0910] Referring to the synthesis of 3-c, 3-b was replaced with 48-a (193.0 mg, 0.36 mmol) and stirred at 80°C for 1 hour. Similar post-treatment yielded 89.0 mg of compound 48-b. MS m / z (ESI): 473.00 [M+H] + .

[0911] Step 3: Synthesis of compound 48

[0912] Referring to the synthesis of compound 3, 1-c (73.2 mg, 0.38 mmol) was replaced with 48-b (89.0 mg, 0.19 mmol) and stirred at 95°C for 2 hours. The reaction solution was directly purified by normal phase chromatography and then by medium pressure preparative purification to obtain 27.8 mg of compound 48. MS m / z (ESI): 587.10 [M+H] + .

[0913] 1 H NMR (400MHz, DMSO-d6) δ8.86(s,1H),8.67(s,1H),7.59(d,J=8.5Hz,2H),7.48(d,J=7.2Hz,2H),6.61(s,1H),4.30(s,2H),3.86(s,3 H),2.50(s,3H),1.85-1.73(m,1H),1.73-1.63(m,1H),1.07-0.99(m,2H),0.98-0.91(m,2H),0.91-0.84(m,2H),0.84-0.78(m,2H).

[0914] Example 49 Preparation of Compound 49

[0915] Step 1: Synthesis of compound 49-b

[0916] Under nitrogen, 41-d (50.0 mg, 0.13 mmol) was dissolved in THF (5 mL), and 49-a (41.9 mg, 0.2 mmol) and Grubbs second-generation catalyst (11.2 mg, 0.01 mmol) were added. The mixture was stirred at 65°C overnight. After the reaction was completed, water (10 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture. The mixture was separated and purified by normal phase chromatography to obtain 45.0 mg of compound 49-b. MS m / z (ESI): 562.21 [M+H] + .

[0917] Step 2: Synthesis of compound 49-c

[0918] Referring to the synthesis of compound 3, 1-c (31.1 mg, 0.2 mmol) was replaced with 49-b (45.0 mg, 0.08 mmol) and stirred at 100°C overnight. Similar post-treatments were performed to obtain a crude product, which was then separated and purified by normal phase chromatography to yield 40.0 mg of compound 49-c. MS m / z (ESI): 676.31 [M+H] + .

[0919] Step 3: Synthesis of compound 49

[0920] Under nitrogen, 49-c (40.0 mg, 0.06 mmol) was dissolved in HCl-dioxane (5 mL), and the mixture was stirred at room temperature overnight. After completion of the reaction, the pH was adjusted to 7 with sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture that was separated and purified by reverse phase chromatography to obtain 7.27 mg of compound 49. MS m / z (ESI): 576.26 [M+H] + .

[0921] 1 H NMR (400MHz, DMSO-d6) δ9.00(s,1H),8.70(s,1H),7.93(d,J=1.1Hz1H),7.66(d,J=8.2Hz,2 H),7.41(d,J=8.2Hz,2H),6.73(d,J=16.0Hz,1H),6.42(dd,J=16.0Hz,6.6Hz,1H),4.34(s,2 H),3.88(s,3H),3.77(s,3H),3.12-3.06(m,2H),2.38-2.34(m,2H),2.44-2.31(m,2H),1.7 7-1.65(m,2H),1.72-1.64(m,1H),1.43-1.35(m,2H),1.09-1.05(m,2H),0.92-0.89(m,2H).

[0922] Example 50 Preparation of Compound 50

[0923] Step 1: Synthesis of compound 50

[0924] Under nitrogen, compound 49 (7.27 mg, 0.01 mmol) was dissolved in MeOH (3 mL), and formaldehyde solution (1.2 mg, 0.03 mmol) was added. The mixture was stirred at 50°C for 1 h, and sodium cyanoborohydride (1.6 mg, 0.03 mmol) was added. After completion of the reaction, the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture that was separated and purified by reverse phase chromatography to obtain 5.52 mg of compound 50. MS m / z (ESI): 590.27 [M+H] + .

[0925] 1 H NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.70(s,1H),7.93(d,J=1.0Hz1H),7.66(d,J=8. 3Hz,2H),7.41(d,J=8.3Hz,2H),6.73(d,J=16.0Hz,1H),6.43(dd,J=16.0Hz,6.6Hz,1 H),4.34(s,2H),3.89(s,3H),3.77(s,3H),2.82-2.76(m,2H),2.18(s,3H),1.98-1.8 8(m,2H),1.83-1.57(m,4H),1.45-1.42(m,2H),1.09-1.04(m,2H),0.92-0.89(m,2H).

[0926] Example 51 Preparation of Compound 51

[0927] Step 1: Synthesis of compound 51-a

[0928] Under nitrogen, 41-a (276.0 mg, 0.5 mmol) was dissolved in dioxane (5 mL). Water (1 mL), potassium allyl trifluoroborate (152.2 mg, 1.0 mmol), Pd(dppf)Cl2 (37.6 mg, 0.05 mmol), and potassium phosphate (213.2 mg, 1.5 mmol) were added. The mixture was stirred at 100°C overnight. After the reaction was completed, water (10 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 100.0 mg of compound 51-a. MS m / z (ESI): 451.11 [M+H]. + .

[0929] Step 2: Synthesis of compound 51-b

[0930] Under nitrogen, 51-a (100.0 mg, 0.22 mmol) was dissolved in acetic acid (3 mL) and concentrated hydrochloric acid (1 mL). The mixture was stirred at 80°C for 1 hour. After the reaction was complete, water (20 mL) was added to the mixture, and the pH was adjusted to 7 with sodium bicarbonate solution. The mixture was extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture that was separated and purified by normal phase chromatography to obtain 40.0 mg of compound 51-b. MS m / z (ESI): 375.14 [M+H]. + .

[0931] Step 3: Synthesis of compound 51-c

[0932] Referring to the synthesis of 38-e, 38-d was replaced with 51-b (40.0 mg, 0.11 mmol) to obtain 30.0 mg of compound 51-c. MS m / z (ESI): 393.10 [M+H] + .

[0933] Step 4: Synthesis of compound 51

[0934] Referring to the synthesis of compound 3, 1-c (29.7 mg, 0.2 mmol) was replaced with 51-c (30.0 mg, 0.08 mmol), and the mixture was stirred at 100°C overnight. Similar post-treatments were performed to obtain a crude product, which was then separated and purified by reverse-phase chromatography to yield 1.23 mg of compound 51. MS m / z (ESI): 507.22 [M+H] + .

[0935] 1 H NMR (400MHz, DMSO-d6) δ9.01(s,1H),8.69(d,J=2.8Hz,1H),7.93(s,1H),7.67(d,J=8.2Hz,2H),7.42(d,J=8.2Hz,2H),6.81(d,J=15.8Hz,1H),6.50(d d,J=15.7Hz,6.6Hz,1H),4.33(s,2H),3.88(d,J=3.1Hz,3H),3.78(s,3H),2 .00-1.91(m,3H),1.71-1.65(m,1H),1.08-1.04(m,2H),0.92-0.88(m,2H).

[0936] Example 52 Preparation of Compound 52

[0937] Step 1: Synthesis of compound 52-a

[0938] I-3-4 (2.0 g, 7.29 mmol) was dissolved in ethyl acetate (50 mL), and Dess-martin oxidant (3.1 g, 7.29 mmol) was added. The mixture was stirred at room temperature for 2 hours. 100 mL of water was added, and the mixture was extracted with ethyl acetate (3 x 20 mL). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by normal phase chromatography to obtain 1.5 g of compound 52-a. MS m / z (ESI): 273.09 [M+H] + .

[0939] Step 2: Synthesis of compound 52-b

[0940] Under nitrogen, 52-a (1.5 g, 5.51 mmol), 1-a (1.0 g, 5.51 mmol), sodium hydride (132.3 mg, 5.51 mmol), and 1,3-dimethylimidazolium iodide (246.9 mg, 1.1 mmol) were dissolved in THF (30 mL) and stirred at 70°C for 1 hour. The mixture was extracted with ethyl acetate (3 x 20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was separated and purified by normal phase chromatography to obtain 2.0 g of compound 52-b. MS m / z (ESI): 415.06 [M+H] + .

[0941] Step 3: Synthesis of compound 52-c

[0942] Referring to the synthesis of compound 2, 2-b was replaced with 1-c (168.4 mg, 0.87 mmol), and 2-a was replaced with 52-b (180.0 mg, 0.43 mmol). Similar post-treatments were performed to obtain a crude product, which was then separated and purified using a normal phase column chromatography to yield 100.0 mg of compound 52-c. MS m / z (ESI): 528.94 [M+H] + .

[0943] Step 4: Synthesis of compound 52

[0944] Under nitrogen, 52-c (80.0 mg, 0.15 mmol) was dissolved in dichloromethane (10 mL), and DAST (122.0 mg, 0.76 mmol) was added. The mixture was stirred at room temperature overnight. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (3 x 20 mL). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by medium pressure preparative method to obtain 3.0 mg of compound 52. MS m / z (ESI): 551.23 [M+H] + .

[0945] 1H NMR (400MHz, DMSO-d6) δ9.06(s,1H),8.71(s,1H),8.07(d,J=1.0Hz,1H),7.80(t,J=7.7Hz,1H),7.63(d,J=10.5Hz,1H), 7.56(d,J=8.3Hz,1H),4.07(s,3H),3.88(s,3H),3.66(s,3H),1.81-1.65(m,1H),1.12-1.03(m,2H),1.01-0.83(m,2H).

[0946] Example 53 Preparation of Compound 53

[0947] Step 1: Synthesis of compound 53-a

[0948] Under nitrogen, I-22 (700.0 mg, 1.87 mmol), 1-a (400.7 mg, 2.24 mmol), potassium phosphate (792.2 mg, 3.73 mmol), and Pd(PPh3)2Cl2 (131.1 mg, 0.19 mmol) were dissolved in toluene (10 mL) and water (2 mL) and stirred at 100°C overnight. The mixture was extracted with ethyl acetate (3 x 20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by normal phase chromatography to obtain 100.0 mg of compound 53-a. MS m / z (ESI): 391.97 [M+H] + .

[0949] Step 2: Synthesis of compound 53

[0950] Referring to the synthesis of compound 2, 2-b was replaced with 1-c (14.9 mg, 0.08 mmol), and 2-a was replaced with 53-a (30.0 mg, 0.08 mmol). Similar post-treatments were performed to obtain a crude product, which was then purified by medium-pressure preparative purification to yield 16.0 mg of compound 53. MS m / z (ESI): 506.18 [M+H] + .

[0951] 1H NMR (400MHz, DMSO-d6) δ8.68(s,1H),8.67(s,1H),7.80(d,J=8.3Hz,2H),7.69(q,J=8.6Hz,2H),7.38(d,J=8.3Hz,2H),6.93(t ,J=55.3Hz,1H),4.20(s,2H),4.03(s,3H),3.91(s,3H),3.86(s,3H),1.76-1.53(m,1H),1.09-1.00(m,2H),0.95-0.82(m,2H).

[0952] Example 54 Preparation of Compound 54

[0953] Step 1: Synthesis of compound 54-b

[0954] Under nitrogen, 1-c (500.0 mg, 2.58 mmol), 54-a (835.1 mg, 5.15 mmol), sodium carbonate (819.6 mg, 7.73 mmol), Pd(PPh3)4 (148.9 mg, 0.13 mmol), dioxane (20 mL), and water (4 mL) were added to a reaction flask and stirred at 100°C for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain 570.0 mg of compound 54-b. MS m / z (ESI): 276.15 [M+H] + .

[0955] Step 2: Synthesis of compound 54

[0956] Under nitrogen, 54-b (50.0 mg, 0.18 mmol), I-3 (139.4 mg, 0.36 mmol), potassium phosphate (125.3 mg, 0.54 mmol), and Pd(PPh3)2Cl2 (12.7 mg, 0.02 mmol) were dissolved in toluene (110 mL) and water (2 mL) and heated with stirring at 100°C overnight. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by normal phase column chromatography to obtain a crude product, which was then purified by reverse phase column chromatography to obtain 1.25 mg of compound 54. MS m / z (ESI): 498.22 [M+H] + .

[0957] 1H NMR (400MHz, DMSO-d6) δ8.64(s,1H),8.51(s,1H),8.00(d,J=1.6Hz,1H),7.57(t,J=8.0Hz,1H),7.35(s,1H),7.30(d,J=11.2Hz,1H),7.22(d d,J=8.0,1.6Hz,1H),4.17(s,2H),3.85(s,3H),3.61(d,J=1.6Hz,3H), 2.33(s,3H),1.87-1.76(m,1H),1.08-1.00(m,2H),0.93-0.84(m,2H).

[0958] Example 55 Preparation of Compound 55

[0959] Step 1: Synthesis of compound 55-b

[0960] Under nitrogen, 55-a (500.0 mg, 2.81 mmol) was dissolved in dioxane (15 mL), and water (3 mL) was added. 1-c (436.0 mg, 2.25 mmol), Pd(PPh3)4 (324.6 mg, 0.28 mmol), and sodium carbonate (893.3 mg, 8.43 mmol) were also added. The mixture was stirred at 80°C for 3 hours. After the reaction was completed, water (50 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 300.0 mg of compound 55-b. MS m / z (ESI): 292.08 [M+H]. + .

[0961] Step 2: Synthesis of compound 55

[0962] Under nitrogen, 55-b (120.0 mg, 0.41 mmol) was dissolved in dioxane (5 mL), and water (1 mL) was added. I-2 (301.3 mg, 0.81 mmol), XPhos-Pd G2 (64.5 mg, 0.08 mmol), XPhos (78.3 mg, 0.16 mmol), and potassium phosphate (260.8 mg, 1.23 mmol) were added. The mixture was stirred at 80°C for 3 hours. After the reaction was completed, water (20 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3*10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture. The mixture was separated and purified by normal phase column chromatography and then by reverse phase column chromatography to obtain 10.8 mg of compound 55. MS m / z (ESI): 496.19 [M+H] + .

[0963] 1 H NMR (400MHz, DMSO-d6) δ8.61(s,1H),8.45(s,1H),7.92(d,J=1.2Hz,1H),7.69-7.64(m,2H),7.41(d,J=8.0Hz,2H),7.3 3(s,1H),4.06(s,2H),3.99(s,3H),3.83(s,3H),3.78(s,3H),1.83-1.74(m,1H),1.06-0.99(m,2H),0.90-0.82(m,2H).

[0964] Example 56 Preparation of Compound 56

[0965] Step 1: Synthesis of compound 56-b

[0966] Under nitrogen, 56-a (18.7 mg, 0.12 mmol), I-3-5 (40.0 mg, 0.12 mmol), Pd(PPh3)4 (13.7 mg, 0.01 mmol), potassium carbonate (49.2 mg, 0.36 mmol), water (2 mL), and THF (4 mL) were added to a reaction flask and stirred at 80°C for 4 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to yield 45.0 mg of compound 56-b. MS m / z (ESI): 370.07 [M+H] + .

[0967] Step 2: Synthesis of compound 56

[0968] Under nitrogen, 56-b (45.0 mg, 0.12 mmol), 1-c (47.2 mg, 0.24 mmol), potassium phosphate (84.1 mg, 0.37 mmol), XPhos (23.2 mg, 0.05 mmol), XPhos-Pd G2 (19.1 mg, 0.02 mmol), water (1 mL), and dioxane (5 mL) were added to a reaction flask and stirred at 100°C for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by medium pressure preparative purification to obtain 16.0 mg of compound 56. MS m / z (ESI): 484.21 [M+H] + .

[0969] 1H NMR(400MHz, DMSO-d6)δ8.66(s,1H),8.63(d,J=5.2Hz,1H),8.01(d,J=1.6Hz, 1H),7.57(t,J=8.0Hz,1H),7.50(s,1H),7.41(dd,J=11.2,1.6Hz,1H),7.37(d d,J=5.2,1.6Hz,1H),7.32(dd,J=8.0,1.6Hz,1H),4.17(s,2H),3.85(s,3H),3 .61(d,J=1.6Hz,3H),1.79-1.71(m,1H),1.08-1.02(m,2H),0.92-0.86(m,2H).

[0970] Example 57 Preparation of Compound 57

[0971] Step 1: Synthesis of compound 57-b

[0972] Referring to the synthesis of 56-b, I-3-5 (50.0 mg, 0.15 mmol) was used to replace 56-a with 57-a (26.0 mg, 0.15 mmol) to obtain 50.0 mg of compound 57-b. MS m / z (ESI): 388.06 [M+H] + .

[0973] Step 2: Synthesis of compound 57

[0974] Referring to the synthesis of compound 56, 1-c (50.0 mg, 0.26 mmol) was used to replace 56-b with 57-b (50.0 mg, 0.13 mmol) to obtain 10.0 mg of compound 57. MS m / z (ESI): 502.17 [M+H] + .

[0975] 1 H NMR (400MHz, DMSO-d6) δ8.68(d,J=1.6Hz,1H),8.66(s,1H),8.01(d,J=1.6Hz,1H),7 .63(d,J=6.0Hz,1H),7.59(t,J=8.0Hz,1H),7.39(d,J=11.2Hz,1H),7.30(dd,J=8.0 1.6Hz,1H),4.23(s,2H),3.86(s,3H),3.61(d,J=1.6Hz,3H),1.82-1.73(m,1H),1.11-1.03(m,2H),0.94-0.86(m,2H).

[0976] Example 58 Preparation of Compound 58

[0977] Step 1: Synthesis of compound 58-a

[0978] Referring to the synthesis of 56-b, 56-a was replaced with 59-b (100.0 mg, 0.58 mmol), and I-3-5 was replaced with I-1-5 (196.7 mg, 0.58 mmol) to obtain 157.0 mg of compound 58-a. MS m / z (ESI): 384.12 [M+H] + .

[0979] Step 2: Synthesis of compound 58

[0980] Referring to the synthesis of compound 56, 1-c (63.7 mg, 0.33 mmol), 56-b was replaced with 58-a (63.0 mg, 0.16 mmol). The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography to yield 60.0 mg of compound 58. MS m / z (ESI): 498.20 [M+H] + .

[0981] 1 H NMR (400MHz, DMSO-d6) δ8.63(s,1H),8.50(s,1H),7.61(t,J=8.0Hz,1H),7.41(dd,J=11.2,2.0Hz,1H),7.33(s,1H),7.25(dd,J=8.4,2 .0Hz,1H),6.78(s,1H),4.18(s,2H),3.83(s,3H),2.32(s,3H),2.20(s,3H),1.87-1.75(m,1H),1.09-0.99(m,2H),0.91-0.83(m,2H).

[0982] Example 59 Preparation of Compound 59

[0983] Step 1: Synthesis of compound 59-b

[0984] Under nitrogen, 59-a (820.0 mg, 3.97 mmol) and trimethyl borate (0.89 mL, 7.94 mmol) were dissolved in THF (10 mL) and stirred at -78°C for half an hour. n-Butyl lithium solution (3.72 mL, 5.96 mmol) was slowly added and stirred at -78°C for half an hour. The mixture was acidified with 1N aqueous HCl, concentrated, and purified by reverse phase column chromatography to yield 350.0 mg of compound 59-b. MS m / z (ESI): 172.12 [M+H] + .

[0985] Step 2: Synthesis of compound 59-c

[0986] Referring to the synthesis of 56-b, I-3-5 (255.7 mg, 0.76 mmol), 56-a was replaced with 59-b (130.0 mg, 0.76 mmol) to obtain 189.0 mg of compound 59-c. MS m / z (ESI): 384.15 [M+H] + .

[0987] Step 3: Synthesis of compound 59

[0988] Referring to the synthesis of compound 56, 1-c was replaced with 2-b (87.4 mg, 0.33 mmol), and 56-b was replaced with 59-c (63.0 mg, 0.16 mmol). The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography to yield 37.0 mg of compound 59. MS m / z (ESI): 488.18 [M+H] + .

[0989] 1 H NMR (400MHz, DMSO-d6) δ8.56(s,1H),8.43(s,1H),8.00(d,J=1.6Hz,1H),7.57(t,J=8.0Hz,1H),7.31-7 .25(m,2H),7.22(dd,J=8.0,1.6Hz,1H),4.14(s,2H),3.87(s,6H),3.61(d,J=1.6Hz,3H),2.30(s,3H).

[0990] Example 60 Preparation of Compound 60

[0991] Step 1: Synthesis of compound 60-a

[0992] Referring to the synthesis of 56-b, I-3-5 was replaced with I-7-3 (255.7 mg, 0.70 mmol), and 56-a was replaced with 59-b (120.0 mg, 0.70 mmol) to obtain 236.0 mg of compound 60-a. MS m / z (ESI): 412.14 [M+H] + .

[0993] 1H NMR (400MHz, DMSO-d6) δ8.29-8.21(m,2H),7.53(t,J=8.0Hz,1H),7.38(s,1H),7.31(dd,J=11.2 ,1.6Hz,1H),7.20(dd,J=8.0,1.6Hz,1H),4.24-4.10(m,3H),2.25(s,3H),1.39(d,J=6.8Hz,6H).

[0994] Step 2: Synthesis of compound 60

[0995] Referring to the synthesis of compound 56, 1-c (47.1 mg, 0.24 mmol) was used to replace 56-b with 60-a (50.0 mg, 0.12 mmol). The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography to yield 25.0 mg of compound 60. MS m / z (ESI): 526.24 [M+H] + .

[0996] 1 H NMR (400MHz, DMSO-d6) δ8.64(s,1H),8.51(s,1H),8.24(d,J=1.6Hz,1H),7.53(t,J=8.0Hz,1H),7.35(s,1H),7.30(dd,J=11.2,1.6Hz,1H),7.23(d d,J=8.0,1.6Hz,1H),4.23-4.09(m,3H),3.85(s,3H),2.33(s,3H),1.86- 1.77(m,1H),1.37(d,J=6.8Hz,6H),1.08-0.98(m,2H),0.93-0.85(m,2H).

[0997] Example 61 Preparation of Compound 61

[0998] Step 1: Synthesis of compound 61-a

[0999] Under nitrogen, 55-b (20.0 mg, 0.07 mmol) was dissolved in dioxane (1 mL), and B2PIN2 (34.8 mg, 0.14 mmol), palladium acetate (324.6 mg, 0.28 mmol), and potassium acetate (20.2 mg, 0.21 mmol) were added. The mixture was stirred at 110°C for 1 hour. After the reaction was completed, water (10 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the mixture. The mixture was separated and purified by normal phase chromatography to obtain 14.0 mg of compound 61-a. MS m / z (ESI): 302.1 [M+H]. + .

[1000] Step 2: Synthesis of compound 61

[1001] Under nitrogen protection, 61-a (14.0 mg, 0.05 mmol) was dissolved in THF (2 mL), water (1 mL) was added, I-3-5 (18.8 mg, 0.06 mmol), Pd(PPh3)4 (10.7 mg, 0.01 mmol) and potassium phosphate (31.2 mg, 0.14 mmol) were added, and the mixture was stirred at 80°C for 3 hours. After the reaction was completed, water (10 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3*10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a mixture that was first purified by normal phase column chromatography and then separated and purified by reverse phase column chromatography to obtain 4.0 mg of compound 61. MS m / z (ESI): 514.18 [M+H] + .

[1002] 1 H NMR (400MHz, DMSO-d6) δ8.63(s,1H),8.47(s,1H),8.00(s,1H),7.55(t,J=7.6Hz,1H),7.39(s,1H),7.35-7.29(m,1H),7.29-7.2 2(m,1H),4.09(s,2H),4.00(s,3H),3.84(s,3H),3.61(d,J=1.6Hz,3H),1.86-1.75(m,1H),1.08-0.99(m,2H),0.92-0.83(m,2H).

[1003] Example 62 Preparation of Compound 62

[1004] Step 1: Synthesis of compound 62-a

[1005] Referring to the synthesis of 16-b, 16-a (870.0 mg, 5.38 mmol) was prepared by replacing tributyltin chloride with iodine (1503.0 mg, 5.92 mmol). The reaction mixture was quenched with water (5 mL), ethyl acetate (50 mL) was added, and the mixture was washed with water (50 mL) and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by normal phase chromatography to obtain 820.0 mg of compound 62-a. MS m / z (ESI): 287.99 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.97 (s, 1H), 4.02 (s, 3H).

[1006] Step 2: Synthesis of compound 62-b

[1007] Referring to the synthesis of 9-a, 1-a was replaced with 62-a (100.0 mg, 0.35 mmol), and I-4 was replaced with I-2 (127.4 mg, 0.35 mmol) to obtain 8.0 mg of compound 62-b. MS m / z (ESI): 400.1 [M+H] + .

[1008] Step 3: Synthesis of compound 62

[1009] Under nitrogen, 62-b (8.0 mg, 0.02 mmol), 1-c (7.8 mg, 0.04 mmol), potassium phosphate (13.8 mg, 0.06 mmol), XPhos (3.8 mg, 0.01 mmol), XPhos-Pd G2 (3.1 mg, 0.00 mmol), water (0.2 mL), and dioxane (2 mL) were added to a reaction flask. The mixture was stirred at 100°C overnight. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain 3.0 mg of compound 62. MS m / z (ESI): 514.17 [M+H] + .

[1010] 1 H NMR (400MHz, DMSO-d6) δ8.70(s,1H),8.45(s,1H),7.93(d,J=1.6Hz,1H),7.68(d,J=8.4Hz,2H),7.37(d,J=8.0Hz,2H),4.12 (s,2H),4.05(s,3H),3.87(s,3H),3.78(s,3H),1.76-1.64(m,1H),1.17-1.06(m,1H),1.07-0.97(m,1H),0.97-0.83(m,2H).

[1011] Example 63 Preparation of Compound 63

[1012] Step 1: Synthesis of compound 63-a

[1013] Referring to the synthesis of 9-a, 1-a was replaced with 62-a (100.0 mg, 0.35 mmol), and I-4 was replaced with I-3 (100.2 mg, 0.26 mmol) to obtain 10.0 mg of compound 63-a. MS m / z (ESI): 418.1 [M+H] + .

[1014] Step 2: Synthesis of compound 63

[1015] Referring to the synthesis of compound 62, 1-c (9.3 mg, 0.05 mmol), 62-b was replaced with 63-a (10.0 mg, 0.02 mmol) to obtain 1.2 mg of compound 63. MS m / z (ESI): 532.18 [M+H] + .

[1016] 1 H NMR (400MHz, DMSO-d6) δ8.70(s,1H),8.47(s,1H),8.00(d,J=1.6Hz,1H),7.56(t,J=8.0Hz,1H),7.24-7.17(m,2H),4.17(s,2H) ,4.06(s,3H),3.87(s,3H),3.61(d,J=1.6Hz,3H),1.76-1.70(m,1H),1.14-1.10(m,1H),1.05-1.00(m,1H),0.98-0.90(m,2H).

[1017] Example 64 Preparation of Compound 64

[1018] Step 1: Synthesis of compound 64-a

[1019] Referring to the synthesis of 9-a, 1-a was replaced with 17-b (250.0 mg, 0.92 mmol), and I-4 was replaced with I-2 (337.2 mg, 0.92 mmol) to obtain 44.0 mg of compound 64-a. MS m / z (ESI): 384.1 [M+H] + .

[1020] Step 2: Synthesis of compound 64

[1021] Referring to the synthesis of compound 4, 1-c (44.5 mg, 0.23 mmol) was prepared by replacing 2-a with 64-a (44.0 mg, 0.11 mmol). The mixture was stirred at 100°C overnight and concentrated under reduced pressure to obtain a crude product. The crude product was purified by medium pressure preparative method to obtain 15.0 mg of compound 64. MS m / z (ESI): 498.16 [M+H] + .

[1022] 1 H NMR (400MHz, DMSO-d6) δ8.71(s,1H),8.44(s,1H),7.93(d,J=1.6Hz,1H),7.70(d,J=8.0Hz,2H),7.33(d,J=8.0Hz,2H),4.21 (s,2H),3.89(s,3H),3.78(s,3H),2.37(s,3H),1.76-1.68(m,1H),1.15-1.10(m,1H),1.05-0.99(m,1H),0.98-0.88(m,2H).

[1023] Example 65 Preparation of Compound 65

[1024] Step 1: Synthesis of compound 65-a

[1025] Referring to the synthesis of 16-c, 16-b (200.0 mg, 0.44 mmol), I-7-3 was replaced with I-8-3 (154.5 mg, 0.44 mmol) to obtain 37.0 mg of compound 65-a. MS m / z (ESI): 429.20 [M+H] + .

[1026] Step 2: Synthesis of compound 65

[1027] Referring to the synthesis of compound 62, 1-c (33.5 mg, 0.17 mmol), 62-b was replaced with 65-a (37.0 mg, 0.09 mmol) to obtain 22.0 mg of compound 65. MS m / z (ESI): 543.3 [M+H] + .

[1028] 1H NMR (400MHz, DMSO-d6) δ8.69 (s, 1H), 8.57 (d, J = 2.4Hz, 1H), 8.45 (s, 1H), 8. 22(d,J=1.6Hz,1H),8.01(d,J=8.0Hz,1H),7.75(dd,J=8.0,2.4Hz,1H),5.78 -5.67(m,1H),4.13(s,2H),4.05(s,3H),3.86(s,3H),1.73-1.66(m,1H),1.4 5(d,J=6.8Hz,6H),1.14-1.07(m,1H),1.05-0.98(m,1H),0.96-0.84(m,2H).

[1029] Example 66 Preparation of Compound 66

[1030] Step 1: Synthesis of compound 66-b

[1031] Referring to the synthesis of 16-b, 16-a was replaced with 66-a (1.0 g, 6.87 mmol), and n-butyllithium was replaced with lithium diisopropylamide (3.61 mL, 7.21 mmol) to obtain 1.05 g of compound 66-b.

[1032] 1 H NMR (400MHz, DMSO-d6) δ8.17 (s, 1H), 2.36 (s, 3H), 1.66-1.38 (m, 6H), 1.37-1.16 (m, 12H), 0.87 (t, J = 7.2Hz, 9H).

[1033] Step 2: Synthesis of compound 66-c

[1034] Referring to the synthesis of 16-c, I-7-3 was replaced by I-8-3 (160.2 mg, 0.46 mmol), and 16-b was replaced by 66-b (200.0 mg, 0.46 mmol) to obtain 8.0 mg of compound 66-c. MS m / z (ESI): 413.11 [M+H] + .

[1035] Step 3: Synthesis of compound 66

[1036] Referring to the synthesis of compound 62, 1-c (7.5 mg, 0.04 mmol), 62-b was replaced with 66-c (8 mg, 0.02 mmol) to obtain 5.5 mg of compound 66. MS m / z (ESI): 527.2 [M+H] + .

[1037] 1H NMR (400MHz, DMSO-d6) δ8.72(s,1H),8.58(d,J=2.0Hz,1H),8.46(s,1H),8.23(s,1H),8.03(d,J=8.4Hz,1H),7.71(dd,J=8.4,2.0Hz,1H),5.80-5.6 7(m,1H),4.24(s,2H),3.88(s,3H),2.41(s,3H),1.76-1.69(m,1H),1.46( d,J=6.8Hz,6H),1.16-1.11(m,1H),1.06-1.00(m,1H),0.98-0.88(m,2H).

[1038] Example 67 Preparation of Compound 67

[1039] Step 1: Synthesis of compound 67-a

[1040] Referring to the synthesis of 16-c, I-7-3 (504.2 mg, 1.38 mmol) was used to replace 16-b with 66-b (600.0 mg, 1.38 mmol) to obtain 24.0 mg of compound 67-a. MS m / z (ESI): 430.1 [M+H] + .

[1041] Step 2: Synthesis of compound 67

[1042] Referring to the synthesis of compound 62, 1-c (21.7 mg, 0.11 mmol) was used to replace 62-b with 67-a (24.0 mg, 0.06 mmol). The mixture was stirred at 100°C overnight and concentrated under reduced pressure to obtain a crude product. The crude product was purified by medium pressure preparative method to obtain 6.5 mg of compound 67. MS m / z (ESI): 544.2 [M+H] + .

[1043] 1 H NMR (400MHz, DMSO-d6) δ8.71(s,1H),8.46(s,1H),8.24(d,J=1.6Hz,1H),7.54(t,J=8.0Hz,1H),7.23(d,J=10.8Hz,1H),7.18-7.12(m,1H),4. 31-4.21(m,2H),4.20-4.11(m,1H),3.88(s,3H),2.39(s,3H),1.78-1. 69(m,1H),1.37(d,J=6.4Hz,6H),1.18-1.10(m,1H),1.05-0.87(m,3H).

[1044] Example 68 Preparation of Compound 68

[1045] Step 1: Synthesis of compound 68-a

[1046] Referring to the synthesis of 16-c, 16-b (600.0 mg, 1.33 mmol), I-7-3 was replaced with I-4-3 (462.3 mg, 1.33 mmol) to obtain 70.0 mg of compound 68-a. MS m / z (ESI): 428.87 [M+H] + .

[1047] Step 2: Synthesis of compound 68

[1048] Referring to the synthesis of compound 4, 1-c (63.5 mg, 0.33 mmol) was used to replace 2-a with 68-a (70.0 mg, 0.16 mmol). The reaction mixture was cooled to room temperature and concentrated to obtain a crude product, which was purified by medium pressure preparative purification and lyophilized to obtain 33.0 mg of compound 68. MS m / z (ESI): 542.22 [M+H] + .

[1049] 1 H NMR (400MHz, DMSO-d6) δ8.68(s,1H),8.43(s,1H),8.15(q,J=1.2Hz,1H),7.54-7.47(m,2H),7.36(d,J=8.0Hz,2H),4.48-4.42( m,1H),4.11(s,2H),4.03(s,3H),3.84(s,3H),1.71-1.65(m,1H),1.39(d,J=6.8Hz,6H),1.13-0.96(m,2H),0.95-0.81(m,2H).

[1050] Example 69 Preparation of Compound 69

[1051] Step 1: Synthesis of compound 69-a

[1052] Referring to the synthesis of 16-c, 16-b (500.0 mg, 1.11 mmol), I-7-3 was replaced with I-1-5 (354.1 mg, 1.11 mmol) to obtain 60.0 mg of compound 69-a. MS m / z (ESI): 400.17 [M+H] + .

[1053] Step 2: Synthesis of compound 69

[1054] Referring to the synthesis of compound 3, 1-c (58.2 mg, 0.30 mmol) was replaced with 69-a (60.0 mg, 0.15 mmol). The mixture was stirred at 95°C for 2 hours. The reaction solution was directly purified by normal phase chromatography and then by medium pressure preparative purification to obtain 26.0 mg of compound 69. MS m / z (ESI): 514.20 [M+H] + .

[1055] 1 H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.43(s,1H),7.55-7.47(m,2H),7.42-7.33(m,2H),6.74(s,1H),4.1 2(s,2H),4.03(s,3H),3.84(s,3H),2.32(s,3H),1.72-1.61(m,1H),1.12-0.95(m,2H),0.95-0.82(m,2H).

[1056] Example 70 Preparation of Compound 70

[1057] Step 1: Synthesis of compound 70-b

[1058] Referring to the synthesis of I-18-5, replace I-18-4 with 70-a (5.0 g, 23.81 mmol) and I-18-3 with dimethylhydroxylamine hydrochloride (2.78 g, 28.57 mmol). The reaction was allowed to proceed at room temperature for 2 hours. Similar post-treatment was performed to obtain 5.1 g of compound 70-b. MS m / z (ESI): 252.99 [M+H] + .

[1059] Step 2: Synthesis of compound 70-c

[1060] Under nitrogen, 70-b (5.1 g, 20.15 mmol) and 1-c (3.9 g, 20.15 mmol) were dissolved in dioxane (50 mL). Water (10 mL), Pd(dppf)Cl2 (0.73 g, 1.01 mmol), and potassium carbonate (5.57 g, 40.3 mmol) were added, and the mixture was stirred at 80°C for 4 hours. After the reaction was completed, water (200 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (2 x 50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture that was separated and purified by normal phase chromatography to yield 4.5 g of compound 70-c. MS m / z (ESI): 367.09 [M+H]. + .

[1061] Step 3: Synthesis of compound 70-d

[1062] Referring to the synthesis of compound 55, I-2 (599.0 mg, 1.64 mmol) was used to replace 55-b with 70-c (300.0 mg, 0.82 mmol). Similar post-treatment was performed to obtain a crude product, which was then separated and purified using a normal phase column chromatography to yield 90.0 mg of compound 70-d. MS m / z (ESI): 571.2 [M+H] + .

[1063] Step 4: Synthesis of compound 70

[1064] Under nitrogen, 70-d (70.0 mg, 0.12 mmol) was dissolved in THF (2 mL), cooled to 0°C, and methylmagnesium bromide (0.4 mL, 1.2 mmol) was added dropwise. The mixture was allowed to warm to room temperature and react for 1 hour. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture. The mixture was purified by medium pressure preparative method to obtain 13.5 mg of compound 70. MS m / z (ESI): 526.18 [M+H] + .

[1065] 1 H NMR (400MHz, DMSO-d6) δ9.13(s,1H),8.75(s,1H),7.95-7.90(m,1H),7.66(d,J=8.0Hz,2H),7.31(d,J=8.0Hz,2H),4.42(s ,2H),3.89(s,3H),3.78(s,3H),2.70(s,3H),1.76-1.67(m,1H),1.19-1.11(m,1H),1.10-0.95(m,2H),0.95-0.85(m,1H).

[1066] Example 71 Preparation of Compound 71

[1067] Step 1: Synthesis of compound 71-a

[1068] Under nitrogen, 70-c (300.0 mg, 0.8 mmol) was dissolved in toluene (5 mL) and water (1 mL). I-3 (629.5 mg, 1.6 mmol), Xphos-Pd G2 (128.9 mg, 0.2 mmol), Xphos (156.3 mg, 0.3 mmol), and potassium phosphate (521.3 mg, 2.5 mmol) were added. The mixture was stirred at 100°C overnight. 10 mL of water was added to the mixture, and the mixture was extracted with ethyl acetate (3*20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a mixture that was separated and purified by normal phase chromatography to obtain 51.0 mg of compound 71-a. MS m / z (ESI): 589.19 [M+H]. + .

[1069] Step 2: Synthesis of compound 71

[1070] Referring to the synthesis of compound 70, 70-d was replaced with 71-a (51.0 mg, 0.1 mmol) and stirred at room temperature for 2 hours. The crude product was purified by reverse phase chromatography to obtain 5.69 mg of compound 71. MS m / z (ESI): 543.93 [M+H] + .

[1071] 1 H NMR (400MHz, DMSO-d6) δ9.16(s,1H),8.75(s,1H),8.00(s,1H),7.55(t,J=7.9Hz,1H),7.19(dd,J=20.0Hz,9.8Hz,2H),4.44 (s,2H),3.88(s,3H),3.60(s,3H),2.73(s,3H),1.79-1.69(m,1H),1.17-1.16(m,1H),1.08-0.96(m,2H),0.93-0.86(m,1H).

[1072] Example 72 Preparation of Compound 72

[1073] Step 1: Synthesis of compound 72-a

[1074] Referring to the synthesis of 3-b, replace I-19 with I-18 (220.0 mg, 0.68 mmol) and 3-a with 1-a (400.7 mg, 2.24 mmol). Stir at room temperature for 1 hour. Following the same post-treatment, 260.0 mg of compound 72-a was obtained. MS m / z (ESI): 467.11 [M+H] + .

[1075] Step 2: Synthesis of compound 72-b

[1076] Referring to the synthesis of 3-c, 3-b was replaced with 72-a (260.0 mg, 0.56 mmol) and stirred at 80°C in a sealed tube for 1 hour. Similar post-treatment yielded 190.0 mg of compound 72-b. MS m / z (ESI): 409.14 [M+H] + .

[1077] Step 3: Synthesis of compound 72

[1078] Referring to the synthesis of compound 4, 1-c (180.3 mg, 0.93 mmol) was used to replace 2-a with 72-b (190.0 mg, 0.46 mmol). The reaction mixture was cooled to room temperature and concentrated to obtain a crude product, which was purified by medium pressure preparative purification and lyophilized to obtain 85.0 mg of compound 72. MS m / z (ESI): 523.18 [M+H] + .

[1079] 1 H NMR (400MHz, DMSO-d6) δ8.66(s,1H),8.65(s,1H),7.77-7.70(m,2H),7.41-7.34(m,2H),4.29(t,J=7.2Hz,2H),4.17(s,2H) ,4.00(s,3H),3.84(s,3H),2.99-2.88(m,2H),2.68-2.62(m,2H),1.64-1.59(m,1H),1.04-1.01(m,2H),0.88-0.84(m,2H).

[1080] Example 73 Preparation of Compound 73

[1081] Step 1: Synthesis of compound 73

[1082] Under nitrogen, 61-a (50.0 mg, 0.17 mmol), I-7-3 (62.1 mg, 0.17 mmol), potassium carbonate (70.4 mg, 0.51 mmol), Pd(PPh3)4 (15.1 mg, 0.01 mmol), THF (2 mL), and water (0.5 mL) were added to a reaction flask and stirred at 80°C for 2 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by medium pressure preparative purification to obtain 31.0 mg of compound 73. MS m / z (ESI): 542.20 [M+H] + .

[1083] 1H NMR (400MHz, DMSO-d6) δ8.61(s,1H),8.45(s,1H),8.22(d,J=1.1Hz,1H),7.48(t,J=7.8Hz,1H),7.37(s,1H),7.34-7.27(m,1H),7.27-7.21(m, 1H),4.18-4.09(m,1H),4.08(s,2H),3.98(s,3H),3.82(s,3H),1.87-1. 75(m,1H),1.35(d,J=6.6Hz,6H),1.06-0.97(m,2H),0.91-0.77(m,2H).

[1084] Example 74 Preparation of Compound 74

[1085] Step 1: Synthesis of compound 74-a

[1086] Referring to the synthesis of 3-b, replace I-19 with 18-b (369.9 mg, 1.07 mmol) and 3-a with 11-b (260.0 mg, 1.07 mmol). Stir at room temperature for 1 hour. Following the same post-treatment, 341.0 mg of compound 74-a was obtained. MS m / z (ESI): 551.02 [M+H] + .

[1087] Step 2: Synthesis of compound 74-b

[1088] Referring to the synthesis of 3-c, 3-b was replaced with 74-a (341.0 mg, 0.47 mmol) and stirred at 80°C for 1.5 hours. Similar post-treatment yielded 86.0 mg of compound 74-b. MS m / z (ESI): 493.16 [M+H] + .

[1089] Step 3: Synthesis of compound 74

[1090] Under nitrogen, compound 74-b (86.0 mg, 0.17 mmol), 1-c (67.8 mg, 0.35 mmol), potassium phosphate (120.8 mg, 0.52 mmol), XPhos (33.3 mg, 0.07 mmol), XPhos-Pd G2 (27.5 mg, 0.03 mmol), dioxane (3 mL), and water (0.5 mL) were added to a reaction flask and stirred at 95°C for 2 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was first purified by normal phase column chromatography and then by reverse phase medium pressure preparative purification. The product was then lyophilized to obtain 39.5 mg of compound 74. MS m / z (ESI): 607.11 [M+H] + .

[1091] 1 H NMR (400MHz, DMSO-d6) δ8.88(s,1H),8.67(s,1H),8.22(d,J=1.1Hz,1H),7.50(t,J=7.8Hz,1H),7.33(d,J=11.1Hz,1H),7.26(dd,J=7.9,1.4Hz, 1H),4.31(s,2H),4.17-4.06(m,1H),3.85(s,3H),2.51(s,3H),1.77-1. 65(m,1H),1.35(d,J=6.6Hz,6H),1.07-0.99(m,2H),0.92-0.81(m,2H).

[1092] Example 75 Preparation of Compound 75

[1093] Step 1: Synthesis of compound 75-b

[1094] Dissolve 75-a (2.0 g, 10.47 mmol) in morpholine (10 mL) and heat to 130°C for 4 hours. After the reaction is complete, add water to slurry, filter and concentrate the solid to obtain 0.9 g of compound 75-b. MS m / z (ESI): 198.08 [M+H] + .

[1095] Step 2: Synthesis of compound 75-c

[1096] 75-b (650.0 mg, 3.3 mmol) was dissolved in phosphorus oxychloride (20 mL), and N,N-diisopropylethylamine (2.92 mL, 16.48 mmol) was added. The mixture was heated to 110°C and reacted for 12 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to dryness, and sodium bicarbonate solution (50 mL) was added. The mixture was extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture. The mixture was separated and purified by normal phase chromatography to obtain 490.0 mg of compound 75-c. MS m / z (ESI): 234.01 [M+H]. + .

[1097] Step 3: Synthesis of compound 75-d

[1098] Referring to the synthesis of 3-b, I-19 was replaced with I-6 (305.8 mg, 1.03 mmol) and 3-a was replaced with 75-c (200.0 mg, 0.85 mmol). The mixture was stirred at room temperature for 1 hour. Similar post-treatment was performed to obtain 330.0 mg of compound 75-d. MS m / z (ESI): 496.13 [M+H] + .

[1099] Step 4: Synthesis of compound 75-e

[1100] Referring to the synthesis of 3-c, 3-b was replaced with 75-d (220.0 mg, 0.44 mmol) and stirred at 70°C in a sealed tube for 2 hours. Similar post-treatment yielded 120.0 mg of compound 75-e. MS m / z (ESI): 438.12 [M+H] + .

[1101] Step 5: Synthesis of compound 75

[1102] Referring to the synthesis of compound 4, 1-c (73.1 mg, 0.38 mmol) was prepared by replacing 2-a with 75-e (110.0 mg, 0.25 mmol) and stirring at 80°C for 3 hours. Similar post-treatment was performed to obtain 1.84 mg of compound 75. MS m / z (ESI): 552.23 [M+H] + .

[1103] 1 H NMR(400MHz,Chloroform-d)δ8.67(s,1H),8.64(s,1H),7.61-7.55(m,2H),7.52-7.46(m,2H),7.34(s,1H),4.38(s,2H), 3.98(s,3H),3.95-3.88(m,4H),3.79(s,3H),3.09-3.00(m,4H),1.72-1.67(m,1H),1.28-1.20(m,2H),0.94-0.86(m,2H).

[1104] Example 76 Preparation of Compound 76

[1105] Step 1: Synthesis of compound 76

[1106] Under nitrogen protection, 61-a (40.0 mg, 0.1 mmol) was dissolved in THF (10 mL), and water (1 mL), I-10-5 (42.2 mg, 0.13 mmol), Pd(PPh3)4 (24.1 mg, 0.02 mmol), and potassium carbonate (43.3 mg, 0.31 mmol) were added. The mixture was stirred at 80°C for 2 hours. After the reaction was completed, water (10 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3*10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture. The mixture was separated and purified by normal phase chromatography and then purified by medium pressure preparative purification to obtain 7.54 mg of compound 76. MS m / z (ESI): 514.18 [M+H]+ .

[1107] 1 H NMR(400MHz, DMSO-d6)δ8.63(s,1H),8.48(s,1H),7.59(t,J=8.0Hz,1H),7.47-7.42(m,1H),7.40(s,1H),7.33-7.27(m,1H) ,6.79(s,1H),4.12(s,2H),4.00(s,3H),3.84(s,3H),2.21(s,3H),1.88-1.78(m,1H),1.08-1.00(m,2H),0.92-0.83(m,2H).

[1108] Example 77 Preparation of Compound 77

[1109] Step 1: Synthesis of compound 77-a

[1110] Referring to the synthesis of 3-b, I-19 was replaced with I-25 (470.5 mg, 1.49 mmol) and 3-a was replaced with 11-b (300.0 mg, 1.24 mmol) to obtain 378.0 mg of compound 77-a. MS m / z (ESI): 523.00 [M+H] + .

[1111] Step 2: Synthesis of compound 77-b

[1112] Referring to the synthesis of 3-c, 3-b was replaced with 77-a (378.0 mg, 0.72 mmol) and stirred at 80°C for 1.5 hours. Similar post-treatment yielded 123.0 mg of compound 77-b. MS m / z (ESI): 464.99 [M+H] + .

[1113] Step 3: Synthesis of compound 77

[1114] Referring to the synthesis of compound 74, 1-c (102.9 mg, 0.53 mmol) was used to replace 74-b with 77-b (123.0 mg, 0.27 mmol). The mixture was stirred at 95°C for 3 hours. Similar post-treatment was performed to obtain 58.8 mg of compound 77. MS m / z (ESI): 579.10 [M+H] + .

[1115] 1H NMR (400MHz, DMSO-d6) δ8.89(s,1H),8.67(s,1H),7.59(t,J=8.1Hz,1H),7.44(dd,J=11.3,1.4Hz,1H),7.30(dd,J=8.2,1.2Hz, 1H),6.77(s,1H),4.33(s,2H),3.85(s,3H),2.52(s,3H),2.17(s,3H),1.76-1.66(m,1H),1.08-0.99(m,2H),0.93-0.83(m,2H).

[1116] Preparation of control compound B

[1117] Step 1: Synthesis of compound B-1

[1118] I-24 (300.0 mg, 1.1 mmol) was dissolved in acetonitrile (5 mL), potassium carbonate (1.6 g, 227.4 mmol) and 1-a (196.7 mg, 1.1 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was added to water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture. The mixture was separated and purified by normal phase chromatography to obtain 322.0 mg of compound B-1. MS m / z (ESI): 416.08 [M+H] + .

[1119] Step 2: Synthesis of control compound B

[1120] Under nitrogen, B-1 (322.0 mg, 0.8 mmol) was dissolved in dioxane (10 mL), water (2 mL) was added, and 1-c (301.1 mg, 1.6 mmol), Xphos-Pd G2 (121.9 mg, 0.2 mmol), Xphos (148.0 mg, 0.3 mmol), and potassium phosphate (493.4 mg, 2.3 mmol) were added. The mixture was stirred at 100°C overnight. After the reaction was completed, water (10 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3*20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture that was separated and purified by reverse phase chromatography to obtain 159.49 mg of reference compound B. MS m / z (ESI): 529.95 [M+H] + .

[1121] 1H NMR (400MHz, DMSO-d6) δ8.59(s,1H),7.99(s,2H),7.87(t,J=6.3Hz,1H),7.52(t,J=7.9Hz,1H),7.28(t,J=7.9Hz,2H),4.64 (d,J=6.3Hz,2H),3.96(s,3H),3.81(s,3H),3.59(d,J=1.0Hz,3H),1.72-1.65(m,1H),0.99-0.94(m,2H),0.81-0.77(m,2H).

[1122] KSQ-4279 Prepared with reference to CN113164485A.

[1123] Control compound A Prepared with reference to WO2023208130A1.

[1124] Example 78 Enzyme Evaluation

[1125] The inhibition of USP1 / UAF1 enzyme activity by the compounds was evaluated by the FI method.

[1126] USP1 / UAF1 (R&D, U-555-050) enzyme solution (USP1 / UAF1 enzyme concentration: 0.03 nM) and Recombinant Human Ubiquitin Rhodamine 110 Protein (R&D, E-568-050) substrate solution (Recombinant Human Ubiquitin Rhodamine 110 Protein concentration: 450 nM) were prepared in reaction buffer (50 mM Tris-HCl, pH 7.8, 0.5 mM EDTA, 0.01% Tween-20, 0.01% BSA, 1 mM DTT). A 10 mM stock solution of the compound was diluted 11.11× with DMSO (Sigma, D5879), followed by a 4× serial dilution. The compound was then diluted 100× in reaction buffer (final reaction system starting concentration: 3 μM, 4× dose dilution, for a total of 8 concentration points). In a 384-well test plate (Coring, 3575), 5 μL of reaction buffer was added to each well of the blank group and protein control group, and 5 μL of diluted compounds of various concentrations were added to each well of the compound group. Then, 5 μL of reaction buffer was added to each well of the blank group, and 5 μL of USP1 / UAF1 enzyme solution was added to each well of the protein control group and compound group. The mixture was centrifuged at 1000 rpm for 1 minute and incubated at 25°C for 10 minutes. Then, 5 μL of Recombinant Human Ubiquitin Rhodamine 110 Protein substrate solution was added to each well of each group (the starting concentration of the compound gradient in the compound group reaction system was 3 μM at this time), centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 30 minutes. Finally, the luminescence signal of the reaction system in the Flourescen Intensity mode was read using a high-throughput drug screening multifunctional microplate reader (TECAN Spark). The FI signal (ex485 / em535) was obtained using GraphPad Prism software. 50 Values ​​and nonlinear regression curve fitting.

[1127] The inhibition percentage (%) of each concentration of compound is calculated based on the signals of the minimum fluorescence signal group (blank group) and the maximum fluorescence signal group (protein control group) contained in each test plate. The minimum fluorescence signal group has no added enzyme and compound, and the others are consistent with the compound group, with the minimum fluorescence signal, which is set to 100% inhibition. The maximum fluorescence signal group has no added compound, and the others are consistent with the compound group, with the maximum fluorescence signal, which is set to 0% inhibition. The inhibition rate of each compound concentration is calculated as follows: inhibition rate % = {1-[(maximum luminescence signal group-luminescence signal of compound group) / (maximum luminescence signal group-minimum luminescence signal group)]}*100%. Finally, the four-parameter logistic dose-response equation is used to determine the compound concentration required for 50% inhibition, that is, IC 50 The results are shown in Table 1.

[1128] Table 1 Inhibitory activity of the compounds of the present invention against USP1 / UAF1

[1129] As shown in Table 1, the compounds of the present invention have excellent USP1 / UAF1 enzyme inhibitory activity and can be used as drugs for the treatment of diseases related to this activity.

[1130] Example 79 Cell assay evaluation

[1131] BRCA1 was cultured in complete medium DMEM (Gibco, 11963092) / 10% FBS (Gibco, 10099141C) / 1% ITS (Gibco, 41400045) / 1% GSH (Sigma, G6013-5G). - / - MDA-MB-436 cell line (Nanjing Kebai Biotechnology Co., Ltd.; Cat. No: CBP60385; Lot. No: CBD2021102422P4) and wild-type CAL-51 cell line (Nanjing Kebai Biotechnology Co., Ltd.; Cat. No: CBP60360; Lot. No: CBD2022022018P4) were cultured in complete medium DMEM (Gibco, 11963092) / 20% FBS (Gibco, 10099141C) to evaluate the effects of compounds on BRCA1 - / - Selective inhibition of cell proliferation of MDA-MB-436 and CAL-51 cell lines. Day 0, on a 96-well cell culture plate (Corning, 3599), BRCA1 - / -MDA-MB-436 cells were added to each well of 800 cells / 100 μL cell suspension, and wild-type CAL-51 cells were added to each well of 50 cells / 100 μL cell suspension. The cells were cultured in a 37°C, 5% CO2 incubator. On Day 1, the 10 mM compound stock solution was diluted 2.5x with DMSO (Sigma, D5879), and then the compound was serially diluted 3x for a total of 10 concentration points. The starting concentration of wild-type CAL-51 cells was the first concentration point. BRCA1 - / - The starting concentration of MDA-MB-436 cells was the third concentration point, and the compound was diluted 200x with the corresponding culture medium using a multichannel pipette (Rainin: Pipet-Lite XLS+) (for wild-type CAL-51 cells, the final starting concentration of the compound in the culture medium was 20 μM; for BRCA1 - / - For MDA-MB-436 cells, the final starting concentration of the compound in the culture medium was 2.2 μM, all diluted 3x, and a total of 8 concentration points. Compounds of various concentrations were added to the cells as the compound group; the control group did not contain any compound, and the rest was the same as the compound group, with a final DMSO concentration of 0.5%. The compound group and the control group were cultured in a 37°C, 5% CO2 incubator for 10 days. The blank group contained only 100 μL of the corresponding culture medium. On Day 11, 20 μL of MTS (CellTiter A Queous One Solution Cell Proliferation Assay (Promega, G3581) was used. After incubation at 37°C, 5% CO2 for 2 h, the cells were read using a Tecan Spark (OD = 490 nM). The data were then analyzed using GraphPad Prism 8 software using the equation "log (inhibitor) vs. normalized response--variable slope" (formula Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope))) perform data analysis to obtain the IC value of the compound 50 Where Y is the inhibition rate, X is the logarithm of the compound concentration, Top refers to the maximum response (inhibition rate when the compound concentration is the maximum), Bottom refers to the baseline response (inhibition rate when the compound concentration is 0), and Hill Slope refers to the IC 50 The slope of the curve, IC 50 The results are shown in Table 2.

[1132] Table 2 Inhibitory activity of the compounds of the present invention on MDA-MB-436 cells

[1133] Note: For wild-type CAL-51 cells, no significant inhibition was observed when the compound was at the maximum concentration of 20 μM.

[1134] As shown in Table 2, the compounds of the present invention have an effect on BRCA1 - / - It has a good inhibitory effect on MDA-MB-436 cells with good selectivity.

[1135] Example 80 Evaluation of metabolic stability of liver microsomes

[1136] Experimental materials: Human liver microsomes (purchased from BIOIVT, catalog number: X008070) were used in the experiment.

[1137] Reagent preparation:

[1138] PBS: 0.1 M KH2PO4 and K2HPO4 buffer, pH 7.4.

[1139] MgCl2: Weigh a certain amount of MgCl2 and prepare a 16mM MgCl2 solution with PBS.

[1140] NADPH (Chinese name: reduced nicotinamide adenine dinucleotide phosphate, purchased from Sigma, product number: 481973-500mg): Weigh a certain amount of NADPH and prepare NADPH to 4mM with 16mM MgCl2 solution, and the final incubation concentration is 1mM.

[1141] Compounds: Test compounds were prepared at 4 μM in PBS, with a final incubation concentration of 1 μM.

[1142] Liver microsomes: Dilute liver microsomes to 1 mg / mL with PBS, and the final incubation concentration is 0.5 mg / mL.

[1143] Experimental steps:

[1144] Add the prepared test compound to the test tube, followed by the prepared NADPH, and mix thoroughly. Pre-incubate in a 37°C, 220rpm incubator. After 5 minutes of pre-incubation, add the prepared liver microsomes to initiate the reaction, and repeat the well operation. At 0 minutes, 15 minutes, 30 minutes, 45 minutes, and 60 minutes, add a certain volume of glacial acetonitrile solution containing internal standard to the corresponding tube to precipitate the protein. Oscillate and vortex for 5 minutes, then centrifuge at 4000rpm for 10 minutes. The supernatant is collected in a 96-well plate. Analyze by LC-MS / MS. The concentration (peak area ratio) of the example compound is determined by LC-MS / MS (Shimadzu LC-30A, AB API 4500). In Excel, plot "Ln (compound residual amount %) against "incubation time" to obtain the rate constant, thereby calculating the half-life and intrinsic clearance of the drug, providing a basis for predicting the in vivo clearance rate.

[1145] Data Analysis:

[1146] CL int =(0.693 / t 1 / 2 , microsomes) × [incubation medium volume (mL) / microsomal protein mass (mg)] × [microsomal protein mass (mg) / liver mass (g)] × [liver mass (g) / body weight (kg)] [1]

[1147] CL H =CL int ×f u ×Q h / (CL int ×f u +Q h )

[1148] Where, CL int --Intrinsic clearance (mL / min / kg); CL H --Hepatic clearance (mL / min / kg); f u --The fraction of plasma proteins not bound is 1; Q h --Hepatic blood flow.

[1149] Table 3 Stability of compounds of the present invention in human liver microsomes

[1150] [1]Davies B, Morris T.Physiological parameters in laboratory animals and humans.Pharm Res.1993;10:1093-5.

[1151] As can be seen from Table 3, the compounds of the present invention have a longer half-life and a longer duration of action in the body, which is beneficial to improving the efficacy.

[1152] Example 81 Pharmacokinetic Evaluation in Mice

[1153] Experimental Materials:

[1154] The experimental animals were healthy adult BALB / c female mice (provided by Sichuan Weitonglihua Experimental Animal Technology Co., Ltd.).

[1155] Experimental process:

[1156] BALB / c female mice were intravenously administered (1 mg / kg, vehicle: 5% DMSO + 5% solutol + 90% saline). 60 μL of whole blood was collected from the retinal venous plexus at different time points, 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration, and plasma was obtained by centrifugation at 4000 rpm for 6 minutes. Following oral gavage administration (10 mg / kg, vehicle: 0.5% CMC-Na / 0.2% Tween 80, CMC-Na, 419273-100G, Sigma; Tween-80, T818929-500mL, McLean), 60 μL of whole blood was collected from the retinal venous plexus at different time points, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration, and plasma was obtained by centrifugation at 4000 rpm for 6 minutes.

[1157] Sample analysis:

[1158] 10 μL of mouse plasma samples were collected and protein was precipitated with a specific volume of acetonitrile solution containing an internal standard. The samples were vortexed for 10 minutes and then centrifuged at 4000 rpm for 10 minutes. The supernatant was then transferred to a 96-well plate and analyzed by LC-MS / MS (Shimadzu LC-30A, AB API 4500). LC-MS / MS was used to determine plasma drug concentrations at different times after administration of the example compounds to mice. The relevant pharmacokinetic parameters were calculated to investigate the pharmacokinetic behavior of the compounds in mice and to evaluate their pharmacokinetic profiles.

[1159] Table 4 Pharmacokinetic parameters of the test compounds in mouse plasma

[1160] Note: DMSO: dimethyl sulfoxide; solutol: polyethylene glycol-15-hydroxystearate; saline: normal saline; CMC-Na: sodium carboxymethylcellulose; Tween 80: Tween 80.

[1161] As shown in Table 4, the compounds of the present invention have good oral absorption properties in mice, and their oral properties are better than those of KSQ-4279, control compound A and control compound B.

[1162] Example 82 Pharmacokinetic Evaluation in Beagle Dogs

[1163] Experimental Materials:

[1164] The experimental animals were healthy adult Beagle dogs (provided by Beijing Mas Biotechnology Co., Ltd.).

[1165] Experimental process:

[1166] Beagle dogs were given intravenous administration (0.5 mg / kg, vehicle: 5% DMSO + 5% solutol + 90% saline). 500-1000 μL of whole blood was collected from the radial vein of the forelimb at different time points, 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration, and plasma was obtained by centrifugation at 4000 rpm for 10 minutes. Following oral gavage administration (2.5 mg / kg, vehicle: 0.5% CMC-Na / 0.2% Tween 80), 500-1000 μL of whole blood was collected from the radial vein of the forelimb at different time points, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration, and plasma was obtained by centrifugation at 4000 rpm for 10 minutes.

[1167] Sample analysis:

[1168] 10 μL of Beagle dog plasma samples were collected and protein was precipitated with a specific volume of acetonitrile solution containing an internal standard. The samples were vortexed for 10 minutes and then centrifuged at 4000 rpm for 10 minutes. The supernatant was collected and transferred to a 96-well plate for analysis by LC-MS / MS. LC-MS / MS was used to determine plasma concentrations of the example compounds at different times after administration to Beagle dogs, and relevant pharmacokinetic parameters were calculated to investigate the pharmacokinetic behavior of the compounds in Beagle dogs and evaluate their pharmacokinetic profiles.

[1169] Table 5 Pharmacokinetic parameters of the test compounds in beagle dog plasma

[1170] Note: DMSO: dimethyl sulfoxide; solutol: polyethylene glycol-15-hydroxystearate; saline...

Claims

1. A compound of formula (XI), or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof: Among them, X1 is selected from N or CR2; X2 is selected from N or CR3; M is selected from C(R4)(R5); R2 and R3 are each independently selected from H, deuterium, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1- 6-alkoxy, C 3-6 cycloalkyl, 4- to 10-membered heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -SCH3, -SF5, -SeR k 、-Se(O)R k 、phenyl, 5- or 6-membered heteroaryl, -C(O)R i 、-C(O)OR i 、-C(O)NR i R j , wherein the 4- to 10-membered heterocycloalkyl group and the 5- or 6-membered heteroaryl group each independently contain 1 to 3 heteroatoms selected from N, O, and S, and the hydroxyl group, amino group, C 1-6 alkyl group, C 1-6 alkoxy group, C 3-6 cycloalkyl group, 4- to 10-membered heterocycloalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, phenyl group, 5- or 6-membered heteroaryl group are each independently unsubstituted or substituted with one or more R a substituents; R1 is selected from H, deuterium, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 4- to 7-membered heterocycloalkyl, the 4- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, the hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl are each independently unsubstituted or substituted by 1 or more R a substituents; R4 and R5 are each independently selected from H, deuterium, halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy; or R4 and R5 together with the atoms to which they are attached form a C 3-6 cycloalkyl; Ring A is selected from C 6-10 aryl or 5- to 10-membered heteroaryl, the 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S, the C 6-10 aryl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted by one or more R b substituents; B is selected from C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclic group, C 3-10 cycloalkyl or C 3-10 cycloalkenyl, wherein the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclic group each independently contain 1 to 3 heteroatoms selected from N, O, and S, and the C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclic group, C 3-10 cycloalkyl, C 3-10 cycloalkenyl are each independently unsubstituted or substituted by one or more R c substituents; Each R b and R c are each independently selected from the same or different halogen, cyano, hydroxy, amino, SH, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 4- to 7-membered heterocyclic group, -SeR k , -C(O)NR i R j , The 4- to 7-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O, and S, and the hydroxyl group, amino group, SH, C 1-6 alkyl group, C 1-6 alkoxy group, C 3-10 cycloalkyl group, and 4- to 7-membered heterocyclic group are each independently unsubstituted or substituted with one or more R a substituents; Each R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are each independently selected from hydrogen, deuterium, amino, C 1-6 alkyl, C 3-10 cycloalkyl or a 4- to 7-membered heterocyclic group, the 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, and S, and the amino, C 1-6 alkyl, C 3-10 cycloalkyl, 4- to 7-membered heterocyclic group are each independently unsubstituted or substituted by one or more R a substituents; or R 11 and R 12 Together with P linked thereto, they form a 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, S and P, and at least one heteroatom is P. The 4- to 7-membered heterocyclic group is unsubstituted or substituted with one or more R a substituents; or R 17 and R 18 together with the atoms to which they are attached form a 4- to 7-membered heterocyclic group containing 2 to 3 heteroatoms selected from N, O, and S, and at least two heteroatoms are N and S, and the 4- to 7-membered heterocyclic group is unsubstituted or substituted by one or more R a substituents; C is selected from -C(O)NR i R j , C 1-6 alkoxy, C 6-10 aryl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocyclic group, each of the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclic group independently contains 1-3 heteroatoms selected from N, O and S, the C 1-6 alkoxy, C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclic group are each independently unsubstituted or substituted by one or more R d substituents; Each R d is independently selected from the same or different phenyl, 5- or 6-membered heteroaryl, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl or 4- to 7-membered heterocyclic group, wherein the 5- or 6-membered heteroaryl and 4- to 7-membered heterocyclic group each independently contain 1 to 3 heteroatoms selected from N, O and S, and the phenyl, 5- or 6-membered heteroaryl, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl and 4- to 7-membered heterocyclic group are each independently unsubstituted or substituted with one or more R a ; or two adjacent substituents R d on C combine with the connected atom to form a 4- to 7-membered heterocyclic group or carbocyclic ring, and the 4- to 7-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O and S; the 4- to 7-membered heterocyclic group or carbocyclic ring is unsubstituted or substituted with one or more R a ; or R c and R d forms a 4- to 10-membered heterocyclic group or carbocyclic ring with the connected atom, and the 4- to 10-membered heterocyclic group contains 1 to 4 heteroatoms selected from N, O, and S; the 4- to 10-membered heterocyclic group or carbocyclic ring is unsubstituted or substituted by one or more R a substituents; Each R a is independently selected from the same or different halogen, cyano, =O, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, -C(O)NR i R j , C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 A cycloalkyl group or a 4- to 7-membered heterocyclic group, the 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, and S, the hydroxyl group, amino group, C 1-6 alkyl group, C 1-6 alkoxy group, C 3-10 cycloalkyl group, 4- to 7-membered heterocyclic group are each independently unsubstituted or substituted by one or more R e substituents; Each R e is independently selected from the same or different deuterium, halogen, cyano, =O, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or a 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, and the hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 4- to 7-membered heterocyclic group are each independently unsubstituted or substituted by one or more R f substituents; Each R f is independently selected from the same or different halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or a 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S; Each R i 、R j 、R k is independently selected from the same or different hydrogen or C 1-6 alkyl groups.

2. A compound of formula (XI), or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, co-crystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof: Among them, X1 is selected from N or CR2; X2 is selected from N or CR3; M is selected from C(R4)(R5); R2 and R3 are each independently selected from H, deuterium, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1- 6 alkoxy, C 3-6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -SCH3, -SF5, -SeR k 、phenyl, 5- or 6-membered heteroaryl, -C(O)R i 、 -C(O)OR i 、 -C(O)NR i R j wherein the 4- to 10-membered heterocycloalkyl group and the 5- or 6-membered heteroaryl group each independently contain 1 to 3 heteroatoms selected from N, O, and S, and the hydroxyl group, amino group, C 1-6 -alkyl group, C 1-6 -alkoxy group, C 3-6 -cycloalkyl group, 4- to 10-membered heterocycloalkyl group, C 2-6 -alkenyl group, C 2-6 -alkynyl group, phenyl group, 5- or 6-membered heteroaryl group are each independently unsubstituted or substituted with 1 or more R a ; R1 is selected from H, deuterium, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 4-7-membered heteroalkyl, the 4-7-membered heteroalkyl containing 1-3 heteroatoms selected from N, O and S, the hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 4-7-membered heteroalkyl are each independently unsubstituted or substituted by one or more R a substituents; R4 and R5 are each independently selected from H, deuterium, halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy; or R4 and R5 together with the atoms to which they are attached form a C 3-6 cycloalkyl; Ring A is selected from C 6-10 aryl or 5- to 10-membered heteroaryl, the 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S, the C 6-10 aryl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted by one or more R b substituents; B is selected from C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclic group, C 3-10 cycloalkyl or C 3-10 cycloalkenyl, wherein the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclic group each independently contain 1 to 3 heteroatoms selected from N, O, and S, and the C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclic group, C 3-10 cycloalkyl, C 3-10 cycloalkenyl are each independently unsubstituted or substituted by one or more R c substituents; Each R b and R c are each independently selected from the same or different halogen, cyano, hydroxy, amino, SH, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 4-7-membered heterocyclic group, -SeR k , -C(O)NR i R j , The 4- to 7-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O, and S, and the hydroxyl group, amino group, SH, C 1-6 alkyl group, C 1-6 alkoxy group, C 3-10 cycloalkyl group, and 4- to 7-membered heterocyclic group are each independently unsubstituted or substituted by one or more R a substituents; Each R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 is independently selected from hydrogen, deuterium, amino, C 1-6 alkyl, C 3-10 cycloalkyl or a 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, and S, and the amino, C 1-6 alkyl, C 3-10 cycloalkyl, 4- to 7-membered heterocyclic group are each independently unsubstituted or substituted by one or more R a substituents; or R 11 and R 12 P, which is connected thereto, together with them forms a 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, S and P, with at least one heteroatom being P, and the 4- to 7-membered heterocyclic group is unsubstituted or substituted by one or more R a substituted; or R 17 and R 18 Together with the atoms connected thereto, form a 4- to 7-membered heterocyclic group, the 4- to 7-membered heterocyclic group containing 2 to 3 heteroatoms selected from N, O and S, and at least two heteroatoms being N and S, the 4- to 7-membered heterocyclic group being unsubstituted or substituted by one or more R a substituents; C is selected from -C(O)NR i R j , C 1-6 alkoxy, C 6-10 aryl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocyclic group, each of the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclic group independently contains 1-3 heteroatoms selected from N, O and S, and the C 1-6 alkoxy, C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclic group are each independently unsubstituted or substituted by one or more R d substituted; Each R d is independently selected from the same or different phenyl, 5- or 6-membered heteroaryl, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl or 4- to 7-membered heterocyclic group, wherein the 5- or 6-membered heteroaryl and 4- to 7-membered heterocyclic group each independently contain 1 to 3 heteroatoms selected from N, O and S, and the phenyl, 5- or 6-membered heteroaryl, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl and 4- to 7-membered heterocyclic group are each independently unsubstituted or substituted by one or more R a ; or two adjacent substituents R d on C combine with the connected atoms to form a 4- to 7-membered heterocyclic group or carbocycle, the 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S; the 4- to 7-membered heterocyclic group or carbocycle is unsubstituted or substituted by one or more R a ; or R c and R d forms a 4- to 10-membered heterocyclic group or carbocyclic ring together with the connected atoms, the 4- to 10-membered heterocyclic group containing 1 to 4 heteroatoms selected from N, O, and S; the 4- to 10-membered heterocyclic group or carbocyclic ring is unsubstituted or substituted by one or more R a substituents; Each R a is independently selected from the same or different halogen, cyano, =O, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, -C(O)NR i R j , C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 a cycloalkyl group or a 4- to 7-membered heterocyclic group, the 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, and S, the hydroxyl group, amino group, C 1-6 alkyl group, C 1-6 alkoxy group, C 3-10 cycloalkyl group, 4- to 7-membered heterocyclic group are each independently unsubstituted or substituted by one or more R e substituents; Each R e is independently selected from the same or different deuterium, halogen, cyano, =O, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or a 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, and the hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 4- to 7-membered heterocyclic group are each independently unsubstituted or substituted by one or more R f substituents; Each R f is independently selected from the same or different halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or a 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S; Each R i 、R j 、R k is independently selected from the same or different hydrogen or C 1-6 alkyl groups.

3. A compound of formula (XI), or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof: Among them, X1 is selected from N or CR2; X2 is selected from N or CR3; M is selected from C(R4)(R5); R2 and R3 are each independently selected from H, deuterium, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1- 6-alkoxy, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, wherein the 4- to 7-membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O and S, and the hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl are each independently unsubstituted or substituted by one or more R a substituents; R1 is selected from H, deuterium, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 4- to 7-membered heteroalkyl, the 4- to 7-membered heteroalkyl containing 1 to 3 heteroatoms selected from N, O and S, the hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 4- to 7-membered heteroalkyl are each independently unsubstituted or substituted by one or more R a substituents; R4 and R5 are each independently selected from H, deuterium, halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy; or R4 and R5, together with the atoms to which they are attached, form C 3-6 cycloalkyl; Ring A is selected from C 6-10 aryl or a 5- to 10-membered heteroaryl, the 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S, the C 6-10 aryl, 5- to 10-membered heteroaryl are each independently unsubstituted or substituted by one or more R b substituted; B is selected from C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclic group, C 3-10 cycloalkyl or C 3-10 cycloalkenyl, wherein the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclic group each independently contain 1 to 3 heteroatoms selected from N, O, and S, and the C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclic group, C 3-10 cycloalkyl, C 3-10 cycloalkenyl are each independently unsubstituted or substituted by one or more R c substituents; Each R b and R c are each independently selected from the same or different halogen, cyano, hydroxy, amino, SH, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 4-7 membered heterocyclic group, -SeR k 、-C(O)NR i R j , The 4- to 7-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O, and S, and the hydroxyl group, amino group, SH, C 1-6 alkyl group, C 1-6 alkoxy group, C 3-10 cycloalkyl group, and 4- to 7-membered heterocyclic group are each independently unsubstituted or substituted with one or more R a substituents; R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 each independently selected from hydrogen, deuterium, amino, C 1-6 alkyl, C 3-10 cycloalkyl or a 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, and S, the amino, C 1-6 alkyl, C 3-10 cycloalkyl, 4- to 7-membered heterocyclic group each independently being unsubstituted or substituted by one or more R a substituents; or R 11 and R 12 together with P linked thereto form a 4- to 7-membered heterocyclic group, the 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, S and P, and at least one heteroatom being P, and the 4- to 7-membered heterocyclic group being unsubstituted or substituted by 1 or more R a substituted; or R 17 and R 18 together with the atoms to which they are attached form a 4- to 7-membered heterocyclic group containing 2 to 3 heteroatoms selected from N, O and S, and at least two of the heteroatoms are N and S, and the 4- to 7-membered heterocyclic group is unsubstituted or substituted by one or more R a substituents; C is selected from -C(O)NR i R j 、C 6-10 aryl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocyclic group, each of the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclic group independently contains 1-3 heteroatoms selected from N, O and S, and the C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclic group are each independently unsubstituted or substituted by one or more R d substituents; Each R d is independently selected from the same or different halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl or a 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, and the hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl and 4- to 7-membered heterocyclic group are each independently unsubstituted or substituted with one or more R a substituents; Each R a is independently selected from the same or different halogen, cyano, =O, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, -C(O)NR i R j , C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 a cycloalkyl group or a 4- to 7-membered heterocyclic group, the 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, the hydroxyl group, amino group, C 1-6 alkyl group, C 1-6 alkoxy group, C 3-10 cycloalkyl group, 4- to 7-membered heterocyclic group are each independently unsubstituted or substituted by one or more R e substituents; Each R e is independently selected from the same or different deuterium, halogen, cyano, =O, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or a 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 4- to 7-membered heterocyclic group are each independently unsubstituted or substituted with one or more R f substituents; Each R f is independently selected from the same or different halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or a 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S; Each R i , R j , R k is independently selected from the same or different hydrogen or C 1-6 alkyl groups.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, characterized in that: X1 is selected from CR2, X2 is selected from N; R2 is selected from H, halogen, cyano, hydroxy, amino, C 1-4 alkyl, C 1-4 alkoxy, 4-8 membered heteroalkyl, C 2-4 alkenyl, C 2-4 alkynyl, -SCH3, -SF5, -SeR k , 5 membered heteroaryl, -C(O)R i 、-C(O)OR i 、-C(O)NR i R j , wherein the 4- to 8-membered heterocycloalkyl group and the 5-membered heteroaryl group each independently contain 1 to 2 heteroatoms selected from N, O, and S, and the hydroxyl group, amino group, C 1-4 -alkyl group, C 1-4 -alkoxy group, 4- to 8-membered heterocycloalkyl group, C 2- -4-enyl group, C 2-4 -alkynyl group, and 5-membered heteroaryl group are each independently unsubstituted or substituted with one or more R a ; R 11 , R 12 , R 13 , R 14 , R 17 and R 18 each independently selected from hydrogen, methyl, or ethyl, and each R i , R j , R k are each independently selected from the same or different hydrogen, methyl, or ethyl; Preferably, X1 is selected from CR2, X2 is selected from N; R2 is selected from H, F, Cl, Br, cyano, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, 4-8 membered heterocycloalkyl, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl, -SCH3, -SF5, -SeCH3, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, The 4- to 8-membered heterocycloalkyl contains 1 to 2 heteroatoms selected from N and O, and the hydroxyl group, amino group, methyl group, ethyl group, n-propyl group, isopropyl group, methoxy group, ethoxy group, 4- to 8-membered heterocycloalkyl, vinyl group, propenyl group, butenyl group, ethynyl group, propynyl group, butynyl group, furyl group, pyrrolyl group, thienyl group, imidazolyl group, pyrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, and isoxazolyl group are each independently unsubstituted or substituted with one or more R a substituted; Preferably, X1 is selected from CR2, X2 is selected from N; R2 is selected from H, F, Cl, cyano, hydroxy, amino, methyl, isopropyl, methoxy, ethoxy, 6-8-membered heteroalkyl, vinyl, propenyl, ethynyl, propynyl, -SCH3, -SF5, -SeCH3, imidazolyl, oxazolyl, The 6- to 8-membered heterocycloalkyl contains 1 to 2 heteroatoms selected from N and O, and the hydroxyl group, amino group, methyl group, isopropyl group, methoxy group, ethoxy group, 6- to 8-membered heterocycloalkyl, vinyl group, propenyl group, ethynyl group, propynyl group, imidazolyl group, and oxazolyl group are each independently unsubstituted or substituted by one or more R a substituted; Preferably, X1 is selected from CR2, X2 is selected from N; R2 is selected from H, F, Cl, cyano, hydroxy, amino, methyl, isopropyl, methoxy, ethoxy, 6- to 7-membered heteroalkyl, vinyl, propenyl, ethynyl, propynyl, -SCH3, -SF5, -SeCH3, imidazolyl, oxazolyl, The 6- to 7-membered heterocycloalkyl contains 1 to 2 heteroatoms selected from N and O, and the hydroxyl group, amino group, methyl group, isopropyl group, methoxy group, ethoxy group, 6- to 7-membered heterocycloalkyl, ethynyl group, and imidazolyl group are each independently unsubstituted or substituted by one or more R a substituted; Each R a is independently selected from the same or different halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, said 4- to 7-membered heterocyclic group being unsubstituted or substituted by one or more identical or different C 1-6 alkyl; Preferably, each R a is independently selected from the same or different halogen, hydroxy, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 4- to 7-membered heteroalkyl, the 4- to 7-membered heteroalkyl containing 1 to 3 heteroatoms selected from N, O and S, the 4- to 7-membered heteroalkyl being unsubstituted or substituted by 1 or more of the same or different C 1-4 alkyl; Preferably, each R a is independently selected from the same or different F, Cl, Br, hydroxy, cyano, C 1-2 alkyl, C 3-4 alkyl, C 1-2 fluoroalkyl, C 3-4 fluoroalkyl, C 1-2 alkoxy, C 3-4 alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4- to 7-membered heterocycloalkyl, said 4- to 7-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O and S, said 4- to 7-membered heterocycloalkyl being unsubstituted or substituted by one or more identical or different C 1-2 alkyl or C 3-4 alkyl; Preferably, each R a is independently selected from the same or different F, Cl, Br, hydroxyl, cyano, methyl, ethyl, fluoromethyl, fluoroethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5- or 6-membered heteroalkyl, the 5- or 6-membered heteroalkyl containing 1 or 2 heteroatoms selected from N and O, and the 5- or 6-membered heteroalkyl being unsubstituted or substituted by 1 or more identical or different methyl or ethyl groups; Preferably, each R a is independently selected from the same or different F, Cl, hydroxyl, cyano, methyl, fluoromethyl, fluoroethyl, methoxy, cyclopropyl, morpholinyl, N-methylpiperazinyl; Preferably, R2 is selected from H, F, Cl, cyano, -SF5, amino, methyl, methoxy, 6-7-membered heteroalkyl, vinyl, propenyl, ethynyl, propynyl, imidazolyl, oxazolyl, the 6-7-membered heteroalkyl contains 1-2 heteroatoms selected from N and O; the 6-7-membered heteroalkyl is unsubstituted or substituted by one or more identical or different methyl groups; the methyl group is unsubstituted or substituted by one or more identical or different F, Cl, cyano, morpholinyl, methoxy or N-methylpiperazinyl groups; the methoxy group is unsubstituted or substituted by one or more identical or different F or Cl groups; the amino group is unsubstituted or substituted by one or more identical or different methyl or fluoroethyl groups; the ethynyl group is unsubstituted or substituted by one fluoromethyl group; the isopropyl group is unsubstituted or substituted by one or more hydroxyl groups; the imidazolyl group is unsubstituted or substituted by one or more methyl groups; Preferably, X1 is CR2, X2 is N, and R2 is selected from H, F, Cl, cyano, amino, methyl, methoxy, -CF3, -CClF2, -OCHF2, -OCF3, -OCClF2, -SF5, vinyl, propenyl, ethynyl, propynyl, 5. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, characterized in that: X1 is selected from N, X2 is selected from N; or X1 is selected from CR2, X2 is selected from N; or X1 is selected from N, X2 is selected from CR3; R3 is selected from H, methyl, F, Cl, Br or cyano; or X1 is selected from CR2, X2 is selected from CH; or X1 is selected from CR2, X2 is selected from CR3; R3 is selected from H, methyl, F, Cl, Br or cyano; R2 is selected from H, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, 4- to 7-membered heterocycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, the 4- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, the hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, 4- to 7-membered heterocycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl are each independently unsubstituted or substituted by one or more R a substituents; Preferably, R2 is selected from H, halogen, cyano, hydroxy, amino, C 1-4 alkyl, C 1-4 alkoxy, 4- to 7-membered heterocycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, the 4- to 7-membered heterocycloalkyl contains 1 to 2 heteroatoms selected from N, O, and S, and the hydroxy, amino, C 1-4 alkyl, C 1-4 alkoxy, 4- to 7-membered heterocycloalkyl, C 2- 4-alkenyl, C 2-4 alkynyl are each independently unsubstituted or substituted by one or more R a substituents; Preferably, R2 is selected from H, F, Cl, Br, cyano, hydroxy, amino, C 1-2 alkyl, C 3-4 alkyl, C 1-2 alkoxy, C 3-4 alkoxy, 4-7 membered heterocycloalkyl, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl, wherein the 4-7 membered heterocycloalkyl contains 1-2 heteroatoms selected from N, O and S, and the hydroxy, amino, C 1-2 alkyl, C 3-4 alkyl, C 1-2 alkoxy, C 3-4 alkoxy, 4-7 membered heterocycloalkyl, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl are each independently unsubstituted or substituted by one or more R a substituents; Preferably, R2 is selected from H, F, Cl, Br, cyano, hydroxy, amino, methyl, ethyl, methoxy, ethoxy, 4- to 7-membered heterocycloalkyl, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl, the 4- to 7-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N and O, and the hydroxy, amino, methyl, ethyl, methoxy, ethoxy, 4- to 7-membered heterocycloalkyl, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl are each independently unsubstituted or substituted by 1 or more R a substituted; Preferably, R2 is selected from H, F, Cl, cyano, hydroxy, amino, methyl, methoxy, ethoxy, 6- or 7-membered heterocycloalkyl, vinyl, propenyl, ethynyl, propynyl, the 6- or 7-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N and O, and the hydroxy, amino, methyl, methoxy, ethoxy, 6- or 7-membered heterocycloalkyl, vinyl, propenyl, ethynyl, propynyl are each independently unsubstituted or substituted by 1 or more R a substituted; Preferably, R2 is selected from H, F, Cl, cyano, hydroxy, amino, methyl, methoxy, ethoxy, 6- or 7-membered heterocycloalkyl, vinyl, propenyl, ethynyl, propynyl, the 6- or 7-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N and O, and the hydroxy, amino, methyl, methoxy, ethoxy, 6- or 7-membered heterocycloalkyl are each independently unsubstituted or substituted by 1 or more R a substituents; Each R a is independently selected from the same or different halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 4- to 7-membered heterocyclic group, the 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, the 4- to 7-membered heterocyclic group being unsubstituted or substituted by 1 or more identical or different C 1-6 alkyl; Preferably, each R a is independently selected from the same or different halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, said 4- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, said 4- to 7-membered heterocycloalkyl being unsubstituted or substituted by 1 or more of the same or different C 1-4 alkyl; Preferably, each R a is independently selected from the same or different F, Cl, Br, cyano, C 1-2 alkyl, C 3-4 alkyl, C 1-2 fluoroalkyl, C 3-4 fluoroalkyl, C 1-2 alkoxy, C 3-4 alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4- to 7-membered heterocycloalkyl, said 4- to 7-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O and S, said 4- to 7-membered heterocycloalkyl being unsubstituted or substituted by 1 or more of the same or different C 1-2 alkyl or C 3-4 alkyl; Preferably, each R a is independently selected from the same or different F, Cl, Br, cyano, methyl, ethyl, fluoromethyl, fluoroethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5- or 6-membered heteroalkyl, the 5- or 6-membered heteroalkyl containing 1 or 2 heteroatoms selected from N and O, and the 5- or 6-membered heteroalkyl being unsubstituted or substituted by 1 or more identical or different methyl or ethyl groups; Preferably, each R a is independently selected from the same or different F, Cl, cyano, methyl, fluoroethyl, methoxy, cyclopropyl, morpholinyl, N-methylpiperazinyl; Preferably, R2 is selected from H, F, Cl, cyano, amino, methyl, methoxy, 6-7-membered heteroalkyl, vinyl, propenyl, ethynyl, propynyl, the 6-7-membered heteroalkyl contains 1-2 heteroatoms selected from N and O; the 6-7-membered heteroalkyl is unsubstituted or substituted by one or more identical or different methyl groups; the methyl group is unsubstituted or substituted by one or more identical or different F, Cl, cyano, morpholinyl or N-methylpiperazinyl groups; the methoxy group is unsubstituted or substituted by one or more identical or different F or Cl groups; the amino group is unsubstituted or substituted by one or more identical or different methyl or fluoroethyl groups; Preferably, R2 is selected from H, F, Cl, cyano, amino, methyl, methoxy, -CF3, -CClF2, -OCHF2, -OCF3, -OCClF2, vinyl, propenyl, ethynyl, propynyl, Preferably, X1 is CR2, X2 is N, and R2 is selected from H, F, Cl, cyano, amino, methyl, methoxy, -CF3, -CClF2, -OCHF2, -OCF3, -OCClF2, vinyl, propenyl, ethynyl, propynyl, Most preferably, X1 is CR2, X2 is N, and R2 is selected from methyl; Most preferably, X1 is CR2, X2 is N, and R2 is selected from methoxy.

6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, characterized in that: R1 is selected from H, halogen, cyano, amino, C 1-4 alkyl or C 1-4 alkoxy, and the amino, C 1-4 alkoxy are each independently unsubstituted or substituted by one or more R a substituents; Preferably, R1 is selected from H, Cl, cyano, amino, methyl or methoxy, and the amino and methoxy are each independently unsubstituted or substituted by one or more R a substituents; Preferably, each R a is independently selected from the same or different C 1-4 alkyl or C 5-6 alkyl; Preferably, each R a is independently selected from the same or different methyl groups; Preferably, R1 is selected from H, Cl, methyl, cyano, methoxy, amino, Most preferably, R1 is selected from H.

7. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, characterized in that: Selected from Preferably, Selected from Preferably, Selected from Most preferably, Selected from Most preferably, Selected from 8. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, characterized in that: M is selected from C(R4)(R5); R4 and R5 are each independently selected from H, deuterium, halogen, cyano, C 1-4 alkyl or C 1-4 alkoxy; or R4 and R5 together with the atoms to which they are attached form C 3-6 cycloalkyl; Preferably, M is selected from C(R4)(R5); R4 and R5 are each independently selected from H, deuterium, F, cyano, methyl or methoxy; or R4 and R5 together with the atoms to which they are attached form cyclopropyl; Preferably, M is selected from C(R4)(R5); R4 and R5 are each independently selected from H, deuterium, C 1-4 alkyl or C 5-6 alkyl; Preferably, M is selected from C(R4)(R5); R4 and R5 are each independently selected from H, deuterium or methyl; Preferably, M is selected from methylene, Most preferably, M is selected from methylene.

9. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, characterized in that: Ring A is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heteroaryl fused to 5-membered heteroaryl, 5-membered heteroaryl fused to 6-membered heteroaryl, 6-membered heteroaryl fused to 6-membered heteroaryl, phenyl fused to 5-membered heteroaryl or phenyl fused to 6-membered heteroaryl, each of the 5-membered heteroaryl and 6-membered heteroaryl independently contains 1-3 heteroatoms selected from N, O and S, and each of the phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heteroaryl fused to 5-membered heteroaryl, 5-membered heteroaryl fused to 6-membered heteroaryl, 6-membered heteroaryl fused to 6-membered heteroaryl, phenyl fused to 5-membered heteroaryl, phenyl fused to 6-membered heteroaryl is independently unsubstituted or substituted by one or more R b substituted; Preferably, ring A is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl or phenyl-fused 5-membered heteroaryl, each of the 5-membered heteroaryl and 6-membered heteroaryl independently contains 1-3 heteroatoms selected from N, O and S, and each of the phenyl, 5-membered heteroaryl, 6-membered heteroaryl and phenyl-fused 5-membered heteroaryl is independently unsubstituted or substituted by one or more R b substituted; Preferably, ring A is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl or phenyl-fused 5-membered heteroaryl, each of the 5-membered heteroaryl and 6-membered heteroaryl independently contains 1-2 N heteroatoms, and each of the phenyl, 5-membered heteroaryl, 6-membered heteroaryl and phenyl-fused 5-membered heteroaryl is independently unsubstituted or substituted with one or more R b substituted; Preferably, ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, benzopyrazolyl or benzimidazolyl, and the phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, benzopyrazolyl, benzimidazolyl are each independently unsubstituted or substituted by one or more R b substituents; Preferably, ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl or benzopyrazolyl, and the phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, benzopyrazolyl are each independently unsubstituted or substituted by one or more R b substituted; Preferably, ring A is selected from Each R b is independently selected from the same or different halogen, amino, SH, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 4- to 7-membered heterocyclic group, -SeR k , -C(O)NR i R j , The 4- to 7-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O, and S, and the amino group, SH, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, and 4- to 7-membered heterocyclic group are each independently unsubstituted or substituted by one or more R a ; R i , R j , R k are each independently selected from H or C 1-4 alkyl; R 11 , R 12 , R 13 , R 14 , R 17 , and R 18 are each independently selected from H or C 1-4 alkyl; Preferably, each R b is independently selected from the same or different halogen, amino, SH, C 1-4 alkyl, C 5-6 alkyl, C 1-4 alkoxy, C 5-6 alkoxy, C 3-8 cycloalkyl, 4-7 membered heterocycloalkyl, -SeR k 、-C(O)NR i R j 、 The 4- to 7-membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, and S, and the amino group, SH, C 1-4 alkyl, C 5-6 alkyl, C 1-4 alkoxy, C 5-6 alkoxy, C 3-8 cycloalkyl, and 4- to 7-membered heterocycloalkyl are each independently unsubstituted or substituted by one or more R a ; R i , R j , R k are each independently selected from H or C 1-4 alkyl; R 11 , R 12 , R 13 , R 14 , R 17 , and R 18 1-4 are each independently selected from H or C 1-4 alkyl; Preferably, each R b is independently selected from the same or different halogen, amino, SH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -SeR k , -C(O)NR i R j , The 4- to 7-membered heterocycloalkyl contains 1 to 2 heteroatoms selected from N, O, and S, and the amino group, SH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, and 4- to 7-membered heterocycloalkyl are each independently unsubstituted or substituted by one or more R a ; R i , R j , R k are each independently selected from H or C 1-4 alkyl; R 11 , R 12 , R 13 , R 14 , R 17 , and R 18 are each independently selected from H or C 1-4 alkyl; Preferably, each R b is independently selected from the same or different F, Cl, Br, amino, SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4- to 7-membered heterocycloalkyl, -SeR k , -C(O)NR i R j , The 4- to 7-membered heterocycloalkyl contains 1 N heteroatom, and each of the amino group, SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4- to 7-membered heterocycloalkyl is independently unsubstituted or substituted by one or more R a ; R i , R j , R k are each independently selected from hydrogen, methyl, ethyl, n-propyl or isopropyl; R 11 , R 12 , R 13 , R 14 , R 17 and R 18 are each independently selected from hydrogen, methyl, ethyl, n-propyl or isopropyl; Preferably, each R b is independently selected from the same or different F, Cl, amino, SH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, azetidinyl, -SeR k , -C(O)NR i R j , The amino group, SH, methyl group, ethyl group, isopropyl group, methoxy group, ethoxy group, isopropoxy group, cyclopropyl group, and azetidinyl group are each independently unsubstituted or substituted with one or more R a substituents; R i , R j , R k are each independently selected from hydrogen, methyl, or ethyl; R 11 , R 12 , R 13 , R 14 , R 17 and R 18 are each independently selected from hydrogen, methyl, or ethyl; Preferably, each R b is independently selected from the same or different F, Cl, amino, SH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, azetidinyl, -SeCH3, The amino group, SH, methyl group, ethyl group, isopropyl group, methoxy group, ethoxy group, isopropoxy group, cyclopropyl group, and azetidinyl group are each independently unsubstituted or substituted with one or more R a substituents; Each R a is independently selected from the same or different halogen, hydroxy, C 1-6 alkyl or C 1-6 alkoxy; Preferably, each R a is independently selected from the same or different halogen, hydroxy, C 1-4 alkyl or C 1- 4-alkoxy; Preferably, each R a is independently selected from the same or different F, Cl, Br, hydroxyl, methyl, ethyl, methoxy or ethoxy; Preferably, each R a is independently selected from the same or different F, hydroxy, methyl or methoxy; Preferably, each R b is independently selected from the same or different F, Cl, amino, methyl-substituted amino, -SCH3, methyl, fluoromethyl, methoxy, fluoromethoxy, fluorochloromethoxy, ethoxy, fluoroethoxy, hydroxy-substituted isopropyl, hydroxy-substituted cyclopropyl, methoxy-substituted ethoxy, isopropyl, isopropoxy, cyclopropyl, azetidinyl, -SeCH3, Preferably, each R b is independently selected from the same or different methyl, methoxy, cyclopropyl, isopropyl, ethoxy, isopropoxy, -SCH3, -SeCH3, Amino group, F, Cl, -OCHF2, -OCClF2, -OCF3, -CF3, Preferably, ring A is selected from 10. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, characterized in that: B is selected from C 2-4 alkynyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl or C 3-8 cycloalkyl, each of the 5-membered heteroaryl, 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl independently contains 1 to 3 heteroatoms selected from N, O and S, and the C 2-4 alkynyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-8 cycloalkyl is independently unsubstituted or substituted by one or more identical or different halogens or C 1-4 alkoxy; Preferably, B is selected from ethynyl, phenyl, pyridyl, pyrimidinyl, cyclohexyl, cubyl, or piperidinyl, said phenyl, pyridyl, pyrimidinyl, cyclohexyl, cubyl, or the piperidinyl group is each independently unsubstituted or substituted by one or more identical or different F, Cl, Br, methoxy or ethoxy; Preferably, B is selected from phenyl, pyridyl, pyrimidinyl, cyclohexyl, cubyl, piperidinyl, fluoropiperidinyl or ethynyl, and the phenyl group is unsubstituted or substituted by one or more identical or different F or methoxy; Preferably, B is selected from C 2-4 alkynyl, phenyl, 6-membered heteroaryl, 4-7-membered heterocycloalkyl or C 3-6 cycloalkyl, wherein each of the 6-membered heteroaryl and 4-7-membered heterocycloalkyl independently contains 1-2 N heteroatoms selected from, and the C 2-4 alkynyl, phenyl, 6-membered heteroaryl, 4-7-membered heterocycloalkyl, C 3-6 cycloalkyl is independently unsubstituted or substituted by one or more identical or different halogens or C 1-4 alkoxy; Preferably, B is selected from ethynyl, phenyl, pyridyl, pyrimidinyl, cyclohexyl or piperidinyl, and the phenyl, pyridyl, pyrimidinyl, cyclohexyl or piperidinyl is each independently unsubstituted or substituted by one or more identical or different F, Cl, Br, methoxy or ethoxy; Preferably, B is selected from phenyl, pyridyl, pyrimidinyl, cyclohexyl, piperidinyl, fluoropiperidinyl or ethynyl, and the phenyl group is unsubstituted or substituted by one or more identical or different F or methoxy; Preferably, B is selected from or ethynyl; Preferably, B is selected from or ethynyl.

11. The compound according to any one of claims 1-10, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, characterized in that: C is selected from -C(O)NR i R j , phenyl, pyridyl, pyrimidinyl, 5-membered heteroaryl, the 5-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, the phenyl, pyridyl, pyrimidinyl, 5-membered heteroaryl each independently being unsubstituted or substituted by one or more R d substituents; R i , R j each independently being selected from H or C 1-4 alkyl; Preferably, C is selected from -C(O)NR i R j , phenyl, pyridyl, pyrimidinyl, 5-membered heteroaryl, the 5-membered heteroaryl containing 1-2 heteroatoms selected from N, O and S, the phenyl, pyridyl, pyrimidinyl, 5-membered heteroaryl being each independently unsubstituted or substituted by one or more R d substituents; R i , R j are each independently selected from hydrogen, methyl, ethyl, n-propyl or isopropyl; Preferably, C is selected from -C(O)NR i R j , phenyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, and the phenyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl are each independently unsubstituted or substituted by one or more R d ; R i , R j are each independently selected from hydrogen, methyl or ethyl; Preferably, C is selected from -C(O)NHCH3, -C(O)N(CH3)2, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, and the pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl are each independently unsubstituted or substituted with one or more R d substituted; Preferably, C is selected from Preferably, C is selected from Each R d is independently selected from the same or different phenyl, 6-membered heteroaryl, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or 4-7-membered heterocycloalkyl, the 6-membered heteroaryl contains 1-2 N atoms, the 4-7-membered heterocycloalkyl contains 1 N heteroatom, the phenyl, 6-membered heteroaryl, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 4-7-membered heterocycloalkyl are each independently unsubstituted or substituted by one or more R a ; or two adjacent substituents R on C d combine to form a 5-6-membered heterocyclic group, the 5-6-membered heterocyclic group contains 1-2 N heteroatoms; Preferably, each R d is independently selected from the same or different pyridyl, F, Cl, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl or azetidinyl, and the pyridyl, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, azetidinyl are each independently unsubstituted or substituted by one or more R a ; or two adjacent substituents R on C d combine to form a 5-membered heterocyclic group containing 1 N heteroatom; Preferably, each R d is independently selected from the same or different pyridyl, Cl, methyl, ethyl, isopropyl, methoxy, cyclopropyl or azetidinyl, and the methyl, ethyl, methoxy and azetidinyl are each independently unsubstituted or substituted by one or more R a ; or two adjacent substituents R on C d combine to form a 5-membered heterocyclic group containing one N heteroatom; Preferably, each R d is independently selected from the same or different halogen, C 1-4 alkyl, C 5-6 alkyl, C 1-4 alkoxy, C 5-6 alkoxy, C 3-8 cycloalkyl or 4-7 membered heterocycloalkyl, the 4-7 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O and S, the C 1-4 alkyl, C 5-6 alkyl, C 1-4 alkoxy, C 5-6 alkoxy, C 3-8 cycloalkyl, 4-7 membered heterocycloalkyl are each independently unsubstituted or substituted by one or more R a substituents; Preferably, each R d is independently selected from the same or different halogen, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or 4-7 membered heterocycloalkyl, the 4-7 membered heterocycloalkyl containing 1 N heteroatom, and the C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl are each independently unsubstituted or substituted by one or more R a substituents; Preferably, each R d is independently selected from the same or different F, Cl, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl or azetidinyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, azetidinyl are each independently unsubstituted or substituted by one or more R a substituents; Preferably, each R d is independently selected from the same or different Cl, methyl, ethyl, isopropyl, methoxy, cyclopropyl or azetidinyl, and the methyl, ethyl, methoxy and azetidinyl are each independently unsubstituted or substituted by one or more R a substituents; Each R a is independently selected from the same or different halogen, =O or C 1-6 alkyl; Preferably, each R a is independently selected from the same or different halogen, =O or C 1-4 alkyl groups; Preferably, each R a is independently selected from the same or different F, Cl, Br, ═O, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; Preferably, each R a is independently selected from the same or different F, =O, or methyl; Preferably, each R d is independently selected from the same or different pyridyl, Cl, fluoromethyl, ethyl, fluoroethyl, isopropyl, methoxy, fluoromethoxy, cyclopropyl, or two adjacent substituents R on C d combine to form a 5-membered heterocyclic group containing 1 N heteroatom; Preferably, each R d is independently selected from the same or different pyrimidinyl, methyl, isopropyl, -CF3, -CHF2, Cyclopropyl, methoxy, Cl, or -OCF3, or two adjacent substituents R on C d combine to form a 5-membered heterocyclic group containing 1 N heteroatom; Preferably, each R d is independently selected from the same or different Cl, methyl, fluoromethyl, ethyl, fluoroethyl, isopropyl, methoxy, fluoromethoxy, cyclopropyl, Preferably, each R d is independently selected from the same or different methyl, isopropyl, -CF3, -CHF2, Cyclopropyl, methoxy, Cl, or -OCF3; Preferably, C is selected from Preferably, C is selected from Most preferably, C is selected from 12. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, characterized in that: B is phenyl, C is a 5- or 6-membered heteroaryl, and B and C together form a tricyclic ring through substituents R c , R d in combination; the monocyclic ring formed by R c , R d in combination is an unsubstituted or 1- or more R a -substituted 4- to 10-membered heterocyclic group; wherein the 5- or 6-membered heteroaryl and 4- to 10-membered heterocyclic group each independently contain 1 to 3 heteroatoms selected from N, O, and S; and wherein C further has a substituent of C 1-4 fluoroalkyl; Preferably, B is phenyl, C is a 5-membered heteroaryl group, and B and C together form a tricyclic ring through substituents R c , R d ; the single ring formed by R c , R d is an unsubstituted or 1- or more R a -substituted 4- to 8-membered heterocyclic group; wherein the 5-membered heteroaryl group and the 4- to 8-membered heterocyclic group each independently contain 1-3 heteroatoms selected from N, O, and S; and wherein C further has a substituent of C 1-4 fluoroalkyl; Preferably, B is phenyl, C is a 5-membered heteroaryl group, and B and C together form a tricyclic ring through substituents R c , R d ; the single ring formed by the combination of R c , R d is an unsubstituted or 1- or more R a -substituted 4- to 8-membered heterocyclic group; wherein each of the 5-membered heteroaryl group and the 4- to 8-membered heterocyclic group independently contains 1 to 2 heteroatoms selected from N, O, and S; and wherein C further has a substituent which is C 1-4 -fluoroalkyl; Preferably, B is phenyl, C is a 5-membered heteroaryl group, and B and C together form a tricyclic ring through substituents R c , R d ; the single ring formed by R c , R d is an unsubstituted or 1- or more R a -substituted 4- to 8-membered heterocyclic group; wherein the 5-membered heteroaryl group contains 1-2 N atoms, and the 4- to 8-membered heterocyclic group contains 1-2 heteroatoms selected from N and O; and wherein C further has a substituent of C 1-2 fluoroalkyl; Preferably, B is phenyl, C is selected from pyrazolyl, imidazolyl, pyrrolyl, and B and C together form a tricyclic ring through the substituents R c , R d combination; the monocyclic ring formed by R c , R d combination is an unsubstituted or 1- or more R a -substituted 5- to 8-membered heterocyclic group; wherein, the 5- to 8-membered heterocyclic group contains 1-2 heteroatoms selected from N and O; and wherein C further has a substituent of fluoromethyl; Preferably, B is phenyl, C is selected from imidazolyl, and B and C together form a tricyclic ring through the substituents R c , R d ; the combination of R c , R d forms an unsubstituted or 1- or more R a -substituted 6- to 7-membered heterocyclic group; wherein the 6- to 7-membered heterocyclic group contains 1 to 2 heteroatoms selected from N and O; and wherein C further has a substituent of -CF3; Preferably, For B and C together with substituents R c , R d combine to form a tricyclic ring together; R c , R d The monocyclic ring formed by the combination is an unsubstituted or 1- or more R a -substituted 6- to 7-membered heterocyclic group; wherein the 6- to 7-membered heterocyclic group contains 1 to 2 heteroatoms selected from N and O, and at least one heteroatom is N; Each R a is independently selected from the same or different ═O, C 1-6 alkyl groups; Preferably, each R a is independently selected from the same or different ═O, C 1-2 alkyl, C 3-4 alkyl; Preferably, each R a is independently selected from the same or different ═O, methyl, ethyl; Preferably, each R a is independently selected from the same or different ═O, methyl; Preferably, Selected from Most preferably, Selected from 13. A compound according to any one of claims 1-11, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, co-crystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, characterized in that: Selected from the following structures:

14. A compound according to any one of claims 1-11, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, co-crystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, characterized in that: Selected from the following structures:

15. A compound according to any one of claims 1-11, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, characterized in that: Selected from the following structures:

16. The compound according to any one of claims 1-11, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, characterized in that: Selected from the following structures:

17. A compound represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof: Among them, X5 is selected from N or CR 20 ; R 20 is selected from H, F, Cl, Br or C 1-4 alkyl; X6 is selected from N or CR 26 ; R 26 is selected from H, F, Cl, Br or C 1-4 alkoxy group; R 21 selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 1-4 deuterated alkyl, C 1-4 haloalkoxy, C 1-4 deuterated alkoxy, C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, -S-C 1-4 alkyl, -Se-C 1-4 alkyl, -C(O)-C 1-4 alkyl, -Se(O)-C 1-4 alkyl, 4- to 8-membered heterocycloalkyl, -C 2-4 alkenylene-4- to 8-membered heterocycloalkyl; each of the 4- to 8-membered heterocycloalkyl independently contains 1-2 heteroatoms selected from N, O and S; each of the 4- to 8-membered heterocycloalkyl is independently unsubstituted or substituted with C 1- 4 alkyl R 22 and R 23 are each independently selected from C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, C 1-4 haloalkoxy; R 24 、R 25 are each independently selected from H, deuterium, F, Cl, Br, methyl, ethyl; or R 24 、R 25 combines with the connected atom to form a C 3-6 cycloalkyl; Ring D is selected from 5-membered heteroaryl, 6-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl, and each of the 5-membered heteroaryl, 6-membered heteroaryl, 9-membered heteroaryl, and 10-membered heteroaryl independently contains 1, 2, or 3 heteroatoms selected from N, O, and S; Ring D is unsubstituted or substituted with one, two, or more Rs m substituents, and each R m is independently selected from C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 deuterated alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl.

18. The compound according to claim 17, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, characterized in that: Selected from Or Selected from Or Selected from R 21 selected from H, F, Cl, Br, C 1-4 alkyl, methoxy, ethoxy, isopropoxy, C 1-4 hydroxyalkyl, fluoromethyl, fluoroethyl, deuteromethyl, deuterioethyl, fluoromethoxy, fluoroethoxy, deuteromethoxy, deuterioethoxy, C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, -S-C 1-2 alkyl, -Se-C 1-2 alkyl, -C(O)-C 1-2 alkyl, -Se(O)-C 1-2 alkyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, -C 2-3 alkenylene-5- or 6-membered heterocycloalkyl; the 5- or 6-membered heterocycloalkyl contains 1 or 2 heteroatoms selected from N and O; the 5- or 6-membered heterocycloalkyl is unsubstituted or substituted with methyl or ethyl; Preferably, R 21 is selected from H, F, methyl, ethyl, isopropyl, tert-butyl, methoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, morpholinyl, -Se(O)CH3, -C(O)CH3, -SCH3, -SeCH3, -OCHF2, -OCH2CH2F, Preferably, R 21 is selected from methyl or methoxy.

19. The compound according to claim 17 or 18, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, characterized in that: R 22 and R 23 are each independently selected from C 1-2 alkyl, C 3-4 alkyl, C 1-2 alkoxy, C 3-4 alkoxy, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, C 1-2 haloalkoxy, C 3-4 haloalkoxy; Preferably, R 22 , R 23 are each independently selected from methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, fluoromethoxy, fluorochloromethoxy, fluoroethoxy, fluoroisopropoxy, fluorotert-butoxy; Preferably, Selected from Preferably, Selected from 20. The compound according to any one of claims 17-19, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, characterized in that: Ring D is selected from 5-membered heteroaryl and 6-membered heteroaryl, each of which independently contains 1, 2 or 3 heteroatoms selected from N, O and S; Ring D is unsubstituted or substituted with one, two or more Rs m substituted; Preferably, ring D is selected from pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl; ring D is unsubstituted or substituted by one, two or more R m substituents; Preferably, ring D is selected from pyrazolyl, imidazolyl, pyridyl; ring D is unsubstituted or substituted by one, two or more R m substituents; Preferably, ring D is selected from Ring D is unsubstituted or substituted by one, two or more Rs m substituted; Each R m is independently selected from C 1-4 alkyl, C 1-2 haloalkyl, C 1-4 deuterated alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl; Preferably, each R m is independently selected from C 1-4 alkyl, fluoromethyl, fluoroethyl, deuteromethyl, deuteroethyl, methoxy, ethoxy, C 3-6 cycloalkyl; Preferably, each R m is independently selected from methyl, ethyl, isopropyl, methoxy, cyclopropyl, -CF3, -CHF2, -CD3; Most preferably, ring D is selected from 21. A compound represented by formula (II), or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof: Among them, R 22 and R 23 each independently selected from methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclopropyl; Ring D is selected from R 27 each independently selected from -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -OCF3, -OCHF2; R 28 each independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated butyl, cyclopropyl, cyclobutyl.

22. A compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereomer, racemate, polymorph, co-crystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, the compound being selected from the following structures:

23. Pharmaceutical composition, characterized in that: Comprising the compound according to any one of claims 1-22 or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, and optionally a pharmaceutical carrier and / or adjuvant and / or diluent.

24. Use of the compound according to any one of claims 1-22 or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, or the pharmaceutical composition according to claim 23 in the preparation of a USP1 inhibitor.

25. Use of the compound according to any one of claims 1-22 or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, or the pharmaceutical composition according to claim 23 in the preparation of a drug for preventing or / and treating tumors or cancers; Preferably, the tumor or cancer is related to USP1 biological activity; Preferably, the tumor or cancer refers to a tumor or cancer related to USP1 biological activity with HR deficiency; Preferably, the tumor or cancer refers to a cancer or tumor with HR deficiency.

26. The compound according to any one of claims 1-22 or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, or the pharmaceutical composition according to claim 23, which is used for treating and / or preventing tumors or cancers; Preferably, the tumor or cancer is related to USP1 biological activity; Preferably, the tumor or cancer refers to a tumor or cancer associated with USP1 biological activity with HR deficiency; Preferably, the tumor or cancer refers to a cancer or tumor with HR deficiency.

27. A method for preventing and / or treating a tumor or cancer, comprising administering to a subject / individual in need thereof a therapeutically and / or prophylactically effective amount of the compound according to any one of claims 1-22 or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, or the pharmaceutical composition according to claim 23; Preferably, the tumor or cancer is associated with USP1 biological activity; Preferably, the tumor or cancer refers to a tumor or cancer associated with USP1 biological activity with HR deficiency; Preferably, the tumor or cancer refers to a cancer or tumor with HR deficiency.

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