USP1 inhibitor as well as preparation method and application thereof

Abstract

The invention relates to a compound as shown in a formula (XI), or pharmaceutically acceptable salts, stereoisomers, tautomers, enantiomers, diastereoisomers, racemate, polymorphic substances, eutectic substances, hydrates, solvates, metabolites, prodrugs and deuterated compounds thereof. The invention also relates to a pharmaceutical composition containing the compound as an active ingredient and application of the compound or the pharmaceutical composition to treatment and / or prevention of USP1 related diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and particularly to USP1 inhibitors and their preparation methods and uses. Background Art

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

[0003] USP1 belongs to the family members of USPs and is one of the most well-studied DUBs. USP1 is highly expressed in a variety of tumors and is also associated with poor prognosis and metastasis of some tumors. USP1 can form a complex with USP1-Associated Factor 1 (UAF1), thereby regulating two DNA damage repair pathways, namely translesion synthesis (TLS) and inter-strand crosslink damage repair pathway (ICL). It can also affect cell differentiation, thus affecting cancer progression. Among them, in the TLS pathway, USP1 regulates the deubiquitination of proliferating cell nuclear antigen (PCNA), thereby regulating the recruitment and conversion of high-fidelity and low-fidelity TLS polymerases; in the ICL repair pathway, USP1 regulates the deubiquitination of FANCD2, targets to nuclear DNA damage sites, co-localizes with BRCA1 and RAD51, and interacts with downstream FA proteins. In addition, USP1 can also affect the ubiquitination of ID proteins (inhibitor of DNA binding protein family), regulating cell proliferation and differentiation. Inhibition of USP1 will lead to obstruction of the FA repair pathway and an increase in error-prone repair in the TLS pathway, resulting in an increase in SSB repair errors, replication fork collapse or premature arrest, etc. SSB forms DSB during S-phase replication.

[0004] Homologous recombination (HR) is a high-fidelity repair pathway involved in repairing double-strand break DNA (DSB). When factors such as BRCA1 / 2 are mutated and the HR repair pathway is damaged, the DSB generated after inhibiting USP1 can only be repaired through error-prone pathways such as NHEJ and MMEJ, which will lead to abnormal mutations such as gene deletion or structural changes, and cannot be repaired correctly in time, resulting in cell cycle arrest and apoptosis. Studies have confirmed that USP1 is more highly expressed in BRCA1-deficient tumors than in wild-type tumors. Knockout or inhibition of 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 synthetic lethal effect.

[0005] In summary, the USP1 small molecule inhibitor is a potential therapy for treating HR pathway-deficient tumors and can provide a new treatment strategy for cancer 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, deuterated compound thereof:

[0007]

[0008] Wherein, X1 is selected from N or CR2; X2 is selected from N or CR3; M is selected from C(R4)(R5);

[0009] 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 , -Se(O)R k , phenyl, 5- or 6-membered heteroaryl, -C(O)R i , -C(O)OR i , -C(O)NR i R j , the 4- to 10-membered heterocycloalkyl and 5- or 6-membered heteroaryl each independently contain 1-3 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 10-membered heterocycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 5- or 6-membered heteroaryl are each independently unsubstituted or substituted by one or more R a ;

[0010] 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 contains 1-3 heteroatoms selected from N, O, and S, and the hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C3-6 The cycloalkyl group and the 4- to 7-membered heteroalkyl group are each independently unsubstituted or substituted by one or more R a substituents;

[0011] 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 group;

[0012] 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;

[0013] 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, the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclic group each independently containing 1 to 3 heteroatoms selected from N, O, and S, 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;

[0014] 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, the hydroxy, amino, SH, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 4- to 7-membered heterocyclic group are each independently unsubstituted or substituted by one or more R a substituents;

[0015] 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 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 ;

[0016] Or R 11 and R 12 together with the P to which they are attached 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, and the 4- to 7-membered heterocyclic group is unsubstituted or substituted by one or more R a ;

[0017] 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 ;

[0018] 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, 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 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 ;

[0019] Each R d is each 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 3-10A cycloalkyl group or a 4- to 7-membered heterocyclic group, wherein each of the 5- or 6-membered heteroaryl group and the 4- to 7-membered heterocyclic group independently contains 1 to 3 heteroatoms selected from N, O, and S, and the phenyl group, 5- or 6-membered heteroaryl group, hydroxyl group, amino group, 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 ; or two adjacent substituents R d on C combine with the connected atom to form a 4- to 7-membered heterocyclic group or a 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 ;

[0020] Or R c and R d combine with the connected atom to form a 4- to 10-membered heterocyclic group or a carbocyclic ring, 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 with one or more R a ;

[0021] Each R a is independently selected from the same or different halogen, cyano, =O, hydroxyl, amino, C 1-6 alkyl group, C 1-6 alkoxy group, -C(O)NR i R j , C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-10 cycloalkyl group or 4- to 7-membered heterocyclic group, the 4- to 7-membered heterocyclic group contains 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 3-10 cycloalkyl group, and 4- to 7-membered heterocyclic group are each independently unsubstituted or substituted with one or more R e ;

[0022] Each R e is independently selected from the same or different deuterium, halogen, cyano, =O, hydroxyl, amino, C 1-6 alkyl group, C 1-6 alkoxy group, C 3-6 cycloalkyl group or 4- to 7-membered heterocyclic group, the 4- to 7-membered heterocyclic group contains 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 3-6The cycloalkyl group and the 4- to 7-membered heterocyclic group are each independently unsubstituted or substituted with one or more R f substituents;

[0023] 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 4- to 7-membered heterocyclic group, the 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S;

[0024] Each R i , R j , R k is independently selected from the same or different hydrogen or C 1-6 alkyl.

[0025] The present invention provides a compound of formula (XI), or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof:

[0026]

[0027] wherein, X1 is selected from N or CR2; X2 is selected from N or CR3; M is selected from C(R4)(R5);

[0028] 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 , the 4- to 10-membered heterocycloalkyl, 5- or 6-membered heteroaryl each independently contain 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 10-membered heterocycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 5- or 6-membered heteroaryl are each independently unsubstituted or substituted with one or more R a substituents;

[0029] 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 heterocycloalkyl, the 4-7 membered heterocycloalkyl 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 heterocycloalkyl are each independently unsubstituted or substituted by one or more R a substituents;

[0030] 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;

[0031] Ring A is selected from C 6-10 aryl or 5-10 membered heteroaryl, the 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, the C 6-10 aryl, 5-10 membered heteroaryl are each independently unsubstituted or substituted by one or more R b substituents;

[0032] B is selected from C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 cycloalkenyl, the 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl 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 heterocycloalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl are each independently unsubstituted or substituted by one or more R c substituents;

[0033] 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 heterocycloalkyl, -SeR k ,-C(O)NR iR j and 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;

[0034] 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 group, C 1-6 alkyl group, C 3-10 cycloalkyl group, or 4- to 7-membered heterocyclic group, the 4- to 7-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O, and S, and the amino group, C 1-6 alkyl 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;

[0035] Or R 11 and R 12 together with the P to which they are attached form a 4- to 7-membered heterocyclic group, the 4- to 7-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O, S, and P, and at least one heteroatom is P, and the 4- to 7-membered heterocyclic group is unsubstituted or substituted with one or more R a substituents;

[0036] Or R 17 and R 18 together with the atoms to which they are attached form a 4- to 7-membered heterocyclic group, the 4- to 7-membered heterocyclic group contains 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 with one or more R a substituents;

[0037] C is selected from -C(O)NR i R j , C 1-6 alkoxy group, C 6-10 aryl group, 5- to 10-membered heteroaryl group, or 4- to 10-membered heterocyclic group, the 5- to 10-membered heteroaryl group and 4- to 10-membered heterocyclic group each independently contain 1 to 3 heteroatoms selected from N, O, and S, and the C 1-6 alkoxy group, C 6-10An aryl group, 5- to 10-membered heteroaryl group, or 4- to 10-membered heterocyclic group is each independently unsubstituted or substituted with one or more R d substituents;

[0038] Each R d is independently selected from the same or different phenyl groups, 5- or 6-membered heteroaryl groups, halogens, cyano groups, hydroxyl groups, amino groups, C 1-6 alkyl groups, C 1-6 alkoxy groups, C 3-10 cycloalkyl groups, or 4- to 7-membered heterocyclic groups, wherein the 5- or 6-membered heteroaryl groups and 4- to 7-membered heterocyclic groups each independently contain 1 to 3 heteroatoms selected from N, O, and S, and the phenyl groups, 5- or 6-membered heteroaryl groups, hydroxyl groups, amino groups, C 1-6 alkyl groups, C 1-6 alkoxy groups, C 3-10 cycloalkyl groups, 4- to 7-membered heterocyclic groups are each independently unsubstituted or substituted with one or more R a substituents; or two adjacent R substituents on C d combine with the connected atoms to form a 4- to 7-membered heterocyclic group or carbocyclic ring, 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 carbocyclic ring is unsubstituted or substituted with one or more R a substituents;

[0039] Or R c and R d combine with the connected atoms to form a 4- to 10-membered heterocyclic group or carbocyclic ring, 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 with one or more R a substituents;

[0040] Each R a is independently selected from the same or different halogens, cyano groups, ═O, hydroxyl groups, amino groups, C 1-6 alkyl groups, C 1-6 alkoxy groups, -C(O)NR i R j 、C 2-6 alkenyl groups, C 2-6 alkynyl groups, C 3-10 cycloalkyl groups, or 4- to 7-membered heterocyclic groups, the 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, and S, and the hydroxyl groups, amino groups, C 1-6 alkyl groups, C 1-6 alkoxy groups, C 3-10 cycloalkyl groups, 4- to 7-membered heterocyclic groups are each independently unsubstituted or substituted with one or more R e substituents;

[0041] Each R eEach 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- to 7-membered heterocyclic group, said 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, and S, said hydroxyl, 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;

[0042] Each R f is 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- to 7-membered heterocyclic group, said 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, and S;

[0043] Each R i , R j , R k is independently selected from the same or different hydrogen or C 1-6 alkyl.

[0044] The present invention provides a compound of formula (XI), or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof:

[0045]

[0046] wherein, X1 is selected from N or CR2; X2 is selected from N or CR3; M is selected from C(R4)(R5);

[0047] 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- to 7-membered heterocycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, said 4- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S, said hydroxyl, 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 Ra Substituted;

[0048] 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 one or more R a Substituted;

[0049] 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;

[0050] 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, 5- to 10-membered heteroaryl are each independently unsubstituted or substituted by one or more R b Substituted;

[0051] 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 heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 cycloalkenyl, the 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl each independently contain 1 to 3 heteroatoms selected from N, O and S, the C<> 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl are each independently unsubstituted or substituted by one or more R c Substituted;

[0052] 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 heterocycloalkyl, -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, 4- to 7-membered heterocyclic group are each independently unsubstituted or substituted by one or more R a substituents;

[0053] 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 group, C 1-6 alkyl group, C 3-10 cycloalkyl group or 4- to 7-membered heterocyclic group, the 4- to 7-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O, and S, and the amino group, C 1-6 alkyl group, C 3-10 cycloalkyl group, 4- to 7-membered heterocyclic group are each independently unsubstituted or substituted by one or more R a substituents;

[0054] Or R 11 and R 12 together with the P to which they are attached form a 4- to 7-membered heterocyclic group, the 4- to 7-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O, S, and P, and at least one heteroatom is P, and the 4- to 7-membered heterocyclic group is unsubstituted or substituted by one or more R a substituents;

[0055] Or R 17 and R 18 together with the atoms to which they are attached form a 4- to 7-membered heterocyclic group, the 4- to 7-membered heterocyclic group contains 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;

[0056] C is selected from -C(O)NR i R j , C 6-10 aryl group, 5- to 10-membered heteroaryl group or 4- to 10-membered heterocyclic group, the 5- to 10-membered heteroaryl group, 4- to 10-membered heterocyclic group each independently contains 1 to 3 heteroatoms selected from N, O, and S, and the C 6-10 aryl group, 5- to 10-membered heteroaryl group, 4- to 10-membered heterocyclic group are each independently unsubstituted or substituted by one or more Rd Substituted;

[0057] 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, 4- to 7-membered heterocyclic group are each independently unsubstituted or substituted by one or more R a Substituted;

[0058] 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 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, 4- to 7-membered heterocyclic group are each independently unsubstituted or substituted by one or more R e Substituted;

[0059] 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 Substituted;

[0060] Each R f is independently selected from the same or different halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6a 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;

[0061] Each R i 、R j 、R k is independently selected from the same or different hydrogen or C 1-6 alkyl.

[0062] In some specific embodiments, for the above compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, 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- to 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- to 8-membered heterocycloalkyl and 5-membered heteroaryl each independently contain 1 to 2 heteroatoms selected from N, O, and S, the hydroxy, amino, C 1-4 alkyl, C 1-4 alkoxy, 4- to 8-membered heterocycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, 5-membered heteroaryl are each independently unsubstituted or substituted by one or more R a ; R 11 、R 12 、R 13 、R 14 、R 17 and R 18 are each independently selected from hydrogen, methyl or ethyl, and each R i 、R j 、R k is independently selected from the same or different hydrogen, methyl or ethyl.

[0063] In some specific embodiments, X1 is selected from CR2, X2 is selected from N; R2 is selected from H, F, Cl, Br, cyano, hydroxyl, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, 4- to 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, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, 4- to 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 substituted.

[0064] In some specific embodiments, X1 is selected from CR2, X2 is selected from N; R2 is selected from H, F, Cl, cyano, hydroxyl, amino, methyl, isopropyl, methoxy, ethoxy, 6- to 8-membered heterocycloalkyl, 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, amino, methyl, isopropyl, methoxy, ethoxy, 6- to 8-membered heterocycloalkyl, vinyl, propenyl, ethynyl, propynyl, imidazolyl, oxazolyl are each independently unsubstituted or substituted by one or more R a substituted.

[0065] In some specific embodiments, X1 is selected from CR2, X2 is selected from N; R2 is selected from H, F, Cl, cyano, hydroxyl, amino, methyl, isopropyl, methoxy, ethoxy, 6- to 7-membered heterocycloalkyl, 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, amino, methyl, isopropyl, methoxy, ethoxy, 6- to 7-membered heterocycloalkyl, ethynyl, imidazolyl are each independently unsubstituted or substituted by one or more R a substituted.

[0066] In some specific embodiments, each R a is independently selected from the same or different halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C1-6 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 groups.

[0067] In some specific embodiments, 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 heterocycloalkyl, the 4- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S, the 4- to 7-membered heterocycloalkyl being unsubstituted or substituted by 1 or more identical or different C 1-4 alkyl groups.

[0068] In some specific embodiments, 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, the 4- to 7-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O, and S, the 4- to 7-membered heterocycloalkyl being unsubstituted or substituted by 1 or more identical or different C 1-2 alkyl or C 3-4 alkyl groups.

[0069] In some specific embodiments, each R a is independently selected from the same or different F, Cl, Br, hydroxy, cyano, methyl, ethyl, fluoromethyl, fluoroethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5- to 6-membered heterocycloalkyl, the 5- to 6-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N and O, the 5- to 6-membered heterocycloalkyl being unsubstituted or substituted by 1 or more identical or different methyl or ethyl groups.

[0070] In some specific embodiments, each R a is independently selected from the same or different F, Cl, hydroxy, cyano, methyl, fluoromethyl, fluoroethyl, methoxy, cyclopropyl, morpholinyl, N-methylpiperazinyl.

[0071] In some specific embodiments, X1 is selected from CR2, X2 is selected from N; R2 is selected from H, F, Cl, cyano, amino, methyl, methoxy, 6-7 membered heterocycloalkyl, vinyl, 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 with one or more identical or different methyl groups; the methyl group is unsubstituted or substituted with one or more identical or different F, Cl, cyano, morpholinyl, methoxy or N-methylpiperazinyl groups; the methoxy group is unsubstituted or substituted with one or more identical or different F or Cl groups; the amino group is unsubstituted or substituted with one or more identical or different methyl or fluoroethyl groups; the ethynyl group is unsubstituted or substituted with one fluoromethyl group; the isopropyl group is unsubstituted or substituted with one or more hydroxyl groups; the imidazolyl group is unsubstituted or substituted with one or more methyl groups.

[0072] In some specific 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,

[0073] In some specific embodiments, for the above compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, 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 is selected from C 1-6 alkyl.

[0074] In some specific embodiments, X1 is selected from CR2, X2 is selected from N; R2 is selected from -Se(O)R k , R k is selected from C 1-4 alkyl.

[0075] In some specific embodiments, X1 is selected from CR2, X2 is selected from N; R2 is selected from -Se(O)R k , R k is selected from C 1-2 alkyl, C 3-4 alkyl.

[0076] In some specific embodiments, X1 is selected from CR2, X2 is selected from N; R2 is selected from -Se(O)R k , Rk Selected from methyl, ethyl.

[0077] In some specific embodiments, X1 is selected from CR2, X2 is selected from N; R2 is selected from -Se(O)R k , R k is selected from methyl.

[0078] In some specific embodiments, for the above compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, X1 is selected from N, and X2 is selected from N.

[0079] In some specific embodiments, for the above compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, X1 is selected from N, and X2 is selected from CR3; R3 is selected from H, methyl, F, Cl, Br or cyano.

[0080] In some specific embodiments, for the above compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, X1 is selected from CR2, and X2 is selected from N.

[0081] In some specific embodiments, for the above compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, X1 is selected from CR2, and X2 is selected from CH.

[0082] In some specific embodiments, for the above compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, X1 is selected from CR2, and X2 is selected from CR3; R3 is selected from H, methyl, F, Cl, Br or cyano.

[0083] In some specific embodiments, for the above compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, 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 2-6An alkynyl group, the 4- to 7-membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, and S, and the hydroxy group, amino group, C 1-6 alkyl group, C 1-6 alkoxy group, 4- to 7-membered heterocycloalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group are each independently unsubstituted or substituted by one or more R a substituents.

[0084] In some specific embodiments, R2 is selected from H, halogen, cyano, hydroxy, amino, C 1-4 alkyl group, C 1-4 alkoxy group, 4- to 7-membered heterocycloalkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, the 4- to 7-membered heterocycloalkyl group contains 1 to 2 heteroatoms selected from N, O, and S, and the hydroxy group, amino group, C 1-4 alkyl group, C 1-4 alkoxy group, 4- to 7-membered heterocycloalkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group are each independently unsubstituted or substituted by one or more R a substituents.

[0085] In some specific embodiments, R2 is selected from H, F, Cl, Br, cyano, hydroxy, amino, C 1-2 alkyl group, C 3-4 alkyl group, C 1-2 alkoxy group, C 3-4 alkoxy group, 4- to 7-membered heterocycloalkyl group, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl, the 4- to 7-membered heterocycloalkyl group contains 1 to 2 heteroatoms selected from N, O, and S, and the hydroxy group, amino group, C 1-2 alkyl group, C 3-4 alkyl group, C 1-2 alkoxy group, C 3-4 alkoxy group, 4- to 7-membered heterocycloalkyl group, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl are each independently unsubstituted or substituted by one or more R a substituents.

[0086] In some specific embodiments, R2 is selected from H, F, Cl, Br, cyano, hydroxy, amino, methyl, ethyl, methoxy, ethoxy, 4- to 7-membered heterocycloalkyl group, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl, the 4- to 7-membered heterocycloalkyl group contains 1 to 2 heteroatoms selected from N and O, and the hydroxy group, amino group, methyl, ethyl, methoxy, ethoxy, 4- to 7-membered heterocycloalkyl group, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl are each independently unsubstituted or substituted by one or more R a substituents.

[0087] In some specific embodiments, R2 is selected from H, F, Cl, cyano, hydroxy, amino, methyl, methoxy, ethoxy, 6- or 7-membered heteroalkyl, vinyl, propenyl, ethynyl, propynyl, the 6- or 7-membered heteroalkyl contains 1 or 2 heteroatoms selected from N and O, and the hydroxy, amino, methyl, methoxy, ethoxy, 6- or 7-membered heteroalkyl, vinyl, propenyl, ethynyl, propynyl are each independently unsubstituted or substituted by one or more R a substituted.

[0088] In some specific embodiments, R2 is selected from H, F, Cl, cyano, hydroxy, amino, methyl, methoxy, ethoxy, 6- or 7-membered heteroalkyl, vinyl, propenyl, ethynyl, propynyl, the 6- or 7-membered heteroalkyl contains 1 or 2 heteroatoms selected from N and O, and the hydroxy, amino, methyl, methoxy, ethoxy, 6- or 7-membered heteroalkyl are each independently unsubstituted or substituted by one or more R a substituted.

[0089] In some specific embodiments, 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 contains 1 to 3 heteroatoms selected from N, O and S, and the 4- to 7-membered heterocyclic group is unsubstituted or substituted by one or more of the same or different C 1-6 alkyl.

[0090] In some specific embodiments, 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 heteroalkyl, the 4- to 7-membered heteroalkyl contains 1 to 3 heteroatoms selected from N, O and S, and the 4- to 7-membered heteroalkyl is unsubstituted or substituted by one or more of the same or different C 1-4 alkyl.

[0091] In some specific embodiments, 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 3-4Alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4- to 7-membered heterocycloalkyl, the 4- to 7-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O, and S, the 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 substitution.

[0092] In some specific embodiments, 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- to 6-membered heterocycloalkyl, the 5- to 6-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N and O, the 5- to 6-membered heterocycloalkyl being unsubstituted or substituted by one or more identical or different methyl or ethyl groups.

[0093] In some specific embodiments, each R a is independently selected from the same or different F, Cl, cyano, methyl, fluoroethyl, methoxy, cyclopropyl, morpholinyl, N-methylpiperazinyl.

[0094] In some specific embodiments, R2 is selected from H, F, Cl, cyano, amino, methyl, methoxy, 6- to 7-membered heterocycloalkyl, vinyl, propenyl, ethynyl, propynyl, the 6- to 7-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N and O; the 6- to 7-membered heterocycloalkyl being unsubstituted or substituted by one or more identical or different methyl groups; the methyl group being unsubstituted or substituted by one or more identical or different F, Cl, cyano, morpholinyl or N-methylpiperazinyl; the methoxy group being unsubstituted or substituted by one or more identical or different F or Cl; the amino group being unsubstituted or substituted by one or more identical or different methyl or fluoroethyl groups.

[0095] In some specific embodiments, R2 is selected from H, F, Cl, cyano, amino, methyl, methoxy, -CF3, -CClF2, -OCHF2, -OCF3, -OCClF2, vinyl, propenyl, ethynyl, propynyl,

[0096] In some specific 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,

[0097] In some specific embodiments, X1 is CR2, X2 is N, and R2 is selected from methyl.

[0098] In some specific embodiments, X1 is CR2, X2 is N, and R2 is selected from methoxy.

[0099] In some specific embodiments, for the above-mentioned compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, R1 is selected from H, halogen, cyano, amino, C 1-4 alkyl or C 1-4 alkoxy, and the amino and C 1-4 alkoxy are each independently unsubstituted or substituted by one or more R a substituents.

[0100] In some specific embodiments, 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.

[0101] In some specific embodiments, each R a is independently selected from the same or different C 1-4 alkyl or C 5-6 alkyl.

[0102] In some specific embodiments, each R a is independently selected from the same or different methyl groups.

[0103] In some specific embodiments, R1 is selected from H, Cl, methyl, cyano, methoxy, amino,

[0104]

[0105] In some specific embodiments, R1 is selected from H.

[0106] In some specific embodiments, is selected from

[0107] In some specific embodiments, is selected from

[0108] In some specific embodiments, is selected from

[0109] In some specific embodiments, is selected from

[0110]

[0111] In some specific embodiments, selected from

[0112] In some specific embodiments, selected from

[0113] In some specific embodiments, the above compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, 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 a C 3-6 cycloalkyl.

[0114] In some specific 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 together with the atoms to which they are attached form cyclopropyl.

[0115] In some specific 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.

[0116] In some specific embodiments, M is selected from C(R4)(R5); R4 and R5 are each independently selected from H, deuterium or methyl.

[0117] In some specific embodiments, M is selected from methylene,

[0118] In some specific embodiments, M is selected from methylene.

[0119] In some specific embodiments, the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, ring A is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heteroaryl-fused-5-membered heteroaryl, 5-membered heteroaryl-fused-6-membered heteroaryl, 6-membered heteroaryl-fused-6-membered heteroaryl, phenyl-fused-5-membered heteroaryl or phenyl-fused-6-membered heteroaryl, 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, 5-membered heteroaryl-fused-5-membered heteroaryl, 5-membered heteroaryl-fused-6-membered heteroaryl, 6-membered heteroaryl-fused-6-membered heteroaryl, phenyl-fused-5-membered heteroaryl, phenyl-fused-6-membered heteroaryl are each independently unsubstituted or substituted by one or more R b substituted.

[0120] In some specific embodiments, ring A is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl or phenyl-fused-5-membered heteroaryl, 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, phenyl-fused-5-membered heteroaryl are each independently unsubstituted or substituted by one or more R b substituted.

[0121] In some specific embodiments, ring A is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl or phenyl-fused-5-membered heteroaryl, the 5-membered heteroaryl and 6-membered heteroaryl each independently contain 1-2 N heteroatoms, and the phenyl, 5-membered heteroaryl, 6-membered heteroaryl, phenyl-fused-5-membered heteroaryl are each independently unsubstituted or substituted by one or more R b substituted.

[0122] In some specific embodiments, 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 substituted.

[0123] In some specific embodiments, 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.

[0124] In some specific embodiments, ring A is selected from

[0125] In some specific embodiments, ring A is selected from

[0126] In some specific embodiments, 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, SH, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 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.

[0127] In some specific embodiments, 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- to 7-membered heteroalkyl, -SeR k , -C(O)NR i R j , the 4- to 7-membered heteroalkyl contains 1 to 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, 4- to 7-membered heteroalkyl 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;

[0128] R 11 、R 12 、R 13 、R 14 、R 17 and R 18 are each independently selected from H or C 1-4 alkyl.

[0129] In some specific embodiments, 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- to 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, SH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl are each independently unsubstituted or substituted with 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.

[0130] In some specific embodiments, 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, and 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.

[0131] In some specific embodiments, each R b is independently selected from the same or different F, Cl, amino group, SH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, azetidinyl, -SeR k , -C(O)NR i R j , The amino group, SH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, and azetidinyl are each independently unsubstituted or substituted by one or more R a ; 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.

[0132] In some specific embodiments, each R b is independently selected from the same or different F, Cl, amino group, SH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, azetidinyl, -SeCH3, The amino group, SH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, and azetidinyl are each independently unsubstituted or substituted by one or more R a .

[0133] In some specific embodiments, each R aEach independently selected from the same or different halogens, hydroxyl groups, C 1-6 alkyl or C 1-6 alkoxy groups.

[0134] In some specific embodiments, each R a is independently selected from the same or different halogens, hydroxyl groups, C 1-4 alkyl or C 1-4 alkoxy groups.

[0135] In some specific embodiments, each R a is independently selected from the same or different F, Cl, Br, hydroxyl group, methyl group, ethyl group, methoxy group or ethoxy group.

[0136] In some specific embodiments, each R a is independently selected from the same or different F, hydroxyl group, methyl group or methoxy group.

[0137] In some specific embodiments, each R b is independently selected from the same or different F, Cl, amino group, methyl-substituted amino group, -SCH3, methyl group, fluoromethyl group, methoxy group, fluoromethoxy group, fluorochloromethoxy group, ethoxy group, fluoroethoxy group, hydroxyl-substituted isopropyl group, hydroxyl-substituted cyclopropyl group, methoxy-substituted ethoxy group, isopropyl group, isopropoxy group, cyclopropyl group, azetidinyl group, -SeCH3,

[0138]

[0139] In some specific embodiments, each R b is independently selected from the same or different methyl group, methoxy group, cyclopropyl group, isopropyl group, ethoxy group, isopropoxy group, -SCH3, -SeCH3, amino group, F, Cl, OCHF2, -OCClF2, -OCF3, -CF3,

[0140] In some specific embodiments, ring A is selected from

[0141] In some specific embodiments, ring A is selected from

[0142] In some specific embodiments, the above compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, 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- to 7-membered heterocycloalkyl or C 3-8 cycloalkyl, wherein 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.

[0143] In some specific embodiments, B is selected from ethynyl, phenyl, pyridyl, pyrimidinyl, cyclohexyl, cubyl, or piperidinyl, and the phenyl, pyridyl, pyrimidinyl, cyclohexyl, cubyl, or piperidinyl is independently unsubstituted or substituted by one or more identical or different F, Cl, Br, methoxy, or ethoxy.

[0144] In some specific embodiments, B is selected from phenyl, pyridyl, pyrimidinyl, cyclohexyl, cubyl, piperidinyl, fluoropiperidinyl, or ethynyl, and the phenyl is unsubstituted or substituted by one or more identical or different F or methoxy.

[0145] In some specific embodiments, B is selected from C 2-4 alkynyl, phenyl, 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, or C 3-6 cycloalkyl, wherein each of the 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl independently contains 1 to 2 N heteroatoms, and the C 2-4 alkynyl, phenyl, 6-membered heteroaryl, 4- to 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.

[0146] In some specific embodiments, B is selected from ethynyl, phenyl, pyridyl, pyrimidinyl, cyclohexyl, or piperidinyl, and the phenyl, pyridyl, pyrimidinyl, cyclohexyl, or piperidinyl is independently unsubstituted or substituted by one or more identical or different F, Cl, Br, methoxy, or ethoxy.

[0147] In some specific embodiments, B is selected from phenyl, pyridyl, pyrimidinyl, cyclohexyl, piperidinyl, fluoropiperidinyl, or ethynyl, and the phenyl is unsubstituted or substituted by one or more identical or different F or methoxy.

[0148] In some specific embodiments, B is selected from

[0149] or ethynyl.

[0150] In some specific embodiments, B is selected from or ethynyl.

[0151] In some specific embodiments, B is selected from or ethynyl.

[0152] In some specific embodiments, B is selected from

[0153] In some specific embodiments, for the above-mentioned compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, C is selected from -C(O)NR i R j , 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, 5- to 10-membered heteroaryl are each independently unsubstituted or substituted by one or more R d ; R i , R j are each independently selected from hydrogen, C 1-4 alkyl or C 5-6 alkyl.

[0154] In some specific embodiments, C is selected from -C(O)NR i R j , phenyl, pyridyl, pyrimidinyl, 5-membered heteroaryl, the 5-membered heteroaryl containing 1 to 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 ; R i , R j are each independently selected from H or C 1-4 alkyl.

[0155] In some specific embodiments, C is selected from -C(O)NR i R j , phenyl, pyridyl, pyrimidinyl, 5-membered heteroaryl, the 5-membered heteroaryl containing 1 to 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 ; R i , R jEach independently selected from hydrogen, methyl, ethyl, n-propyl or isopropyl.

[0156] In some specific embodiments, 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 substituted; R i , R j Each independently selected from hydrogen, methyl or ethyl.

[0157] In some specific 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 by one or more R d substituted.

[0158] In some specific embodiments, C is selected from

[0159] In some specific embodiments, C is selected from

[0160] In some specific embodiments, 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, and 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 substituted; or two adjacent substituents R d on C combine to form a 5-6 membered heterocyclic group containing 1-2 N heteroatoms.

[0161] In some specific embodiments, each R dEach independently selected from the same or different pyridyl groups, F, Cl, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl or azetidinyl, and the pyridyl group, 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.

[0162] In some specific embodiments, each R d is independently selected from the same or different pyridyl groups, Cl, methyl, ethyl, isopropyl, methoxy, cyclopropyl or azetidinyl, and the methyl, ethyl, methoxy, 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.

[0163] In some specific embodiments, each R d is independently selected from the same or different halogens, 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 containing 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, 4-7 membered heterocycloalkyl are each independently unsubstituted or substituted by one or more R a .

[0164] In some specific embodiments, each R d is independently selected from the same or different halogens, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or 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 .

[0165] In some specific embodiments, each Rd Each 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 are each independently unsubstituted or substituted by one or more R a substituted.

[0166] In some specific embodiments, each R d Each independently selected from the same or different Cl, methyl, ethyl, isopropyl, methoxy, cyclopropyl or azetidinyl, wherein the methyl, ethyl, methoxy, azetidinyl are each independently unsubstituted or substituted by one or more R a substituted.

[0167] In some specific embodiments, each R a Each independently selected from the same or different halogen, =O or C 1-6 alkyl.

[0168] In some specific embodiments, each R a Each independently selected from the same or different halogen, =O or C 1-4 alkyl.

[0169] In some specific embodiments, each R a Each independently selected from the same or different F, Cl, Br, =O, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0170] In some specific embodiments, each R a Each independently selected from the same or different F, =O or methyl.

[0171] In some specific embodiments, each R d Each independently selected from the same or different pyridyl, Cl, fluoromethyl, ethyl, fluoroethyl, isopropyl, methoxy, fluoromethoxy, cyclopropyl,

[0172] Or two adjacent substituents R on C d Combine to form a 5-membered heterocyclic group containing 1 N heteroatom.

[0173] In some specific 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 dCombined to form a 5-membered heterocyclic group containing 1 N heteroatom.

[0174] In some specific embodiments, each R d is independently selected from the same or different Cl, methyl, fluoromethyl, ethyl, fluoroethyl, isopropyl, methoxy, fluoromethoxy, cyclopropyl,

[0175]

[0176] In some specific embodiments, each R d is independently selected from the same or different methyl, isopropyl, -CF3, -CHF2, cyclopropyl, methoxy, Cl, or -OCF3.

[0177] In some specific embodiments, C is selected from

[0178]

[0179] In some specific embodiments, C is selected from

[0180] In some specific embodiments, C is selected from

[0181] In some specific embodiments, the above compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, B is phenyl, C is a 5-6 membered heteroaryl, B and C form a tricyclic ring together through the substituents R c 、R d combination; the single ring formed by R c 、R d combination is an unsubstituted or 4-10 membered heterocyclic group substituted by one or more R a ; wherein, the 5-6 membered heteroaryl and 4-10 membered heterocyclic group each independently contain 1-3 heteroatoms selected from N, O and S; wherein C also has a substituent which is C 1-4 fluoroalkyl.

[0182] In some specific embodiments, B is phenyl, C is a 5-membered heteroaryl, B and C form a tricyclic ring together through the substituents R c 、R d combination; the single ring formed by R c 、R d combination is an unsubstituted or 4-10 membered heterocyclic group substituted by one or more R aA 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 3 heteroatoms selected from N, O, and S; and wherein C further has a substituent of C 1-4 Fluoroalkyl.

[0183] In some specific embodiments, B is a phenyl group, C is a 5-membered heteroaryl group, and B and C together form a tricyclic ring through the substituents R c 、R d Combination; the single ring formed by R c 、R d Combination 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 of C 1-4 Fluoroalkyl.

[0184] In some specific embodiments, B is a phenyl group, C is a 5-membered heteroaryl group, and B and C together form a tricyclic ring through the substituents R c 、R d Combination; the single ring formed by R c 、R d Combination is an unsubstituted or 1- or more R a Substituted 4- to 8-membered heterocyclic group; wherein the 5-membered heteroaryl group contains 1 to 2 N atoms, and the 4- to 8-membered heterocyclic group contains 1 to 2 heteroatoms selected from N and O; and wherein C further has a substituent of C 1-2 Fluoroalkyl.

[0185] In some specific embodiments, B is a phenyl group, 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 single 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 to 2 heteroatoms selected from N and O; and wherein C further has a substituent of fluoromethyl.

[0186] In some specific embodiments, B is a phenyl group, C is selected from imidazolyl, and B and C together form a tricyclic ring through the substituents R c 、R d Combination; the single ring formed by R c 、R d 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 wherein C further has a substituent of -CF3.

[0187] In some specific embodiments, For B and C together form a tricyclic ring through the substituents R c , R d combination; the single ring formed by the R c , R d 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 1-2 heteroatoms selected from N and O, and at least one heteroatom is N.

[0188] In some specific embodiments, each R a is independently selected from the same or different ═O, C 1-6 alkyl.

[0189] In some specific embodiments, each R a is independently selected from the same or different ═O, C 1-2 alkyl, C 3-4 alkyl.

[0190] In some specific embodiments, each R a is independently selected from the same or different ═O, methyl, ethyl.

[0191] In some specific embodiments, each R a is independently selected from the same or different ═O, methyl.

[0192] In some specific embodiments, is selected from

[0193] In some specific embodiments, is selected from

[0194] A preferred technical solution of the present invention is that the above compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, has the structure shown in Formula XIa:

[0195]

[0196] Wherein, R2 is defined as shown above.

[0197] In a preferred technical solution of the present invention, the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, co-crystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, has the structure shown in Formula XIb:

[0198]

[0199] Wherein, R b is defined as shown above.

[0200] In a preferred technical solution of the present invention, the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, co-crystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, has the structure shown in Formula XIc:

[0201]

[0202] Wherein, R b is defined as shown above.

[0203] In a preferred technical solution of the present invention, the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, co-crystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, has the structure shown in Formula XId:

[0204]

[0205] Wherein, R d is defined as shown above.

[0206] In a preferred technical solution of the present invention, the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, co-crystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, has the structure shown in Formula XIe:

[0207]

[0208] Wherein, R d is defined as shown above.

[0209] In a preferred technical solution of the present invention, the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, co-crystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, has the structure shown in Formula XIf:

[0210]

[0211] wherein, R d is defined as shown above.

[0212] In a preferred technical solution of the present invention, the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, has the structure shown in Formula XI g:

[0213]

[0214] wherein, R d is defined as shown above.

[0215] In a preferred technical solution of the present invention, the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, has the structure shown in Formula XI h:

[0216]

[0217] wherein, R2 is defined as shown above.

[0218] In a preferred technical solution of the present invention, the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, has the structure shown in Formula XI i:

[0219]

[0220] wherein, R b is defined as shown above.

[0221] In a preferred technical solution of the present invention, the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, has the structure shown in Formula XI j:

[0222]

[0223] wherein, R b is defined as shown above.

[0224] In a preferred technical solution of the present invention, the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, has the structure shown in Formula XIk:

[0225]

[0226] wherein, R d is defined as shown above.

[0227] In a preferred technical solution of the present invention, the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, has the structure shown in Formula XIl:

[0228]

[0229] wherein, R d is defined as shown above.

[0230] In a preferred technical solution of the present invention, the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, has the structure shown in Formula XIm:

[0231]

[0232] wherein, R d is defined as shown above.

[0233] In a preferred technical solution of the present invention, the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, has the structure shown in Formula XIn:

[0234]

[0235] wherein, R d is defined as shown above.

[0236] In a preferred technical solution of the present invention, the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, has the structure shown in Formula XIq:

[0237]

[0238] wherein, R d is defined as shown above.

[0239] The present invention also provides 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:

[0240]

[0241] wherein, X5 is selected from N or CR 20 ; R 20 is selected from H, F, Cl, Br or C 1-4 alkyl;

[0242] X6 is selected from N or CR 26 ; R 26 is selected from H, F, Cl, Br or C 1-4 alkoxy;

[0243] R 21 is 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, 4-8 membered heterocycloalkyl, -C 2-4 alkenylene-4-8 membered heterocycloalkyl; each of the 4-8 membered heterocycloalkyl independently contains 1-2 heteroatoms selected from N, O and S; each of the 4-8 membered heterocycloalkyl is independently unsubstituted or substituted by C 1-4 alkyl;

[0244] R 22 , 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;

[0245] R24 , 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;

[0246] Ring D is selected from 5-membered heteroaryl, 6-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl, and the 5-membered heteroaryl, 6-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl each independently contain 1, 2 or 3 heteroatoms selected from N, O and S; Ring D is unsubstituted or substituted by one, two or more R 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.

[0247] In some specific embodiments, selected from

[0248] In some specific embodiments, selected from

[0249] In some specific embodiments, selected from

[0250] In some specific embodiments, R 21 is selected from H, F, Cl, Br, C 1-4 alkyl, methoxy, ethoxy, isopropoxy, C 1-4 hydroxyalkyl, fluoromethyl, fluoroethyl, deuteromethyl, deuteroethyl, fluoromethoxy, fluoroethoxy, deuteromethoxy, deuteroethoxy, 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-5-6-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.

[0251] In some specific embodiments, R21 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,

[0252] In some specific embodiments, R 21 is selected from methyl or methoxy.

[0253] In some specific embodiments, R 22 , 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.

[0254] In some specific embodiments, 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, cyclopentoxy, cyclohexyloxy, fluoromethoxy, fluorochloromethoxy, fluoroethoxy, fluoroisopropoxy, fluorotert-butoxy.

[0255] In some specific embodiments, is selected from

[0256] In some specific embodiments, is selected from

[0257] In some specific embodiments, ring D is selected from 5-membered heteroaryl, 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 .

[0258] In some specific embodiments, ring D is selected from pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl; ring D is unsubstituted or substituted by 1, 2, or more R m .

[0259] In some specific embodiments, ring D is selected from a pyrazolyl group, an imidazolyl group, and a pyridyl group; ring D is unsubstituted or substituted with one, two, or more Rs m substituted.

[0260] In some specific embodiments, ring D is selected from Ring D is unsubstituted or substituted with one, two, or more Rs m substituted.

[0261] In some specific embodiments, 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.

[0262] In some specific embodiments, each R m is independently selected from C 1-4 alkyl, fluoromethyl, fluoroethyl, deuterated methyl, deuterated ethyl, methoxy, ethoxy, C 3-6 cycloalkyl.

[0263] In some specific embodiments, each R m is independently selected from methyl, ethyl, isopropyl, methoxy, cyclopropyl, -CF3, -CHF2, -CD3.

[0264] In some specific embodiments, ring D is selected from

[0265] 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, deuterated compound thereof:

[0266]

[0267] wherein, R 22 , R 23 are independently selected from methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclopropyl; ring D is selected from R 27 are independently selected from -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -OCF3, -OCHF2; R 28 are 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.

[0268] In a preferred technical solution of the present invention, the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, and the compound is selected from the following structures:

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is prepared from a compound having specific substituents found in the present invention and a relatively non-toxic acid or base. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting such a compound with a sufficient amount of base in a pure solution or a suitable inert solvent. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting such a compound with a sufficient amount of acid in a pure solution or a suitable inert solvent.

[0276] The term "prodrug" refers to a derivative of the indicated compound having specific substituents found in the present invention, which may itself have weak activity or even no activity, but after administration, it is converted in physiological conditions (e.g., by metabolism, solvolysis or other means) into the compound having specific substituents found in the present invention, producing the corresponding biological activity in vivo.

[0277] The term "metabolite" refers to the product obtained by the metabolism of the indicated compound having specific substituents found in the present invention in vivo. The metabolites of a compound can be identified by techniques well known in the art, and their activities can be characterized by experimental methods as described in the present invention. Such products can be obtained by methods such as oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes the metabolites of the compound, including the metabolites produced by contacting the compound of the present invention with a mammal for a sufficient period of time.

[0278] 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 the compound of the present invention can be replaced or substituted by deuterium atoms. 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.

[0279] Preparation method:

[0280] The present invention also provides a method for preparing the compound. The preparation of the compound represented by the general formula of the present invention can be completed by the following exemplary methods and examples, but these methods and examples should not be considered as limiting the scope of the present invention in any way. The compounds of the present invention can also be synthesized by synthetic techniques known to those skilled in the art, or by combining synthetic methods known in the art and the methods of the present invention. The products obtained from each step of the reaction are obtained by 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 synthesized conventionally according to the literature (such as provided by Scifinder) or purchased.

[0281]

[0282] Step 1: The compound represented by formula Ia-1 reacts with the compound represented by formula Id-1 through a Negishi coupling reaction to obtain the compound represented by formula Ia-6;

[0283] Step 2: The compound represented by formula Ia-6 reacts with the compound represented by formula Ia-4 or the compound represented by formula Ia-5 through a Suzuki coupling to obtain the compound represented by formula XI;

[0284] Wherein, the definitions of X1, X2, R1, R4, R5, ring A, B, and C are as shown above.

[0285] Pharmaceutical composition

[0286] The present invention also provides a pharmaceutical composition, which contains the compound represented by 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, diastereoisomer, racemate, polymorph, eutectic, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, and optionally a pharmaceutical carrier and / or adjuvant and / or diluent.

[0287] Methods for preparing various pharmaceutical compositions containing a certain amount of an active ingredient are known or will be apparent to those skilled in the art from the disclosure of the present invention. As described in REMINGTON’S PHARMACEUTICAL SCIENCES, Martin, E.W., ed., Mack Publishing Company, 19th ed. (1995), methods for preparing the pharmaceutical compositions include incorporating suitable pharmaceutical excipients, carriers, diluents, etc.

[0288] Medical use

[0289] In another aspect, the present invention also provides the 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, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, or the pharmaceutical composition, in the preparation of a USP1 inhibitor.

[0290] In another aspect, the present invention also provides the 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, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, or the pharmaceutical composition, in the preparation of a drug for preventing and / or treating USP1-mediated diseases.

[0291] Preferably, the USP1-mediated disease is a tumor or cancer.

[0292] Preferably, the USP1-mediated disease refers to a USP1-mediated related disease with HR deficiency.

[0293] Preferably, the USP1-mediated disease refers to a cancer or tumor with HR deficiency.

[0294] On the other hand, the present invention also provides the use of the compounds of formula (XI), (XIa), (XIb), (XIc), (XId), (XIe), (XIf), (XIg), (XIh), (XIi), (XIj), (XIk), (XIl), (XIm), (XIn), (XIq), (I) or (II), or pharmaceutically acceptable salts, stereoisomers, tautomers, enantiomers, diastereoisomers, racemates, polymorphs, cocrystals, hydrates, solvates, metabolites, prodrugs, deuterated compounds thereof, or the said pharmaceutical compositions, in the preparation of a drug for preventing and / or treating tumors or cancers.

[0295] Preferably, the tumor or cancer is related to the biological activity of USP1.

[0296] Preferably, the tumor or cancer refers to a tumor or cancer related to the biological activity of USP1 with HR deficiency.

[0297] Preferably, the tumor or cancer refers to a cancer or tumor with HR deficiency.

[0298] On the other hand, the present invention also provides the compounds of formula (XI), (XIa), (XIb), (XIc), (XId), (XIe), (XIf), (XIg), (XIh), (XIi), (XIj), (XIk), (XIl), (XIm), (XIn), (XIq), (I) or (II), or pharmaceutically acceptable salts, stereoisomers, tautomers, enantiomers, diastereoisomers, racemates, polymorphs, cocrystals, hydrates, solvates, metabolites, prodrugs, deuterated compounds thereof, or the said pharmaceutical compositions, for treating and / or preventing diseases mediated by USP1.

[0299] Preferably, the diseases mediated by USP1 are tumors or cancers.

[0300] Preferably, the diseases mediated by USP1 refer to USP1-mediated related diseases with HR deficiency.

[0301] Preferably, the diseases mediated by USP1 refer to cancers or tumors with HR deficiency.

[0302] On the other hand, the present invention also provides the compounds of formula (XI), (XIa), (XIb), (XIc), (XId), (XIe), (XIf), (XIg), (XIh), (XIi), (XIj), (XIk), (XIl), (XIm),

[0303] (XIn), (XIq), the compound of formula (I) or (II), or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, or the pharmaceutical composition as described above, for the treatment and / or prevention of tumors or cancers.

[0304] Preferably, the tumor or cancer is related to the biological activity of USP1.

[0305] Preferably, the tumor or cancer refers to a tumor or cancer related to the biological activity of USP1 with HR deficiency.

[0306] Preferably, the tumor or cancer refers to a cancer or tumor with HR deficiency.

[0307] In another aspect, the present invention also provides a method for treating and / or preventing a disease mediated by USP1, which comprises: administering to a subject / individual in need a therapeutically and / or prophylactically effective amount of the 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, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, or the pharmaceutical composition as described above.

[0308] Preferably, the disease mediated by USP1 is a tumor or cancer.

[0309] Preferably, the disease mediated by USP1 refers to a USP1-mediated related disease with HR deficiency.

[0310] Preferably, the disease mediated by USP1 refers to a cancer or tumor with HR deficiency.

[0311] In another aspect, the present invention also provides a method for preventing and / or treating a tumor or cancer, which comprises: 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, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, or the pharmaceutical composition as described above.

[0312] Preferably, the tumor or cancer is related to USP1 biological activity.

[0313] Preferably, the tumor or cancer refers to a tumor or cancer related to USP1 biological activity with HR deficiency.

[0314] Preferably, the tumor or cancer refers to a cancer or tumor with HR deficiency.

[0315] In the present invention, "treatment" generally refers to obtaining the desired pharmacological and / or physiological effects. Such effects can be prophylactic according to completely or partially preventing a disease or its symptoms; and / or can be therapeutic according to partially or completely stabilizing or curing a disease and / or side effects caused by the disease. "Treatment" as used herein covers any treatment of a patient's disease, including: (a) preventing a disease or symptom from occurring in a patient who is susceptible to the disease or symptom but has not been diagnosed with the disease; (b) inhibiting the symptoms of the disease, i.e., preventing its development; or (c) alleviating the symptoms of the disease, i.e., causing the disease or symptom to regress.

[0316] In the present invention, "subject / individual" refers to a vertebrate. In certain embodiments, the vertebrate refers to a mammal. Mammals include, but are not limited to, livestock (such as cows), pets (such as cats, dogs, and horses), primates, mice, and rats. In certain embodiments, the mammal refers to a human.

[0317] In the present invention, "effective amount" refers to the amount that is effective in achieving the desired therapeutic or prophylactic effect at the required dosage and for the required time. The "therapeutically effective amount" of the substance / molecule of the present invention may vary depending on 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. The therapeutically effective amount also encompasses the amount where the therapeutic beneficial effects of the substance / molecule outweigh any toxic or detrimental effects. "Prophylactically effective amount" refers to the amount that is effective in achieving the desired prophylactic effect at the required dosage and for the required time. Generally but not necessarily, since the prophylactic dosage is administered to a subject before the onset of the disease or in the early stages of the disease, the prophylactically effective amount will be lower than the therapeutically effective amount. In the case of cancer, the therapeutically effective amount of a drug may reduce the number of cancer cells; shrink the tumor volume; inhibit (i.e., slow down to a certain extent, preferably stop) the infiltration of cancer cells 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.

[0318] Term definitions:

[0319] According to the convention in the art, In the structural formulas herein, a bond used to describe the point of attachment of this moiety or substituent to the parent nucleus or main structure.

[0320] 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.

[0321] In the present invention, the term "optionally" means that it can be selected or not selected.

[0322] In the present invention, the term "substituted" means that an atom or atomic group formally replaces hydrogen and is attached as a "substituent" to another group. Unless otherwise indicated, the term "substituted" refers to any degree of substitution where such substitution is permitted, such as mono-substitution, di-substitution, tri-substitution, tetra-substitution, or penta-substitution. Substituents are independently selected, and the substitution can occur at any chemically accessible position. It should be understood that the substitution on a specified atom is limited by the valence of the atom. It should be understood that the substitution on a specified atom results in a chemically stable molecule.

[0323] In the present invention, the term "alkyl", used alone or in combination with other terms, refers to a saturated hydrocarbon group that can be straight-chain or branched-chain. The term "C 1-10"Alkyl" refers to an alkyl group having 1 to 10 carbon atoms. An alkyl group formally corresponds to an alkane in which one C-H bond is replaced by a point of attachment of the alkyl group to the remainder 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.

[0324] In the present invention, the term "alkoxy", used alone or in combination with other terms, refers to a group having the formula -O-alkyl, where the term "alkyl" is as defined above. The term "C 1-8 alkoxy" refers to an alkoxy group in which the alkyl group has 1 to 8 carbons. 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.

[0325] In the present invention, the term "alkenyl", used alone or in combination with other terms, refers to a straight-chain or branched-chain hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon double bonds. An alkenyl group formally corresponds to an alkene in which one C-H bond is replaced by a point of attachment of the alkyl group to the remainder 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, vinyl, prop-1-enyl, prop-2-enyl, 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.

[0326] In the present invention, the term "alkynyl", used alone or in combination with other terms, refers to a straight-chain or branched-chain hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon triple bonds. An alkynyl group formally corresponds to an alkyne in which one C-H bond is replaced by a point of attachment of the alkyl group to the remainder of the compound. The term "C 2-8 alkynyl" refers to an alkynyl group having 2 to 8 carbons. Example alkynyl groups include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, 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.

[0327] 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.

[0328] 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 halogen atoms, where the terms "halogen", "alkyl", and "alkoxy" are as defined above. In some embodiments, the term "C 1-6 haloalkyl" is preferably fluoro, and can be, for example, -CF3, -CHF2, -CH2F, -CH2CH2F, -CH2CHF2, -CH2CF3, etc. In some embodiments, the term "C 1-6 haloalkoxy" is preferably fluoro, and can be, for example, -OCF3, -OCHF2, -OCH2F, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, etc.

[0329] 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, where the term "alkyl" is as defined above.

[0330] 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, where the term "alkyl" is as defined above.

[0331] In the present invention, the term "heteroatom", used alone or in combination with other terms, includes B, P, S, O, and N.

[0332] In the present invention, the term "aryl", used alone or in combination with other terms, refers to an aromatic hydrocarbon group, which can be monocyclic or polycyclic (e.g., having 2 fused rings). The term "C 6-10 aryl" refers to an aryl group having 6 to 10 ring carbon atoms. Aryl includes, for example, phenyl, naphthyl, indanyl, indenyl, etc. In some embodiments, the aryl has 6 carbon atoms. In some embodiments, the aryl has 10 carbon atoms. In some embodiments, the aryl is phenyl. In some embodiments, the aryl is naphthyl.

[0333] 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 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 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 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 is a five- or six-membered heteroaryl ring. In other embodiments, the heteroaryl is an eight-, nine-, or ten-membered fused bicyclic heteroaryl ring. Exemplary heteroaryls include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, furyl, thienyl, quinolinyl, isoquinolinyl, 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, etc.

[0334] 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 a cyclized alkyl group. The term "C 3-8 cycloalkyl" or "C 3-14 cycloalkyl" refers to a cycloalkyl having 3 to 8 or 3 to 14 ring member carbon atoms, respectively. Cycloalkyl can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spiro, bridged rings. Cycloalkyl can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring-forming carbons (C 3-14 ). In some embodiments, cycloalkyl 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, cycloalkyl is monocyclic. In some embodiments, cycloalkyl is monocyclic or bicyclic. In some embodiments, cycloalkyl is C 3-8Monocyclic cycloalkyl. Cycloalkyl also includes cycloalkylene. In some embodiments, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, norpinyl, norcaranyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, and the like. In some embodiments, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0335] In the present invention, the term "heterocyclic group" refers to a monocyclic, fused-ring, spiro-ring or bridged-ring group that is fully saturated or partially saturated (but not aromatic as a whole). When the "heterocyclic group" is bicyclic or tricyclic, heteroatoms can be contained on any ring, or heteroatoms can be contained on both the bicyclic or tricyclic rings simultaneously. The "heterocyclic group" includes "heterocycloalkyl", "heterocycloalkenyl" and "heterocycloalkynyl".

[0336] In the present invention, the term "heterocycloalkyl" used alone or in combination with other terms refers to a fully saturated ring system (monocyclic, bicyclic or polycyclic) 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-membered, 5-membered, 6-membered and 7-membered heterocycloalkyl. Heterocycloalkyl can include a monocyclic or bicyclic (e.g., having two fused or bridged rings, spiro-connected rings) ring system. In some embodiments, the heterocycloalkyl is a monocyclic group having 1, 2 or 3 heteroatoms independently selected from N, S and O. Heterocycloalkyl can be linked via a ring-forming carbon atom or a ring-forming heteroatom. Examples of heterocycloalkyl include azetidinyl, azepanyl, N-morpholinyl, 3-oxa-9-azaspiro[5.5]undecanyl, 1-oxa-8-azaspiro[4.5]decanyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tropanyl.

[0337] In the present invention, the term "cycloalkenyl" used alone or in combination with other terms refers to a partially saturated ring system (monocyclic, fused-ring, spiro-ring or bridged-ring) that contains at least one carbon-carbon double bond and is not aromatic as a whole. When the "cycloalkenyl" is bicyclic or tricyclic, the bicyclic or tricyclic ring as a whole does not form an aromatic ring. For example, one or two of the rings can be partially saturated or aromatic rings, and the remaining rings are saturated rings or partially saturated rings.

[0338] In the present invention, when the "phenyl-fused 5-membered heteroaryl" is connected to the main structure, it can be connected from the phenyl or from the 5-membered heteroaryl. Other similar compound names can be understood with reference to the foregoing content.

[0339] In the present invention, it is preferred that the left connecting point of B is connected to M, and the right connecting point of B is connected to C.

[0340] Those skilled in the art should understand that when "-C(O)-" is used herein, it refers to the group When "-S(O)2-" is used, it refers to the group

[0341] In this article, unless otherwise clearly indicated, the description method "each independently selected from" adopted throughout this article can either mean that among different groups, the specific options expressed between the same or different symbols do not affect each other, or it can also mean that within the same group, the specific options expressed between the same or different symbols do not affect each other.

[0342] Advantages of the present invention:

[0343] The compounds of the present invention have excellent USP1 inhibitory activity, and at the same time have effects such as a longer half-life, a higher exposure amount, and good oral absorption performance, achieving unexpected technical effects. Description of the drawings

[0344] Figure 1 Tumor volume of human breast cancer MDA-MB-436 CDX model

[0345] Figure 2 Body weight of human breast cancer MDA-MB-436 CDX model Detailed implementation manners

[0346] The following further elaborates the content of the present invention in combination with specific examples, but the protection scope of the present invention is not limited to these examples only.

[0347] It should be understood that the terms adopted here are intended to describe specific implementation manners and are not intended to be limiting. In addition, although any methods, devices, and materials similar or equivalent to those described here can be used to implement or test the present invention, the methods, devices, and materials described now are preferred.

[0348] The NMR measurement was performed using a Bruker ASCENA-400 nuclear magnetic resonance instrument, the reaction monitoring and MS measurement were performed using a Thermofisher ESQ (ESI) mass spectrometer, the HPLC measurement was performed using a Thermo Fisher U3000 DAD high-pressure liquid chromatograph, the reverse-phase and normal-phase purification was performed using a biotage isera one type, and the preparative liquid chromatograph (prep-HPLC) model was Agilent 1290 Infinity 2nd generation.

[0349] Abbreviation description

[0350]

[0351] Intermediate I-1

[0352]

[0353] Step 1: Synthesis of I-1-3

[0354] 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 separate the residue by silica gel column chromatography to obtain 9.2 g of compound I-1-3. MS m / z (ESI): 285.08 [M+H] + 。

[0355] Step 2: Synthesis of I-1-4

[0356] Dissolve I-1-3 (9.2 g, 32.4 mmol) in THF (90 mL), add DIBAL-H (1 M, 97.2 mL, 97.2 mmol) dropwise at 0 °C. After the addition is complete, stir at 20 °C for 2 h. Slowly quench the reaction with water, add saturated ammonium chloride aqueous solution (100 mL) and EA (150 mL) for extraction and liquid separation. Dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the residue by silica gel column chromatography to obtain 8.2 g of compound I-1-4. MS m / z (ESI): 257.08 [M+H] + 。

[0357] Step 3: Synthesis of I-1-5

[0358] 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 solution under reduced pressure to obtain a crude product, and separate the crude product by silica gel column chromatography to obtain 8.1 g of compound I-1-5. MS m / z (ESI): 319.00 [M+H] + 。

[0359] Step 4: Synthesis of I-1

[0360] Under nitrogen protection, dissolve 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) in dioxane (150 mL), and stir at 100 °C for 3 hours. Filter, concentrate the filtrate under reduced pressure to obtain a crude product, and separate the crude product by silica gel column chromatography to obtain 5.6 g of compound I-1. MS m / z (ESI): 367.17 [M+H]+ .

[0361] Intermediate I-2

[0362]

[0363] Step 1: Synthesis of I-2-3

[0364] 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. 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 methanol (100 mL) solution containing I-2-1 (5.0 g, 30.5 mmol). Then, ammonia water (35 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 16 h. After the resulting mixture was concentrated under reduced pressure to remove the solvent, the obtained 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 obtained by silica gel column chromatography. MS m / z (ESI): 271.06 [M+H] + .

[0365] Step 2: Synthesis of I-2-4

[0366] 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. After the reaction solution was stirred at 0 °C for 0.5 h, methyl iodide (3.2 g, 22.0 mmol) was added, and the mixture was slowly warmed to room temperature and reacted for 2 h. The reaction solution was added to ice water (30 mL), and extracted with ethyl acetate (3 × 20 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-2-4. MS m / z (ESI): 285.08 [M+H] + .

[0367] Step 3: Synthesis of I-2-5

[0368] I-2-4 (3.0 g, 11.0 mmol) was added to THF (60 mL), and lithium aluminum hydride (1.3 g, 33.0 mmol) was added portionwise at 0 °C. The resulting mixture was stirred at 0 °C for 1 h, and then slowly warmed to room temperature and reacted for 1 h. Water (10 mL) and 15% aqueous NaOH solution (10 mL), and water (30 mL) were successively added to the reaction solution at 0 °C. The resulting mixture was stirred at room temperature for 1 h and then filtered through diatomaceous earth. The filter cake was rinsed with dichloromethane, and the combined filtrates were 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] + 。

[0369] Step 4: Synthesis of I-2-6

[0370] I-2-5 (2.0 g, 7.8 mmol) and triphenylphosphine (3.1 g, 11.7 mmol) were dissolved in acetonitrile (40 mL), and carbon tetrabromide (3.9 g, 11.7 mmol) was added at 0 °C. The mixture was stirred at room temperature for 3 h. The reaction solution was concentrated under reduced pressure to obtain a crude product, and the crude product was separated by silica gel column chromatography to obtain 1.5 g of compound I-2-6. MS m / z (ESI): 319.00 [M+H] + 。

[0371] Step 5: Synthesis of I-2

[0372] Under nitrogen protection, 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 the mixture was stirred at 100 °C for 3 h. 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 880.0 mg of compound I-2. MS m / z (ESI): 367.17 [M+H] + 。

[0373] Intermediate I-3

[0374]

[0375] Step 1: Synthesis of I-3-2

[0376] 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 methanol (200 mL) solution containing I-3-1 (15.0 g, 82.3 mmol). Then, ammonia water (70 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 16 h. After the resulting mixture was concentrated under reduced pressure to remove the solvent, the obtained 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] + 。

[0377] Step 2: Synthesis of I-3-3

[0378] I-3-2 (11.0 g, 38.2 mmol) was dissolved in DMF (200 mL), and the temperature was lowered to 0 °C. Under nitrogen protection, potassium carbonate (10.5 g, 76.4 mmol) was added thereto, and 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 the mixture was stirred at room temperature for 2 h. The reaction solution was slowly poured into ice water (500 mL), stirred for 2 minutes, extracted with ethyl acetate (3 × 50 mL), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 11.0 g of compound I-3-3. MS m / z (ESI): 303.07 [M+H] + 。

[0379] Step 3: Synthesis of I-3-4

[0380] 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, and the reaction was allowed to warm to room temperature and stirred overnight. LC-MS monitored the completion of the reaction of the raw materials. After cooling to room temperature, it was filtered and concentrated, and purified by silica gel column chromatography to give 8.6 g of compound I-3-4. MS m / z (ESI): 275.12 [M+H] + 。

[0381] Step 4: Synthesis of I-3-5

[0382] 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 solution under reduced pressure to obtain the crude product, and separate the crude product by silica gel column chromatography to obtain 8.5 g of compound I-3-5. MS m / z (ESI): 336.99 [M+H] + 。

[0383] Step 5: Synthesis of I-3

[0384] Under nitrogen protection, dissolve 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) in dioxane (150 mL) and stir at 100 °C for 3 hours. Filter, concentrate the filtrate under reduced pressure to obtain the crude product, and separate the crude product by silica gel column chromatography to obtain 5.2 g of compound I-3. MS m / z (ESI): 385.16 [M+H] + 。

[0385] Intermediate I-4

[0386]

[0387] Step 1: Synthesis of I-4-1

[0388] Under nitrogen protection, dissolve I-2-3 (3.0 g, 10.8 mmol) in DMF (50 mL). Add sodium hydride (0.5 g, 12.9 mmol) portionwise in an ice-water bath, stir in the ice-water bath for 1 hour, and then add 2-iodopropane (2.8 g, 16.5 mmol). Then stir at 70 °C for 4 hours. After the reaction solution is cooled to room temperature, slowly pour the reaction solution into ice water, extract with ethyl acetate (3×100 mL), wash with saturated brine 3 times, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain the crude product, and purify the crude product by normal-phase medium-pressure preparation to obtain 3.1 g of compound I-4-1. MS m / z (ESI): 313.11 [M+H] + 。

[0389] Step 2: Synthesis of I-4-2

[0390] Under nitrogen protection, 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 reaction 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 (3 N). It was extracted with ethyl acetate (2 × 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 medium-pressure preparative normal-phase chromatography to obtain 2.2 g of compound I-4-2. MS m / z (ESI): 285.11 [M+H] + 。

[0391] Step 3: Synthesis of I-4-3

[0392] I-4-2 (2.0 g, 7.0 mmol) and triphenylphosphine (2.8 g, 10.5 mmol) were dissolved in acetonitrile (100 mL). Carbon tetrabromide (3.5 g, 10.5 mmol) was added under an ice-water bath, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by medium-pressure preparative normal-phase chromatography to obtain 2.1 g of compound I-4-3. MS m / z (ESI): 347.03 [M+H] + 。

[0393] Step 4: Synthesis of I-4

[0394] Under nitrogen protection, 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 the mixture was stirred at 100 °C for 3 hours. It 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] + 。

[0395] Intermediate I-5

[0396]

[0397] Step 1: Synthesis of I-5-2

[0398] 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 h. 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, then ammonia water (25 mL) was added to the reaction solution, and stirring was continued overnight at room temperature. 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] + 。

[0399] Step 2: Synthesis of I-5-3

[0400] I-5-2 (4.4 g, 16.2 mmol) was dissolved in DMF (60 mL), potassium carbonate (3.4 g, 24.3 mmol) and methyl iodide (1.51 mL, 24.3 mmol) were added, and the mixture was stirred overnight at room temperature. Water (60 mL) was added, and the mixture was extracted with ethyl acetate (2×60 mL), washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 4.1 g of compound I-5-3. MS m / z (ESI): 286.07 [M+H] + 。

[0401] Step 3: Synthesis of I-5-4

[0402] I-5-3 (4.1 g, 14.4 mmol) was dissolved in dioxane (50 mL) and THF (50 mL), lithium borohydride (0.94 g, 43.1 mmol) was added at room temperature, and the mixture was stirred at 90 °C for 3 h. After cooling to room temperature, the reaction solution was slowly poured into ice water. The mixture was 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 by silica gel column chromatography to obtain 2.77 g of compound I-5-4. MS m / z (ESI): 258.08 [M+H] + 。

[0403] Step 4: Synthesis of I-5-5

[0404] I-5-4 (2.77 g, 10.8 mmol) and triphenylphosphine (4.2 g, 16.2 mmol) were dissolved in acetonitrile (100 mL), carbon tetrabromide (5.4 g, 16.2 mmol) was added, and the mixture was stirred at room temperature for 3 h. Silica gel was directly added for sample mixing. The mixture was separated by silica gel column chromatography to obtain 2.4 g of compound I-5-5. MS m / z (ESI): 319.99 [M+H]+ .

[0405] Step 5: Synthesis of I-5-6

[0406] 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), extract with ethyl acetate (2 × 50 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 by silica gel column chromatography to obtain 1.8 g of compound I-5-6. MS m / z (ESI): 267.08 [M+H] + .

[0407] Step 6: Synthesis of I-5

[0408] Dissolve I-5-6 (1.8 g, 6.8 mmol) in methanol (20 mL), add TMSCl (8.5 mL, 67.6 mmol) at room temperature, and stir at 65 °C for 4 hours. Concentrate the reaction solution under reduced pressure. Dilute the obtained residue with water, adjust the pH to 7 - 8 with saturated sodium bicarbonate, extract with ethyl acetate (2 × 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 by silica gel column chromatography to obtain 1.5 g of compound I-5. MS m / z (ESI): 300.09 [M+H] + .

[0409] Intermediate I-6

[0410]

[0411] Step 1: Synthesis of I-6-1

[0412] Under nitrogen protection, dissolve I-2-6 (21.0 g, 65.8 mmol) and TMSCN (16.1 mL, 92.2 mmol) in acetonitrile (200 mL), add TBAF (85.5 mL, 85.5 mmol) in an ice bath, and stir at room temperature for 2 hours. Add water (400 mL), extract with ethyl acetate (2 × 300 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 by silica gel column chromatography to obtain 14.0 g of compound I-6-1. MS m / z (ESI): 266.08 [M+H] + .

[0413] Step 2: Synthesis of I-6

[0414] Dissolve I-6-1 (14.0 g, 52.8 mmol) in methanol (200 mL), add TMSCl (66 mL, 528.3 mmol) at room temperature, and stir at 65 °C for 4 hours. Concentrate the reaction solution under reduced pressure. Dilute the obtained residue with water, adjust the pH to 7 - 8 with saturated sodium bicarbonate, extract with ethyl acetate (2 × 300 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 by silica gel column chromatography to obtain 14.9 g of compound I-6. MS m / z (ESI): 299.09 [M+H] + 。

[0415] Intermediate I-7

[0416]

[0417] Step 1: Synthesis of I-7-1

[0418] Dissolve I-3-2 (12.4 g, 43.0 mmol) in DMF (100 mL), add cesium carbonate (70.1 g, 215.1 mmol) and isopropyl iodide (36.6 g, 215.1 mmol), and stir at 90 °C overnight. Slowly pour the reaction solution into ice water (300 mL), stir for 2 minutes, then extract with ethyl acetate (3 × 200 mL). Combine the organic phases, wash with saturated brine (3 × 100 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the residue by silica gel column chromatography to obtain 11.2 g of compound I-7-1. MS m / z (ESI): 331.20 [M+H] + 。

[0419] Step 2: Synthesis of I-7-2

[0420] Dissolve I-7-1 (11.2 g, 33.9 mmol) in THF (20 mL) and 1,4-dioxane (40 mL), add lithium borohydride (2.2 g, 101.7 mmol), heat to 90 °C under nitrogen protection, and stir for 2 hours. Cool to room temperature, quench with ice water (50 mL), add saturated brine (100 mL), extract with ethyl acetate (2 × 100 mL). Combine the organic phases, wash with saturated brine (2 × 60 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the residue by silica gel column chromatography to obtain 7.1 g of compound I-7-2. MS m / z (ESI): 303.19 [M+H] + 。

[0421] Step 3: Synthesis of I-7-3

[0422] 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 an ice-water bath, and stir at room temperature for 3 hours. Concentrate under reduced pressure. 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] + 。

[0423] Step 4: Synthesis of I-7

[0424] Under nitrogen protection, dissolve I-7-3 (400.0 mg, 1.10 mmol) in dioxane (5 mL). Add 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). Stir the mixture at 100 °C overnight. After the reaction is completed, add 200 mL of water to the mixture, extract with ethyl acetate (3×20 mL). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. The obtained mixture is separated and purified by normal-phase chromatography column to obtain 300.0 mg of compound I-7. MS m / z (ESI): 413.30 [M+H] + 。

[0425] Intermediate I-8

[0426]

[0427] Step 1: Synthesis of I-8-1

[0428] Under nitrogen protection, dissolve I-5-2 (2.2 g, 8.11 mmol) in DMF (20 mL). Add sodium hydride (1.0 g, 24.34 mmol) portionwise under an ice bath. Stir for 1 hour under the ice bath, then add isopropyl iodide (3.24 mL, 32.45 mmol), and then stir at 70 °C for 4 hours. After the reaction solution is cooled to room temperature, slowly pour the reaction solution into ice water, extract with ethyl acetate (2×20 mL), wash with saturated brine 3 times, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 2.3 g of crude compound I-8-1. MS m / z (ESI): 314.0 [M+H] + 。

[0429] Step 2: Synthesis of I-8-2

[0430] Dissolve I-8-1 (2.3 g, 7.34 mmol) in a mixed solvent of dioxane (20 mL) and THF (20 mL), add lithium borohydride (0.5 g, 22.02 mmol), and stir at 90 °C for 2 hours. Cool to room temperature, slowly pour the reaction solution into ice water, extract with ethyl acetate (2×20 mL), wash twice 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 565.0 mg of compound I-8-2. MS m / z (ESI): 286.2 [M+H] + 。

[0431] Step 3: Synthesis of I-8-3

[0432] 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. Directly add silica gel for sample mixing, and purify by silica gel column chromatography to obtain 220.0 mg of compound I-8-3. MS m / z (ESI): 348.1 [M+H] + 。

[0433] Step 4: Synthesis of I-8-4

[0434] Under nitrogen protection, dissolve I-8-3 (220.0 mg, 0.63 mmol) and TMSCN (0.11 mL, 0.88 mmol) in acetonitrile (5 mL), add TBAF (0.82 mL, 0.82 mmol) under ice bath, and stir at room temperature for 2 hours. Add water (10 mL), extract with ethyl acetate (2×10 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 purified by silica gel column chromatography to obtain 173.0 mg of compound I-8-4. MS m / z (ESI): 295.0 [M+H] + 。

[0435] Step 5: Synthesis of I-8

[0436] Dissolve I-8-4 (173.0 mg, 0.59 mmol) in methanol (5 mL), add TMSCl (0.74 mL, 5.88 mmol) at room temperature, and stir at 70 °C for 4 hours. Concentrate the reaction solution under reduced pressure. Add water (5 mL) to the obtained residue, adjust the pH to 7 - 8 with sodium carbonate, extract with ethyl acetate (2×10 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 purified by silica gel column chromatography to obtain 152.0 mg of compound I-8. MS m / z (ESI): 328.0 [M+H] + 。

[0437] Intermediate I-9

[0438]

[0439] Step 1: Synthesis of I-9-3

[0440] Under nitrogen protection, dissolve I-9-1 (3.0 g, 35.19 mmol) and I-9-2 (5.0 g, 35.19 mmol) in THF (100 mL) and methanol (100 mL), add sodium methoxide (14.08 mL, 5 M), stir the mixture at 60 °C overnight. After the reaction is completed, cool it in an ice-water bath, add 2N dilute hydrochloric acid to quench the reaction, extract with ethyl acetate (3 * 50 mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. The obtained mixture is separated and purified by a normal-phase chromatography column to obtain 4.0 g of compound I-9-3. MS m / z (ESI): 181.04 [M+H] + 。

[0441] Step 2: Synthesis of I-9-4

[0442] 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 separate the residue by silica gel column chromatography to obtain 4.0 g of compound I-9-4. MS m / z (ESI): 311.08 [M+H] + 。

[0443] Step 3: Synthesis of I-9-5

[0444] Dissolve I-9-4 (4.0 g, 12.89 mmol) in THF (90 mL), add DIBAL-H (1 M, 19.3 mL, 19.33 mmol) dropwise at 0 °C. After the addition is complete, stir at 20 °C for 2 h. Slowly add water to quench the reaction, add saturated ammonium chloride aqueous solution (100 mL) and EA (150 mL) for extraction and separation. Dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the residue by silica gel column chromatography to obtain 3.0 g of compound I-9-5. MS m / z (ESI): 283.10 [M+H] + 。

[0445] Step 4: Synthesis of I-9-6

[0446] 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 solution under reduced pressure to obtain a crude product, and separate the crude product by silica gel column chromatography to obtain 3.0 g of compound I-9-6. MS m / z (ESI): 345.01 [M+H] + 。

[0447] Step 5: Synthesis of I-9

[0448] Under nitrogen protection, dissolve I-9-6 (400.0 mg, 1.10 mmol) in 5 mL of dioxane, add 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). Stir the mixture at 100 °C overnight. After the reaction is completed, add water (200 mL) to the mixture, extract with ethyl acetate (3 × 20 mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. The obtained mixture is separated and purified by a normal-phase chromatography column to obtain 300.0 mg of compound I-9. MS m / z (ESI): 393.30 [M+H] + 。

[0449] Intermediate I-10

[0450]

[0451] Step 1: Synthesis of I-10-2

[0452] Dissolve I-10-1 (20.0 g, 118.20 mmol) in 37% aqueous hydrochloric acid (100 mL). Add an aqueous solution (40 mL) of sodium nitrite (8.2 g, 118.20 mmol) at 0 °C. After addition, stir for 10 minutes. Then, dropwise add stannous chloride (112.1 g, 591.02 mmol) dissolved in 37% aqueous hydrochloric acid (100 mL) at 0 °C. After addition, warm up to 25 °C and stir for 2 hours. Filter to obtain a filter cake, wash the filter cake with ethyl acetate (3 × 50 mL), and dry to obtain 24.0 g of compound I-10-2. MS m / z (ESI): 185.14 [M+H] + 。

[0453] Step 2: Synthesis of I-10-3

[0454] Dissolve I-10-2 (23.0 g, 124.86 mmol) and 1,1,1-trifluoro-2,4-pentanedione (15.15 mL, 124.86 mmol) in hexafluoroisopropanol (150 mL). Dropwise add triethylamine (34.62 mL, 249.73 mmol) dissolved in hexafluoroisopropanol (100 mL) at 0 °C. After addition, warm the temperature to 25 °C and stir for 1 hour. Add water (200 mL), extract with dichloromethane (200 mL), wash with saturated brine (200 mL), dry over anhydrous sodium sulfate, filter to obtain a filtrate, concentrate under reduced pressure to get a crude product, and purify the crude product by silica gel column chromatography to obtain 27.4 g of compound I-10-3. MS m / z (ESI): 303.12 [M+H] + 。

[0455] Step 3: Synthesis of I-10-4

[0456] Dissolve I-10-3 (26.4 g, 87.36 mmol) in a mixed solvent of 1,4-dioxane (120 mL) and THF (30 mL). Add lithium borohydride (5.7 g, 262.08 mmol) at room temperature and stir at 90 °C for 2 hours. Cool to room temperature, slowly pour the reaction solution into ice water, extract with ethyl acetate (500 mL), wash with saturated brine (500 mL), dry over anhydrous sodium sulfate, filter to obtain a filtrate, concentrate under reduced pressure to get a crude product, and purify the crude product by silica gel column chromatography to obtain 23.0 g of compound I-10-4. MS m / z (ESI): 275.13 [M+H] + 。

[0457] Step 4: Synthesis of I-10-5

[0458] 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. Concentrate the reaction solution to get a crude product, and purify the crude product by silica gel column chromatography to obtain 24.6 g of compound I-10-5. MS m / z (ESI): 339.10 [M+H] + 。

[0459] Step 5: Synthesis of I-10

[0460] Under nitrogen protection, dissolve I-10-5 (6.0 g, 17.80 mmol) in 1,4-dioxane (90 mL), add 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), and stir at 100 °C for 2 hours. Cool the reaction mixture to room temperature, filter to obtain the filtrate, concentrate it under reduced pressure to obtain the crude product, and purify the crude product by silica gel column chromatography to obtain 4.2 g of compound I-10. MS m / z (ESI): 385.22 [M+H] + 。

[0461] Intermediate I-11

[0462]

[0463] Step 1: Synthesis of I-11-1

[0464] Dissolve I-3-2 (3.0 g, 10.41 mmol) in DMF (50 mL), add potassium carbonate (2.9 g, 20.82 mmol) and methyl iodide-d (2.3 g, 15.61 mmol) at room temperature, and react at room temperature for 2 h. Add the reaction mixture to ice water (100 mL), extract with ethyl acetate (2×50 mL), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 3.0 g of compound I-11-1. MS m / z (ESI): 306.10 [M+H] + 。

[0465] Step 2: Synthesis of I-11-2

[0466] Dissolve I-11-1 (3.0 g, 9.83 mmol) in THF (30 mL) and 1,4-dioxane (30 mL), add lithium borohydride (0.6 g, 29.49 mmol) at room temperature, heat to 80 °C and stir for 2 hours. Monitor the reaction of the raw materials by LC-MS until completion, cool to room temperature, slowly pour the reaction mixture into ice water, extract with ethyl acetate (2×50 mL), wash twice with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography to obtain 2.0 g of compound I-11-2. MS m / z (ESI): 278.10 [M+H] + 。

[0467] Step 3: Synthesis of I-11-3

[0468] 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 the mixture overnight at room temperature. Concentrate the reaction solution under reduced pressure to obtain a crude product, and separate the crude product by silica gel column chromatography to obtain 2.0 g of compound I-11-3. MS m / z (ESI): 340.00 [M+H] + 。

[0469] Step 4: Synthesis of I-11

[0470] Under nitrogen protection, dissolve I-11-3 (2.0 g, 5.88 mmol) in dioxane (50 mL), add 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). Stir the mixture at 100 °C overnight. After the reaction is completed, add water (50 mL) to the mixture, extract with ethyl acetate (2 × 50 mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. Purify the obtained mixture by normal-phase chromatography column to obtain 2.1 g of compound I-11. MS m / z (ESI): 388.20 [M+H] + 。

[0471] Intermediate I-12

[0472]

[0473] Step 1: Synthesis of I-12-b

[0474] Dissolve I-12-a (1.0 g, 5.65 mmol) in dichloromethane (20 mL), add m-chloroperoxybenzoic acid (1.0 g, 5.65 mmol), and stir the mixture overnight at room temperature. After the reaction is completed, add water (100 mL) to the mixture, extract with dichloromethane (3 × 20 mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. Purify the obtained mixture by normal-phase chromatography column to obtain 700.0 mg of compound I-12-b. MS m / z (ESI): 194.10 [M+H] + 。

[0475] Step 2: Synthesis of I-12-c

[0476] Dissolve I-12-b (700.0 mg, 3.63 mmol) in toluene (20 mL), add phosphorus oxychloride (2078.6 mg, 7.25 mmol), stir the mixture at 100 °C overnight. After the reaction is completed, add water (100 mL) to the mixture, extract with ethyl acetate (3×20 mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. The resulting mixture is 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] + 。

[0477] Step 3: Synthesis of I-12-e

[0478] Under nitrogen protection, dissolve I-12-c (300.0 mg, 1.17 mmol) in dioxane (10 mL), add 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), stir the mixture at 80 °C overnight. After the reaction is completed, add water (50 mL) to the mixture, extract with ethyl acetate (3×20 mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. The resulting mixture is 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] + 。

[0479] Step 4: Synthesis of I-12-f

[0480] Dissolve I-12-e (250.0 mg, 0.94 mmol) in carbon tetrachloride (20 mL), add AIBN (153.6 mg, 0.94 mmol) and NBS (199.8 mg, 1.20 mmol) under nitrogen protection, stir the mixture at 80 °C overnight. After the reaction is completed, add water (IOO mL) to the mixture, extract with ethyl acetate (3×20 mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. The resulting mixture is 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] + 。

[0481] Step 5: Synthesis of I-12

[0482] Dissolve I-12-f (200.0 mg, 0.58 mmol) in dioxane (10 mL). Under nitrogen protection, add 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). Stir the mixture at 100 °C overnight. After the reaction is completed, add water (200 mL) to the mixture, extract with ethyl acetate (3 × 20 mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. The obtained mixture is separated and purified by a normal-phase chromatography column to obtain 180.0 mg of compound I-12. MS m / z (ESI): 394.21 [M+H] + 。

[0483] Intermediate I-13

[0484]

[0485] Step 1: Synthesis of I-13-c

[0486] Dissolve I-13-a (2.0 g, 8.85 mmol) in dioxane (50 mL). Under nitrogen protection, add 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). Stir the mixture at 100 °C overnight. After the reaction is completed, add water (200 mL) to the mixture, extract with ethyl acetate (3 × 20 mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. The obtained mixture is separated and purified by a normal-phase chromatography column to obtain 1.0 g of compound I-13-c. MS m / z (ESI): 162.08 [M+H] + 。

[0487] Step 2: Synthesis of I-13-d

[0488] Dissolve I-13-c (1.0 g, 6.21 mmol) in dichloromethane (20 mL). Add m-chloroperbenzoic acid (2.1 g, 12.42 mmol). Stir the mixture at room temperature overnight. After the reaction is completed, add water (100 mL) to the mixture, extract with dichloromethane (3 × 20 mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. The obtained mixture is separated and purified by a normal-phase chromatography column to obtain 800.0 mg of compound I-13-d. MS m / z (ESI): 178.12 [M+H] + 。

[0489] Step 3: Synthesis of I-13-e

[0490] I-13-d (800.0 mg, 4.52 mmol) was dissolved in toluene (20 mL), and phosphorus oxychloride (2590.2 mg, 9.03 mmol) was added. The mixture was stirred overnight at 100 °C. 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. The resulting 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] + 。

[0491] Step 4: Synthesis of I-13-f

[0492] Under nitrogen protection, 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 overnight at 80 °C. 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. The resulting mixture 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] + 。

[0493] Step 5: Synthesis of I-13-g

[0494] I-13-f (230.0 mg, 0.92 mmol) was dissolved in carbon tetrachloride (20 mL). Under nitrogen protection, AIBN (150.3 mg, 0.92 mmol) and NBS (162.9 mg, 0.92 mmol) were added. The mixture was stirred overnight at 80 °C. 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. The resulting 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] + 。

[0495] Step 6: Synthesis of I-13

[0496] Dissolve I-13-g (100.0 mg, 0.30 mmol) in dioxane (10 mL). Under nitrogen protection, add 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). Stir the mixture at 100 °C overnight. After the reaction is completed, add water (200 mL) to the mixture, extract with ethyl acetate (3×20 mL). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. The resulting mixture is separated and purified by normal-phase chromatography to obtain 100.0 mg of compound I-13. MS m / z (ESI): 378.23 [M+H] + 。

[0497] Intermediate I-14

[0498]

[0499] Step 1: Synthesis of I-14-2

[0500] Referring to the synthesis of I-4-1, use I-2-3 (1.0 g, 3.70 mmol) and replace 2-iodopropane with I-14-1 (0.9 g, 7.40 mmol). React at room temperature for 2 h. After the same post-treatment, concentrate under reduced pressure to obtain 600.0 mg of compound I-14-2. MS m / z (ESI): 311.28 [M+H] + 。

[0501] Step 2: Synthesis of I-14-3

[0502] Referring to the synthesis of I-1-4, replace I-1-3 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] + 。

[0503] Step 3: Synthesis of I-14-4

[0504] Referring to the synthesis of I-1-5, replace I-1-4 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] + 。

[0505] Step 4: Synthesis of I-14

[0506] With reference to the synthesis of I-7, replace I-7-3 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] + 。

[0507] Intermediate I-15

[0508]

[0509] Step 1: Preparation of I-15-1

[0510] With reference to the synthesis of I-11-1, replace I-3-2 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] + 。

[0511] Step 2: Synthesis of I-15-2

[0512] With reference to the synthesis of I-11-2, replace I-11-1 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] + 。

[0513] Step 3: Synthesis of I-15-3

[0514] With reference to the synthesis of I-1-5, replace I-1-4 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] + 。

[0515] Step 4: Synthesis of I-15

[0516] With reference to the synthesis of I-7, replace I-7-3 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] + 。

[0517] Intermediate I-16

[0518]

[0519] Step 1: Synthesis of I-16-2

[0520] Dissolve I-16-1 (24.0 g, 104.8 mmol) in DMF (200 mL), add potassium carbonate (29.0 g, 209.6 mmol) and methyl iodide (9.8 mL, 157.21 mmol), react at room temperature for 3 hours. Add the reaction solution to water (1000 mL), extract with ethyl acetate (3 * 300 mL). Combine the organic phases, wash with saturated brine (300 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify by silica gel column chromatography to obtain 22.5 g of compound I-16-2. MS m / z (ESI): 242.96 [M+H] + 。

[0521] Step 2: Synthesis of I-16-3

[0522] At room temperature, add I-2-2 (37.5 g, 138.83 mmol) and sodium acetate (12.8 g, 138.83 mmol) to water (200 mL). Stir and heat the resulting mixture at 100 °C for 1 h. Cool the reaction solution to room temperature, slowly add it dropwise to a methanol (200 mL) solution containing I-16-2 (22.5 g, 92.55 mmol). Then add ammonia water (200 mL) to the reaction solution and stir and react at 90 °C for 2 h. After concentrating the resulting mixture under reduced pressure to remove the solvent, add the resulting residue to water (300 mL), extract with ethyl acetate (3 * 100 mL), wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify by silica gel column chromatography to obtain 8.7 g of compound I-16-3. MS m / z (ESI): 348.97 [M+H] + 。

[0523] Step 3: Synthesis of I-16-4

[0524] Dissolve I-16-3 (8.6 g, 24.63 mmol) in DMF (100 mL), add potassium carbonate (6.8 g, 49.27 mmol) and benzyl bromide (6.3 g, 36.95 mmol), react at room temperature for 4 h. Add the reaction solution to ice water (500 mL), extract with ethyl acetate (3 * 200 mL). Combine the organic phases, wash with saturated brine (200 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify by silica gel column chromatography to obtain 8.3 g of compound I-16-4. MS m / z (ESI): 439.02 [M+H] + 。

[0525] Step 4: Synthesis of I-16-5

[0526] Under nitrogen protection, dissolve I-16-4 (3.3 g, 7.51 mmol) in triethylamine (30 mL), add but-3-yn-2-ol (2.87 g, 22.54 mmol, 55% in water), Pd(PPh3)2Cl2 (1.05 g, 1.5 mmol) and copper(I) iodide (572 mg, 3.0 mmol), stir at 80 °C for 12 h, add the reaction solution to water (50 mL), extract with ethyl acetate (3 × 20 mL), combine the organic phases, wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify by silica gel column chromatography to obtain 2.4 g of compound I-16-5. MS m / z (ESI): 429.13 [M+H] + 。

[0527] Step 5: Synthesis of I-16-6

[0528] Dissolve I-16-5 (2.4 g, 5.6 mmol) in methanol (30 mL), add palladium on carbon (500.0 mg) and palladium hydroxide (500.0 mg), displace with hydrogen, heat to 50 °C and react for 12 h, filter through diatomaceous earth, 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] + 。

[0529] Step 6: Synthesis of I-16-7

[0530] Dissolve I-16-6 (2.4 g, 5.6 mmol) in THF (30 mL), add palladium on carbon (500.0 mg) and palladium hydroxide (500.0 mg), displace with hydrogen, heat to 50 °C and react for 12 h, filter through diatomaceous earth, 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] + 。

[0531] Step 7: Synthesis of I-16-8

[0532] Under nitrogen protection, dissolve I-16-7 (1.2 g, 3.5 mmol) in THF (10 mL), add triphenylphosphine (3.68 g, 14.02 mmol), cool to 0 °C, dropwise add diethyl azodicarboxylate (12.44 g, 14.02 mmol), allow to warm to room temperature and react for 12 h, add the reaction solution to water (30 mL), extract with ethyl acetate (3 × 10 mL), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify by silica gel column chromatography to obtain 1.08 g of compound I-16-8. MS m / z (ESI): 325.11 [M+H] + 。

[0533] Step 8: Synthesis of I-16-9

[0534] Under nitrogen protection, dissolve I-16-8 (1.03 g, 3.18 mmol) in THF (10 mL), cool down to 0 °C, add lithium aluminum hydride (362.5 mg, 9.54 mmol), naturally warm up to room temperature and react for 1 hour. Add the reaction solution to water (50 mL), extract with ethyl acetate (3×20 mL). Combine the organic phases, wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify by silica gel column chromatography to obtain 580.0 mg of compound I-16-9. MS m / z (ESI): 297.11 [M+H] + 。

[0535] Step 9: Synthesis of I-16-10

[0536] Under nitrogen protection, dissolve I-16-9 (530.0 mg, 1.79 mmol) and triphenylphosphine (938.4 mg, 3.58 mmol) in acetonitrile (5 mL), add carbon tetrabromide (1186.3 mg, 3.58 mmol) under ice bath, stir at room temperature for 4 hours. Concentrate the reaction solution under reduced pressure to obtain the crude product, and purify the crude product by medium-pressure preparative purification in the normal phase to obtain 430.0 mg of compound I-16-10. MS m / z (ESI): 359.03 [M+H] + 。

[0537] Step 10: Synthesis of I-16

[0538] Under nitrogen protection, dissolve 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) in dioxane (5 mL), heat from room temperature to 80 °C, stir for 2 hours, concentrate under reduced pressure to obtain the crude product, and purify by silica gel column chromatography to obtain 300.0 mg of compound I-16. MS m / z (ESI): 407.2 [M+H] + 。

[0539] Intermediate I-17

[0540]

[0541] Step 1: Synthesis of I-17-2

[0542] 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 combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography gave 3.2 g of compound I-17-2. MS m / z (ESI): 401.14 [M+H] + 。

[0543] Step 2: Synthesis of I-17-3

[0544] Compound I-17-2 (3.0 g, 7.49 mmol) was dissolved in THF (50 mL). The atmosphere was replaced with nitrogen, and the temperature was lowered to 0 °C. Borane-tetrahydrofuran complex (22.5 mL, 22.47 mmol) was added dropwise. The mixture was allowed to warm to room temperature and react for 3 hours. Then, hydrogen peroxide (20 mL) was slowly added under an ice-water bath, and the mixture was 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 combined organic phases were 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] + 。

[0545] Step 3: Synthesis of I-17-4

[0546] I-17-3 (1.35 g, 3.23 mmol) was dissolved in methanol (20 mL). Palladium on 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 diatomaceous earth, 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] + 。

[0547] Step 4: Synthesis of I-17-5

[0548] 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] + 。

[0549] Step 5: Synthesis of I-17-6

[0550] Under nitrogen protection, I-17-5 (700.0 mg, 2.25 mmol) was dissolved in THF (10 mL), the temperature was lowered to 0 °C, lithium borohydride (124.0 mg, 5.64 mmol) was added, and the mixture was allowed to rise to room temperature and react for 1 hour. The reaction solution was added to water (30 mL), and extracted with ethyl acetate (3 × 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 360.0 mg of compound I-17-6. MS m / z (ESI): 283.1 [M+H] + 。

[0551] Step 6: Synthesis of I-17-7

[0552] Referring to the synthesis of I-16-10, I-16-9 was replaced with I-17-6 (360.0 mg, 1.28 mmol), and the mixture was stirred at room temperature for 6 hours. After the same work-up, 300.0 mg of compound I-17-7 was obtained. MS m / z (ESI): 345.01 [M+H] + 。

[0553] Step 7: Synthesis of I-17

[0554] 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] + 。

[0555] Intermediate I-18

[0556]

[0557] Step 1: Synthesis of I-18-2

[0558] Under nitrogen protection, 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 the mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding saturated ammonium chloride aqueous solution, and extracted with ethyl acetate (2 × 100 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered to obtain a filtrate, and concentrated under reduced pressure to obtain a crude product. The crude product 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] + 。

[0559] Step 2: Synthesis of I-18-3

[0560] Dissolve I-18-2 (15.7 g, 58.3 mmol) in DCM (20 mL), add HCl / 1,4-dioxane (62.01 mL, 4N), and stir at room temperature for 1 hour. Concentrate the reaction solution and dry to obtain 10.7 g of compound I-18-3 hydrochloride. MS m / z (ESI): 170.12 [M+H] + 。

[0561] Step 3: Synthesis of I-18-5

[0562] Dissolve I-18-3 (10.7 g, 52.05 mmol) and I-18-4 (9.7 g, 53.83 mmol) in DMF (120 mL), add HATU (24.6 g, 64.59 mmol), stir at room temperature for 5 minutes, then add DIEA (37.49 mL, 215.32 mmol), and stir at room temperature for 1 hour. Quench with water (300 mL), extract with ethyl acetate (2 * 200 mL), combine the organic phases, wash with saturated brine (2 * 200 mL), dry over anhydrous sodium sulfate, filter to obtain the filtrate, concentrate under reduced pressure to obtain the crude product, and purify the crude product by silica gel column chromatography to obtain 16.3 g of compound I-18-5. MS m / z (ESI): 332.12 [M+H] + 。

[0563] Step 4: Synthesis of I-18-6

[0564] Under nitrogen protection, dissolve I-18-5 (15.0 g, 45.28 mmol) in DCM (150 mL), add Dess-Martin oxidant (25.0 g, 58.86 mmol) under an ice-water bath, and stir at room temperature overnight. Add saturated aqueous sodium thiosulfate solution (150 mL) and stir for 20 minutes, then add saturated aqueous sodium bicarbonate solution (150 mL) and stir for 10 minutes, separate the layers, wash with saturated brine (200 mL), dry over anhydrous sodium sulfate, filter to obtain the filtrate, concentrate under reduced pressure to obtain the crude product, and purify the crude product by silica gel column chromatography to obtain 14.5 g of compound I-18-6. MS m / z (ESI): 330.11 [M+H] + 。

[0565] Step 5: Synthesis of I-18-7

[0566] I-18-6 (7.0 g, 21.26 mmol) and ammonium trifluoroacetate (4.35 mL, 46.16 mmol) were added to a reaction flask and heated to 130 °C with stirring for 1.5 h. After cooling to room temperature, the reaction was quenched by adding water (30 mL), and the mixture was extracted with ethyl acetate (2 × 50 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered to obtain a filtrate, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography to give 6.0 g of compound I-18-7. MS m / z (ESI): 311.13 [M+H] + 。

[0567] Step 6: Synthesis of I-18-8

[0568] 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] + 。

[0569] Step 7: Synthesis of I-18-9

[0570] Under nitrogen protection, I-18-8 (4.88 g, 17.27 mmol) was dissolved in DCM (50 mL), and phosphorus tribromide (4.67 g, 17.27 mmol) was added under an ice-water bath. The mixture was stirred at room temperature overnight. The pH was adjusted to 9 by adding saturated aqueous sodium bicarbonate solution, and the layers were separated. The organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered to obtain a filtrate, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography to give 4.47 g of compound I-18-9. MS m / z (ESI): 345.20 [M+H] + 。

[0571] Step 8: Synthesis of I-18-10

[0572] 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] + 。

[0573] Step 9: Synthesis of I-18

[0574] Referring to the synthesis of I-5, I-5-6 was replaced with I-18-10 (2.7 g, 9.27 mmol), and the mixture was stirred at 70 °C overnight. After the same post-treatment, 2.6 g of compound I-18 was obtained. MS m / z (ESI): 325.14 [M+H] + 。

[0575] Intermediate I-19

[0576]

[0577] Step 1: Synthesis of I-19-1

[0578] Under nitrogen protection, I-3-5 (8.0 g, 23.73 mmol) and TMSCN (3.7 g, 33.22 mmol) were dissolved in acetonitrile (150 mL). A THF solution of TBAF (30.85 mL, 1 M) was added under an ice bath, 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 × 100 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 4.1 g of compound I-19-1. MS m / z (ESI): 284.1 [M+H] + 。

[0579] Step 2: Synthesis of I-19

[0580] Referring to the synthesis of I-5, I-5-6 was replaced with I-19-1 (4.1 g, 14.48 mmol), and the mixture was stirred at 65 °C overnight. After the same post-treatment, 3.8 g of compound I-19 was obtained. MS m / z (ESI): 317.1 [M+H] + 。

[0581] Intermediate I-20

[0582]

[0583] Step 1: Synthesis of I-20-1

[0584] 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] + 。

[0585] Step 2: Synthesis of I-20

[0586] Referring to the synthesis of I-5, I-5-6 was replaced with I-20-1 (826.0 mg, 2.8 mmol), and the mixture was stirred at 70 °C for 4 hours. After the same post-treatment, 803.0 mg of compound I-20 was obtained. MS m / z (ESI): 327.20 [M+H] + 。

[0587] Intermediate I-21

[0588]

[0589] Step 1: Synthesis of I-21-1

[0590] Referring to the synthesis of I-5-6, replace I-5-5 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] + .

[0591] Step 1: Synthesis of I-21

[0592] Referring to the synthesis of I-5, replace I-5-6 with I-21-1 (658.0 mg, 2.5 mmol), and stir at 70 °C for 4 hours. After the same post-treatment, 573.0 mg of compound I-21 was obtained. MS m / z (ESI): 302.00 [M+H] + .

[0593] Intermediate I-22

[0594]

[0595] Step 1: Synthesis of I-22-b

[0596] Referring to the synthesis of I-12-b, replace I-12-a 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] + .

[0597] Step 2: Synthesis of I-22-c

[0598] Referring to the synthesis of I-12-c, replace I-12-b with I-22-b (1.2 g, 6.85 mmol), and replace phosphorus oxychloride with phosphorus trichloride (2.1 g, 13.71 mmol) to obtain 800.0 mg of compound I-22-c. MS m / z (ESI): 194.09 [M+H] + .

[0599] Step 3: Synthesis of I-22-d

[0600] Referring to the synthesis of I-12-e, I-12-d (674.44 mg, 4.96 mmol), replace I-12-c 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] + .

[0601] Step 4: Synthesis of I-22-e

[0602] With reference to the synthesis of I-12-f, replace I-12-e 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] + 。

[0603] Step 5: Synthesis of I-22

[0604] With reference to the synthesis of I-7, replace I-7-3 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] + 。

[0605] Intermediate I-23

[0606]

[0607] Step 1: Synthesis of I-23-1

[0608] With reference to the synthesis of I-5-6, replace I-5-5 with I-9-6 (5.0 g, 14.5 mmol). After the same post-treatment, concentrate the filtrate under reduced pressure to obtain 5.1 g of crude compound I-23-1. MS m / z (ESI): 292.10 [M+H] + 。

[0609] Step 2: Synthesis of I-23

[0610] With reference to the synthesis of I-5, replace I-5-6 with I-23-1 (5.1 g, 14.0 mmol), and stir at 70 °C for 4 hours. After the same post-treatment, 4.2 g of compound I-23 is obtained. MS m / z (ESI): 325.20 [M+H] + 。

[0611] Intermediate I-24

[0612]

[0613] Step 1: Synthesis of I-24-2

[0614] 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 h. The reaction solution was cooled to room temperature and slowly added dropwise to a methanol (50 mL) solution containing I-2-2 (9.9 g, 36.9 mmol). Then, ammonia water (25 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 16 h. After the resulting mixture was concentrated under reduced pressure to remove the solvent, the obtained 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 obtained by silica gel column chromatography. MS m / z (ESI): 256.04 [M+H] + 。

[0615] Step 2: Synthesis of I-24-3

[0616] 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. After the reaction solution was stirred at 20 °C for 0.5 h, methyl iodide (8.4 g, 58.8 mmol) was added and stirred for 2 h. The reaction solution was added to water (30 mL), and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4.0 g of compound I-24-3. MS m / z (ESI): 270.06 [M+H] + 。

[0617] Step 3: Synthesis of I-24

[0618] 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 h and then slowly returned to room temperature and reacted for 8 h. After the same post-treatment, 3.0 g of compound I-24 was obtained. MS m / z (ESI): 274.09 [M+H] + 。

[0619] Intermediate I-25

[0620]

[0621] Step 1: Synthesis of I-25-1

[0622] 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] + 。

[0623] Step 2: Synthesis of I-25

[0624] Referring to the synthesis of I-5, replace I-5-6 with I-25-1 (5.0 g, 17.7 mmol), and stir at 70 °C overnight. After the same post-treatment, 5.1 g of compound I-25 was obtained. MS m / z (ESI): 317.08 [M+H] + .

[0625] Preparation of Compound 1 in Example 1

[0626]

[0627] Step 1: Synthesis of Compound 1-b

[0628] Under nitrogen protection, zinc powder (983.8 mg, 15.0 mmol) and iodine (95.4 mg, 0.4 mmol) were dissolved in DMF (5 mL). 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. Then I-2-6 (400.0 mg, 1.3 mmol) was added, and the mixture was stirred at 45 °C for 1 hour. Next, 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 the reaction was completed, 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. The resulting mixture was separated and purified by a normal-phase chromatographic column to obtain 30.0 mg of compound 1-b. MS m / z (ESI): 383.13 [M+H] + .

[0629] Step 2: Synthesis of Compound 1

[0630] Under nitrogen protection, 1-b (30.0 mg, 0.08 mmol) was dissolved in dioxane (2 mL), water (0.5 mL) was added, and 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. The mixture was stirred overnight at 100 °C. After the reaction was completed, water (50 mL) was added to the mixture, and it 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. The resulting mixture was separated and purified by reverse-phase chromatography to obtain 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] + 。

[0631] 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.66 (s, 1H), 7.92 (s, 1H), 7.65 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.2 Hz, 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).

[0632] Preparation of Compound 2 in Example 2

[0633]

[0634] Step 1: Synthesis of Compound 2-a

[0635] Under nitrogen protection, 1-a (100.0 mg, 0.56 mmol) was dissolved in toluene (6 mL), water (1.5 mL) was added, and 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 added. The mixture was stirred overnight at 100 °C. After the reaction was completed, water (30 mL) was added to the mixture, and it 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. The resulting mixture was separated and purified by normal-phase chromatography to obtain 80.0 mg of compound 2-a. MS m / z (ESI): 401.12 [M+H] + 。

[0636] Step 2: Synthesis of Compound 2

[0637] Under nitrogen protection, 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, Pd(dppf)Cl2 (16 mg, 0.02 mmol) and potassium carbonate (41.0 mg, 0.30 mmol) were added, and the mixture was stirred overnight at 100 °C. After the reaction was completed, water (20 mL) was added to the mixture, and it was extracted with ethyl acetate (2 × 30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The mixture was separated and purified by a reverse-phase chromatographic column and freeze-dried to obtain 21.0 mg of compound 2. MS m / z (ESI): 505.16 [M+H] + 。

[0638] 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.60 (s, 1H), 8.00 (d, J = 1.2 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.34 - 7.25 (m, 2H), 4.23 (s, 2H), 4.02 (s, 3H), 3.89 (s, 6H), 3.61 (d, J = 1.6 Hz, 3H).

[0639] Preparation of Compound 3 in Example 3

[0640]

[0641] Step 1: Synthesis of Compound 3-b

[0642] 3-a (6.0 g, 36.8 mmol) and I-19 (3.1 g, 9.9 mmol) were dissolved in THF (100 mL). Under nitrogen protection, a solution of KHMDS in THF (18.4 mL, 1 M) was added dropwise in an ice bath, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water, 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 purified by silica gel column chromatography to obtain 4.3 g of compound 3-b. MS m / z (ESI): 443.08 [M+H] + 。

[0643] Step 2: Synthesis of Compound 3-c

[0644] 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 for 1.5 h in a sealed tube at 90 °C. Pour the reaction solution into ice water. Adjust the pH to 7 - 8 with saturated sodium bicarbonate solution. Extract with ethyl acetate (2×50 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] + 。

[0645] Step 3: Synthesis of compound 3

[0646] Under nitrogen protection, add 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) to the reaction flask, and stir at 95 °C overnight. Extract with ethyl acetate (2×20 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 first purified by silica gel column chromatography and then by medium-pressure preparative reverse-phase purification, and freeze-dried to obtain 1.6 g of compound 3. MS m / z (ESI): 499.20 [M+H] + 。

[0647] 1 H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.66 (s, 1H), 7.98 (s, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.33 (d, J = 11.4 Hz, 1H), 7.27 (d, J = 7.8 Hz, 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).

[0648] Example 4 Preparation of compound 4

[0649]

[0650] Step 1: Synthesis of compound 4

[0651] 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. The mixture was 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 by medium-pressure preparative reverse-phase purification. After lyophilization, 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) was obtained. MS m / z (ESI): 515.17 [M+H] + 。

[0652] 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.65 (s, 1H), 7.98 (d, J = 1.0 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 11.4 Hz, 1H), 7.26 (dd, J = 7.8, 1.4 Hz, 1H), 4.25 (s, 2H), 4.02 (s, 3H), 3.84 (s, 3H), 3.58 (d, J = 1.2 Hz, 3H), 1.70 - 1.60 (m, 1H), 1.06 - 0.99 (m, 2H), 0.89 - 0.81 (m, 2H).

[0653] Preparation of Compound 5 in Example 5

[0654]

[0655] Step 1: Synthesis of Compound 5-a

[0656] Under nitrogen protection, zinc powder (983.8 mg, 15.4 mmol) and iodine (95.4 mg, 0.38 mmol) were dissolved in DMF (5 mL). The mixture was stirred at 30 °C for 10 minutes, then TMSCl (40.8 mg, 0.4 mmol) was added. The mixture was stirred at 45 °C for 30 minutes, then I-1-5 (400.0 mg, 1.3 mmol) was added. The mixture was stirred at 45 °C for 1 hour, then 3-a (204.3 mg, 1.3 mmol) and Pd(PPh3)4 (144.9 mg, 0.13 mmol) were added. The mixture was stirred at 60 °C overnight. After the reaction was completed, 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. The resulting mixture was separated and purified by normal-phase chromatography column to obtain 50.0 mg of compound 5-a. MS m / z (ESI): 367.12 [M+H] + 。

[0657] Step 2: Synthesis of compound 5

[0658] Under nitrogen protection, 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. LC-MS monitored the completion of the reaction of the raw materials. After cooling to room temperature, the mixture was filtered and concentrated. It was purified by reverse-phase medium-pressure preparation and vacuum freeze-dried to obtain 20.0 mg of compound 5. MS m / z (ESI): 481.21 [M+H] + 。

[0659] 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.68 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 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).

[0660] Preparation of compound 6 in Example 6

[0661]

[0662] Step 1: Synthesis of compound 6-b

[0663] Under nitrogen protection, 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. After monitoring the reaction of the starting materials by LC-MS until completion, it was cooled to room temperature, filtered and concentrated. It was purified by medium-pressure preparative reverse-phase chromatography and concentrated under reduced pressure to obtain 80.0 mg of compound 6-b. MS m / z (ESI): 371.24 [M+H] + 。

[0664] Step 2: Synthesis of compound 6

[0665] Under nitrogen protection, 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. After monitoring the reaction of the starting materials by LC-MS until completion, it was cooled to room temperature, filtered and concentrated. It was purified by medium-pressure preparative reverse-phase chromatography and lyophilized in vacuo to obtain 1.0 mg of compound 6. MS m / z (ESI): 485.23 [M+H] + 。

[0666] Preparation of compound 7 in Example 7

[0667]

[0668] Step 1: Synthesis of compound 7-a

[0669] Under nitrogen protection, zinc powder (983.8 mg, 15.4 mmol) and iodine (95.4 mg, 0.38 mmol) were dissolved in DMF (5 mL). The mixture was stirred at 30 °C for 10 minutes, then TMSCl (40.8 mg, 0.38 mmol) was added. The mixture was stirred at 45 °C for 30 minutes, then I-2-6 (400.0 mg, 1.25 mmol) was added. The mixture was stirred at 45 °C for 1 hour, then 3-a (204.3 mg, 1.25 mmol) and Pd(PPh3)4 (144.9 mg, 0.13 mmol) were added. The mixture was stirred at 60 °C overnight. After the reaction was completed, water (200 mL) was added to the mixture, and it 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. The resulting mixture was separated and purified by normal-phase chromatography column to obtain 80.0 mg of compound 7-a. MS m / z (ESI): 367.12 [M+H] + 。

[0670] Step 2: Synthesis of Compound 7

[0671] Under nitrogen protection, 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 of the starting materials was monitored by LC-MS. After cooling to room temperature, the mixture was filtered and concentrated, and then purified by medium-pressure preparative reverse-phase chromatography and vacuum freeze-dried to obtain 5.0 mg of Compound 7. MS m / z (ESI): 481.20 [M+H] + 。

[0672] 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.69 (s, 1H), 7.93 (d, J = 1.0 Hz, 1H), 7.68 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.4 Hz, 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). Preparation of Compound 8 in Example 8

[0673]

[0674] Step 1: Synthesis of Compound 8-a

[0675] 1-a (1.0 g, 6.1 mmol) and I-5 (500.0 mg, 1.7 mmol) were dissolved in THF (20 mL). Under nitrogen protection, KHMDS (3.4 mL, 1 M) was added dropwise in an ice bath, and the mixture was stirred at room temperature for 2 h. The reaction solution was poured into ice water, 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 and purified by a normal-phase chromatography column to obtain 333.0 mg of Compound 8-a. MS m / z (ESI): 442.08 [M+H] + 。

[0676] Step 2: Synthesis of Compound 8-b

[0677] Dissolve 8-a (333.0 mg, 0.75 mmol) in acetic acid (6 mL), add concentrated hydrochloric acid (2 mL), and stir in a sealed tube at 90 °C for 1 hour. Cool to room temperature, pour the reaction solution into ice water, and adjust the pH to 7 - 8 with saturated sodium carbonate. Extract with ethyl acetate (2 × 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 chromatography column to obtain 214.0 mg of compound 8-b. MS m / z (ESI): 384.08 [M+H] + 。

[0678] Step 3: Synthesis of Compound 8

[0679] Under nitrogen protection, add 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) to the reaction flask, stir at 95 °C overnight, extract with ethyl acetate (2 × 10 mL), wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is first separated by normal-phase chromatography column and then purified by reverse-phase medium-pressure preparation, and freeze-dried to obtain 181.0 mg of compound 8. MS m / z (ESI): 498.18 [M+H] + 。

[0680] 1 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.63 (s, 1H), 8.60 (d, J = 1.8 Hz, 1H), 8.04 - 7.93 (m, 2H), 7.80 (dd, J = 8.2, 2.2 Hz, 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). Preparation of Compound 9 in Example 9

[0681]

[0682] Step 1: Synthesis of Compound 9-a

[0683] Under nitrogen protection, 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. After monitoring the reaction of the starting materials by LC-MS until completion, it was cooled to room temperature, filtered and concentrated. Then it was purified by medium-pressure preparative reverse-phase chromatography and freeze-dried to obtain 200.0 mg of compound 9-a. MS m / z (ESI): 411.21 [M+H] + 。

[0684] Step 2: Synthesis of compound 9

[0685] Under nitrogen protection, 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. After monitoring the reaction of the starting materials by LC-MS until completion, it was cooled to room temperature, filtered and concentrated. Then it was purified by medium-pressure preparative reverse-phase chromatography and vacuum freeze-dried 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] + 。

[0686] 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.67 (s, 1H), 8.16 (d, J = 1.2 Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 4.56 - 4.37 (m, 1H), 4.23 (s, 2H), 4.03 (s, 3H), 3.86 (s, 3H), 1.71 - 1.57 (m, 1H), 1.41 (d, J = 6.6 Hz, 6H), 1.11 - 0.98 (m, 2H), 0.91 - 0.81 (m, 2H).

[0687] Preparation of compound 10 in Example 10

[0688]

[0689] Step 1: Synthesis of compound 10-b

[0690] 10-a (3.0 g, 18.2 mmol) was dissolved in DCM (30 mL), 2-(trimethylsilyl)ethoxymethyl chloride (4.8 mL, 27.3 mmol) and N,N-diisopropylethylamine (9.7 mL, 54.6 mmol) were added, and the reaction was carried out at room temperature for 2 hours. The reaction solution was poured into water, extracted with dichloromethane (2×100 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 4.8 g of compound 10-b. MS m / z (ESI): 295.04 [M+H] + 。

[0691] Step 2: Synthesis of compound 10-c

[0692] 10-b (4.8 g, 16.3 mmol) and I-6 (7.3 g, 24.4 mmol) were dissolved in dry THF (50 mL). Under nitrogen protection, a solution of KHMDS in tetrahydrofuran (25 mL, 1 M) was added dropwise under an ice bath, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water, extracted with ethyl acetate (2×100 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 6.7 g of compound 10-c. MS m / z (ESI): 557.15 [M+H] + 。

[0693] Step 3: Synthesis of compound 10-d

[0694] 10-c (6.7 g, 12.1 mmol) was dissolved in acetic acid (9 mL), and concentrated hydrochloric acid (3 mL) was added. The mixture was stirred in a sealed tube at 80 °C for 1 hour. After cooling to room temperature, the reaction solution was poured into ice water, and the pH was adjusted to 7-8 with saturated sodium carbonate solution. It was extracted with ethyl acetate (2×100 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 3.9 g of compound 10-d. MS m / z (ESI): 369.07 [M+H] + 。

[0695] Step 4: Synthesis of compound 10-e

[0696] Under nitrogen protection, 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 overnight at 95 °C, 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 1.9 g of compound 10-e. MS m / z (ESI): 483.17 [M+H] + 。

[0697] Step 5: Synthesis of compound 10

[0698] 10-e (150.0 mg, 0.3 mmol) and potassium hydroxide (210.0 mg, 3.7 mmol) were dissolved in a mixed solution of acetonitrile (2 mL) and water (2 mL). 10-f (141.0 mg, 0.5 mmol) was added dropwise, and the reaction was carried out at room temperature for 2 hours. The reaction solution was poured into water, extracted with ethyl acetate (2 × 100 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 preparation to obtain 23.6 mg of compound 10. MS m / z (ESI): 533.16 [M+H] + 。

[0699] 1 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.70 (s, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.49 (t, J = 72.0 Hz, 1H), 7.45 (d, J = 8.4 Hz, 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).

[0700] Preparation of compound 11 in Example 11

[0701]

[0702] Step 1: Synthesis of compound 11-b

[0703] Dissolve 11-a (2.5 g, 9.1 mmol) in dry THF (45 mL). Under nitrogen protection, slowly add a n-hexane solution of n-butyllithium (5.7 mL, 9.2 mmol, 1.6 M) dropwise at -78 °C and stir at -78 °C for 1 hour. Then add dropwise a THF solution (5 mL) of diluted dimethyldiselenide (2.2 mL, 22.7 mmol), stir at -78 °C for 40 minutes, and naturally warm to room temperature and stir for 2 hours. Quench with water, extract with ethyl acetate (2×50 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 242.0 mg of compound 11-b. MS m / z (ESI): 243.0 [M+H] + 。

[0704] Step 2: Synthesis of compound 11-c

[0705] 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 protection, add a THF solution of KHMDS (433.9 μL, 1 M) dropwise in an ice bath and stir at room temperature for 1 hour. Pour the reaction solution into ice water, extract with ethyl acetate (2×10 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 81.0 mg of compound 11-c. MS m / z (ESI): 505.11 [M+H] + 。

[0706] Step 3: Synthesis of compound 11-d

[0707] Dissolve 11-c (81.0 mg, 0.16 mmol) in acetic acid (1.5 mL), add concentrated hydrochloric acid (0.5 mL), and stir in a sealed tube at 80 °C for 1 hour. Cool to room temperature, pour the reaction solution into ice water, and adjust the pH to 7 - 8 with saturated sodium carbonate. Extract with ethyl acetate (2×10 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] + 。

[0708] Step 4: Synthesis of compound 11

[0709] Under nitrogen protection, 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 overnight at 95 °C. 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 preparation to obtain 7.0 mg of compound 11. MS m / z (ESI): 561.11 [M+H] + 。

[0710] 1 1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.67 (s, 1H), 7.91 (d, J = 1.1 Hz, 1H), 7.65 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.3 Hz, 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). Preparation of compound 12 in Example 12

[0711]

[0712] Step 1: Synthesis of compound 12-b

[0713] Under nitrogen protection, 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), water (1 mL), and stirred overnight at 100 °C. The mixture was extracted with ethyl acetate (3 × 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 and purified by a normal-phase chromatography column to obtain 30.0 mg of compound 12-b. MS m / z (ESI): 410.12 [M+H] + 。

[0714] Step 2: Synthesis of compound 12

[0715] Under nitrogen protection, 12-b (30.0 mg, 0.07 mmol) was dissolved in dioxane (5 mL), 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 overnight at 100 °C. After the reaction was completed, water (50 mL) was added to the mixture, and it was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was purified by medium-pressure preparation to obtain 6.0 mg of compound 12. MS m / z (ESI): 524.21 [M+H] + 。

[0716] 1 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.67 (s, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.80 (d, J = 8.2 Hz, 2H), 7.76 (d, J = 8.6 Hz, 1H), 7.40 (d, J = 8.3 Hz, 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).

[0717] Preparation of Compound 13 in Example 13

[0718]

[0719] Step 1: Synthesis of Compound 13-a

[0720] Under nitrogen protection, I-13 (50.0 mg, 0.13 mmol), 1-a (47.5 mg, 0.27 mmol), potassium phosphate (56.3 mg, 0.27 mmol), Pd(PPh3)2Cl2 (4.7 mg, 0.01 mmol) were dissolved in toluene (5 mL), water (1 mL), and stirred overnight at 100 °C. It was extracted with ethyl acetate (3 × 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 a normal-phase chromatography column to obtain 20.0 mg of compound 13-a. MS m / z (ESI): 394.12 [M+H] + 。

[0721] Step 2: Synthesis of Compound 13

[0722] Under nitrogen protection, 13-a (20.0 mg, 0.05 mmol) was dissolved in dioxane (5 mL), 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 overnight at 100 °C. After the reaction was completed, water (50 mL) was added to the mixture, and it was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was purified by medium-pressure preparation to obtain 2.0 mg of compound 13. MS m / z (ESI): 508.21 [M+H] + 。

[0723] 1 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.67 (s, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 8.1 Hz, 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).

[0724] Preparation of Compound 14 in Example 14

[0725]

[0726] Step 1: Synthesis of Compound 14-a

[0727] Under nitrogen protection, 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. The mixture was stirred overnight at 100 °C. The reaction solution was cooled to room temperature, saturated brine (20 mL) was added, and it was extracted with ethyl acetate (2 × 20 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered to obtain a filtrate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 220.0 mg of compound 14-a. MS m / z (ESI): 401.17 [M+H] + 。

[0728] Step 2: Synthesis of Compound 14

[0729] Under nitrogen protection, 14-a (120.0 mg, 0.30 mmol) was dissolved in 1,4-dioxane (10 mL) and water (2 mL), and 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) were added. The mixture was stirred at 95 °C overnight. The reaction solution was cooled to room temperature and concentrated to obtain a crude product, which was purified by medium-pressure preparation and freeze-dried to obtain 50.0 mg of compound 14. MS m / z (ESI): 515.16 [M+H] + 。

[0730] 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.67 (s, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.44 (dd, J = 11.6, 2.0 Hz, 1H), 7.32 (dd, J = 8.0, 2.0 Hz, 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).

[0731] Preparation of Compound 15 in Example 15

[0732]

[0733] Step 1: Synthesis of Compound 15-a

[0734] 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 in an ice bath, and the mixture was stirred at room temperature for 2 hours. Water (50 mL) was added, and the mixture was 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 8.1 g of crude compound 15-a. MS m / z (ESI): 266.10 [M+H] + 。

[0735] Step 2: Synthesis of Compound 15-b

[0736] Dissolve 15-a (7.1 g, 12.05 mmol) in methanol (100 mL), add TMSCl (22.8 mL, 180.7 mmol), stir at 70 °C for 4 h, concentrate under reduced pressure. Add ice water to the residue, adjust the pH to 8 with saturated sodium bicarbonate, extract with ethyl acetate (2 × 50 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 was separated and purified by normal-phase chromatography column to obtain 3.5 g of compound 15-b. MS m / z (ESI): 299.10 [M+H] + 。

[0737] Step 3: Synthesis of compound 15-c

[0738] Dissolve 11-b (0.2 g, 0.83 mmol) and 15-b (246.5 mg, 0.83 mmol) in THF (5 mL). Under nitrogen protection, add KHMDS (0.9 mL, 1 M) dropwise in an ice bath, and stir at room temperature for 2 h. Pour the reaction solution into ice water, extract with ethyl acetate (2 × 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 was separated and purified by normal-phase chromatography column to obtain 139.0 mg of compound 15-c. MS m / z (ESI): 505.00 [M+H] + 。

[0739] Step 4: Synthesis of compound 15-d

[0740] Dissolve 15-c (139.0 mg, 0.14 mmol) in acetic acid (3 mL), add concentrated hydrochloric acid (1 mL). Stir in a sealed tube at 80 °C for 1 h. Cool to room temperature, pour the reaction solution into ice water, adjust the pH to 8 with saturated sodium carbonate, extract with ethyl acetate (2 × 5 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 was separated and purified by normal-phase chromatography column to obtain 31.0 mg of compound 15-d. MS m / z (ESI): 446.70 [M+H] + 。

[0741] Step 5: Synthesis of compound 15

[0742] Under nitrogen protection, 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 the reaction flask, and the mixture was stirred at 95 °C for 2 hours. The reaction solution was first separated and purified by normal-phase chromatography column, and then purified by medium-pressure preparation to obtain 12.1 mg of compound 15. MS m / z (ESI): 561.00 [M+H] + 。

[0743] 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.67 (s, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.5 Hz, 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).

[0744] Preparation of Compound 16 in Example 16

[0745]

[0746] Step 1: Synthesis of Compound 16-b

[0747] Under nitrogen protection, 16-a (1.0 g, 6.19 mmol) was dissolved in dry THF (5 mL), and a n-hexane solution of n-butyllithium (4.06 mL, 6.50 mmol, 1.6 M) was slowly added dropwise at -78 °C, and the mixture was stirred at -78 °C for 1 hour. Then tributyltin chloride (1.76 mL, 6.50 mmol) was added dropwise, and the mixture was stirred at -78 °C for half an hour and then warmed to room temperature and stirred overnight. The crude product of the reaction solution was separated and purified by normal-phase chromatography column to obtain 1.7 g of compound 16-b. MS m / z (ESI): 452.12 [M+H] + 。

[0748] Step 2: Synthesis of Compound 16-c

[0749] Under nitrogen protection, 16-b (400.0 mg, 0.89 mmol), I-7-3 (324.2 mg, 0.89 mmol), Pd(PPh3)2Cl2 (63.1 mg, 0.09 mmol) were dissolved in N-methylpyrrolidone (5 mL), and the mixture was 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) respectively, 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] + 。

[0750] Step 3: Synthesis of compound 16

[0751] Under nitrogen protection, 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 the reaction flask. The mixture was stirred at 100 °C overnight, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by medium-pressure preparation to obtain 4.5 mg of compound 16. MS m / z (ESI): 560.2 [M+H] + 。

[0752] 1 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.47 (s, 1H), 8.26 - 8.22 (m, 1H), 7.51 (t, J = 8.0 Hz, 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 = 6.4 Hz, 6H), 1.15 - 1.08 (m, 1H), 1.05 - 0.83 (m, 3H). Preparation of compound 17 in Example 17

[0753]

[0754] Step 1: Synthesis of compound 17-b

[0755] Under nitrogen protection, dissolve 17-a (1.6 g, 10.99 mmol) in dry THF (10 mL), slowly add a solution of lithium diisopropylamide (7.14 mL, 14.29 mmol) dropwise at -78 °C, and stir at -78 °C for 1 hour. Then add dropwise a solution of diluted iodine (3067.9 mg, 12.09 mmol) in tetrahydrofuran (10 mL), and stir at -78 °C for 1 hour. Quench with water (5 mL), add ethyl acetate (100 mL), wash with water (100 mL) and saturated brine (100 mL), 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 a normal-phase chromatography column to obtain 2.07 g of compound 17-b. MS m / z (ESI): 272.0 [M+H] + 。

[0756] Step 2: Synthesis of compound 17-c

[0757] Under nitrogen protection, dissolve 17-b (70.0 mg, 0.26 mmol), I-3 (99.1 mg, 0.26 mmol), potassium phosphate (178.1 mg, 0.77 mmol), Pd(PPh3)2Cl2 (18.1 mg, 0.03 mmol) in toluene (15 mL) and water (3 mL), and heat and stir at 100 °C overnight. Concentrate the reaction solution under reduced pressure to obtain a crude product. The crude product is purified by medium-pressure preparative normal-phase chromatography to obtain 3.0 mg of compound 17-c. MS m / z (ESI): 402.14 [M+H] + 。

[0758] Step 3: Synthesis of compound 17

[0759] Under nitrogen protection, add 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) to a reaction flask, stir at 100 °C overnight, concentrate the filtrate under reduced pressure to obtain a crude product, and purify the crude product by medium-pressure preparative chromatography to obtain 2.0 mg of compound 17. MS m / z (ESI): 516.22 [M+H] + 。

[0760] 11H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.46 (s, 1H), 8.02 - 7.98 (m, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 11.2 Hz, 1H), 7.16 (dd, J = 8.0, 1.6 Hz, 1H), 4.26 (s, 2H), 3.89 (s, 3H), 3.61 (d, J = 1.6 Hz, 3H), 2.38 (s, 3H), 1.77 - 1.70 (m, 1H), 1.17 - 1.11 (m, 1H), 1.05 - 0.87 (m, 3H).

[0761] Example 18 Preparation of Compound 18

[0762]

[0763] Step 1: Synthesis of Compound 18-a

[0764] Dissolve I-7-3 (2.0 g, 5.48 mmol) in acetonitrile (40 mL), add TMSCN (0.76 g, 7.67 mmol), protect with nitrogen, cool to 0 °C, dropwise add TBAF solution (7.12 mL, 7.12 mmol). After dropping, let it rise to room temperature and react for 2 hours. Pour the reaction solution into water, extract with ethyl acetate (2 × 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 and purified by a normal-phase chromatographic column to obtain 1.6 g of Compound 18-a. MS m / z (ESI): 312.1 [M + H] + .

[0765] Step 2: Synthesis of Compound 18-b

[0766] Dissolve 18-a (1.6 g, 5.14 mmol) in methanol (20 mL), add TMSCl (6.5 mL, 51.4 mmol) at room temperature, and stir at 70 °C for 6 hours. Concentrate the reaction solution under reduced pressure. Dilute the obtained residue with water, adjust the pH to 7 - 8 with saturated sodium bicarbonate, extract with ethyl acetate (2 × 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 1.62 g of Compound 18-b. MS m / z (ESI): 345.11 [M + H] + .

[0767] Step 3: Synthesis of Compound 18-c

[0768] Dissolve 18-b (300.0 mg, 0.87 mmol) in dry THF (10 mL). Under nitrogen protection, dropwise add a tetrahydrofuran solution of KHMDS (1.3 mL, 1.31 mmol) in an ice bath, react for 10 minutes in the ice bath, and then dropwise add a tetrahydrofuran solution of 1-a (187.2 mg, 1.05 mmol) (1 mL). Stir at room temperature for 1 hour. Pour the reaction solution into ice water, extract with ethyl acetate (2 × 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 a normal-phase chromatographic column to obtain 210.0 mg of compound 18-c. MS m / z (ESI): 487.11 [M + H] + 。

[0769] Step 4: Synthesis of compound 18-d

[0770] 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 hour. Cool to room temperature, pour the reaction solution into ice water, and adjust the pH to 7 - 8 with saturated sodium carbonate. Extract with ethyl acetate (2 × 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 a normal-phase chromatographic column to obtain 180.0 mg of compound 18-d. MS m / z (ESI): 429.1 [M + H] + 。

[0771] Step 5: Synthesis of compound 18

[0772] Under nitrogen protection, add 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) to a reaction flask, stir at 95 °C overnight, extract with ethyl acetate (2 × 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 purified by medium-pressure preparation to obtain 108.0 mg of compound 18. MS m / z (ESI): 543.21 [M + H] + 。

[0773] 11H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.67 (s, 1H), 8.24 (d, J = 1.2 Hz, 1H), 7.50 (t, J = 8.0 Hz, 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 = 6.4 Hz, 6H), 1.08 - 1.01 (m, 2H), 0.91 - 0.83 (m, 2H).

[0774] Example 19 Preparation of Compound 19

[0775]

[0776] Step 1: Synthesis of Compound 19

[0777] Dissolve 10-e (100.0 mg, 0.21 mmol) in acetonitrile (2 mL), add 19-a (72.2 mg, 0.42 mmol) and cesium carbonate (135.0 mg, 0.42 mmol), heat to 50 °C and react for 12 hours. Pour the reaction solution into water, extract with ethyl acetate (2×10 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 purified by medium-pressure preparation to obtain 11.28 mg of Compound 19. MS m / z (ESI): 529.19 [M+H] + .

[0778] 1 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.68 (s, 1H), 7.93 (d, J = 1.2 Hz, 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).

[0779] Example 20 Preparation of Compound 20

[0780]

[0781] Step 1: Synthesis of Compound 20-a

[0782] Under nitrogen protection, 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 the mixture was stirred at 100 °C overnight. It was extracted with ethyl acetate (3 × 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. The crude product 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] + 。

[0783] Step 2: Synthesis of compound 20

[0784] Under nitrogen protection, 20-a (20.0 mg, 0.05 mmol) was dissolved in dioxane (5 mL), 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 it was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was purified by medium-pressure preparation to obtain 2.5 mg of compound 20. MS m / z (ESI): 497.19 [M+H] + 。

[0785] 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.66 (s, 1H), 7.51 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.5 Hz, 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).

[0786] Preparation of compound 21 in Example 21

[0787]

[0788] Step 1: Synthesis of compound 21-a

[0789] Under nitrogen protection, 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), water (2 mL), and stirred at 100 °C overnight. Extracted with ethyl acetate (3×20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by normal-phase chromatography column to obtain 100.0 mg of compound 21-a. MS m / z (ESI): 408.93 [M+H] + 。

[0790] Step 2: Synthesis of compound 21

[0791] Under nitrogen protection, 21-a (50.0 mg, 0.12 mmol) was dissolved in dioxane (5 mL), 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 it was extracted with ethyl acetate (3×20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was purified by medium-pressure preparation to obtain 20.0 mg of compound 21. MS m / z (ESI): 522.91 [M+H] + 。

[0792] 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.67 (s, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 6.63 (s, 1H), 4.25 (s, 2H), 4.04 (s, 3H), 3.86 (d, J = 4.8 Hz, 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).

[0793] Preparation of compound 22 in Example 22

[0794]

[0795] Step 1: Synthesis of compound 22

[0796] Compound 19 (30.0 mg, 0.06 mmol) was dissolved in diethylaminosulfur trifluoride (1 mL), and the reaction was carried out at room temperature for 12 hours. The reaction solution was poured into water, 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 preparation to obtain 4.81 mg of compound 22. MS m / z (ESI): 565.17 [M + H] + 。

[0797] 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.71 (s, 1H), 7.99 (s, 1H), 7.89 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 8.0 Hz, 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).

[0798] Example 23 Preparation of Compound 23

[0799]

[0800] Step 1: Synthesis of Compound 23-b

[0801] 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 then a methanol (400 mL) solution of 23-a (50.0 g, 246.31 mmol) was added dropwise to the above mixture. Then, ammonia water (250 mL) was added to the reaction solution, and the mixture was stirred 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 a normal-phase chromatographic column to obtain 68.0 g of compound 23-b. MS m / z (ESI): 309.10 [M + H] + 。

[0802] Step 2: Synthesis of Compound 23-c

[0803] 23-b (9.7 g, 31.38 mmol), methyl iodide-d3 (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 h. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (2 × 100 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 separated and purified by normal-phase column chromatography to obtain 6.3 g of compound 23-c. MS m / z (ESI): 325.90 [M+H] + 。

[0804] Step 3: Synthesis of compound 23-e

[0805] Under nitrogen protection, 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 × 60 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 separated and purified by normal-phase column chromatography to obtain 863.0 mg of compound 23-e. MS m / z (ESI): 287.14 [M+H] + 。

[0806] Step 4: Synthesis of compound 23-f

[0807] 23-e (863.0 mg, 3.02 mmol) was dissolved in methanol (10 mL), TMSCl (5.7 mL, 45.23 mmol) was added, and the mixture was stirred at 70 °C for 4 h 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 × 60 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 separated and purified by normal-phase column chromatography to obtain 562.0 mg of compound 23-f. MS m / z (ESI): 320.03 [M+H] + 。

[0808] Step 5: Synthesis of compound 23-g

[0809] Dissolve 1-a (1.0 g, 6.13 mmol) and 23-f (561.9 mg, 1.76 mmol) in THF (20 mL). Under nitrogen protection, add KHMDS (2.9 mL, 1 M) dropwise in an ice bath, and stir at room temperature for 1 hour. Pour the reaction solution into ice water, extract with ethyl acetate (2 * 15 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 column to obtain 688.0 mg of compound 23-g. MS m / z (ESI): 461.89 [M+H] + .

[0810] Step 6: Synthesis of compound 23-h

[0811] Add 23-g (688.0 mg, 1.49 mmol), concentrated hydrochloric acid (4 mL), and acetic acid (12 mL) into a sealed tube. Stir at 80 °C for 1.5 hours, cool to room temperature, pour the reaction solution into ice water, adjust the pH to 8 with saturated sodium carbonate, extract with ethyl acetate (2 * 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 column to obtain 537.0 mg of compound 23-h. MS m / z (ESI): 403.90 [M+H] + .

[0812] Step 7: Synthesis of compound 23

[0813] Under nitrogen protection, add 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), XPho s-Pd G2 (209.0 mg, 0.27 mmol), dioxane (12 mL), and water (3 mL) into the reaction flask, and stir at 95 °C for 1.5 hours. Extract with ethyl acetate (2 * 10 mL), wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is first separated and purified by normal-phase chromatography column, then purified by medium-pressure preparation, and freeze-dried to obtain 336.0 mg of compound 23. MS m / z (ESI): 517.97 [M+H] + .

[0814] 11H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.65 (s, 1H), 7.99 - 7.95 (m, 1H), 7.52 (t, J = 7.8 Hz, 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).

[0815] Example 24 Preparation of Compound 24

[0816]

[0817] Step 1: Synthesis of Compound 24-a

[0818] Dissolve 11-b (300.0 mg, 1.24 mmol) and I-19 (392.1 mg, 1.24 mmol) in THF (8 mL). Under nitrogen protection, add KHMDS (1.3 mL, 1 M) dropwise in an ice bath. Stir at room temperature for 1 hour. Pour the reaction solution into ice water, extract with ethyl acetate (2 × 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 a normal-phase chromatography column to obtain 298.0 mg of Compound 24-a. MS m / z (ESI): 522.90 [M + H] + 。

[0819] Step 4: Synthesis of Compound 24-b

[0820] Dissolve 24-a (298.0 mg, 0.57 mmol) in acetic acid (6 mL), add concentrated hydrochloric acid (2 mL), and stir in a sealed tube at 80 °C for 1 hour. Cool to room temperature, pour the reaction solution into ice water, adjust the pH to 8 with saturated sodium carbonate, extract with ethyl acetate (2 × 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 a normal-phase chromatography column to obtain 85.0 mg of Compound 24-b. MS m / z (ESI): 465.00 [M + H] + 。

[0821] Step 5: Synthesis of Compound 24

[0822] Under nitrogen protection, 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. The mixture was stirred at 95 °C overnight, 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 chromatography column, and then purified by medium-pressure preparation to obtain 35.0 mg of compound 24. MS m / z (ESI): 579.20 [M+H] + 。

[0823] 1 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.67 (s, 1H), 7.98 (d, J = 0.9 Hz, 1H), 7.53 (t, J = 7.8 Hz, 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 = 0.9 Hz, 3H), 2.50 (s, 3H), 1.77 - 1.65 (m, 1H), 1.07 - 1.00 (m, 2H), 0.91 - 0.84 (m, 2H).

[0824] Preparation of Compound 25 in Example 25

[0825]

[0826] Step 1: Synthesis of Compound 25

[0827] Compound 11 (5.5 mg, 0.01 mmol) was dissolved in dichloromethane (1 mL), and meta-chloroperoxybenzoic acid (1.7 mg, 0.01 mmol) was added under ice bath. The mixture was stirred at ice bath for 30 minutes. The reaction solution was purified by reverse-phase medium-pressure preparation and freeze-dried to obtain 2.8 mg of compound 25. MS m / z (ESI): 577.14 [M+H] + 。

[0828] 11H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.72 (s, 1H), 7.94 (s, 1H), 7.70 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 4.47 (d, J = 6.0 Hz, 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).

[0829] Preparation of Compound 26 in Example 26

[0830]

[0831] Step 1: Synthesis of Compound 26

[0832] Dissolve Compound 15 (6.0 mg, 0.01 mmol) in dichloromethane (1.5 mL), add m-chloroperoxybenzoic acid (1.9 mg, 0.01 mmol) under ice bath, and stir for 30 minutes under ice bath. The reaction solution was purified by medium-pressure preparative reverse phase and freeze-dried to obtain 2.6 mg of Compound 26. MS m / z (ESI): 577.10 [M + H] + 。

[0833] 1 1H NMR (400 MHz, CDCl3) δ 9.42 (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).

[0834] Preparation of Compound 27 in Example 27

[0835]

[0836] Step 1: Synthesis of Compound 27

[0837] Dissolve Compound 24 (22.0 mg, 0.04 mmol) in dichloromethane (2 mL), add m-chloroperoxybenzoic acid (6.6 mg, 0.04 mmol) under ice bath, and stir for 30 minutes under ice bath. The reaction solution was purified by medium-pressure preparative reverse phase and freeze-dried to obtain 10.7 mg of Compound 27. MS m / z (ESI): 595.16 [M + H] + 。

[0838] 11H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.69 (s, 1H), 7.99 (s, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.38 (d, J = 11.3 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 4.49 (d, J = 2.4 Hz, 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).

[0839] Preparation of Compound 28 in Example 28

[0840]

[0841] Step 1: Synthesis of Compound 28-b

[0842] Referring to the synthesis of 2-a, I-3 (1.38 g, 3.59 mmol), replacing 1-a with 28-a (300.0 mg, 1.80 mmol), 100.0 mg of Compound 28-b was obtained. MS m / z (ESI): 389.07 [M + H] + .

[0843] Step 2: Synthesis of Compound 28

[0844] Under nitrogen protection, 28-b (90.0 mg, 0.23 mmol) was dissolved in a mixed solvent 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 was cooled to room temperature, concentrated to obtain a crude product, and the crude product was purified by medium-pressure preparation and freeze-dried to obtain 38.0 mg of Compound 28. MS m / z (ESI): 503.18 [M + H] + .

[0845] 11H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 1.8 Hz, 1H), 8.70 (s, 1H), 8.01 (s, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 11.2 Hz, 1H), 7.35 - 7.28 (m, 1H), 4.40 (d, J = 2.0 Hz, 2H), 3.87 (s, 3H), 3.61 (d, J = 1.6 Hz, 3H), 1.71 - 1.66 (m, 1H), 1.08 - 1.04 (m, 2H), 0.91 - 0.87 (m, 2H).

[0846] Example 29 Preparation of Compound 29

[0847]

[0848] Step 1: Synthesis of Compound 29-a

[0849] Referring to the synthesis of 2-a, replacing I-3 with I-10 (4.24 g, 11.04 mmol) and 1-a with 3-a (900.0 mg, 5.52 mmol), 1.10 g of Compound 29-a was obtained. MS m / z (ESI): 384.94 [M+H] + .

[0850] Step 2: Synthesis of Compound 29

[0851] Referring to the synthesis of Compound 14, using 1-c (100.8 mg, 0.52 mmol) and replacing 14-a with 29-a (100.0 mg, 0.26 mmol), 25.0 mg of Compound 29 was obtained. MS m / z (ESI): 499.19 [M+H] + .

[0852] 1 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.68 (s, 1H), 7.60 (t, J = 8.4 Hz, 1H), 7.46 (dd, J = 11.6, 2.0 Hz, 1H), 7.33 (dd, J = 8.4, 2.0 Hz, 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).

[0853] Example 30 Preparation of Compound 30

[0854]

[0855] Step 1: Synthesis of Compound 30

[0856] Referring to the synthesis of Compound 3, 3-c (886.0 mg, 2.3 mmol), replace 1-c 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] + .

[0857] 1 1H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.60 (s, 1H), 7.98 (s, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 11.5 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 4.25 (s, 2H), 3.87 (s, 6H), 3.59 (s, 3H), 2.32 (s, 3H).

[0858] Preparation of Compound 31 in Example 31

[0859]

[0860] Step 1: Synthesis of Compound 31-a

[0861] Under nitrogen protection, add 40-b (155.0 mg, 0.3 mmol), trimethylsilylacetylene (88.2 μL, 0.6 mmol), Pd(PPh3)2Cl2 (43.8 mg, 0.06 mmol), copper(I) iodide (9.9 mg, 0.03 mmol), triethylamine (86.5 μL, 0.6 mmol), and 2-methyltetrahydrofuran (6 mL) to the reaction flask, and stir at 55 °C overnight. Filter, concentrate the filtrate under reduced pressure to obtain the crude product, and purify the crude product by normal-phase chromatography column to obtain 76.0 mg of Compound 31-a. MS m / z (ESI): 467.10 [M+H] + .

[0862] Step 2: Synthesis of Compound 31

[0863] Referring to the synthesis of Compound 3, 1-c (39.9 mg, 0.2 mmol), replace 3-c with 31-a (48.0 mg, 0.1 mmol), and stir at 80 °C for 2 hours. After the same post-treatment, 7.2 mg of Compound 31 is obtained. MS m / z (ESI): 509.20 [M+H] + .

[0864] 11H NMR (400 MHz, CDCl3) δ 8.92 (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 = 2.3 Hz, 3H), 1.70 - 1.63 (m, 1H), 1.25 - 1.20 (m, 2H), 0.93 - 0.87 (m, 2H).

[0865] Example 32 Preparation of Compound 32

[0866]

[0867] Step 1: Synthesis of Compound 32-a

[0868] Referring to the synthesis of 18-c, for 18-b (500.0 mg, 1.45 mmol), replace 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] + .

[0869] Step 2: Synthesis of Compound 32-b

[0870] Referring to the synthesis of 3-c, replace 3-b with 32-a (480.0 mg, 1.02 mmol), and stir in a sealed tube at 80 °C for 0.5 h. After the same work-up, 320.0 mg of Compound 32-b is obtained. MS m / z (ESI): 413.11 [M+H] + .

[0871] Step 3: Synthesis of Compound 32

[0872] Referring to the synthesis of Compound 4, for 1-c (90.2 mg, 0.47 mmol), replace 2-a with 32-b (160.0 mg, 0.39 mmol), and stir the mixture at 80 °C for 3 h. After the same work-up, a crude product is obtained. The crude product is purified by a normal-phase chromatographic column and then separated and purified by a reverse-phase chromatographic column to obtain 69.0 mg of Compound 32. MS m / z (ESI): 527.21 [M+H] + .

[0873] 11H NMR (400 MHz, DMSO-d6) δ 8.75 (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 = 6.4 Hz, 6H), 1.08 - 1.02 (m, 2H), 0.92 - 0.84 (m, 2H).

[0874] Example 33 Preparation of Compound 33

[0875]

[0876] Step 1: Synthesis of Compound 33-a

[0877] Referring to the synthesis of 3-b, replace 3-a with 11-b (67.4 mg, 0.28 mmol) and I-19 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] + .

[0878] Step 2: Synthesis of Compound 33-b

[0879] Referring to the synthesis of 3-c, replace 3-b with 33-a (40.0 mg, 0.08 mmol) and stir at 80 °C for 1 hour. After the same post-treatment, 15.0 mg of Compound 33-b is obtained. MS m / z (ESI): 476.00 [M + H] + .

[0880] Step 3: Synthesis of Compound 33

[0881] Referring to the synthesis of Compound 3, replace 3-c with 33-b (15.0 mg, 0.03 mmol) and 1-c (12.3 mg, 0.06 mmol). After the same post-treatment, a crude product is obtained. The crude product is first purified by a normal-phase chromatography column and then by medium-pressure preparation purification, and lyophilized to obtain 4.5 mg of Compound 33. MS m / z (ESI): 590.10 [M + H] + .

[0882] 11H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.65 (s, 1H), 8.63 (d, J = 1.7 Hz, 1H), 8.10 (d, J = 8.2 Hz, 1H), 7.77 (dd, J = 8.2, 2.3 Hz, 1H), 7.46 (d, J = 1.0 Hz, 1H), 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 = 6.7 Hz, 6H), 1.24 - 1.19 (m, 2H), 0.92 - 0.86 (m, 2H).

[0883] Example 34 Preparation of Compound 34

[0884]

[0885] Step 1: Synthesis of Compound 34-b

[0886] Referring to the synthesis of 3-b, I-19 (99.2 mg, 0.3 mmol), replacing 3-a with 34-a (200.0 mg, 1.0 mmol), 73.0 mg of compound 34-b was obtained. MS m / z (ESI): 470.12 [M + H] + .

[0887] Step 2: Synthesis of Compound 34-c

[0888] Referring to the synthesis of 3-c, replacing 3-b with 34-b (73.0 mg, 0.2 mmol), stirred at 80 °C for 1 hour. After the same post-treatment, 15.0 mg of compound 34-c was obtained. MS m / z (ESI): 413.09 [M + H] + .

[0889] Step 3: Synthesis of Compound 34

[0890] Referring to the synthesis of compound 3, 1-c (14.1 mg, 0.1 mmol), replacing 3-c with 34-c (15.0 mg, 0.04 mmol), stirred at 100 °C overnight. After the same post-treatment, the crude product was obtained, and the crude product was separated and purified by reverse-phase chromatography column to obtain 7.21 mg of compound 34. MS m / z (ESI): 526.97 [M + H] + .

[0891] 11H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.69 (s, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.38 - 7.24 (m, 2H), 4.39 (s, 2H), 3.88 (s, 3H), 3.60 (d, J = 1.3 Hz, 3H), 3.45 - 3.24 (m, 1H), 1.72 - 1.64 (m, 1H), 1.27 (d, J = 6.9 Hz, 6H), 1.09 - 1.04 (m, 2H), 0.92 - 0.89 (m, 2H).

[0892] Example 35 Preparation of Compound 35

[0893]

[0894] Step 1: Synthesis of Compound 35-b

[0895] Referring to the synthesis of 3-b, I-19 (215.5 mg, 0.7 mmol), replacing 3-a with 35-a (400.0 mg, 2.3 mmol), 144.0 mg of compound 35-b was obtained. MS m / z (ESI): 456.88 [M+H] + .

[0896] Step 2: Synthesis of Compound 35-c

[0897] Referring to the synthesis of 3-c, replacing 3-b with 35-b (144.0 mg, 0.3 mmol), stirring at 80 °C for 1 hour. After the same work-up, 61.0 mg of compound 35-c was obtained. MS m / z (ESI): 399.09 [M+H] + .

[0898] Step 3: Synthesis of Compound 35

[0899] Referring to the synthesis of Compound 3, 1-c (59.5 mg, 0.3 mmol), replacing 3-c with 35-c (61.0 mg, 0.2 mmol), stirring at 100 °C overnight. After the same work-up, a crude product was obtained, and the crude product was separated and purified by reverse-phase chromatography column to obtain 18.51 mg of compound 35. MS m / z (ESI): 513.12 [M+H] + .

[0900] 11H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.69 (s, 1H), 8.00 (d, J = 1.0 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.40 - 7.26 (m, 2H), 4.35 (s, 2H), 3.88 (s, 3H), 3.60 (d, J = 1.2 Hz, 3H), 2.80 (q, J = 7.5 Hz, 2H), 1.71 - 1.68 (m, 1H), 1.23 (t, J = 7.5 Hz, 3H), 1.08 - 1.02 (m, 2H), 0.91 - 0.88 (m, 2H).

[0901] Example 36 Preparation of Compound 36

[0902]

[0903] Step 1: Synthesis of Compound 36-b

[0904] Referring to the synthesis of 3-b, I-19 (324.2 mg, 1.03 mmol), replace 3-a with 36-a (200.0 mg, 1.03 mmol), stir at room temperature for 1 hour. After the same post-treatment, 310.0 mg of compound 36-b was obtained. MS m / z (ESI): 475.10 [M + H] + .

[0905] Step 2: Synthesis of Compound 36-c

[0906] Referring to the synthesis of 3-c, replace 3-b with 36-b (310.0 mg, 0.65 mmol), stir in a sealed tube at 80 °C for 1 hour. After the same post-treatment, 138.0 mg of compound 36-c was obtained. MS m / z (ESI): 417.10 [M + H] + .

[0907] Step 3: Synthesis of Compound 36

[0908] Referring to the synthesis of compound 4, 1-c (125.7 mg, 0.65 mmol), replace 2-a with 36-c (135.0 mg, 0.32 mmol). After the same post-treatment, a crude product was obtained. The crude product was purified by medium-pressure preparation and freeze-dried to obtain 10.0 mg of compound 36. MS m / z (ESI): 531.20 [M + H] + .

[0909] 11H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.69 (s, 1H), 8.00 (d, J = 1.2 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.35 (d, J = 11.2 Hz, 1H), 7.29 (dd, J = 8.0, 1.6 Hz, 1H), 4.31 (s, 2H), 3.88 (s, 3H), 3.60 (d, J = 1.6 Hz, 3H), 2.67 (s, 3H), 1.75 - 1.70 (m, 1H), 1.08 - 1.05 (m, 2H), 0.93 - 0.88 (m, 2H).

[0910] Example 37 Preparation of Compound 37

[0911]

[0912] Step 1: Synthesis of Compound 37-b

[0913] Under nitrogen protection, 40-b (600.0 mg, 1.21 mmol) was dissolved in dioxane (10 mL), 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 completed, water (20 mL) was added to the mixture, and it was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate, filtered and concentrated. The resulting mixture was separated and purified by a normal-phase chromatography column to obtain 380.0 mg of Compound 37-b. MS m / z (ESI): 441.1 [M + H] + .

[0914] Step 2: Synthesis of Compound 37-c

[0915] Referring to the synthesis of Compound 4, 1-c (308.1 mg, 1.59 mmol), 2-a was replaced with 37-b (350.0 mg, 0.79 mmol), and the mixture was stirred at 80 °C for 3 hours. After the same post-treatment, the crude product was obtained. The crude product was separated and purified by a normal-phase chromatography column to obtain 380.0 mg of Compound 37-c. MS m / z (ESI): 555.21 [M + H] + .

[0916] Step 3: Synthesis of Compound 37

[0917] 37-c (100.0 mg, 0.18 mmol) was dissolved in THF (10 mL), 2N HCl (2 mL) was added, and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, 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. The resulting mixture was separated and purified by normal-phase chromatography column, and further purified by medium-pressure preparation to obtain 23.3 mg of compound 37. MS m / z (ESI): 527.17 [M+H] + 。

[0918] 1 H NMR (400 MHz, DMSO-d6) δ 9.46 (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). Preparation of Compound 38 in Example 38

[0919]

[0920] Step 1: Synthesis of Compound 38-b

[0921] Under nitrogen protection, 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 the mixture was stirred overnight at room temperature. After the reaction was completed, water (20 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. The resulting mixture was separated and purified by normal-phase chromatography column to obtain 12.0 g of compound 38-b. MS m / z (ESI): 173.11 [M+H] + 。

[0922] Step 2: Synthesis of Compound 38-c

[0923] Under nitrogen protection, 38-b (12.0 g, 69.8 mmol) and thiourea (15.9 g, 209.3 mmol) were dissolved in H2O (150 mL), and the mixture was stirred overnight at 100 °C. After the reaction was completed, the mixture was adjusted to pH = 2 with dilute hydrochloric acid, extracted with ethyl acetate (3×50 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting mixture was separated and purified by normal-phase chromatography to obtain 1.8 g of compound 38-c. MS m / z (ESI): 185.07 [M+H] + 。

[0924] Step 3: Synthesis of compound 38-d

[0925] Under nitrogen protection, 38-c (1.8 g, 9.8 mmol) and chloroacetic acid (2.8 g, 29.3 mmol) were dissolved in HCl (6N, 20 mL), and the mixture was stirred overnight at 100 °C. After the reaction was completed, the mixture was adjusted to pH = 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate (3×50 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting 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] + 。

[0926] Step 4: Synthesis of compound 38-e

[0927] Under nitrogen protection, 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), and the mixture was stirred overnight at 120 °C. After the reaction was completed, the mixture was adjusted to pH = 8 with sodium bicarbonate solution, extracted with ethyl acetate (3×50 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting mixture was separated and purified by normal-phase chromatography to obtain 98.0 mg of compound 38-e. MS m / z (ESI): 205.02 [M+H] + 。

[0928] Step 5: Synthesis of compound 38-f

[0929] Referring to the synthesis of 3-b, I-19 (45.5 mg, 0.1 mmol), replacing 3-a with 38-e (98.0 mg, 0.5 mmol), 68.0 mg of compound 38-f was obtained. MS m / z (ESI): 485.13 [M+H] + 。

[0930] Step 6: Synthesis of Compound 38-g

[0931] Referring to the synthesis of 3-c, replace 3-b with 38-f (68.0 mg, 0.1 mmol), and stir the mixture at 80 °C for 1 hour. After the same post-treatment, 23.0 mg of Compound 38-g was obtained. MS m / z (ESI): 427.12 [M+H] + 。

[0932] Step 7: Synthesis of Compound 38

[0933] Referring to the synthesis of Compound 3, 1-c (19.9 mg, 0.1 mmol), replace 3-c with 38-g (23.0 mg, 0.1 mmol), and stir at 100 °C overnight. After the same post-treatment, the crude product was obtained, and the crude product was separated and purified by a reverse-phase chromatography column to obtain 6.6 mg of Compound 38. MS m / z (ESI): 541.23 [M+H] + 。

[0934] 1 H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.67 (s, 1H), 8.00 (d, J = 1.l Hz 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.25 (d, J = 11.5 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 4.57 (s, 2H), 3.86 (s, 3H), 3.60 (d, J = 1.2 Hz, 3H), 1.71 - 1.66 (s, 1H), 1.50 (s, 9H), 1.08 - 1.02 (m, 2H), 0.88 - 0.82 (m, 2H).

[0935] Preparation of Compound 39 in Example 39

[0936]

[0937] Step 1: Synthesis of Compound 39-a

[0938] Referring to the synthesis of 3-b, replace I-19 with I-20 (400.0 mg, 1.2 mmol), replace 3-a with 11-b (296.7 mg, 1.2 mmol), and stir at room temperature for 1 hour. After the same post-treatment, 244.0 mg of Compound 39-a was obtained. MS m / z (ESI): 532.90 [M+H] + 。

[0939] Step 2: Synthesis of Compound 39-b

[0940] Referring to the synthesis of 3-c, replace 3-b with 39-a (244.0 mg, 0.46 mmol), and stir at 80 °C for 1 hour. After the same post-treatment, 94.0 mg of compound 39-b was obtained. MS m / z (ESI): 475.00 [M+H] + 。

[0941] Step 3: Synthesis of compound 39

[0942] Referring to the synthesis of compound 3, 1-c (77.0 mg, 0.4 mmol), replace 3-c with 39-b (94.0 mg, 0.2 mmol). After the same post-treatment, the crude product was obtained. The crude product was purified by medium-pressure preparation and freeze-dried to obtain 31.4 mg of compound 39. MS m / z (ESI): 588.60 [M+H] + 。

[0943] 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.67 (s, 1H), 8.15 (d, J = 1.0 Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H), 4.48 - 4.40 (m, 1H), 4.28 (s, 2H), 3.86 (s, 3H), 2.50 (s, 3H), 1.72 - 1.62 (m, 1H), 1.39 (d, J = 6.6 Hz, 6H), 1.07 - 1.00 (m, 2H), 0.93 - 0.82 (m, 2H).

[0944] Preparation of compound 40 in Example 40

[0945]

[0946] Step 1: Synthesis of compound 40-a

[0947] Referring to the synthesis of 3-b, I-19 (103.8 mg, 0.3 mmol), replace 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] + 。

[0948] Step 2: Synthesis of compound 40-b

[0949] Referring to the synthesis of 3-c, replace 3-b with 40-a (180.0 mg, 0.3 mmol), and stir in a sealed tube at 80 °C for 1 hour. After the same post-treatment, 100.0 mg of compound 40-b was obtained. MS m / z (ESI): 496.96 [M+H] + 。

[0950] Step 3: Synthesis of Compound 40-d

[0951] Under nitrogen protection, 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), and stirred at 100 °C overnight. After the reaction was completed, it 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. The resulting mixture was separated and purified by normal-phase chromatography column to obtain 37.0 mg of Compound 40-d. MS m / z (ESI): 411.09 [M+H] + 。

[0952] Step 4: Synthesis of Compound 40

[0953] Referring to the synthesis of Compound 3, 1-c (35.0 mg, 0.2 mmol), and 3-c was replaced with 40-d (37.0 mg, 0.1 mmol). The mixture was stirred at 100 °C overnight. After the same post-treatment, the crude product was obtained. The crude product was separated and purified by reverse-phase chromatography column to obtain 16.99 mg of Compound 40. MS m / z (ESI): 525.19 [M+H] + 。

[0954] 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.58 (s, 1H), 8.00 (d, J = 1.0 Hz 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.37 (d, J = 11.4 Hz, 1H), 7.31 (dd, J = 7.9 Hz, 1.3 Hz, 1H), 4.46 (s, 2H), 3.86 (s, 3H), 3.60 (d, J = 1.2 Hz, 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).

[0955] Preparation of Compound 41 in Example 41

[0956]

[0957] Step 1: Synthesis of Compound 41-a

[0958] Referring to the synthesis of 3-b, replace I-19 with I-6 (163.1 mg, 0.5 mmol) and replace 3-a with 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] + 。

[0959] Step 2: Synthesis of compound 41-b

[0960] Referring to the synthesis of 3-c, replace 3-b with 41-a (263.0 mg, 0.5 mmol), and stir in a sealed tube at 80 °C for 1 hour. After the same work-up, 67.0 mg of compound 41-b was obtained. MS m / z (ESI): 478.97 [M+H] + 。

[0961] Step 3: Synthesis of compound 41-d

[0962] Under nitrogen protection, dissolve 41-b (67.0 mg, 0.1 mmol) in THF (5 mL), add 41-c (59.5 mg, 0.3 mmol) and Pd(PPh3)2Cl2 (9.8 mg, 0.01 mmol), stir the mixture at 65 °C overnight. After the reaction is complete, add water (10 mL) to the mixture, extract with ethyl acetate (3 * 20 mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. The resulting mixture 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] + 。

[0963] Step 4: Synthesis of compound 41

[0964] Referring to the synthesis of compound 3, 1-c (40.0 mg, 0.2 mmol), replace 3-c with 41-d (39.0 mg, 0.1 mmol), and stir the mixture at 100 °C overnight. After the same work-up, the crude product was obtained, and the crude product was separated and purified by reverse-phase chromatography to obtain 14.78 mg of compound 41. MS m / z (ESI): 493.10 [M+H] + 。

[0965] 11H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.70 (s, 1H), 7.92 (d, J = 1.0 Hz 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H), 7.15 (dd, J = 17.5 Hz, 11.3 Hz, 1H), 6.05 (d, J = 17.5 Hz, 1H), 5.59 (d, J = 11.6 Hz, 1H), 4.36 (s, 2H), 3.88 (s, 3H), 3.77 (s, 3H), 1.73 - 1.59 (m, 1H), 1.10 - 1.02 (m, 2H), 0.93 - 0.90 (m, 2H).

[0966] Example 42 Preparation of Compound 42

[0967]

[0968] Step 1: Synthesis of Compound 42

[0969] Under nitrogen protection, dissolve Compound 37 (60.0 mg, 0.11 mmol) in THF (2 mL), cool to -78 °C, add methylmagnesium bromide (0.38 mL, 1.14 mmol), allow to warm to room temperature and react for 1 hour. After the reaction is complete, add water, extract with ethyl acetate (3 × 10 mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. The resulting mixture is separated and purified by a normal-phase chromatography column, and further purified by medium-pressure preparation to obtain 5.03 mg of Compound 42. MS m / z (ESI): 543.21 [M + H] + 。

[0970] 1 1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.67 (s, 1H), 8.00 (d, J = 1.2 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.33 - 7.21 (m, 2H), 5.56 (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).

[0971] Example 43 Preparation of Compound 43

[0972]

[0973] Step 1: Synthesis of Compound 43-a

[0974] With reference to the synthesis of 3-b, replace I-19 with I-8 (548.5 mg, 1.7 mmol) and replace 3-a with 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] + 。

[0975] Step 2: Synthesis of compound 43-b

[0976] With reference to the synthesis of 3-c, replace 3-b with 43-a (434.0 mg, 0.92 mmol) and react at 80 °C for 1 hour. After the same post-treatment, 358.0 mg of compound 43-b was obtained. MS m / z (ESI): 412.00 [M+H] + 。

[0977] Step 3: Synthesis of compound 43

[0978] With reference to the synthesis of compound 3, 1-c (141.3 mg, 0.73 mmol), replace 3-c 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] + 。

[0979] 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.63 (s, 1H), 8.6 - 8.58 (m, 1H), 8.20 (s, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.81 (dd, J = 8.2, 2.0 Hz, 1H), 5.75 - 5.66 (m, 1H), 4.22 (d, J = 12.3 Hz, 2H), 4.03 (s, 3H), 3.83 (s, 3H), 1.67 - 1.57 (m, 1H), 1.44 (d, J = 6.7 Hz, 6H), 1.05 - 0.96 (m, 2H), 0.88 - 0.79 (m, 2H).

[0980] Preparation of compound 44 in Example 44

[0981]

[0982] Step 1: Synthesis of compound 44-a

[0983] Under nitrogen protection, I-16 (80.0 mg, 0.2 mmol), 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. The mixture was stirred at 80 °C for 4 hours. After the reaction was completed, water (10 mL) was added to the mixture, and it was extracted with ethyl acetate (2×10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The mixture was separated and purified by a normal-phase chromatography column to obtain 30.0 mg of compound 44-a. MS m / z (ESI): 423.11 [M+H] + 。

[0984] Step 2: Synthesis of compound 44

[0985] Referring to the synthesis of compound 4, 1-c (27.5 mg, 0.14 mmol), and 2-a was replaced with 44-a (30.0 mg, 0.07 mmol). The mixture was stirred at 80 °C for 3 hours. After the same post-treatment, 7.15 mg of compound 44 was obtained. MS m / z (ESI): 537.21 [M+H] + 。

[0986] 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.67 (s, 1H), 7.96 (d, J = 1.2 Hz, 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). Preparation of compound 45 in Example 45

[0987]

[0988] Step 1: Synthesis of compound 45-a

[0989] With reference to the synthesis of 3-b, replace I-19 with I-21 (149.4 mg, 0.50 mmol), replace 3-a with 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] + 。

[0990] Step 2: Synthesis of compound 45-b

[0991] With reference to the synthesis of 3-c, replace 3-b with 45-a (74.0 mg, 0.15 mmol), stir at 80 °C for 1 hour. After the same work-up, 20.0 mg of compound 45-b was obtained. MS m / z (ESI): 450.00 [M+H] + 。

[0992] Step 3: Synthesis of compound 45

[0993] With reference to the synthesis of compound 3, 1-c (17.3 mg, 0.09 mmol), replace 3-c 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] + 。

[0994] 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.67 (s, 1H), 7.91 (d, J = 1.2 Hz, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 8.3 Hz, 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).

[0995] Preparation of compound 46 in Example 46

[0996]

[0997] Step 1: Synthesis of compound 46-a

[0998] Under nitrogen protection, add 40-b (60.0 mg, 0.12 mmol), tributyl(propargyl)stannane (0.06 mL, 0.18 mmol), Pd(PPh3)2Cl2 (8.5 mg, 0.01 mmol), and toluene (2 mL) to the reaction flask, stir at 100 °C for 2 hours. The reaction solution was directly purified by medium-pressure preparative chromatography in the normal phase to obtain 38.0 mg of compound 46-a. MS m / z (ESI): 409.10 [M+H]+ .

[0999] Step 2: Synthesis of Compound 46

[1000] Referring to the synthesis of Compound 3, 1-c (36.1 mg, 0.19 mmol), replace 3-c with 46-a (38.0 mg, 0.09 mmol), stir at 95 °C for 2 hours. After the same post-treatment, 13.5 mg of Compound 46 was obtained. MS m / z (ESI): 523.20 [M+H] + .

[1001] 1 H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.68 (s, 1H), 8.00 - 7.96 (m, 1H), 7.55 (t, J = 7.8 Hz, 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 = 1.1 Hz, 3H), 2.22 (s, 3H), 1.73 - 1.63 (m, 1H), 1.08 - 0.99 (m, 2H), 0.92 - 0.82 (m, 2H).

[1002] Preparation of Compound 47 in Example 47

[1003]

[1004] Step 1: Synthesis of Compound 47-a

[1005] Referring to the synthesis of 44-a, 1-a (54.8 mg, 0.31 mmol), replace I-16 with I-17 (80.0 mg, 0.2 mmol), 30.0 mg of Compound 47-a was obtained. MS m / z (ESI): 409.1 [M+H] + .

[1006] Step 2: Synthesis of Compound 47

[1007] Referring to the synthesis of Compound 4, 1-c (28.5 mg, 0.15 mmol), replace 2-a with 47-a (30.0 mg, 0.07 mmol), stir the mixture at 80 °C for 3 hours. After the same post-treatment, 9.11 mg of Compound 47 was obtained. MS m / z (ESI): 523.2 [M+H] + .

[1008] 11H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.67 (s, 1H), 7.97 (d, J = 1.2 Hz, 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 = 6.8 Hz, 2H), 3.86 (s, 3H), 2.66 (t, J = 6.8 Hz, 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).

[1009] Example 48 Preparation of Compound 48

[1010]

[1011] Step 1: Synthesis of Compound 48-a

[1012] Referring to the synthesis of 3-b, replace I-19 with I-23 (268.0 mg, 0.83 mmol), and replace 3-a 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] + .

[1013] Step 2: Synthesis of Compound 48-b

[1014] Referring to the synthesis of 3-c, replace 3-b with 48-a (193.0 mg, 0.36 mmol), and stir at 80 °C for 1 hour. After the same post-treatment, 89.0 mg of Compound 48-b is obtained. MS m / z (ESI): 473.00 [M + H] + .

[1015] Step 3: Synthesis of Compound 48

[1016] Referring to the synthesis of Compound 3, 1-c (73.2 mg, 0.38 mmol), replace 3-c with 48-b (89.0 mg, 0.19 mmol), and stir at 95 °C for 2 hours. The reaction solution is directly purified by a normal-phase chromatographic column first, and then purified by medium-pressure preparation to obtain 27.8 mg of Compound 48. MS m / z (ESI): 587.10 [M + H] + .

[1017] 11H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.67 (s, 1H), 7.59 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 7.2 Hz, 2H), 6.61 (s, 1H), 4.30 (s, 2H), 3.86 (s, 3H), 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).

[1018] Example 49 Preparation of Compound 49

[1019]

[1020] Step 1: Synthesis of Compound 49-b

[1021] Under nitrogen protection, 41-d (50.0 mg, 0.13 mmol) was dissolved in THF (5 mL), 49-a (41.9 mg, 0.2 mmol) and Grubbs 2nd 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 it was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting mixture was separated and purified by a normal-phase chromatographic column to obtain 45.0 mg of Compound 49-b. MS m / z (ESI): 562.21 [M + H] + .

[1022] Step 2: Synthesis of Compound 49-c

[1023] Referring to the synthesis of Compound 3, 1-c (31.1 mg, 0.2 mmol), replacing 3-c with 49-b (45.0 mg, 0.08 mmol), stirred at 100 °C overnight. After the same post-treatment, the crude product was obtained. The crude product was separated and purified by a normal-phase chromatographic column to obtain 40.0 mg of Compound 49-c. MS m / z (ESI): 676.31 [M + H] + .

[1024] Step 3: Synthesis of Compound 49

[1025] Under nitrogen protection, 49-c (40.0 mg, 0.06 mmol) was dissolved in HCl-dioxane (5 mL). The mixture was stirred overnight at room temperature. After the reaction was completed, the pH was adjusted to 7 with sodium bicarbonate solution, 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. The resulting mixture was separated and purified by reverse-phase chromatography to obtain 7.27 mg of compound 49. MS m / z (ESI): 576.26 [M+H] + 。

[1026] 1 H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.70 (s, 1H), 7.93 (d, J = 1.1 Hz 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 8.2 Hz, 2H), 6.73 (d, J = 16.0 Hz, 1H), 6.42 (dd, J = 16.0 Hz, 6.6 Hz, 1H), 4.34 (s, 2H), 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), 1.77 - 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).

[1027] Preparation of Compound 50 in Example 50

[1028]

[1029] Step 1: Synthesis of Compound 50

[1030] Under nitrogen protection, compound 49 (7.27 mg, 0.01 mmol) was dissolved in MeOH (3 mL). Formaldehyde solution (1.2 mg, 0.03 mmol) was added, and the mixture was stirred at 50 °C for 1 h. Then sodium cyanoborohydride (1.6 mg, 0.03 mmol) was added. After the reaction was completed, 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. The resulting mixture was separated and purified by reverse-phase chromatography to obtain 5.52 mg of compound 50. MS m / z (ESI): 590.27 [M+H] + 。

[1031] 11H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.70 (s, 1H), 7.93 (d, J = 1.0 Hz 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.3 Hz, 2H), 6.73 (d, J = 16.0 Hz, 1H), 6.43 (dd, J = 16.0 Hz, 6.6 Hz, 1H), 4.34 (s, 2H), 3.89 (s, 3H), 3.77 (s, 3H), 2.82 - 2.76 (m, 2H), 2.18 (s, 3H), 1.98 - 1.88 (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).

[1032] Example 51 Preparation of Compound 51

[1033]

[1034] Step 1: Synthesis of Compound 51-a

[1035] Under nitrogen protection, 41-a (276.0 mg, 0.5 mmol) was dissolved in dioxane (5 mL), water (1 mL) was added, potassium allyltrifluoroborate (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 overnight at 100 °C. After the reaction was completed, water (10 mL) was added to the mixture, and it was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting mixture was separated and purified by a normal-phase chromatography column to obtain 100.0 mg of Compound 51-a. MS m / z (ESI): 451.11 [M + H] + .

[1036] Step 2: Synthesis of Compound 51-b

[1037] Under nitrogen protection, 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 completed, water (20 mL) was added to the mixture, and the pH was adjusted to 7 with sodium bicarbonate solution. It was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting mixture was separated and purified by a normal-phase chromatography column to obtain 40.0 mg of Compound 51-b. MS m / z (ESI): 375.14 [M + H] + .

[1038] Step 3: Synthesis of Compound 51-c

[1039] With reference 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] + 。

[1040] Step 4: Synthesis of Compound 51

[1041] With reference to the synthesis of Compound 3, 1-c (29.7 mg, 0.2 mmol), 3-c was replaced with 51-c (30.0 mg, 0.08 mmol), and the mixture was stirred overnight at 100 °C. After the same post-treatment, the crude product was obtained, and the crude product was separated and purified by a reverse-phase chromatographic column to obtain 1.23 mg of Compound 51. MS m / z (ESI): 507.22 [M+H] + 。

[1042] 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.69 (d, J = 2.8 Hz, 1H), 7.93 (s, 1H), 7.67 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H), 6.81 (d, J = 15.8 Hz, 1H), 6.50 (dd, J = 15.7 Hz, 6.6 Hz, 1H), 4.33 (s, 2H), 3.88 (d, J = 3.1 Hz, 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).

[1043] Example 52 Preparation of Compound 52

[1044]

[1045] Step 1: Synthesis of Compound 52-a

[1046] Dissolve I-3-4 (2.0 g, 7.29 mmol) in ethyl acetate (50 mL), add Dess-Martin oxidant (3.1 g, 7.29 mmol), and stir at room temperature for 2 hours. Add 100 mL of water, extract with ethyl acetate (3 * 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 was separated and purified by a normal-phase chromatographic column to obtain 1.5 g of Compound 52-a. MS m / z (ESI): 273.09 [M+H] + 。

[1047] Step 2: Synthesis of Compound 52-b

[1048] Under nitrogen protection, 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 the mixture was stirred at 70 °C for 1 hour. It was extracted with ethyl acetate (3 × 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 and purified by a normal-phase chromatography column to obtain 2.0 g of Compound 52-b. MS m / z (ESI): 415.06 [M+H] + 。

[1049] Step 3: Synthesis of Compound 52-c

[1050] 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 Compound 52-b (180.0 mg, 0.43 mmol). After the same post-treatment, a crude product was obtained. The crude product was separated and purified by a normal-phase chromatography column to obtain 100.0 mg of Compound 52-c. MS m / z (ESI): 528.94 [M+H] + 。

[1051] Step 4: Synthesis of Compound 52

[1052] Under nitrogen protection, Compound 52-c (80.0 mg, 0.15 mmol) was dissolved in dichloromethane (10 mL), DAST (122.0 mg, 0.76 mmol) was added, and the mixture was stirred at room temperature overnight. Water (100 mL) was added, and it was extracted with ethyl acetate (3 × 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 purified by medium-pressure preparation to obtain 3.0 mg of Compound 52. MS m / z (ESI): 551.23 [M+H] + 。

[1053] 1 H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.71 (s, 1H), 8.07 (d, J = 1.0 Hz, 1H), 7.80 (t, J = 7.7 Hz, 1H), 7.63 (d, J = 10.5 Hz, 1H), 7.56 (d, J = 8.3 Hz, 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).

[1054] Preparation of Compound 53 in Example 53

[1055]

[1056] Step 1: Synthesis of Compound 53-a

[1057] Under nitrogen protection, 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. Extracted with ethyl acetate (3 × 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 and purified by a normal-phase chromatography column to obtain 100.0 mg of Compound 53-a. MS m / z (ESI): 391.97 [M+H] + 。

[1058] Step 2: Synthesis of Compound 53

[1059] 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). After the same post-treatment, a crude product was obtained. The crude product was purified by medium-pressure preparation to obtain 16.0 mg of Compound 53. MS m / z (ESI): 506.18 [M+H] + 。

[1060] 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.67 (s, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.69 (q, J = 8.6 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 6.93 (t, J = 55.3 Hz, 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).

[1061] Preparation of Compound 54 in Example 54

[1062]

[1063] Step 1: Synthesis of Compound 54-b

[1064] Under nitrogen protection, 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, and the crude product was purified by silica gel column chromatography to obtain 570.0 mg of compound 54-b. MS m / z (ESI): 276.15 [M+H] + 。

[1065] Step 2: Synthesis of compound 54

[1066] Under nitrogen protection, 54-b (50.0 mg, 0.18 mmol), I-3 (139.4 mg, 0.36 mmol), potassium phosphate (125.3 mg, 0.54 mmol), Pd(PPh3)2Cl2 (12.7 mg, 0.02 mmol) were dissolved in toluene (110 mL) and water (2 mL), and heated and stirred at 100 °C overnight. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by a normal-phase chromatographic column to obtain a crude product, and then further purified by a reverse-phase chromatographic column to obtain 1.25 mg of compound 54. MS m / z (ESI): 498.22 [M+H] + 。

[1067] 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.51 (s, 1H), 8.00 (d, J = 1.6 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.35 (s, 1H), 7.30 (d, J = 11.2 Hz, 1H), 7.22 (dd, J = 8.0, 1.6 Hz, 1H), 4.17 (s, 2H), 3.85 (s, 3H), 3.61 (d, J = 1.6 Hz, 3H), 2.33 (s, 3H), 1.87 - 1.76 (m, 1H), 1.08 - 1.00 (m, 2H), 0.93 - 0.84 (m, 2H).

[1068] Example 55 Preparation of compound 55

[1069]

[1070] Step 1: Synthesis of compound 55-b

[1071] Under nitrogen protection, 55-a (500.0 mg, 2.81 mmol) was dissolved in dioxane (15 mL), 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 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 it 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. The resulting mixture was separated and purified by normal-phase chromatography to obtain 300.0 mg of compound 55-b. MS m / z (ESI): 292.08 [M+H] + 。

[1072] Step 2: Synthesis of compound 55

[1073] Under nitrogen protection, 55-b (120.0 mg, 0.41 mmol) was dissolved in dioxane (5 mL), 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 it 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. The resulting mixture was separated and purified by normal-phase chromatography and then by reverse-phase chromatography to obtain 10.8 mg of compound 55. MS m / z (ESI): 496.19 [M+H] + 。

[1074] 1 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.45 (s, 1H), 7.92 (d, J = 1.2 Hz, 1H), 7.69 - 7.64 (m, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.33 (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).

[1075] Preparation of Example 56 Compound 56

[1076]

[1077] Step 1: Synthesis of Compound 56-b

[1078] Under nitrogen protection, 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 mixture was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography to obtain 45.0 mg of Compound 56-b. MS m / z (ESI): 370.07 [M+H] + 。

[1079] Step 2: Synthesis of Compound 56

[1080] Under nitrogen protection, 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 mixture was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by medium-pressure preparation to obtain 16.0 mg of Compound 56. MS m / z (ESI): 484.21 [M+H] + 。

[1081] 1 1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.63 (d, J = 5.2 Hz, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.50 (s, 1H), 7.41 (dd, J = 11.2, 1.6 Hz, 1H), 7.37 (dd, J = 5.2, 1.6 Hz, 1H), 7.32 (dd, J = 8.0, 1.6 Hz, 1H), 4.17 (s, 2H), 3.85 (s, 3H), 3.61 (d, J = 1.6 Hz, 3H), 1.79 - 1.71 (m, 1H), 1.08 - 1.02 (m, 2H), 0.92 - 0.86 (m, 2H). Preparation of Compound 57 in Example 57

[1082]

[1083] Step 1: Synthesis of Compound 57-b

[1084] With reference to the synthesis of 56-b, I-3-5 (50.0 mg, 0.15 mmol), 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] + 。

[1085] Step 2: Synthesis of compound 57

[1086] With reference to the synthesis of compound 56, 1-c (50.0 mg, 0.26 mmol), 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] + 。

[1087] 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 1.6 Hz, 1H), 8.66 (s, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.63 (d, J = 6.0 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 11.2 Hz, 1H), 7.30 (dd, J = 8.0 1.6 Hz, 1H), 4.23 (s, 2H), 3.86 (s, 3H), 3.61 (d, J = 1.6 Hz, 3H), 1.82 - 1.73 (m, 1H), 1.11 - 1.03 (m, 2H), 0.94 - 0.86 (m, 2H).

[1088] Preparation of compound 58 in Example 58

[1089]

[1090] Step 1: Synthesis of compound 58-a

[1091] With reference to the synthesis of 56-b, replace 56-a with 59-b (100.0 mg, 0.58 mmol), replace I-3-5 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] + 。

[1092] Step 2: Synthesis of compound 58

[1093] Referring to the synthesis of reference compound 56, 1-c (63.7 mg, 0.33 mmol), replace 56-b with 58-a (63.0 mg, 0.16 mmol). The reaction solution was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography to obtain 60.0 mg of compound 58. MS m / z (ESI): 498.20 [M+H] + 。

[1094] 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.50 (s, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.41 (dd, J = 11.2, 2.0 Hz, 1H), 7.33 (s, 1H), 7.25 (dd, J = 8.4, 2.0 Hz, 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).

[1095] Preparation of Compound 59 in Example 59

[1096]

[1097] Step 1: Synthesis of Compound 59-b

[1098] Under nitrogen protection, 59-a (820.0 mg, 3.97 mmol) and trimethyl borate (0.89 mL, 7.94 mmol) were dissolved in THF (10 mL), stirred at -78 °C for half an hour, and a solution of n-butyllithium (3.72 mL, 5.96 mmol) was slowly added thereto, and stirred at -78 °C for half an hour. Acidified with 1N aqueous HCl solution, concentrated, and purified by reverse-phase column to obtain 350.0 mg of compound 59-b. MS m / z (ESI): 172.12 [M+H] + 。

[1099] Step 2: Synthesis of Compound 59-c

[1100] Referring to the synthesis of 56-b, I-3-5 (255.7 mg, 0.76 mmol), replace 56-a 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] + 。

[1101] Step 3: Synthesis of Compound 59

[1102] Referring to the synthesis of reference compound 56, replace 1-c with 2-b (87.4 mg, 0.33 mmol), and replace 56-b with 59-c (63.0 mg, 0.16 mmol). The reaction solution was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography to obtain 37.0 mg of compound 59. MS m / z (ESI): 488.18 [M+H] + 。

[1103] 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.43 (s, 1H), 8.00 (d, J = 1.6 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.31 - 7.25 (m, 2H), 7.22 (dd, J = 8.0, 1.6 Hz, 1H), 4.14 (s, 2H), 3.87 (s, 6H), 3.61 (d, J = 1.6 Hz, 3H), 2.30 (s, 3H).

[1104] Preparation of Compound 60 in Example 60

[1105]

[1106] Step 1: Synthesis of Compound 60-a

[1107] Referring to the synthesis of 56-b, replace I-3-5 with I-7-3 (255.7 mg, 0.70 mmol), and replace 56-a 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] + 。

[1108] 1 H NMR (400 MHz, DMSO-d6) δ 8.29 - 8.21 (m, 2H), 7.53 (t, J = 8.0 Hz, 1H), 7.38 (s, 1H), 7.31 (dd, J = 11.2, 1.6 Hz, 1H), 7.20 (dd, J = 8.0, 1.6 Hz, 1H), 4.24 - 4.10 (m, 3H), 2.25 (s, 3H), 1.39 (d, J = 6.8 Hz, 6H).

[1109] Step 2: Synthesis of Compound 60

[1110] With reference to the synthesis of reference compound 56, 1-c (47.1 mg, 0.24 mmol), replace 56-b with 60-a (50.0 mg, 0.12 mmol). The reaction solution was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography to obtain 25.0 mg of compound 60. MS m / z (ESI): 526.24 [M+H] + 。

[1111] 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.51 (s, 1H), 8.24 (d, J = 1.6 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.35 (s, 1H), 7.30 (dd, J = 11.2, 1.6 Hz, 1H), 7.23 (dd, J = 8.0, 1.6 Hz, 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 = 6.8 Hz, 6H), 1.08 - 0.98 (m, 2H), 0.93 - 0.85 (m, 2H).

[1112] Preparation of Compound 61 in Example 61

[1113]

[1114] Step 1: Synthesis of Compound 61-a

[1115] Under nitrogen protection, dissolve 55-b (20.0 mg, 0.07 mmol) in dioxane (1 mL), add B2PIN2 (34.8 mg, 0.14 mmol), palladium acetate (324.6 mg, 0.28 mmol) and potassium acetate (20.2 mg, 0.21 mmol). The mixture was stirred at 110 °C for 1 hour. After the reaction was completed, add water (10 mL) to the mixture, extract with ethyl acetate (3 * 10 mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. The resulting mixture was separated and purified by a normal-phase chromatography column to obtain 14.0 mg of compound 61-a. MS m / z (ESI): 302.1 [M+H] + 。

[1116] Step 2: Synthesis of Compound 61

[1117] Under nitrogen protection, 61-a (14.0 mg, 0.05 mmol) was dissolved in THF (2 mL), water (1 mL) was added, followed by 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). The mixture was stirred at 80 °C for 3 hours. After the reaction was completed, water (10 mL) was added to the mixture, and it 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. The resulting mixture was first purified by a normal-phase chromatography column and then separated and purified by a reverse-phase chromatography column to obtain 4.0 mg of compound 61. MS m / z (ESI): 514.18 [M+H] + 。

[1118] 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.47 (s, 1H), 8.00 (s, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.39 (s, 1H), 7.35 - 7.29 (m, 1H), 7.29 - 7.22 (m, 1H), 4.09 (s, 2H), 4.00 (s, 3H), 3.84 (s, 3H), 3.61 (d, J = 1.6 Hz, 3H), 1.86 - 1.75 (m, 1H), 1.08 - 0.99 (m, 2H), 0.92 - 0.83 (m, 2H).

[1119] Example 62 Preparation of Compound 62

[1120]

[1121] Step 1: Synthesis of Compound 62-a

[1122] Referring to the synthesis of 16-b, 16-a (870.0 mg, 5.38 mmol), replacing tributyltin chloride with iodine (1503.0 mg, 5.92 mmol). The reaction solution was quenched with water (5 mL), ethyl acetate (50 mL) was added, and then it was washed with water (50 mL) and saturated brine (50 mL), 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 a normal-phase chromatography column to obtain 820.0 mg of compound 62-a. MS m / z (ESI): 287.99 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 4.02 (s, 3H).

[1123] Step 2: Synthesis of Compound 62-b

[1124] With reference to the synthesis of 9-a, replace 1-a with 62-a (100.0 mg, 0.35 mmol) and replace I-4 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] + 。

[1125] Step 3: Synthesis of compound 62

[1126] Under nitrogen protection, add 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) to the reaction flask. Stir at 100 °C overnight, concentrate the filtrate under reduced pressure to obtain the crude product, and purify the crude product by silica gel column chromatography to obtain 3.0 mg of compound 62. MS m / z (ESI): 514.17 [M+H] + 。

[1127] 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.45 (s, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.0 Hz, 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).

[1128] Example 63 Preparation of compound 63

[1129]

[1130] Step 1: Synthesis of compound 63-a

[1131] With reference to the synthesis of 9-a, replace 1-a with 62-a (100.0 mg, 0.35 mmol) and replace I-4 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] + 。

[1132] Step 2: Synthesis of compound 63

[1133] Referring to the synthesis of reference compound 62, 1-c (9.3 mg, 0.05 mmol), replacing 62-b with 63-a (10.0 mg, 0.02 mmol), 1.2 mg of compound 63 was obtained. MS m / z (ESI): 532.18 [M+H] + .

[1134] 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.47 (s, 1H), 8.00 (d, J = 1.6 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.24 - 7.17 (m, 2H), 4.17 (s, 2H), 4.06 (s, 3H), 3.87 (s, 3H), 3.61 (d, J = 1.6 Hz, 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).

[1135] Preparation of Compound 64 in Example 64

[1136]

[1137] Step 1: Synthesis of Compound 64-a

[1138] Referring to the synthesis of 9-a, replacing 1-a with 17-b (250.0 mg, 0.92 mmol), and replacing I-4 with I-2 (337.2 mg, 0.92 mmol), 44.0 mg of compound 64-a was obtained. MS m / z (ESI): 384.1 [M+H] + .

[1139] Step 2: Synthesis of Compound 64

[1140] Referring to the synthesis of compound 4, 1-c (44.5 mg, 0.23 mmol), replacing 2-a with 64-a (44.0 mg, 0.11 mmol), stirring overnight at 100 °C, concentrating under reduced pressure to obtain a crude product, and purifying the crude product by medium-pressure preparation to obtain 15.0 mg of compound 64. MS m / z (ESI): 498.16 [M+H] + .

[1141] 11H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.44 (s, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 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).

[1142] Example 65 Preparation of Compound 65

[1143]

[1144] Step 1: Synthesis of Compound 65-a

[1145] Referring to the synthesis of 16-c, 16-b (200.0 mg, 0.44 mmol), replacing I-7-3 with I-8-3 (154.5 mg, 0.44 mmol), 37.0 mg of Compound 65-a was obtained. MS m / z (ESI): 429.20 [M+H] + .

[1146] Step 2: Synthesis of Compound 65

[1147] Referring to the synthesis of Compound 62, using 1-c (33.5 mg, 0.17 mmol) and replacing 62-b with 65-a (37.0 mg, 0.09 mmol), 22.0 mg of Compound 65 was obtained. MS m / z (ESI): 543.3 [M+H] + .

[1148] 1 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.57 (d, J = 2.4 Hz, 1H), 8.45 (s, 1H), 8.22 (d, J = 1.6 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.75 (dd, J = 8.0, 2.4 Hz, 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), 1.45 (d, J = 6.8 Hz, 6H), 1.14 - 1.07 (m, 1H), 1.05 - 0.98 (m, 1H), 0.96 - 0.84 (m, 2H).

[1149] Example 66 Preparation of Compound 66

[1150]

[1151] Step 1: Synthesis of Compound 66-b

[1152] Referring to the synthesis of 16-b, replace 16-a with 66-a (1.0 g, 6.87 mmol), and replace n-butyllithium with lithium diisopropylamide (3.61 mL, 7.21 mmol) to obtain 1.05 g of Compound 66-b.

[1153] 1 H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 2.36 (s, 3H), 1.66 - 1.38 (m, 6H), 1.37 - 1.16 (m, 12H), 0.87 (t, J = 7.2 Hz, 9H).

[1154] Step 2: Synthesis of Compound 66-c

[1155] Referring to the synthesis of 16-c, replace I-7-3 with I-8-3 (160.2 mg, 0.46 mmol), and replace 16-b with 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] + 。

[1156] Step 3: Synthesis of Compound 66

[1157] Referring to the synthesis of Compound 62, use 1-c (7.5 mg, 0.04 mmol), and replace 62-b with 66-c (8 mg, 0.02 mmol) to obtain 5.5 mg of Compound 66. MS m / z (ESI): 527.2 [M+H] + 。

[1158] 1 H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.46 (s, 1H), 8.23 (s, 1H), 8.03 (d, J = 8.� Hz, 1H), 7.71 (dd, J = 8.�, 2.0 Hz, 1H), 5.80 - 5.67 (m, 1H), 4.24 (s, 2H), 3.88 (s, 3H), 2.41 (s, 3H), 1.76 - 1.69 (m, 1H), 1.46 (d, J = 6.8 Hz, 6H), 1.16 - 1.11 (m, 1H), 1.06 - 1.00 (m, 1H), 0.98 - 0.88 (m, 2H).

[1159] Example 67 Preparation of Compound 67

[1160]

[1161] Step 1: Synthesis of Compound 67-a

[1162] Referring to the synthesis of 16-c, I-7-3 (504.2 mg, 1.38 mmol), replacing 16-b with 66-b (600.0 mg, 1.38 mmol), 24.0 mg of Compound 67-a was obtained. MS m / z (ESI): 430.1 [M+H] + 。

[1163] Step 2: Synthesis of Compound 67

[1164] Referring to the synthesis of Compound 62, 1-c (21.7 mg, 0.11 mmol), replacing 62-b with 67-a (24.0 mg, 0.06 mmol), stirring overnight at 100 °C, concentrating under reduced pressure to obtain a crude product, and purifying the crude product by medium-pressure preparation to obtain 6.5 mg of Compound 67. MS m / z (ESI): 544.2 [M+H] + 。

[1165] 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.46 (s, 1H), 8.24 (d, J = 1.6 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 10.8 Hz, 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 = 6.4 Hz, 6H), 1.18 - 1.10 (m, 1H), 1.05 - 0.87 (m, 3H).

[1166] Preparation of Compound 68 in Example 68

[1167]

[1168] Step 1: Synthesis of Compound 68-a

[1169] Referring to the synthesis of 16-c, 16-b (600.0 mg, 1.33 mmol), replacing I-7-3 with I-4-3 (462.3 mg, 1.33 mmol), 70.0 mg of Compound 68-a was obtained. MS m / z (ESI): 428.87 [M+H] + 。

[1170] Step 2: Synthesis of Compound 68

[1171] With reference to the synthesis of Compound 4, for 1-c (63.5 mg, 0.33 mmol), 2-a was replaced with 68-a (70.0 mg, 0.16 mmol). The reaction was cooled to room temperature and concentrated to obtain the crude product. The crude product was purified by medium-pressure preparation and freeze-dried to obtain 33.0 mg of Compound 68. MS m / z (ESI): 542.22 [M+H] + 。

[1172] 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.43 (s, 1H), 8.15 (q, J = 1.2 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.36 (d, J = 8.0 Hz, 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 = 6.8 Hz, 6H), 1.13 - 0.96 (m, 2H), 0.95 - 0.81 (m, 2H).

[1173] Preparation of Compound 69 in Example 69

[1174]

[1175] Step 1: Synthesis of Compound 69-a

[1176] With reference to the synthesis of 16-c, for 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] + 。

[1177] Step 2: Synthesis of Compound 69

[1178] With reference to the synthesis of Compound 3, for 1-c (58.2 mg, 0.30 mmol), 3-c was replaced with 69-a (60.0 mg, 0.15 mmol), and the mixture was stirred at 95 °C for 2 hours. The reaction solution was directly purified by normal-phase chromatography column first and then by medium-pressure preparation to obtain 26.0 mg of Compound 69. MS m / z (ESI): 514.20 [M+H] + 。

[1179] 11H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.43 (s, 1H), 7.55 - 7.47 (m, 2H), 7.42 - 7.33 (m, 2H), 6.74 (s, 1H), 4.12 (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).

[1180] Example 70 Preparation of Compound 70

[1181]

[1182] Step 1: Synthesis of Compound 70-b

[1183] With reference to the synthesis of I-18-5, replace I-18-4 with 70-a (5.0 g, 23.81 mmol), replace I-18-3 with dimethylhydroxylamine hydrochloride (2.78 g, 28.57 mmol), and react at room temperature for 2 hours. After the same post-treatment, 5.1 g of compound 70-b was obtained. MS m / z (ESI): 252.99 [M + H] + .

[1184] Step 2: Synthesis of Compound 70-c

[1185] Under nitrogen protection, dissolve 70-b (5.1 g, 20.15 mmol) and 1-c (3.9 g, 20.15 mmol) in dioxane (50 mL), add water (10 mL), Pd(dppf)Cl2 (0.73 g, 1.01 mmol) and potassium carbonate (5.57 g, 40.3 mmol), and stir the mixture at 80 °C for 4 hours. After the reaction is completed, add water (200 mL) to the mixture, extract with ethyl acetate (2 * 50 mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. The resulting mixture is separated and purified by a normal-phase chromatography column to obtain 4.5 g of compound 70-c. MS m / z (ESI): 367.09 [M + H] + .

[1186] Step 3: Synthesis of Compound 70-d

[1187] With reference to the synthesis of compound 55, I-2 (599.0 mg, 1.64 mmol), replace 55-b with 70-c (300.0 mg, 0.82 mmol). After the same post-treatment, the crude product is obtained, and the crude product is separated and purified by a normal-phase chromatography column to obtain 90.0 mg of compound 70-d. MS m / z (ESI): 571.2 [M + H] + .

[1188] Step 4: Synthesis of Compound 70

[1189] Under nitrogen protection, dissolve 70-d (70.0 mg, 0.12 mmol) in THF (2 mL), cool down to 0 °C, dropwise add methylmagnesium bromide (0.4 mL, 1.2 mmol), naturally warm up to room temperature and react for 1 hour. After the reaction is completed, add water, extract with ethyl acetate (3×10 mL), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate to obtain a mixture, which is purified by medium-pressure preparation to obtain 13.5 mg of Compound 70. MS m / z (ESI): 526.18 [M+H] + 。

[1190] 1 H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.75 (s, 1H), 7.95 - 7.90 (m, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 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).

[1191] Example 71 Preparation of Compound 71

[1192]

[1193] Step 1: Synthesis of Compound 71-a

[1194] Under nitrogen protection, dissolve 70-c (300.0 mg, 0.8 mmol) in toluene (5 mL) and water (1 mL), add 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), stir the mixture overnight at 100 °C, add 10 mL of water to the mixture, extract with ethyl acetate (3×20 mL), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate to obtain a mixture, which is separated and purified by a normal-phase chromatography column to obtain 51.0 mg of Compound 71-a. MS m / z (ESI): 589.19 [M+H] + 。

[1195] Step 2: Synthesis of Compound 71

[1196] Referring to the synthesis of reference compound 70, replace 70-d with 71-a (51.0 mg, 0.1 mmol), and stir at room temperature for 2 hours. After the same post-treatment, the crude product is obtained. The crude product is separated and purified by reverse-phase chromatography column to obtain 5.69 mg of compound 71. MS m / z (ESI): 543.93 [M+H] + 。

[1197] 1 H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.75 (s, 1H), 8.00 (s, 1H), 7.55 (t, J = 7.9 Hz, 1H), 7.19 (dd, J = 20.0 Hz, 9.8 Hz, 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).

[1198] Preparation of Compound 72 in Example 72

[1199]

[1200] Step 1: Synthesis of Compound 72-a

[1201] Referring to the synthesis of 3-b, replace I-19 with I-18 (220.0 mg, 0.68 mmol), and replace 3-a with 1-a (400.7 mg, 2.24 mmol), and stir at room temperature for 1 hour. After the same post-treatment, 260.0 mg of compound 72-a is obtained. MS m / z (ESI): 467.11 [M+H] + 。

[1202] Step 2: Synthesis of Compound 72-b

[1203] Referring to the synthesis of 3-c, replace 3-b with 72-a (260.0 mg, 0.56 mmol), and stir in a sealed tube at 80 °C for 1 hour. After the same post-treatment, 190.0 mg of compound 72-b is obtained. MS m / z (ESI): 409.14 [M+H] + 。

[1204] Step 3: Synthesis of Compound 72

[1205] With reference to the synthesis of reference compound 4, 1-c (180.3 mg, 0.93 mmol), 2-a was replaced with 72-b (190.0 mg, 0.46 mmol). The reaction was cooled to room temperature and concentrated to obtain a crude product. The crude product was purified by medium-pressure preparation and freeze-dried to obtain 85.0 mg of compound 72. MS m / z (ESI): 523.18 [M+H] + 。

[1206] 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.65 (s, 1H), 7.77 - 7.70 (m, 2H), 7.41 - 7.34 (m, 2H), 4.29 (t, J = 7.2 Hz, 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).

[1207] Preparation of Compound 73 in Example 73

[1208]

[1209] Step 1: Synthesis of Compound 73

[1210] Under nitrogen protection, 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 reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by medium-pressure preparation to obtain 31.0 mg of compound 73. MS m / z (ESI): 542.20 [M+H] + 。

[1211] 11H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.45 (s, 1H), 8.22 (d, J = 1.1 Hz, 1H), 7.48 (t, J = 7.8 Hz, 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 = 6.6 Hz, 6H), 1.06 - 0.97 (m, 2H), 0.91 - 0.77 (m, 2H).

[1212] Example 74 Preparation of Compound 74

[1213]

[1214] Step 1: Synthesis of Compound 74-a

[1215] Referring to the synthesis of 3-b, replace I-19 with 18-b (369.9 mg, 1.07 mmol), replace 3-a with 11-b (260.0 mg, 1.07 mmol), and stir at room temperature for 1 hour. After the same post-treatment, 341.0 mg of compound 74-a was obtained. MS m / z (ESI): 551.02 [M + H] + .

[1216] Step 2: Synthesis of Compound 74-b

[1217] Referring to the synthesis of 3-c, replace 3-b with 74-a (341.0 mg, 0.47 mmol), and stir at 80 °C for 1.5 hours. After the same post-treatment, 86.0 mg of compound 74-b was obtained. MS m / z (ESI): 493.16 [M + H] + .

[1218] Step 3: Synthesis of Compound 74

[1219] Under nitrogen protection, add 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) to the reaction flask, and stir at 95 °C for 2 hours. Concentrate under reduced pressure to obtain the crude product. The crude product was first purified by a normal-phase chromatography column, then purified by medium-pressure preparative reverse-phase chromatography, and freeze-dried to obtain 39.5 mg of compound 74. MS m / z (ESI): 607.11 [M + H] +。

[1220] 1 H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.67 (s, 1H), 8.22 (d, J = 1.1 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.33 (d, J = 11.1 Hz, 1H), 7.26 (dd, J = 7.9, 1.4 Hz, 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 = 6.6 Hz, 6H), 1.07 - 0.99 (m, 2H), 0.92 - 0.81 (m, 2H).

[1221] Preparation of Compound 75 in Example 75

[1222]

[1223] Step 1: Synthesis of Compound 75-b

[1224] Dissolve 75-a (2.0 g, 10.47 mmol) in morpholine (10 mL), heat to 130 °C and react for 4 hours. After the reaction is completed, add water for pulping, filter the solid, concentrate it to dryness, and obtain 0.9 g of Compound 75-b. MS m / z (ESI): 198.08 [M + H] + 。

[1225] Step 2: Synthesis of Compound 75-c

[1226] Dissolve 75-b (650.0 mg, 3.3 mmol) in phosphorus oxychloride (20 mL), add N,N-diisopropylethylamine (2.92 mL, 16.48 mmol), heat to 110 °C and react for 12 hours. After the reaction is completed, concentrate it to dryness under reduced pressure, add sodium bicarbonate solution (50 mL), extract with ethyl acetate (3 * 20 mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. The obtained mixture is separated and purified by a normal-phase chromatographic column to obtain 490.0 mg of Compound 75-c. MS m / z (ESI): 234.01 [M + H] + 。

[1227] Step 3: Synthesis of Compound 75-d

[1228] With reference to the synthesis of 3-b, replace I-19 with I-6 (305.8 mg, 1.03 mmol), replace 3-a with 75-c (200.0 mg, 0.85 mmol), and stir at room temperature for 1 hour. After the same post-treatment, 330.0 mg of compound 75-d was obtained. MS m / z (ESI): 496.13 [M+H] + 。

[1229] Step 4: Synthesis of compound 75-e

[1230] With reference to the synthesis of 3-c, replace 3-b with 75-d (220.0 mg, 0.44 mmol), and stir in a sealed tube at 70 °C for 2 hours. After the same post-treatment, 120.0 mg of compound 75-e was obtained. MS m / z (ESI): 438.12 [M+H] + 。

[1231] Step 5: Synthesis of compound 75

[1232] With reference to the synthesis of compound 4, 1-c (73.1 mg, 0.38 mmol), replace 2-a with 75-e (110.0 mg, 0.25 mmol), and stir at 80 °C for 3 hours. After the same post-treatment, 1.84 mg of compound 75 was obtained. MS m / z (ESI): 552.23 [M+H] + 。

[1233] 1 H NMR (400 MHz, Chloroform-d) δ 8.67 (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).

[1234] Preparation of compound 76 in Example 76

[1235]

[1236] Step 1: Synthesis of compound 76

[1237] Under nitrogen protection, 61-a (40.0 mg, 0.1 mmol) was dissolved in THF (10 mL), 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 it 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. The resulting mixture was separated and purified by a normal-phase chromatography column, and further purified by medium-pressure preparation to obtain 7.54 mg of compound 76. MS m / z (ESI): 514.18 [M+H] + 。

[1238] 1 1H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.48 (s, 1H), 7.59 (t, J = 8.0 Hz, 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).

[1239] Example 77 Preparation of Compound 77

[1240]

[1241] Step 1: Synthesis of Compound 77-a

[1242] 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] + 。

[1243] Step 2: Synthesis of Compound 77-b

[1244] Referring to the synthesis of 3-c, 3-b was replaced with 77-a (378.0 mg, 0.72 mmol), and the mixture was stirred at 80 °C for 1.5 hours. After the same post-treatment, 123.0 mg of compound 77-b was obtained. MS m / z (ESI): 464.99 [M+H] + 。

[1245] Step 3: Synthesis of Compound 77

[1246] Referring to the synthesis of Compound 74, 1-c (102.9 mg, 0.53 mmol), replace 74-b with 77-b (123.0 mg, 0.27 mmol), stir at 95 °C for 3 hours. After the same post-treatment, 58.8 mg of Compound 77 was obtained. MS m / z (ESI): 579.10 [M+H] + 。

[1247] 1 H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.67 (s, 1H), 7.59 (t, J = 8.1 Hz, 1H), 7.44 (dd, J = 11.3, 1.4 Hz, 1H), 7.30 (dd, J = 8.2, 1.2 Hz, 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).

[1248] Preparation of Control Compound B

[1249]

[1250] Step 1: Synthesis of Compound B-1

[1251] Dissolve I-24 (300.0 mg, 1.1 mmol) in acetonitrile (5 mL), add potassium carbonate (1.6 g, 227.4 mmol) and 1-a (196.7 mg, 1.1 mmol), stir at room temperature overnight. Add the reaction solution to water (10 mL), extract with ethyl acetate (3 * 10 mL), combine the organic phases, wash with saturated brine (10 mL), dry over anhydrous sodium sulfate, filter and concentrate, and separate and purify the mixture by normal-phase chromatography column to obtain 322.0 mg of Compound B-1. MS m / z (ESI): 416.08 [M+H] + 。

[1252] Step 2: Synthesis of Control Compound B

[1253] Under nitrogen protection, B-1 (322.0 mg, 0.8 mmol) was dissolved in dioxane (10 mL), water (2 mL) was added, 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, and the mixture was stirred overnight at 100 °C. 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. The resulting mixture was separated and purified by reverse-phase chromatography to obtain 159.49 mg of the reference compound B. MS m / z (ESI): 529.95 [M+H] + 。

[1254] 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.99 (s, 2H), 7.87 (t, J = 6.3 Hz, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.28 (t, J = 7.9 Hz, 2H), 4.64 (d, J = 6.3 Hz, 2H), 3.96 (s, 3H), 3.81 (s, 3H), 3.59 (d, J = 1.0 Hz, 3H), 1.72 - 1.65 (m, 1H), 0.99 - 0.94 (m, 2H), 0.81 - 0.77 (m, 2H).

[1255] KSQ-4279 Prepared by referring to CN113164485A

[1256] Reference compound A Prepared by referring to WO2023208130A1

[1257] Enzymatic evaluation of Example 78

[1258] The inhibitory effect of the compound on the USP1 / UAF1 enzyme activity was evaluated by the FI method

[1259] Prepare the USP1 / UAF1 (R&D, U-555-050) enzyme solution (USP1 / UAF1 enzyme concentration is 0.03 nM) and the Recombinant Human Ubiquitin Rhodamine 110 Protein (R&D, E-568-050) substrate solution (Recombinant Human Ubiquitin Rhodamine 110 Protein concentration is 450 nM) respectively using the reaction buffer (50 mM Tris-HCl, pH 7.8, 0.5 mM EDTA, 0.01% Tween-20, 0.01% BSA, 1 mM DTT). Dilute the 10 mM compound stock solution 11.11× with DMSO (Sigma, D5879), then perform a 4× serial dilution, and then dilute the compound 100× with the reaction buffer (the starting concentration of the compound in the final reaction system is 3 μM, 4× dose dilution, a total of 8 concentration points). In a 384-well test plate (Coring, 3575), add 5 μL of the reaction buffer to each well in the blank group and the protein control group, and add 5 μL of each diluted compound at various concentrations to each well in the compound group. Then add 5 μL of the reaction buffer to each well in the blank group, add 5 μL of the USP1 / UAF1 enzyme solution to each well in the protein control group and the compound group, centrifuge at 1000 rpm for 1 minute, and incubate at 25 °C for 10 min. Then add 5 μL of the Recombinant Human Ubiquitin Rhodamine 110 Protein substrate solution to each well in each group (at this time, the starting concentration of the compound gradient concentration in the reaction system of the compound group is 3 μM), centrifuge at 1000 rpm for 1 minute, and incubate at 25 °C for 30 minutes. Finally, use a high-throughput drug screening multi-functional microplate reader (TECAN Spark) to read the luminescence signal of the reaction system in the Flourescen Intensity mode to read the FI signal (ex485 / em535). Use GraphPad Prism software to obtain the IC 50 value and perform non-linear regression curve fitting.

[1260] The inhibition percentage (%) of the compound at each concentration was calculated based on the signals of the minimum fluorescence signal group (blank group) and the maximum fluorescence signal group (protein control group) included in each test plate. The minimum fluorescence signal group had no enzyme and compound added, and was consistent with the compound group in other aspects, with the minimum fluorescence signal, which was set as 100% inhibition. The maximum fluorescence signal group had no compound added, and was consistent with the compound group in other aspects, with the maximum fluorescence signal, which was set as 0% inhibition. The inhibition rate calculation method for each compound concentration was as follows: Inhibition rate % = {1 - [(luminescence signal of the maximum luminescence signal group - luminescence signal of the compound group) / (luminescence signal of the maximum luminescence signal group - luminescence signal of the minimum luminescence signal group)]} * 100%. Finally, the four-parameter logistic dose-response equation was used to determine the compound concentration required to inhibit 50%, that is, the IC 50 value. The results are shown in Table 1.

[1261] Table 1 Inhibitory activity of the compounds of the present invention against USP1 / UAF1

[1262] Compound <![CDATA[IC 50 (nM)]]> Compound <![CDATA[IC 50 (nM)]]> Compound <![CDATA[IC 50 (nM)]]> Compound <![CDATA[IC 50 (nM)]]> 1 20.5 2 21.9 3 11.0 4 25.9 5 49.3 6 - 7 14.5 8 39.6 9 11.6 10 19.1 11 10.0 12 21.1 13 27.6 14 35.3 15 45.7 16 15.6 17 22.1 18 25.7 19 30.8 20 45.4 21 42.3 22 - 23 17.6 24 14.0 25 12.9 26 44.4 27 12.6 28 26.5 29 33.9 30 22.3 31 34.7 32 18.5 33 45.2 34 12.7 35 11.8 36 10.0 37 14.3 38 33.1 39 22.4 40 14.1 41 11.8 42 33.7 43 25.7 44 11.7 45 14.4 46 30.8 47 10.9 48 - 49 17.9 50 30.4 51 35.9 52 - 53 26.8 54 17.2 55 12.0 56 21.3 57 - 58 44.5 59 22.7 60 21.0 61 16.3 62 16.7 63 33.1 64 21.7 65 - 66 - 67 13.4 68 - 69 - 70 40.1 71 41.0 72 10.4 73 13.4 74 26.9 75 40.7 76 35.3 77 - KSQ-4279 <![CDATA[15.2 (n = 14)]]>

[1263] As can be seen from Table 1, the compounds of the present invention have excellent inhibitory activity against the USP1 / UAF1 enzyme and can be used as drugs related to the treatment of diseases associated with this effect.

[1264] Example 79 Cell assay evaluation

[1265] BRCA1 was cultured using 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) was cultured using complete medium DMEM (Gibco, 11963092) / 20% FBS (Gibco, 10099141C) to evaluate the inhibitory effect of the compound on the cell proliferation selectivity of BRCA1 - / - MDA-MB-436 and CAL-51 cell lines. On Day 0, on a 96-well cell culture plate (Corning, 3599), BRCA1 - / -For MDA-MB-436 cells, 800 cells / 100 μL cell suspension were added per well, and for wild-type CAL-51 cells, 50 cells / 100 μL cell suspension were added per well. The cells were placed in an incubator at 37 °C and 5% CO2 for culture. On Day 1, the 10 mM compound stock solution was 2.5x diluted with DMSO (Sigma, D5879), and then the compound was 3x serially diluted to a total of 10 concentration points. The starting concentration of wild-type CAL-51 cells was the first concentration point, and BRCA1 - / - The starting concentration of MDA-MB-436 cells was the third concentration point. A multi-channel pipette (Rainin: Pipet-Lite XLS+) was used to dilute the compound 200x with the corresponding culture medium (for wild-type CAL-51 cells, the final starting concentration of the compound in the culture medium was 20 μM; for BRCA1 - / - MDA-MB-436 cells, the final starting concentration of the compound in the culture medium was 2.2 μM, both were 3x dilutions, and both had a total of 8 concentration points). Each concentration of the compound was added to the cells to form the compound group; the control group contained no compound, and other conditions were the same as the compound group, with the final concentration of DMSO being 0.5%. The compound group and the control group were continued to be cultured in an incubator at 37 °C and 5% CO2 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 SolutionCell Proliferation Assay) (Promega, G3581) was added to each well of the compound group, the control group, and the blank group. After continuing to culture in an incubator at 37 °C and 5% CO2 for 2 h, the readings were taken by Tecan Spark (OD = 490 nM). Then, the data analysis software GraphPad Prism 8 was used, and the equation "log(inhibitor) vs. normalized response--variable slope" (formula Y = Bottom+(Top - Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope))) was used for data analysis to obtain the IC 50 value of the compound. 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 highest), Bottom refers to the baseline response (inhibition rate when the compound concentration is 0), Hill Slope refers to the slope of the IC 50 curve, and IC 50 is the compound concentration a...

Claims

1. 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 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, and 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 4-7 membered heterocycloalkyl, said 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, said hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl 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 is 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 hydroxy, amino, SH, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 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 are 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, 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 attached thereto 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, 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 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 with 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 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 by 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 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 atoms to which it is attached, 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 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 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, 4- to 7-membered heterocyclic group are each independently unsubstituted or substituted by one or more R e ; 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, 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 are each 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 , the 4- to 10-membered heterocycloalkyl and 5- or 6-membered heteroaryl each independently contain 1-3 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 10-membered heterocycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 5- or 6-membered heteroaryl 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 4-7 membered heterocycloalkyl, the 4-7 membered heterocycloalkyl 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 heterocycloalkyl 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- 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 hydroxy, amino, SH, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 4- to 7-membered heterocyclic group are each independently unsubstituted or substituted by 1 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 ; Or R 11 And R 12 Together with P connected 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, the 4- to 7-membered heterocyclic group being 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 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 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 attached atoms to form a 4- to 7-membered heterocyclic group or a 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 atoms, 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 cycloalkyl or a 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, wherein 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 e ; 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 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, 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 1 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 are each 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, 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 7-membered heterocycloalkyl, C 2-6 alkenyl or 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, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl are each independently unsubstituted or substituted by 1 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 a 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 hydroxy, amino, SH, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 4- to 7-membered heterocyclic group are each independently unsubstituted or substituted by one or more R a substituents; 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 containing 1 to 3 heteroatoms selected from N, O and S, and the amino, C 1-6 alkyl, C 3-10 cycloalkyl and 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 connected thereto, 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, 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 to which they are attached form a 4- to 7-membered heterocyclic group, said 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, and said 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 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 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, 4- to 7-membered heterocyclic group are each independently unsubstituted or substituted by one or more R e ; 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 and 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.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, co-crystal, 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- to 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- to 8-membered heterocycloalkyl and 5-membered heteroaryl each independently contain 1 to 2 heteroatoms selected from N, O, and S, the hydroxy, amino, C 1-4 alkyl, C 1-4 alkoxy, 4- to 8-membered heterocycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, 5-membered heteroaryl are each independently unsubstituted or substituted by one or more R a ; R 11 , R 12 , R 13 , R 14 , R 17 and R 18 are each independently selected from hydrogen, methyl, or ethyl, 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, hydroxyl, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, 4- to 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, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, 4- to 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 1 or more R a substituents; 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 6-8 membered heteroalkyl contains 1-2 heteroatoms selected from N and O, and the hydroxy, amino, methyl, isopropyl, methoxy, ethoxy, 6-8 membered heteroalkyl, vinyl, propenyl, ethynyl, propynyl, imidazolyl, oxazolyl are each independently unsubstituted or substituted by 1 or more R a substituents; 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- or 7-membered heterocycloalkyl, vinyl, propenyl, ethynyl, propynyl, -SCH3, -SF5, -SeCH3, imidazolyl, oxazolyl, the 6- or 7-membered heterocycloalkyl contains 1 or 2 heteroatoms selected from N and O, and the hydroxy, amino, methyl, isopropyl, methoxy, ethoxy, 6- or 7-membered heterocycloalkyl, ethynyl, imidazolyl are each independently unsubstituted or substituted by 1 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 heterocycloalkyl, the 4- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, the 4- to 7-membered heterocycloalkyl being unsubstituted or substituted by one or more identical 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, the 4- to 7-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O and S, the 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, hydroxy, 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- to 7-membered heterocycloalkyl, vinyl, propenyl, ethynyl, propynyl, imidazolyl, oxazolyl, wherein the 6- to 7-membered heterocycloalkyl contains 1 to 2 heteroatoms selected from N and O; the 6- to 7-membered heterocycloalkyl is unsubstituted or substituted with 1 or more identical or different methyl groups; the methyl group is unsubstituted or substituted with 1 or more identical or different F, Cl, cyano, morpholinyl, methoxy or N-methylpiperazinyl groups; the methoxy group is unsubstituted or substituted with 1 or more identical or different F or Cl groups; the amino group is unsubstituted or substituted with 1 or more identical or different methyl or fluoroethyl groups; the ethynyl group is unsubstituted or substituted with 1 fluoromethyl group; the isopropyl group is unsubstituted or substituted with 1 or more hydroxy groups; the imidazolyl group is unsubstituted or substituted with 1 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, co-crystal, 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, wherein the 4- to 7-membered heterocycloalkyl contains 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, 6-7 membered heteroalkyl, vinyl, propenyl, ethynyl, propynyl, the 6-7 membered heteroalkyl containing 1-2 heteroatoms selected from N and O, and the hydroxy, amino, methyl, methoxy, ethoxy, 6-7 membered heteroalkyl, 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, hydroxyl, amino, methyl, methoxy, ethoxy, 6- or 7-membered heteroalkyl, vinyl, propenyl, ethynyl, propynyl, the 6- or 7-membered heteroalkyl containing 1 or 2 heteroatoms selected from N and O, and the hydroxyl, amino, methyl, methoxy, ethoxy, 6- or 7-membered heteroalkyl 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 1-3 heteroatoms selected from N, O and S, the 4- to 7-membered heterocyclic group being unsubstituted or substituted by 1 or more of the same 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 to 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, the 4- to 7-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O, and S, the 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, cyano, methyl, ethyl, fluoromethyl, fluoroethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5- to 6-membered heterocycloalkyl, the 5- to 6-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N and O, the 5- to 6-membered heterocycloalkyl being unsubstituted or substituted by 1 or more of the same or different methyl or ethyl; 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- to 7-membered heterocycloalkyl, vinyl, propenyl, ethynyl, propynyl, wherein the 6- to 7-membered heterocycloalkyl contains 1 to 2 heteroatoms selected from N and O; the 6- to 7-membered heterocycloalkyl 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, co-crystal, 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, co-crystal, 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-5-membered heteroaryl, 5-membered heteroaryl-fused-6-membered heteroaryl, 6-membered heteroaryl-fused-6-membered heteroaryl, phenyl-fused-5-membered heteroaryl or phenyl-fused-6-membered heteroaryl, wherein each of the 5-membered heteroaryl and 6-membered heteroaryl independently contains 1-3 heteroatoms selected from N, O and S, and the phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heteroaryl-fused-5-membered heteroaryl, 5-membered heteroaryl-fused-6-membered heteroaryl, 6-membered heteroaryl-fused-6-membered heteroaryl, phenyl-fused-5-membered heteroaryl, phenyl-fused-6-membered heteroaryl are each independently unsubstituted or substituted with one or more R b substituents; 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 by 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 substituted; 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, SH, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 4- to 7-membered heterocyclic group are each independently unsubstituted or substituted with 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 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- to 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, SH, C 1-4 alkyl, C 5-6 alkyl, C 1-4 alkoxy, C 5-6 alkoxy, C 3-8 cycloalkyl, 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 halogen, amino, SH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 4- to 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, SH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 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, 4-7 membered heterocycloalkyl, -SeR k , -C(O)NR i R j , The 4- to 7-membered heterocycloalkyl contains 1 N heteroatom, and 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 are each independently unsubstituted or substituted by one or more R a substituted; 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, SH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, azetidinyl are each independently unsubstituted or substituted by one or more R a ; 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, wherein the amino, SH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, 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, hydroxyl, 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, hydroxyl, 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, 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, wherein 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, and the phenyl, pyridyl, pyrimidinyl, cyclohexyl, cubyl, or piperidinyl is each independently unsubstituted or substituted with 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 is unsubstituted or substituted by one or more identical or different F or methoxy groups; 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 therefrom, 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 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, said 5-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, said 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 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 each independently being unsubstituted or substituted by one or more R d substituted; R i , R j each independently being 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 with 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 containing 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 one 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 and 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 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 10-membered heterocyclic group; wherein the 5- or 6-membered heteroaryl group and the 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 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 the combination of 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 the substituents R c , R d combination; the monocyclic ring formed by the R c , R d combination 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 to 2 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 the 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 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 with substituents R c , R d combine to form a tricyclic ring; R c , R d The monocyclic ring formed by the 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 substituents R c and R d combinations; the monocyclic ring formed by R c and R d combinations 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 1-2 heteroatoms selected from N and O; and wherein C further has a substituent of -CF3; Preferably, is B and C together form a tricyclic ring through 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 6- to 7-membered heterocyclic group; wherein, the 6- to 7-membered heterocyclic group contains 1-2 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; 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, cocrystal, 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, cocrystal, 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, diastereomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, characterized in that: Selected from the following structures:

16. 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:

17. The compound of 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 heterocycloalkyls independently contains 1 to 2 heteroatoms selected from N, O and S; each of the 4- to 8-membered heterocycloalkyls is independently unsubstituted or substituted by 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, 10-membered heteroaryl independently contains 1, 2 or 3 heteroatoms selected from N, O and S; Ring D is unsubstituted or substituted by one, two or more R 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, deuteroethyl, fluoromethoxy, fluoroethoxy, deuteromethoxy, deuteroethoxy, 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-5-6 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 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. A 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 、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, -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. A 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 Rs m substituted; Preferably, ring D is selected from pyrazolyl, imidazolyl, pyridyl; ring D is unsubstituted or substituted by one, two or more Rs m substituted; 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 of formula (II), or a pharmaceutically acceptable salt, stereoisomer, tautomer, enantiomer, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof: Among them, R 22 and R 23 are each independently selected from methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclopropyl; Ring D is selected from R 27 are each independently selected from -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -OCF3, -OCHF2; R 28 are 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, diastereoisomer, racemate, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, said compound being selected from the following structures:

23. Pharmaceutical composition, characterized in that: Comprising a 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 a 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 a pharmaceutical composition according to claim 23 for the preparation of a USP1 inhibitor.

25. Use of a 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 a pharmaceutical composition according to claim 23 for the preparation of a drug for preventing or / and treating a tumor or cancer; 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. A 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 a pharmaceutical composition according to claim 23, for treating and / or preventing a tumor or cancer; 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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