Nitrogen-containing heterocyclic derivative inhibitor, preparation method therefor, and use thereof

Abstract

The present invention relates to a nitrogen-containing heterocyclic derivative inhibitor, a preparation method therefor, and a use thereof. In particular, the present invention relates to a compound represented by formula (I), a preparation method therefor, a pharmaceutical composition containing said compound, and a use thereof in the treatment of cancer, each substituent in formula (I) being as defined in the description.

Description

Nitrogen-containing heterocyclic derivative inhibitors, their preparation methods and applications Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a nitrogen-containing heterocyclic derivative inhibitor, its preparation method, and its application. Background Technology

[0002] EGFR (Epidermal Growth Factor Receptor) is a member of the ErbB family of transmembrane receptor tyrosine kinases, activated by binding to its ligands epidermal growth factor (EGF) or transforming growth factor α (TGFα). Activated EGFR forms homodimers on the cell membrane or heterodimers with other receptors in the family (such as ErbB-2, ErbB-3, or ErbB-4), leading to phosphorylation of key intracellular tyrosine residues of EGFR. This activates downstream signaling pathways, playing a crucial role in cell proliferation, survival, and anti-apoptosis. Activating mutations, overexpression, or gene amplification of EGFR can lead to excessive activation, promoting cell transformation into tumor cells and playing a vital role in tumor cell proliferation, invasion, metastasis, and angiogenesis. Therefore, EGFR is an important target for the development of anticancer drugs, particularly for lung cancer treatment.

[0003] First-generation EGFR small molecule inhibitors, including gefitinib (Iressa) and erlotinib (Tarceva), have shown good efficacy in the treatment of lung cancer and have been used as first-line drugs for the treatment of non-small cell lung cancer (NSCLC) with classic EGFR mutations (including L858R and delE746_A750). The deIE746_A750 mutation (EGFR exon 19 deletion) has a higher affinity for EGFR TKIs, thus exhibiting better downstream signal blocking effects, while the L858R mutation has a relatively lower affinity for EGFR TKIs and slightly poorer selectivity. However, after 10-12 months of treatment with first-generation small molecule EGFR inhibitors, almost all NSCLC patients develop resistance to these inhibitors, with more than half of these resistance mechanisms being due to secondary mutations in the EGFR gate gene residue T790M.

[0004] Third-generation EGFR orthoform inhibitors, represented by osimertinib (AZD9291), can efficiently and selectively inhibit classical EGFR mutations (exon 19 deletion mutations and exon 21 L858R activating mutations) and resistance mutations caused by EGFR T790M mutations. Several third-generation EGFR inhibitors have been approved for marketing as first-line or second-line treatment for patients with advanced non-small cell lung cancer with classical EGFR mutations or EGFR T790M resistance mutations. However, in clinical practice, the treatment effect for patients with EGFR L858R mutations is significantly weaker than that for patients with EGFR Del19 mutations. For example, in the FLAURA study, the progression-free survival (PFS) of patients with EGFR L858R mutations treated as first-line patients was 14.4 months, while the PFS of patients with EGFR Del19 mutations treated as first-line patients was 21.4 months. The overall survival (OS) benefit of patients with EGFR L858R mutations was also lower than that of patients with EGFR Del19 mutations. Furthermore, resistance can also develop after 1-2 years of treatment with third-generation inhibitors. The rate of EGFR C797S double mutation resistance after first-line therapy is approximately 7%, and the rate of EGFR C797S triple mutation resistance after second-line therapy is approximately 10-26%. The EGFR C797S mutation changes the cysteine ​​residue at position 797 to serine, preventing osimertinib from forming a covalent bond with the EGFR protein, thus leading to resistance. Therefore, there is unmet clinical need for treatment with EGFR L858R single mutation, EGFR L858R C797S double mutation, and EGFR L858R / T790M / C797S triple mutation.

[0005] Several companies are currently developing fourth-generation EGFR inhibitors targeting the EGFR C797S mutation. One type targets allosteric inhibitors of the classic and resistance mutations of EGFR L858R. These inhibitors have a high window of activity against EGFR wild-type and show promising development prospects. Companies with relatively advanced development in this area include Dana Farber and Roche. Meanwhile, companies like C4 Biotech are also developing EGFR protacs. CFT8919 is currently in Phase I clinical trials in China. Because it inhibits the phosphorylation activity of the EGFR L858R mutant protein while simultaneously degrading the EGFR L858R protein through the ubiquitin-protease system and maintaining high selectivity for EGFR wild-type protein, it also shows promising development potential.

[0006] The purpose of this invention is to develop a PROTAC targeting the EGFR L858R mutant protein, which can not only treat EGFR L858R-related drug resistance mutations, but also act as a monotherapy or in combination with third-generation EGFR inhibitors as first-line treatment for EGFR L858R single mutations. This aims to improve the clinical efficacy of existing inhibitors for indications such as non-small cell lung cancer and overcome drug resistance, and has significant market potential. Summary of the Invention

[0007] The object of this invention is to provide a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the following structure.

[0008] in:

[0009] Ar1 is a 5-14 member heteroaryl group;

[0010] Ar2 is selected from 5-10-membered heteroaryl, 5-10-membered heteroaryl with 5-8-membered heterocyclic, or 5-10-membered heteroaryl with C 5-8 cycloalkyl;

[0011] L1 is selected from either NHCO or NHCO;

[0012] L2 is selected from the bond, C 2-6 imidene group, C 2-6 alkynyl, 5-10 quinone heteroaryl, phenylene, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, phenyl-C 5-8 cycloalkyl, 5-10-membered heteroaryl benzo[C] 5-8 Cycloalkyl, 5-10-membered heteroaryl, or phenyl 5-8-membered heterocyclic, wherein the C 2-6 imidene group, C 2-6 alkynyl, 5-10 methyl aryl, phenylene, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, phenyl-C 5- 8-cycloalkyl, 5-10-membered heteroaryl benzo[C] 5-8 Cycloalkyl, 5-10-membered heteroaryl, and phenyl 5-8-membered heterocyclic groups may be further substituted with 1-4 R4 groups;

[0013] L3, L4, L5, L6, and L7 are each independently selected from the bond, -(CH2). n7 O(CH2) n8 -、-(CH2) n7 C=O(CH2) n8 -、-(CH2) n7 C = S(CH2) n8 -、-(CH2) n7 C = OO(CH2)n8 -、-(CH2) n7 NR bb (CH2) n8 -、-(CH2) n7 S(CH2) n8 -、-(CH2) n7 CONH(CH2) n8 -、(CH2) n7 NHCONH(CH2) n8 -、(CH2) n7 NHC(=NH)NH(CH2) n8 -、(CH2) n7 POR bb (CH2) n8 -、O(CH2) n7 POR bb (CH2) n8 -、C 1-6 Alkylene, C 2-6 imidene group, C 2-6 alkynyl, 5-10 methyl aryl, phenylene, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, phenyl-C 5-8 cycloalkyl, 5-10-membered heteroaryl benzo[C] 5-8 Cycloalkyl, 5-10-membered heteroaryl, or phenyl-5-8-membered heterocyclic; wherein the -(CH2) group... n7 O(CH2) n8 -、-(CH2) n7 C=O(CH2) n8 -、-(CH2) n7 C = S(CH2) n8 -、-(CH2) n7 C = OO(CH2) n8 -、-(CH2) n7 NR bb (CH2) n8 -、-(CH2) n7 S(CH2) n8 -、-(CH2) n7 CONH(CH2) n8 -、(CH2) n7 NHCONH(CH2) n8 -、(CH2) n7 NHC(=NH)NH(CH2) n8 -、(CH2) n7 POR bb (CH2) n8 -、O(CH2) n7 PORbb (CH2) n8 -、C 1-6 Alkylene, C 2-6 imidene group, C 2-6 alkynyl, 5-10 methyl aryl, phenylene, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, phenyl-C 5- 8-cycloalkyl, 5-10-membered heteroaryl benzo[C] 5-8 Cycloalkyl, 5-10-membered heteroaryl, and phenyl 5-8-membered heterocyclic groups may be further modified by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2). n R aa -(CH2) n OR dd -O(CH2) n R aa -(CH2) n SR dd -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R dd -(CH2) n C(O)NR aa R dd -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R dd -(CH2) n P(O)R aa R dd -O(CH2) n P(O)R aa R dd -(CH2) n NR cc C(=NH)NR aa R dd (CH2) n NR dd S(O) m R cc -OC(R) aa Rdd ) n (CH2) m R aa -NR dd (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R dd -CH=CH(CH2) n NR dd C(O)R cc -CH=CH(CH2) n NR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1- 6-alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0014] Alternatively, L3, L4, L5, L6, and L7 can each be independently selected from -(CH2). n7 S(O) m (CH2) n8 -、-(CH2) n7 S(O) m NR bb (CH2) n8 -or-(CH2) n7 S(=NH)(=O)(CH2) n8 -, optionally replaced by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -(CH2). n R aa -(CH2) n OR dd -O(CH2)n R aa 、-(CH2) n SR dd 、-(CH2) n C(O)R cc 、-(CH2) n C(O)OR cc 、-(CH2) n S(O) m R cc 、-(CH2) n NR aa R dd 、-(CH2) n C(O)NR aa R dd 、-(CH2) n NR bb C(O)R cc 、-(CH2) n NR cc C(O)NR aa R dd 、-(CH2) n P(O)R aa R dd 、-O(CH2) n P(O)R aa R dd 、-(CH2) n NR cc C(=NH)NR aa R dd 、(CH2) n NR dd S(O) m R cc 、-OC(R aa R dd ) n (CH2) m R aa 、-NR dd (CH2) n R aa 、-CH=CH(CH2) n R aa 、-CH=CH(CH2) n NR aa R dd 、-CH=CH(CH2) n NR dd C(O)R cc 、-CH=CH(CH2) n NR cc C(O)NR aa R dd=N-OR dd or = CR aa R cc C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3- 12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0015] The constraint is that L3, L4, L5, L6, and L7 cannot all be keys simultaneously;

[0016] Alternatively, R4 can be linked with L3 to form a substituted or unsubstituted 5-14 heteroaryl group, or a substituted or unsubstituted C group. 3- 14 Phenyl, substituted or unsubstituted C 3-14 Cycloalkyl, substituted or unsubstituted 3-14 heterocyclic groups, wherein the substitution refers to the presence of 1-4 R groups. 4-1 replace;

[0017] M is selected from

[0018] Preferably, M is selected from

[0019] Preferably, M is selected from

[0020] Preferably, M is selected from

[0021] M1 and M2 are each independently selected from N or CH;

[0022] M3 is selected from bonds, NH, O, or CONH;

[0023] M9, M 10 M 11 and M 12 Each is independently selected from C, N, or CH;

[0024] M 13 and M 14 Each is independently selected from C, N, or CH;

[0025] Y0, Y1, and Y2 are each independently selected from bonds, NH, O, S, or -(CH2). v -;

[0026] Lx is -(CH2) n -(CH2) n O、-(CH2) n S、-(CH2) n C(O), -(CH2) n C(O)O、-(CH2) n S(O) m -(CH2) n NR ee -、-(CH2) n C(O)NR ee -、-(CH2) n NR ee C(O)-、-(CH2) n NR ee C(O)NR ff -; X1 is selected from N or CH;

[0027] R1, R2, R3, R4, R 4-1 R5 and R6 are each independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n R aa -(CH2) n OR dd -O(CH2) n R aa -(CH2) n SR dd -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R dd -(CH2)n C(O)NR aa R dd -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R dd -(CH2) n P(O)R aa R dd -O(CH2) n P(O)R aa R dd -(CH2) n NR cc C(=NH)NR aa R dd (CH2) n NR dd S(O) m R cc -OC(R) aa R dd ) n (CH2) m R aa -NR dd (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R dd -CH=CH(CH2) n NR dd C(O)R cc -CH=CH(CH2) n NR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc The C mentioned therein 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3- 12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14The aryl and 5-14 heteroaryl groups may be further substituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or unsubstituted C groups. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1- 6-alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0028] Alternatively, any two R5 atoms and their connected ring atoms can form substituted or unsubstituted C atoms. 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 aryl or substituted or unsubstituted 5-14 heteroaryl groups; wherein the substitution refers to the presence of one or more R groups. 5c replace;

[0029] R7 is selected from H or D;

[0030] R 5c R aa R bb R cc R dd R ee and R ff Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1- 6-alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl and 5-14 heteroaryl groups may be further substituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or unsubstituted C groups. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0031] v, n, n1, n2, n3, n5, n6, n7, and n8 are each independently 0, 1, 2, 3, 4, 5, or 6;

[0032] m is 1 or 2;

[0033] Qualifications:

[0034] When M is At that time; L2 is selected from C 2-6 imidene group, C 2-6 alkynyl, 5-10 methyl methacrylate, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, phenyl-C 5-8 cycloalkyl, 5-10-membered heteroaryl benzo[C] 5-8 Cycloalkyl, 5-10-membered heteroaryl, or phenyl 5-8-membered heterocyclic, wherein the C 2-6 imidene group, C 2-6 alkynyl, 5-10 methyl aryl, phenylene, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, phenyl-C 5-8 cycloalkyl, 5-10-membered heteroaryl benzo[C] 5-8 The cycloalkyl, 5-10-membered heteroaryl, 5-8-membered heterocyclic and phenyl 5-8-membered heterocyclic groups may be further substituted with 1-4 R4 groups.

[0035] In some embodiments of the present invention, Lx is NH or CONH.

[0036] In some embodiments of the present invention, M is selected from...

[0037] Preferably, M is selected from

[0038] Among them, the ring Cy2 is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl or 5-14 heteroaryl; preferably, M is selected from...

[0039] Preferably, M is selected from

[0040] More preferably, Selected from

[0041] Or more preferably, Selected from

[0042] In some embodiments of the present invention, M is preferably selected from...

[0043] In some embodiments of the present invention, Selected from

[0044] In some embodiments of the present invention, or more preferably, Selected from

[0045] In some embodiments of the present invention, L2 is selected from the group consisting of substituted or unsubstituted groups: C 2-3 alkynyl, 5-6 quinone heteroaryl, phenylene, C 5-8 Cycloalkylene, 5-8 membered heterocyclic alkylene, phenyl-C 5-8 cycloalkyl, 5-6-membered heteroaryl benzo[C] 5-8 Cycloalkyl, 5-6-membered heteroaryl, or phenyl 5-8-membered heterocyclic group; preferably substituted or unsubstituted of the following groups: ethynyl, phenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxadiazole, oxazolyl, thiophene, furanyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazinyl, Wherein, the substitution refers to being replaced by 1-4 R4 atoms; more preferably, L2 is selected from...

[0046] More preferably, L2 is selected from

[0047] More preferably, L2 is selected from

[0048] in, It can be a single or double bond; M4 is selected from N or CH;

[0049] M5 is selected from N or CH;

[0050] M6 is selected from N or CH;

[0051] M7 is selected from N or CH;

[0052] M8 is selected from N or CH;

[0053] M 15 Selected from N or CH; n9 and n10 are each independently selected from 0, 1, 2 or 3;

[0054] n21, n22, n23, and n24 are each independently selected from 0, 1, 2, or 3;

[0055] n4 can be 0, 1, 2, 3 or 4;

[0056] The definition of R4 is as described above.

[0057] In certain embodiments of the present invention, Ar2 is selected from 5-6 member N-containing heteroaryl groups or 5-6 member N-containing heteroaryl groups with 5-8 member heterocyclic groups, preferably. Cy1 is selected from non-existent or 5-8 membered heterocyclic groups; preferably 5-6 membered heterocyclic groups.

[0058] In some embodiments of the present invention, the compound is as shown in formula (IB).

[0059] Preferably, the compound is as shown in formula (IA).

[0060] Preferably, the compound is as shown in formulas (I-1) to (I-8).

[0061] M4 is selected from N or CH;

[0062] M5 is selected from N or CH;

[0063] M6 is selected from N or CH;

[0064] M7 is selected from N or CH;

[0065] M8 is selected from N or CH;

[0066] M 15 Selected from N or CH;

[0067] M1 is selected from CR 3-1Or N; R 3-1 The definition is the same as R3;

[0068] Y4, Y5, Y7, Y9 and Y 10 Each is independently selected from bonds, NH, N, O, CH, S, or -(CH2). u -;

[0069] Y6, Y8 and Y 11 Each is independently selected from N, C, or CH;

[0070] n9 and n10 are each independently selected from 0, 1, 2 or 3;

[0071] n4 can be 0, 1, 2, 3 or 4;

[0072] n4' is 0, 1, 2 or 3;

[0073] "n4" can be 0, 1, 2, 3 or 4;

[0074] u can be 0, 1, 2, 3 or 4;

[0075] Cy1 is selected from non-existent or 5-8 membered heterocyclic groups; preferably 5-6 membered heterocyclic groups;

[0076] n'3 is 0, 1, 2, 3, 4 or 5;

[0077] n1, n2, n3, n6, M, Ar1, R1, R2, R3, R4, R 4-1 The definitions of R6, R7, L1, L3, L4, L5, L6, L7 and X1 are as described above.

[0078] In some embodiments of the present invention, the compound is as shown in formula (I-3-1), formula (I-4-1)-(I-4-2) to formula (I-9-1).

[0079] Preferably, the compounds are as shown in formulas (I-3-1-1)-(I-3-1-2), (I-4-1-1)-(I-4-1-5), to (I-9-1-1)-(I-9-1-2).

[0080] M4 is selected from N or CH;

[0081] M5 is selected from N or CH;

[0082] M6 is selected from N or CH;

[0083] M7 is selected from N or CH;

[0084] M8 is selected from N or CH;

[0085] M 16 Selected from N, O, S, CH, NH or CH2;

[0086] M 17 Selected from N, O, S, CH, NH or CH2;

[0087] It can be a single bond or a double bond;

[0088] Y4, Y5, Y7, Y9 and Y 10 Each is independently selected from bonds, NH, N, O, CH, S, or -(CH2). u -;

[0089] Y6, Y8 and Y 11 Each is independently selected from N, C, or CH;

[0090] n9 and n10 are each independently selected from 0, 1, 2 or 3;

[0091] n21, n22, n23, and n24 are each independently selected from 0, 1, 2, or 3;

[0092] n4 can be 0, 1, 2, 3 or 4;

[0093] n4' is 0, 1, 2 or 3;

[0094] "n4" can be 0, 1, 2, 3 or 4;

[0095] u can be 0, 1, 2, 3 or 4;

[0096] Cy1 is selected from non-existent or 5-8 membered heterocyclic groups; preferably 5-6 membered heterocyclic groups;

[0097] n'3 is 0, 1, 2, 3, 4 or 5;

[0098] Cy2 is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0099] n1, n2, n3, n6, M, M9, Ar1, R1, R2, R3, R4, R 4-1 The definitions of R6, R7, L1, L3, L4, L5, L6, L7 and X1 are as described above.

[0100] In some embodiments of the present invention, Ar1 is a 5-10 member heteroaryl, preferably a 5-9 member heteroaryl, more preferably a 5 member heteroaryl or a 5 member heteroaryl-6 member heteroaryl, and even more preferably a 5 member heteroaryl or More preferably, indole, thiazolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxadiazole, oxazolyl, thiophene, furanyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, and more preferably...

[0101] Ar3 is selected from 6-membered heteroaryl groups, preferably pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl.

[0102] Ar4 is selected from 5-membered heteroaryl groups, preferably pyrrole, thiazolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxadiazole, oxazolyl, thiophene, and furanyl.

[0103] In some embodiments of the invention, the compound is as shown in formula (I-4-1-1-1)-(I-4-1-1-4) or (I-6-1-1-1).

[0104] Preferably, the compound is as shown in formula (I-1-1).

[0105] in,

[0106] Cy1 is selected from non-existent or 5-8 membered heterocyclic groups; preferably 5-6 membered heterocyclic groups;

[0107] n'3 is 0, 1, 2, 3, 4 or 5;

[0108] n4 can be 0, 1, 2, 3 or 4;

[0109] M4 is selected from N or CH;

[0110] M5 is selected from N or CH;

[0111] M6 is selected from N or CH;

[0112] n4' is 0, 1, 2 or 3;

[0113] "n4" can be 0, 1, 2, 3 or 4;

[0114] n1, n2, n3, n6, M, R1, R2, R3, R4, R 4-1 The definitions of R6, R7, L1, L3, L4, L5, L6, L7 and X1 are as described above.

[0115] In some embodiments of the present invention, L3 and L5 are each independently selected from the following group of substituted or unsubstituted groups: CH2, 4-6 membered monocyclic heterocyclic groups, 7-11 membered spirocyclic heterocyclic groups, 5-8 membered bridged heterocyclic groups, 8-10 membered fused heterocyclic groups, or C 4-6 Monocyclic cycloalkyl, C 7-11 Spirocycloalkyl, C 5-8Bridged cycloalkyl, C 8-10 Fused cycloalkyl groups; preferably substituted or unsubstituted groups from the following group:

[0116] Preferred substituted or unsubstituted groups:

[0117] Alternatively, L3 can be selected from NH or NC. 1-3 Alkyl, CO, COCH2, C 1-3 Alkylene, C 1-3 Halogenated alkylene oxides, CONH, CONC 1-3 Alkyl, CONHCH2, CONC 1-3 Alkyl CH2;

[0118] Or L5 is the key;

[0119] Wherein, substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2). n R aa -(CH2) n OR dd -O(CH2) n R aa -(CH2) n SR dd -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R dd -(CH2) n C(O)NR aa R dd -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R dd -(CH2) n P(O)R aa R dd -O(CH2) n P(O)R aa R dd -(CH2)n NR cc C(=NH)NR aa R dd (CH2) n NR dd S(O) m R cc -OC(R) aa R dd ) n (CH2) m R aa -NR dd (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R dd -CH=CH(CH2) n NR dd C(O)R cc -CH=CH(CH2) n NR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1- 6-alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents from a group consisting of aryl and substituted or unsubstituted 5-14 heteroaryl groups; preferably, the substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2)R. aa -(CH2)OR dd -(CH2)2OR dd C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy groups, C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-6 The substance is substituted by one or more substituents selected from cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl;

[0120] n21, n22, n23, and n24 are each independently selected from 0, 1, 2, or 3;

[0121] n11, n12, n13, and n14 are each independently selected from 0, 1, 2, or 3;

[0122] R aa R cc R dd The definitions of m and n are as described above.

[0123] In some embodiments of the present invention, L4 is selected from C. 1-6 Alkylene, -(CH2) n7 C=O, C=O(CH2) n8 -、-(CH2) n7 CONH, CONH(CH2) n8 -、-(CH2) n7 S(O)2, S(O)2(CH2) n8 -、-(CH2) n7 S(O)2NR bb S(O)2NR bb (CH2) n8 -、-(CH2) n7 S(=NH)(=O) or S(=NH)(=O)(CH2) n8 -, wherein C 1- 6-alkylene group, -(CH2) n7 C=O, C=O(CH2) n8 -、-(CH2) n7 CONH, CONH(CH2) n8 -、-(CH2) n7 S(O)2, S(O)2(CH2) n8 -、-(CH2) n7 S(O)2NR bb S(O)2NR bb (CH2) n8 -、-(CH2) n7 S(=NH)(=O) or S(=NH)(=O)(CH2) n8 -Optionally controlled by one or more R bb Replacement; preferably, R bbSelected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy group; wherein n7 and n8 are each independently 0, 1 or 2; preferably, L4 is selected from NR. bb COCH2, COCHCH3, COCH(CH3)CH2, CH(CH3)CH2, C(CH3)(OH)CH2, CHFCH2, CHFCHF, CF2CH2, CF2CF2, SO2, SO2CH2, SO2NR bb SO2NR bb CH2, CONR bb CH2, CH2CH2, COCH2, COCH2CH2, CH2, CO, NR bb or CONR bb Preferably, L4 is selected from COCH2, COCH2CH2, CH2, CO, NR bb CONR bb More preferably, L4 is selected from COCH2, COCH2CH2, CH2, CO, NH, NCH3, CONH, CON(CH3), SO2, SO2CH2, COCHCH3, CH(CH3)CH2, C(CH3)(OH)CH2, CHFCH2, CHFCHF, CF2CH2, CF2CF2, CH2NHCO, NHCOCH2, CH2N(CH3)CO, N(CH3)COCH2 or COCH(CH3)CH2; and / or

[0124] L6 is selected from the following group of groups: bonded, substituted, or unsubstituted: 4-6 membered monocyclic heterocyclic groups, 7-11 membered spirocyclic heterocyclic groups, 5-8 membered bridged heterocyclic groups, 8-10 membered fused heterocyclic groups, or C 4-6 Monocyclic cycloalkyl, C 7-11 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 8-10 Fused cycloalkyl group; preferably bonded or substituted or unsubstituted of the following groups: More preferably, the following group of groups are either bonded, substituted, or unsubstituted:

[0125] Wherein, substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2). n R aa -(CH2) n OR dd、-O(CH2) n R aa 、-(CH2) n SR dd 、-(CH2) n C(O)R cc 、-(CH2) n C(O)OR cc 、-(CH2) n S(O) m R cc 、-(CH2) n NR aa R dd 、-(CH2) n C(O)NR aa R dd 、-(CH2) n NR bb C(O)R cc 、-(CH2) n NR cc C(O)NR aa R dd 、-(CH2) n P(O)R aa R dd 、-O(CH2) n P(O)R aa R dd 、-(CH2) n NR cc C(=NH)NR aa R dd 、(CH2) n NR dd S(O) m R cc 、-OC(R aa R dd ) n (CH2) m R aa 、-NR dd (CH2) n R aa 、-CH=CH(CH2) n R aa 、-CH=CH(CH2) n NR aa R dd 、-CH=CH(CH2) n NR dd C(O)R cc 、-CH=CH(CH2) n NR cc C(O)NR aa Rdd =N-OR dd or = CR aa R cc C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1- 6-alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents from a group consisting of aryl and substituted or unsubstituted 5-14 heteroaryl groups; preferably, the substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2)R. aa -(CH2)OR dd -(CH2)2OR dd C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-6 The substance is substituted by one or more substituents selected from cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl;

[0126] n11, n12, n13, and n14 are each independently selected from 0, 1, 2, or 3;

[0127] R aa R bb R cc R dd The definitions of m and n are as described above.

[0128] In some embodiments of the present invention, L7 is selected from a key.

[0129] In some embodiments of the present invention, L6 is selected from a key.

[0130] In some embodiments of the present invention, L6 is selected from a key and L7 is selected from a key.

[0131] In some embodiments of the present invention, Selected from

[0132] In some embodiments of the present invention, Selected from

[0133] Among them, R 2-1 R 2-2 and R 2-3 The definition is the same as R2; preferably R 2-1 R 2-2 and R 2-3 Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-3 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -(CH2) n R aa -(CH2) n OR dd -O(CH2) n R aa -(CH2) n SR dd -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R dd -(CH2) n C(O)NR aa R dd -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R dd -(CH2) n P(O)R aa R dd -O(CH2) n P(O)R aa R dd-(CH2) n NR cc C(=NH)NR aa R dd (CH2) n NR dd S(O) m R cc -OC(R) aa R dd ) n (CH2) m R aa -NR dd (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R dd -CH=CH(CH2) n NR dd C(O)R cc -CH=CH(CH2) n NR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc The C mentioned therein 1-3 Alkyl, C 1- 3-Hydroalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-3 alkenyl, C 2-4 alkynyl group, C 3- 6-cycloalkyl, 3-6-membered heterocyclic, phenyl, and 5-6-membered heteroaryl groups may be further substituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14The aryl group is substituted with one or more substituents in a group of substituted or unsubstituted 5-14 heteroaryl groups; more preferably R 2-1 R 2-2 and R 2-3 Each is independently selected from hydrogen and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

[0134] In some embodiments of the present invention, for

[0135] or for

[0136] or for

[0137] In this group, ring A and ring B are each independently selected from the following group of substituted or unsubstituted groups: 4-6 membered monocyclic heterocyclic groups, 7-11 membered spirocyclic heterocyclic groups, 5-8 membered bridged ring heterocyclic groups, 8-10 membered fused ring heterocyclic groups, or C 4-6 Monocyclic cycloalkyl, C 7-11 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 8-10 Fused cycloalkyl group; preferably, ring A and ring B are each independently selected from the group consisting of substituted or unsubstituted groups: More preferably, ring A and ring B are each independently selected from the group consisting of substituted or unsubstituted groups:

[0138] Wherein, substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2). n R aa -(CH2) n OR dd -O(CH2) n R aa -(CH2) n SR dd -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R dd-(CH2) n C(O)NR aa R dd -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R dd -(CH2) n P(O)R aa R dd -O(CH2) n P(O)R aa R dd -(CH2) n NR cc C(=NH)NR aa R dd (CH2) n NR dd S(O) m R cc -OC(R) aa R dd ) n (CH2) m R aa -NR dd (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R dd -CH=CH(CH2) n NR dd C(O)R cc -CH=CH(CH2) n NR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1- 6-alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents from a group consisting of aryl and substituted or unsubstituted 5-14 heteroaryl groups; preferably, the substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2)R. aa -(CH2)OR dd -(CH2)2OR dd C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-6 The substance is substituted by one or more substituents selected from cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl;

[0139] n21, n22, n23, n24, n11, n12, n13, n14, R aa R bb R cc R dd The definitions of m and n are as described above;

[0140] L3 is selected from NH and NC. 1-3 Alkyl, CO, COCH2, C 1-3 Alkylene, C 1-3 Halogenated alkylene oxides, CONH, CONC 1-3 Alkyl, CONHCH2, CONC 1-3 Alkyl CH2;

[0141] L 4' L4 and L4 are each independently selected from C 1-6 Alkylene, -(CH2) n7 C=O, C=O(CH2) n8 -、-(CH2) n7 CONH, CONH(CH2) n8 -、-(CH2) n7 S(O)2, S(O)2(CH2) n8 -、-(CH2) n7 S(O)2NR bb S(O)2NR bb (CH2) n8 -、-(CH2) n7 S(=NH)(=O) or S(=NH)(=O)(CH2)n8 -, wherein C 1- 6-alkylene group, -(CH2) n7 C=O, C=O(CH2) n8 -、-(CH2) n7 CONH, CONH(CH2) n8 -、-(CH2) n7 S(O)2, S(O)2(CH2) n8 -、-(CH2) n7 S(O)2NR bb S(O)2NR bb (CH2) n8 -、-(CH2) n7 S(=NH)(=O) or S(=NH)(=O)(CH2) n8 -Optionally controlled by one or more R bb Replacement; preferably, R bb Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy; wherein n7 and n8 are each independently 0, 1 or 2;

[0142] Preferably, L 4' L4 and L4 are each independently selected from NR bb COCH2, COCHCH3, COCH(CH3)CH2, CH(CH3)CH2, C(CH3)(OH)CH2, CHFCH2, CHFCHF, CF2CH2, CF2CF2, SO2, SO2CH2, SO2NR bb SO2NR bb CH2, CONR bb CH2, CH2CH2, COCH2, COCH2CH2, CH2, CO, NR bb or CONR bb Preferably, L 4' L4 is selected from COCH2, COCH2CH2, CH2, CO, NR bb CONR bb More preferably, L 4'L4 is independently selected from COCH2, COCH2CH2, CH2, CO, NH, NCH3, CONH, CON(CH3), SO2, SO2CH2, COCHCH3, CH(CH3)CH2, C(CH3)(OH)CH2, CHFCH2, CHFCHF, CF2CH2, CF2CF2, CH2NHCO, NHCOCH2, CH2N(CH3)CO, N(CH3)COCH2 or COCH(CH3)CH2;

[0143] Preferably Selected from the following group of groups, whether substituted or unsubstituted:

[0144] Preferably, Selected from the following group of groups, whether substituted or unsubstituted:

[0145] or Selected from the following group of groups, whether substituted or unsubstituted:

[0146] Preferably Selected from the following group of groups, whether substituted or unsubstituted:

[0147] Preferably, Selected from the following group of groups, whether substituted or unsubstituted:

[0148] Wherein, substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2). n R aa -(CH2) n OR dd -O(CH2) n R aa -(CH2) n SR dd -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R dd -(CH2) n C(O)NR aaR dd -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R dd -(CH2) n P(O)R aa R dd -O(CH2) n P(O)R aa R dd -(CH2) n NR cc C(=NH)NR aa R dd (CH2) n NR dd S(O) m R cc -OC(R) aa R dd ) n (CH2) m R aa -NR dd (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R dd -CH=CH(CH2) n NR dd C(O)R cc -CH=CH(CH2) n NR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1- 6-alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents from a group consisting of aryl and substituted or unsubstituted 5-14 heteroaryl groups; preferably, the substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2)R. aa -(CH2)OR dd -(CH2)2OR dd C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-6 The substance is substituted by one or more substituents selected from cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl;

[0149] R aa R cc R dd The definitions of m and n are as described above;

[0150] Preferably, Selected from

[0151] Preferably, Selected from

[0152] Or preferably Selected from

[0153] In some embodiments of the present invention Selected from the following group of groups, whether substituted or unsubstituted:

[0154] Wherein, substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2). n R aa -(CH2) n OR dd -O(CH2) n R aa -(CH2) n SR dd -(CH2) n C(O)Rcc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R dd -(CH2) n C(O)NR aa R dd -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R dd -(CH2) n P(O)R aa R dd -O(CH2) n P(O)R aa R dd -(CH2) n NR cc C(=NH)NR aa R dd (CH2) n NR dd S(O) m R cc -OC(R) aa R dd ) n (CH2) m R aa -NR dd (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R dd -CH=CH(CH2) n NR dd C(O)R cc -CH=CH(CH2) n NR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1- 6-alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents from a group consisting of aryl and substituted or unsubstituted 5-14 heteroaryl groups; preferably, the substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2)R. aa -(CH2)OR dd -(CH2)2OR dd C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-6 The substance is substituted by one or more substituents selected from cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl;

[0155] R aa R cc R dd The definitions of m and n are as described above;

[0156] Preferably, Selected from the following group groups:

[0157] In some embodiments of the present invention Selected from

[0158] In some embodiments of the invention, ring A and ring B are each independently selected from the following group of substituted or unsubstituted groups: 4-6 membered monocyclic heterocyclic groups, 7-11 membered spirocyclic heterocyclic groups, 5-8 membered bridged ring heterocyclic groups, 8-10 membered fused ring heterocyclic groups, or C 4-6 Monocyclic cycloalkyl, C 7-11 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 8-10 Fused cycloalkyl groups;

[0159] The heterocyclic group preferably contains 1-3 heteroatoms, wherein the heteroatoms are N, O or S; more preferably, the heteroatoms are 1 or 2 nitrogen atoms;

[0160] Preferably, ring A and ring B are each independently selected from the following group of substituted or unsubstituted groups:

[0161] Each can be a single bond or a double bond independently;

[0162] Z1, Z4, Z8, Z 10 Z 12 Z 14 Z 15 and Z 16 Each is independently selected from N, C, or CH;

[0163] Z 25 Z 26 Z 27 and Z 28 Each is independently selected from N or CH;

[0164] Z2, Z3, Z5, Z6, Z7, Z9, Z 11 Z 13 Z 17 -Z 24 Z 29 -Z 36 Each is independently selected from bonds, O, S, N, NH, CH, CH2 or CH2CH2;

[0165] Wherein, substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2). n R aa -(CH2) n OR dd -O(CH2) n R aa -(CH2) n SR dd -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R dd -(CH2) n C(O)NR aa R dd-(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R dd -(CH2) n P(O)R aa R dd -O(CH2) n P(O)R aa R dd -(CH2) n NR cc C(=NH)NR aa R dd (CH2) n NR dd S(O) m R cc -OC(R) aa R dd ) n (CH2) m R aa -NR dd (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R dd -CH=CH(CH2) n NR dd C(O)R cc -CH=CH(CH2) n NR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1- 6-alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14The aryl group is substituted with one or more substituents from a group consisting of aryl and substituted or unsubstituted 5-14 heteroaryl groups; preferably, the substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2)R. aa -(CH2)OR dd -(CH2)2OR dd C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-6 It is substituted by one or more substituents selected from cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl.

[0166] In some embodiments of the present invention, Cy2 is selected from C. 4-8 Cycloalkyl or 4-8 membered heterocyclic groups, preferably C 4- 6-cycloalkyl or 5-8-membered heterocyclic groups.

[0167] In some embodiments of the present invention, R4 is selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1- 3-Haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-14 Aryl, 5-10 heteroaryl, -R aa -OR dd -SR dd -C(O)R cc -C(O)OR cc -S(O) m R cc -NR aa R dd -C(O)NR aa R dd -NR bb C(O)R cc -NR cc C(O)NR aa R dd -P(O)R aa R dd -O(CH2)P(O)Raa R dd -NR cc C(=NH)NR aa R dd NR dd S(O) m R cc -O(CR) aa R dd ) n R aa -CH=CHNR aa R dd -CH=CHNR dd C(O)R cc -CH=CHNR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc The C mentioned therein 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-14 The aryl group and 5-10 heteroaryl group may be further substituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2- 6-Alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents selected from substituted or unsubstituted 5-14 membered heteroaryl groups; preferably, R4 is selected from hydrogen, halogen, amino, nitro, hydroxyl, C 1- 3-alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups.

[0168] In some embodiments of the present invention, R5 is selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1- 3-Haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-14 Aryl, 5-10 heteroaryl, -R aa -OR dd -SR dd -C(O)R cc -C(O)OR cc -S(O) m R cc -NR aa R dd -C(O)NR aa R dd -NR bb C(O)R cc -NR cc C(O)NR aa R dd -P(O)R aa R dd -O(CH2)P(O)R aa R dd -NR cc C(=NH)NR aa R dd NR dd S(O) m R cc -O(CR) aa R dd ) n R aa -CH=CHNR aa R dd -CH=CHNR dd C(O)R cc -CH=CHNR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc The C mentioned therein 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-14 The aryl group and 5-10 heteroaryl group may be further substituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2- 6-Alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 It is substituted by one or more substituents in the aryl group and substituted or unsubstituted 5-14 heteroaryl groups.

[0169] In some embodiments of the present invention, R5 is selected from hydroxyl, SCH3, I, In some embodiments of the invention, two R5 atoms on the same or adjacent ring atoms, together with the ring atoms they are connected to, form substituted or unsubstituted C atoms. 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 aryl or substituted or unsubstituted 5-14 heteroaryl groups; wherein the substitution refers to the presence of one or more R groups. 5c replace.

[0170] In some embodiments of the present invention, the compounds are as shown in formulas (I-3-1-1-1)-(I-3-1-2-1), (I-4-1-1-1)-(I-4-1-5-1) to (I-9-1-1-1)-(I-9-1-2-1).

[0171] Among them, L4, cyclic A, cyclic B and other groups are as described above.

[0172] In some embodiments of the present invention, the compounds are as shown in formulas (I-3-1-1-1-1)-(I-3-1-2-1-1), (I-4-1-1-1-1)-(I-4-2-1-1-1) to (I-9-1-1-1-1)-(I-9-1-2-1-1).

[0173] M b Selected from N or CH;

[0174] R L Each group is independently selected from hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and -(CH2). n R aa -(CH2) n OR dd -O(CH2) n R aa -(CH2) n SR dd -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R dd -(CH2) n C(O)NR aa R dd -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R dd -(CH2) n P(O)R aa R dd -O(CH2) n P(O)R aa R dd -(CH2) n NR cc C(=NH)NR aa R dd (CH2) n NR dd S(O) m R cc -OC(R) aa R dd ) n (CH2) m R aa -NR dd (CH2) n R aa -CH=CH(CH2)n R aa -CH=CH(CH2) n NR aa R dd -CH=CH(CH2) n NR dd C(O)R cc -CH=CH(CH2) n NR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1- 6-alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents from a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; preferably, R L Each is independently selected from hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -(CH2)R aa -(CH2)OR dd -(CH2)2OR dd C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl;

[0175] j can be 0, 1, 2, 3, 4, 5 or 6.

[0176] In certain embodiments of the present invention, the compounds are as shown in formulas (I-3-1-1-1-1)-(I-3-1-2-1-1-1), (I-4-1-1-1-1)-(I-4-2-1-1-1) to (I-9-1-1-1-1-1)-(I-9-1-2-1-1-1).

[0177] Where * indicates R or S configuration.

[0178] In some embodiments of the present invention, ring A and ring B are each independently selected from the following group of substituted or unsubstituted groups: 4-6 membered monocyclic heterocyclic groups, 7-11 membered spirocyclic heterocyclic groups, 5-8 membered bridged ring heterocyclic groups, 8-10 membered fused ring heterocyclic groups, or C 4-6 Monocyclic cycloalkyl, C 7-11 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 8-10 Fused cycloalkyl group; preferably, ring A and ring B are each independently selected from the following group, whether substituted or unsubstituted:

[0179] Wherein, substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2). n R aa -(CH2) n OR dd -O(CH2) n R aa -(CH2) n SR dd -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R dd -(CH2) n C(O)NR aa R dd -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R dd-(CH2) n P(O)R aa R dd -O(CH2) n P(O)R aa R dd -(CH2) n NR cc C(=NH)NR aa R dd (CH2) n NR dd S(O) m R cc -OC(R) aa R dd ) n (CH2) m R aa -NR dd (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R dd -CH=CH(CH2) n NR dd C(O)R cc -CH=CH(CH2) n NR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1- 6-alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents from a group consisting of aryl and substituted or unsubstituted 5-14 heteroaryl groups; preferably, the substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2)R. aa -(CH2)OR dd-(CH2)2OR dd C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-6 The substance is substituted by one or more substituents selected from cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl;

[0180] Preferably, L4 is selected from C 1-6 Alkylene, -(CH2) n7 C=O, C=O(CH2) n8 -、-(CH2) n7 CONH, CONH(CH2) n8 -、-(CH2) n7 S(O)2, S(O)2(CH2) n8 -、-(CH2) n7 S(O)2NR bb S(O)2NR bb (CH2) n8 -、-(CH2) n7 S(=NH)(=O) or S(=NH)(=O)(CH2) n8 -, wherein C 1- 6-alkylene group, -(CH2) n7 C=O, C=O(CH2) n8 -、-(CH2) n7 CONH, CONH(CH2) n8 -、-(CH2) n7 S(O)2, S(O)2(CH2) n8 -、-(CH2) n7 S(O)2NR bb S(O)2NR bb (CH2) n8 -、-(CH2) n7 S(=NH)(=O) or S(=NH)(=O)(CH2) n8 -Optionally controlled by one or more R bb Replacement; preferably, R bb Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C1-6 Haloalkoxy group; wherein n7 and n8 are each independently 0, 1 or 2; more preferably, L4 is selected from COCH2, COCH2CH2, CH2, CO, NH, NCH3, CONH, CON(CH3), SO2, SO2CH2, COCHCH3, CH(CH3)CH2, C(CH3)(OH)CH2, CHFCH2, CHFCHF, CF2CH2, CF2CF2, CH2NHCO, NHCOCH2, CH2N(CH3)CO, N(CH3)COCH2 or COCH(CH3)CH2.

[0181] The present invention also relates to a compound or a pharmaceutically acceptable salt thereof, comprising a structural unit as shown in formula (I').

[0182] The definitions of M, X1, R6, and n6 are as described above;

[0183] Preferably, the structural unit has the structure shown in formula (I'-1) or (I'-2).

[0184] in,

[0185] M9, M 10 M 11 M 13 M 14 The definitions of Y0, Y1, Y2, X1, R5, n5, R6 and n6 are as described above.

[0186] In some embodiments of the present invention, the structural unit has a structure as shown in formula (I'-1-1) or (I'-2-1).

[0187] Preferably, the structural unit has the structure shown in formula (I'-1-1-1)-(I'-1-1-2) or (I'-2-1-1)-(I'-2-1-2).

[0188] Where * indicates R or S configuration.

[0189] In some embodiments of the present invention, the compound comprises the structural unit represented by formula (I'-3).

[0190] Wherein, ring B is selected from the following group, either substituted or unsubstituted: 4-6 membered monocyclic heterocyclic group, 7-11 membered spirocyclic heterocyclic group, 5-8 membered bridged ring heterocyclic group, 8-10 membered fused ring heterocyclic group, or C. 4-6 Monocyclic cycloalkyl, C 7-11 Spirocycloalkyl, C 5-8Bridged cycloalkyl, C 8-10 Fused cycloalkyl group; preferably, ring B is selected from the group consisting of substituted or unsubstituted groups:

[0191] Wherein, substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2). n R aa -(CH2) n OR dd -O(CH2) n R aa -(CH2) n SR dd -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R dd -(CH2) n C(O)NR aa R dd -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R dd -(CH2) n P(O)R aa R dd -O(CH2) n P(O)R aa R dd -(CH2) n NR cc C(=NH)NR aa R dd (CH2) n NR dd S(O) m R cc -OC(R) aa R dd ) n (CH2) m R aa -NR dd (CH2) n R aa -CH=CH(CH2)n R aa -CH=CH(CH2) n NR aa R dd -CH=CH(CH2) n NR dd C(O)R cc -CH=CH(CH2) n NR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1- 6-alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents from a group consisting of aryl and substituted or unsubstituted 5-14 heteroaryl groups; preferably, the substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2)R. aa -(CH2)OR dd -(CH2)2OR dd C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-6 It is substituted by one or more substituents selected from cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl.

[0192] In certain embodiments of the present invention, the compound further comprises structural units represented by formulas (I'-3-3) to (I'-3-12).

[0193] In some embodiments of the present invention, the compound comprises structural units represented by formula (I'-3-1) or formula (I'-3-2).

[0194] Among them, M b Selected from N or CH;

[0195] R L Each group is independently selected from hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and -(CH2). n R aa -(CH2) n OR dd -O(CH2) n R aa -(CH2) n SR dd -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R dd -(CH2) n C(O)NR aa R dd -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R dd -(CH2) n P(O)R aa R dd -O(CH2) n P(O)R aa R dd -(CH2) n NR cc C(=NH)NR aa R dd (CH2) n NR dd S(O) m R cc -OC(R) aa R dd ) n (CH2) m R aa -NR dd (CH2) n R aa -CH=CH(CH2)n R aa -CH=CH(CH2) n NR aa R dd -CH=CH(CH2) n NR dd C(O)R cc -CH=CH(CH2) n NR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1- 6-alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents from a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; preferably, R L Each is independently selected from hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -(CH2)R aa -(CH2)OR dd -(CH2)2OR dd C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl;

[0196] j is 0, 1, 2, 3, 4, 5 or 6;

[0197] R aa R cc R dd The definitions of m and n are as described above;

[0198] Preferably, the compound comprises structural units represented by formula (I'-3-1-1)-(I'-3-1-2) or formula (I'-3-2-1)-(I'-3-2-2).

[0199] Where * indicates R or S configuration.

[0200] In some embodiments of the present invention, the compound further comprises structural units represented by formula (I'-4).

[0201] Preferably, the compound further comprises structural units as shown in formulas (I'-4-1)-(I'-4-3).

[0202] Preferably, the compound further comprises structural units represented by the formula (I'-4-1-1)-(I'-4-1-3).

[0203] The definitions of ring A, ring B, and L4 are as described above.

[0204] In some embodiments of the present invention, the compound is PROTAC, further comprising a target protein binding unit; preferably, the target protein is selected from EGFR, preferably, the EGFR is a mutated and / or overexpressed EGFR, particularly preferably a single or multiple mutated EGFR associated with the L858R mutation.

[0205] In some embodiments of the present invention, the compound has the following structure

[0206] Preferably, the compound further comprises structural units as shown in formulas (I'-5-1)-(I'-5-3).

[0207] Preferably, the compound further comprises structural units represented by formulas (I'-5-1-1) to (I'-5-1-12).

[0208] R L-2 The definition is the same as R L ;

[0209] j1 is 0, 1, 2, 3, 4, 5 or 6;

[0210] Among them, P, P-L2-, P-L2-L3-, P-L2-L3-L4-, P-L2-L3-L4-L5-, For target protein binding units;

[0211] Preferably, the target protein is selected from EGFR, AR, BRD9, BCL6, or BTK; the target protein further comprises one or more of the following structural units: thiazolyl, pyridyl, indole, pyrimidinyl, phenyl, pyridone, oxadiazolyl, pyrazolyl, quinolinyl, piperidinyl, piperazine, cyclobutyl, cyclopentyl, cyclohexylbenzopyridine, benzopyrimidine, benzopyrazole, pyrimidopyrrole, pyridopyridone, benzopyridone, isodihydroindole, furan, triazole, and analogues, preferably an EGFR inhibitor; the EGFR is further preferably a mutated and / or overexpressed EGFR, particularly preferably a single or multiple mutated EGFR associated with the L858R mutation.

[0212] In some embodiments of the present invention, the compound is PROTAC, further comprising a linker; preferably, the target protein binding unit is linked to an E3 ubiquitin ligase binding unit via the linker; preferably, the linker is one or more of L3, L4, L5, L6 and L7, wherein L3, L4, L5, L6 and L7 are defined as described above.

[0213] The present invention also relates to a compound of formula (I”) or (I”’) or a pharmaceutically acceptable salt thereof:

[0214] Wherein, ring B is selected from the following group, either substituted or unsubstituted: 4-6 membered monocyclic heterocyclic group, 7-11 membered spirocyclic heterocyclic group, 5-8 membered bridged ring heterocyclic group, 8-10 membered fused ring heterocyclic group, or C. 4-6 Monocyclic cycloalkyl, C 7-11 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 8-10 Fused cycloalkyl group; the heterocyclic group preferably contains 1-3 heteroatoms, wherein the heteroatoms are N, O or S; more preferably, the heteroatoms are 1 or 2 nitrogen atoms;

[0215] Preferably, each ring B is independently selected from the following group, either substituted or unsubstituted:

[0216] Each can be a single bond or a double bond independently;

[0217] Z1, Z4, Z8, Z 10 Z 12 Z 14 Z 15 and Z 16 Each is independently selected from N, C, or CH;

[0218] Z 25 Z 26 Z 27 and Z28 Each is independently selected from N or CH;

[0219] Z2, Z3, Z5, Z6, Z7, Z9, Z 11 Z 13 Z 17 -Z 24 Z 29 -Z 36 Each is independently selected from bonds, O, S, N, NH, CH, CH2 or CH2CH2;

[0220] Preferably, ring B is selected from the following group: substituted or unsubstituted groups. Wherein, substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2). n R aa -(CH2) n OR dd -O(CH2) n R aa -(CH2) n SR dd -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R dd -(CH2) n C(O)NR aa R dd -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R dd -(CH2) n P(O)R aa R dd -O(CH2) n P(O)R aa R dd -(CH2) n NR cc C(=NH)NR aa R dd(CH2) n NR dd S(O) m R cc -OC(R) aa R dd ) n (CH2) m R aa -NR dd (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R dd -CH=CH(CH2) n NR dd C(O)R cc -CH=CH(CH2) n NR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3- 12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents from a group consisting of aryl and substituted or unsubstituted 5-14 heteroaryl groups; preferably, the substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2)R. aa -(CH2)OR dd -(CH2)2OR dd C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1- 6-alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6The substance is substituted by one or more substituents selected from cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl;

[0221] M9, M 10 M 11 X1, R5, n5, R6, n6, R aa R cc R dd The definitions of m and n are as described above.

[0222] In certain embodiments of the present invention, the compound has the structures shown in formulas (I”’-2) to (I”’-11).

[0223] Among them, R L-1 The definition is the same as R L ;

[0224] R L Each group is independently selected from hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and -(CH2). n R aa -(CH2) n OR dd -O(CH2) n R aa -(CH2) n SR dd -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R dd -(CH2) n C(O)NR aa R dd -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R dd -(CH2) n P(O)R aa R dd -O(CH2) n P(O)R aa R dd-(CH2) n NR cc C(=NH)NR aa R dd (CH2) n NR dd S(O) m R cc -OC(R) aa R dd ) n (CH2) m R aa -NR dd (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R dd -CH=CH(CH2) n NR dd C(O)R cc -CH=CH(CH2) n NR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1- 6-alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents from a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; preferably, R L Each is independently selected from hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -(CH2)R aa -(CH2)OR dd -(CH2)2OR dd C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl;

[0225] j is 0, 1, 2, 3, 4, 5 or 6;

[0226] R aa R cc R dd The definitions of m and n are as described above.

[0227] In some embodiments of the present invention, the compound has the structure shown in formula (I”'-1).

[0228] Among them, M b Selected from N or CH;

[0229] R L-1 The definition is the same as R L ;

[0230] R L Each group is independently selected from hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and -(CH2). n R aa -(CH2) n OR dd -O(CH2) n R aa -(CH2) n SR dd -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R dd -(CH2) n C(O)NR aa R dd -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R dd -(CH2) n P(O)Raa R dd -O(CH2) n P(O)R aa R dd -(CH2) n NR cc C(=NH)NR aa R dd (CH2) n NR dd S(O) m R cc -OC(R) aa R dd ) n (CH2) m R aa -NR dd (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R dd -CH=CH(CH2) n NR dd C(O)R cc -CH=CH(CH2) n NR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1- 6-alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents from a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; preferably, R L Each is independently selected from hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -(CH2)R aa -(CH2)OR dd -(CH2)2ORdd C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl;

[0231] j is 0, 1, 2, 3, 4, 5 or 6;

[0232] R aa R cc R dd The definitions of m and n are as described above;

[0233] Preferably, the compound has the structure shown in formula (I”’-1-1)-(I”’-1-2).

[0234] Where * indicates R or S configuration.

[0235] The present invention also provides a method for preparing a compound of formula (I-3-1-1-1-1) or formula (I-4-1-1-1-1) or a pharmaceutically acceptable salt thereof, characterized in that it includes the step of

[0236] Method 1: React the compounds shown in formula (INT-1) and formula (INT-2) to prepare the compound shown in formula (I-3-1-1-1-1).

[0237] Method 2: React the compounds shown in formula (INT-3) and formula (INT-4) to prepare the compound shown in formula (I-4-1-1-1-1).

[0238] Preferably, the reactions described in methods one and two are carried out in the presence of a base and a catalyst, wherein the base is an organic base and the catalyst is an amide condensing agent; wherein, R O Selected from OH or C 1-6 Alkoxy; R O1 and R N1 Each is independently selected from H, NH2, and NHC. 1-6 Alkyl, COOH, COC 1-6 Alkoxy, CH2COOH or CH2COC 1- 6-alkoxy;

[0239] R NSelected from H or an amino protecting group; wherein the amino protecting group is selected from allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, triphenylmethyl, phosphomethoxycarbonyl, 9-fluorenmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl;

[0240] Ring Ar1, Ring Cy1, L1, L4, Ring A, Ring B, R1, R2, R3, R4, R5, R6, R7, R L The definitions of M4, M5, Mb, j, n1, n2, n'3, n4, n5, and n6 are as described above.

[0241] In some embodiments of the present invention, X1 is connected to the 6-membered aromatic portion of M.

[0242] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of the above-described compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0243] In some embodiments of the invention, the pharmaceutical composition, based on free base, comprises 0.1% to 95% by weight of the compound, its stereoisomers, or a pharmaceutically acceptable salt thereof, preferably 90%, 85%, 80%, 75%, 70%, 60%, or 50%.

[0244] In some embodiments of the invention, the pharmaceutical composition is selected from tablets, capsules, liquid formulations or injections, preferably also containing a filler, optionally a disintegrant, or further containing one or more of a flow aid or lubricant.

[0245] The present invention further relates to the use of the compounds described above or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions described above, in the preparation of EGFR inhibitor medicaments.

[0246] In some embodiments of the present invention, the EGFR is a mutated EGFR, preferably a single or multiple mutated EGFR related to the L858R mutation.

[0247] The present invention also provides the use of the said compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, in the preparation of a medicament for treating or preventing diseases related to cerebellar protein (CRBN), preferably, the diseases being selected from abnormal cell proliferation, tumors, immune diseases, diabetes, cardiovascular diseases, infectious diseases, and inflammatory diseases; more preferably tumors and infectious diseases. Preferably, the tumor is cancer; more preferably breast cancer, endometrial cancer, uterine cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian tumor, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, renal cell carcinoma, bladder cancer, colorectal cancer, esophageal cancer, head cancer, kidney cancer, hepatocellular carcinoma, lung cancer, cervical cancer, pancreatic cancer, gastric cancer, lymphoma, non-Hodgkin's lymphoma, melanoma, myeloproliferative disorders, sarcoma, angiosarcoma, peripheral neuroepithelial tumor, astrocytoma, glioma, ependymoma, neuroblastoma, gangliocytoma, ductoblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, schwannoma, bile duct cancer, myeloma, mesothelioma, gastrointestinal stromal tumor, thyroid cancer, esophageal cancer, Hodgkin's tumor, Wilms' tumor, and teratoma.

[0248] The present invention further relates to the use of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above, in the preparation of a medicament for treating cancer; preferably, the cancer is selected from ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, renal cancer, anaplastic large cell lymphoma, multiple myeloma, or mesothelioma; more preferably, the cancer is non-small cell lung cancer; even more preferably, the cancer is non-small cell lung cancer with EGFR L858R, EGFR L858R / T790M, L858R / C797S, or L858R / T790M / C797S mutations.

[0249] The present invention further relates to the use of the said compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating cancer.

[0250] The present invention also provides a method for treating disease conditions using the compounds or pharmaceutical compositions of the present invention, including but not limited to conditions related to EGFR kinase dysfunction.

[0251] The present invention also relates to a method of treating, preventing and / or treating cancer, comprising administering to a patient a therapeutically effective dose of the compound as described above or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0252] In some embodiments of the present invention, the cancer is selected from ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, renal cancer, anaplastic large cell lymphoma, multiple myeloma, melanoma, or mesothelioma; more preferably, the cancer is non-small cell lung cancer; even more preferably, the cancer is non-small cell lung cancer with EGFR L858R, EGFR L858R / T790M, L858R / C797S, or L858R / T790M / C797S mutations.

[0253] The E3 ligand of this invention has been validated using target protein binding units (e.g., ARV776, FHD-609, etc.) in PROTAC molecules targeting other targets, achieving the same or similar degradation activities. This indicates that the linker and / or E3 ligand studied in this invention can be widely applied in PROTAC-related fields targeting various targets. The target is selected from EGFR, AR, BRD9, BCL6, or BTK. Preferably, the EGFR is a mutated and / or overexpressed EGFR, and particularly preferred are single or multiple mutated EGFRs related to the L858R mutation.

[0254] Detailed description of the invention

[0255] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0256] Unless otherwise stated, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art, and in particular, the terms used in the specification and claims have the following meanings.

[0257] The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, which may optionally be substituted with one or more substituents. In certain embodiments, alkyl refers to a group having a chain length of 1 to 20 (C1-C2). 20 ), 1 to 15 (C1-C 15 ), 1 to 12 (C1-C 12 ), 1 to 10 (C1-C 10 Straight-chain saturated hydrocarbon groups with 1 to 8 (C1-C8), 1 to 6 (C1-C6), or 1 to 3 (C1-C3) carbon atoms, or having 3 to 20 (C3-C4) carbon atoms. 20 ), 3 to 15 (C3-C) 15 ), 3 to 12 (C3-C 12 ), 3 to 10 (C3-C) 10A branched saturated hydrocarbon group with 3 to 8 (C3-C8) or 3 to 6 (C3-C6) carbon atoms. The straight-chain C3 group used here... 1- -C6 alkyl and branched C 3- -C6 alkyl groups are also called "lower alkyl groups". For example, C6 alkyl groups... 1- -C6 alkyl refers to a linear saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C... 1- -C6 alkyl groups contain 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. In one embodiment, the alkyl group is an optionally substituted alkyl group as described elsewhere herein.

[0258] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, wherein "alkyl" is defined as described above. Non-limiting examples of "alkylene" include methylene (-CH2-), ethylene (-(CH2)2-), propylene (-(CH2)3-), or butylene (-(CH2)4-). In one embodiment, the alkylene is an optionally substituted alkyl group as described elsewhere herein.

[0259] The term "alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which can be located at any position within the alkenyl group. The alkenyl group may optionally be substituted by one or more substituents. In certain embodiments, the alkenyl group has a carbon-carbon double bond of 2 to 20 (C2-C2).20 ), 2 to 15 (C2-C 15 ), 2 to 12 (C2-C 12 ), 2 to 10 (C2-C) 10 Straight-chain unsaturated hydrocarbon groups with 2 to 8 (C2-C8), 2 to 6 (C2-C6), or 2 to 4 (C2-C4) carbon atoms, or having 3 to 20 (C3-C4) carbon atoms. 20 ), 3 to 15 (C3-C) 15 ), 3 to 12 (C3-C 12 ), 3 to 10 (C3-C) 10 A branched unsaturated hydrocarbon group having 2 to 8 (C3-C8) or 3 to 6 (C3-C6) carbon atoms. Unless otherwise specified, the term "alkenyl" as used herein includes both straight-chain and branched alkenyl groups. For example, a C2-C6 alkenyl group refers to a straight-chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C2-C6 alkenyl group contains 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkenyl groups include: Those skilled in the art will understand that the term "alkenyl" may also include groups having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations. In one embodiment, the alkenyl is an optionally substituted alkenyl as described elsewhere herein.

[0260] The term "alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, which can be located at any position within the alkynyl group. The alkynyl group may optionally be substituted by one or more substituents. In a particular embodiment, the alkynyl group has a carbon group of 2 to 20 (C2-C2) 20 ), 2 to 15 (C2-C 15 ), 2 to 12 (C2-C 12 ), 2 to 10 (C2-C) 10 Straight-chain unsaturated hydrocarbon groups with 2 to 8 (C2-C8), 2 to 6 (C2-C6), or 2 to 4 (C2-C4) carbon atoms, or having 3 to 20 (C3-C4) carbon atoms. 20 ), 3 to 15 (C3-C) 15 ), 3 to 12 (C3-C 12 ), 3 to 10 (C3-C) 10A branched unsaturated hydrocarbon group having 2 to 8 (C3-C8) or 3 to 6 (C3-C6) carbon atoms. Unless otherwise specified, the term "alkynyl" as used herein includes both straight-chain and branched alkynyl groups. For example, a C2-C6 alkynyl group refers to a straight-chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C2-C6 alkynyl group contains 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkynyl groups include: In one embodiment, the alkynyl group is an optionally substituted alkynyl group as described elsewhere herein.

[0261] The term "cycloalkyl" refers to a monocyclic or polycyclic (two or more) cyclic group of a saturated or partially unsaturated aliphatic hydrocarbon, which may optionally be substituted with one or more substituents. In certain embodiments, the cycloalkyl ring comprises 3 to 20 (C3-C4) rings. 20 ), 3 to 12 (C3-C 12 ), 3 to 10 (C3-C) 10 3 to 8 (C3-C8) or 3 to 6 (C3-C6) carbon atoms; in one embodiment, the cycloalkyl ring comprises 6 to 14 (C6-C8) carbon atoms. 14 ) or 7 to 10 (C7-C 10 It has 10 carbon atoms; it may contain one or more double bonds, but does not have a fully conjugated π-electron system. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, or cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic alkyl, fused cycloalkyl, and bridged cycloalkyl groups in one embodiment. In one embodiment, the cycloalkyl group is an optionally substituted cycloalkyl group or an optionally fused cycloalkyl group with a heterocyclic group, aryl group, or heteroaryl group as described elsewhere herein, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.

[0262] The term "spirocycloalkyl" refers to an aliphatic hydrocarbon polycyclic group in which the monocyclic rings share a single carbon atom (called a spiro atom), and it may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, the spirocycloalkyl group comprises 5 to 20 (C5-C6) carbon atoms. 20 ), 6 to 14 (C6-C 14 ) or 7 to 10 (C7-C 10(e.g., 7, 8, 9, 10) carbon atoms. Spirocycloalkyl groups are classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between rings, with one embodiment being monospirocycloalkyl and bispirocycloalkyl. In one embodiment, it is a 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl. In one embodiment, the spirocycloalkyl group is an optionally substituted spirocycloalkyl group described elsewhere herein. Non-limiting examples of spirocycloalkyl groups include:

[0263] The term "fused-cyclic alkyl" refers to a fully carbon polycyclic group in which each ring in a system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. In a particular embodiment, the fused-cyclic alkyl group comprises 5 to 20 (C5-C6) atoms. 20 ), 6 to 14 (C6-C 14 ) or 7 to 10 (C7-C 10 (e.g., 7, 8, 9, 10) carbon atoms. Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused-ring alkyl groups. In one embodiment, they are bicyclic or tricyclic, and in another embodiment, they are 3-membered / 5-membered, 4-membered / 5-membered, 5-membered / 5-membered, or 5-membered / 6-membered bicyclic alkyl groups. In one embodiment, the fused-ring alkyl group is an optionally substituted fused-ring alkyl group described elsewhere herein or an fused-ring alkyl group optionally fused with a heterocyclic group, aryl group, or heteroaryl group. Non-limiting examples of fused-ring alkyl groups include:

[0264] The term "bridged cycloalkyl" refers to a fully carbon polycyclic group in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, the bridged cycloalkyl group comprises 5 to 20 (C5-C6) carbon atoms. 20 ), 6 to 14 (C6-C 14 ) or 7 to 10 (C7-C 10 (e.g., 7, 8, 9, 10) carbon atoms. Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged alkyl groups, preferably bicyclic or tricyclic. In one embodiment, the bridged alkyl group is an optionally substituted bridged alkyl group described elsewhere herein. Non-limiting examples of bridged alkyl groups include:

[0265] The term "cycloalkylene" refers to a cycloalkyl group in which one hydrogen atom is further substituted, and the definition of "cycloalkyl" is as described above.

[0266] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, wherein the nitrogen, phosphorus, or sulfur atom may optionally be oxidized, the nitrogen atom may optionally be quaternized, the ring carbon atom may optionally be substituted with oxygen but excluding the -OO-, -OS- ring moiety, and the remaining ring atoms are carbon, which may contain one or more double bonds but does not have a fully conjugated π-electron system. In a particular embodiment, the heterocyclic group comprises 3 to 20, 3 to 12, 3 to 10, 3 to 8, 4 to 10, 4 to 8, 3 to 6, or 4 to 6 ring atoms, wherein 1 to 4 are heteroatoms, such as nitrogen, oxygen, or sulfur; in one embodiment, the heterocyclic group comprises 3 to 6, 4 to 6, 3 to 8, 3 to 10, 6 to 10, or 7 to 11 ring atoms; in one embodiment, the heterocyclic group comprises 3 to 8 (e.g., 3, 4, 5, 6, 7, 8) ring atoms. Non-limiting examples of monocyclic heterocyclic groups include tetrahydropyrrole, azahexacyclic butyl, oxacyclobutyl, oxacyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrole, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl. Polycyclic heterocyclic groups include spiroheterocyclic, fused heterocyclic, and bridged heterocyclic groups. In one embodiment, the heterocyclic group is optionally substituted as described elsewhere herein, or is a heterocyclic group further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

[0267] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group in which one or more ring atoms share a single atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, the spiroheterocyclic group comprises 5 to 20 or 6 to 14 ring atoms; in one embodiment, it comprises 7 to 11 (e.g., 7, 8, 9, 10, 11) ring atoms; spiroheterocyclic groups are classified as monospirocyclic, bispirocyclic, or multispirocyclic groups according to the number of spiro atoms shared between the rings; monospirocyclic and bispirocyclic groups are preferred; in one embodiment, the spiroheterocyclic group is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic group; in one embodiment, the spiroheterocyclic group is an optionally substituted spiroheterocyclic group described elsewhere herein; non-limiting examples of spiroheterocyclic groups include:

[0268] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in a system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. In a particular embodiment, the fused heterocyclic group comprises 5 to 20 or 6 to 14 ring atoms, and in one embodiment comprises 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups depending on the number of constituent rings; bicyclic or tricyclic is preferred; in one embodiment, it is a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group; in one embodiment, the fused heterocyclic group is optionally substituted as described elsewhere herein, or a fused heterocyclic group that can be fused with cycloalkyl, heterocyclic, aryl, or heteroaryl groups; non-limiting examples of fused heterocyclic groups include:

[0269] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. In certain embodiments, the bridged heterocyclic group comprises 5 to 20 or 6 to 14 ring atoms; in one embodiment, it comprises 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group; preferably bicyclic, tricyclic, or tetracyclic; in one embodiment, it is bicyclic or tricyclic; in one embodiment, the bridged heterocyclic group is an optionally substituted bridged heterocyclic group described elsewhere herein; non-limiting examples of bridged heterocyclic groups include:

[0270] The term "subheterocyclic group" refers to a heterocyclic group in which one hydrogen atom is further substituted, and the definition of "heterocyclic group" is as described above.

[0271] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group containing at least one conjugated π-electron system, which may optionally be substituted by one or more substituents. In certain embodiments, the aryl group comprises 6 to 20, 6 to 14, or 6 to 10 ring atoms; in one embodiment, the aryl group may further refer to a bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring is an aromatic ring, and the other rings may be saturated, partially unsaturated carbon rings, or rings containing one or more heteroatoms independently selected from O, S, and N. In one embodiment, the aryl group is selected from benzo5-10-membered heteroaryl, benzo3-10-membered cycloalkyl, or benzo3-10-membered heterocyclic groups. In one embodiment, the aryl group is selected from benzo5-6-membered heteroaryl, benzo3-6 (e.g., 5-6)-membered cycloalkyl, or benzo3-6 (e.g., 5-6)-membered heterocyclic groups, wherein the heterocyclic group is a heterocyclic group containing 1 to 3 nitrogen, oxygen, or sulfur atoms. Non-limiting examples include phenyl, naphthyl, fluorenyl, chamomilecycloyl, anthraceneyl, phenanthryl, pyrene, biphenyl, terphenyl, dihydronaphthyl, indene, tetrahydronaphthyl (naphthyl),

[0272] The term "arylene" refers to a divalent aryl group formed by further substitution of one hydrogen atom of an aryl group, wherein the arylene group may be optionally substituted or unsubstituted, as defined above for aryl groups.

[0273] The term "heteroaryl" refers to an optionally substituted monocyclic, polycyclic group or ring system comprising at least one aromatic ring having one or more heteroatoms independently selected from O, S, and N. In certain embodiments, the heteroaryl comprises 5 to 20, 5 to 15, or 5 to 10 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heteroaryl comprises 5 or 6 ring atoms; in certain embodiments, the heteroaryl may further refer to a bicyclic, tricyclic, or tetracyclic ring, wherein at least one ring is an aromatic ring having one or more heteroatoms independently selected from O, S, and N, and the other rings may be saturated, partially unsaturated carbocyclic rings, or rings comprising one or more heteroatoms independently selected from O, S, and N. In one embodiment, the heteroaryl group is selected from heteroaryl-6-10 aryl, heteroaryl-3-10 cycloalkyl, or heteroaryl-3-10 heterocyclic group; in a further embodiment, the heteroaryl group is selected from 5- or 6-membered heteroaryl-6-10 aryl, 5- or 6-membered heteroaryl-3-6 cycloalkyl, or 5- or 6-membered heteroaryl-3-6 heterocyclic group, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting examples include: furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrroloyl, thiadiazolyl, thiazolyl, thiophene, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benziisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiaphenyl, benzobenzenethio, benzothiaphenyl, benzotriazolyl, imidazopyridyl, imidazothiazolyl Indazinyl, indolyl, inzolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolinyl, naphridinyl, oxazolopyridyl, phthalazinyl, pteridinyl, purine, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxolinyl, quinazolinyl, thiadiazopyrimidinyl, thienenopyridyl, acridineyl, benzoindolyl, carbazole, biphenylfuranyl, phenanthrololinyl, phenanthidyl, phenpyrazinyl, phenazinyl, phenthiazinyl, phenoxazinyl, xanthonyl,

[0274] The term "heteroaryl" refers to a divalent heteroaryl group formed by further substitution of one hydrogen atom of a cycloalkyl group, wherein the heteroaryl group may be optionally substituted or unsubstituted, as defined above.

[0275] The term "heteroalkyl" refers to a stable straight-chain or branched, or cyclic, hydrocarbon group, or a combination thereof, consisting of the indicated number of carbon atoms and one or more (one to three in one embodiment) heteroatoms selected from O, N, Si, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom may optionally be quaternized. In one embodiment, the heteroatoms O, N, and S may be placed at any internal position within the heteroalkyl group. In one embodiment, the heteroatom Si may be placed at any position within the heteroalkyl group (e.g., internal or terminal positions), including positions where the alkyl group is attached to the remainder of the molecule. Non-limiting examples include: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. At most two heteroatoms can be consecutive, for example, -CH2-NH-O-CH3 and -CH2-O-Si(CH3)3. In certain embodiments, the heteroalkyl group is an optionally substituted heteroalkyl group described elsewhere herein.

[0276] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein the definition of alkyl or cycloalkyl is as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexyloxy. In one embodiment, the alkoxy group is an optionally substituted alkoxy group as described elsewhere herein.

[0277] The term "alkylacyl" refers to -C(O)-alkyl, where the definition of alkyl is as described above.

[0278] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein the definition of alkyl is as described above. Non-limiting examples of said haloalkyl groups include: trifluoromethyl, -CH2CF3, The term “haloalkoxy” refers to an alkoxy group that has been substituted with one or more halogens, where the definition of an alkoxy group is as described above.

[0279] The term "hydroxyalkyl" refers to an alkyl group that has been substituted with a hydroxyl group, where the definition of alkyl is as described above.

[0280] The term "alkathio" refers to -S- (alkyl) and -S- (unsubstituted cycloalkyl), wherein the definition of alkyl or cycloalkyl is as described above. Non-limiting examples of alkathio groups include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, or cyclohexylthio. In one embodiment, the alkathio group is an optionally substituted alkathio group described elsewhere herein.

[0281] The term "haloalkylthio" refers to an alkylthio group substituted with one or more halogens, wherein the definition of alkylthio is as described above.

[0282] The term "alkenyl carbonyl" refers to -C(O)-(alkenyl), where alkenyl is defined as previously stated. Non-limiting examples of alkenyl carbonyl include vinyl carbonyl, propenyl carbonyl, or butenyl carbonyl. In one embodiment, the alkenyl carbonyl is an optionally substituted alkenyl carbonyl as described elsewhere herein.

[0283] The term "aminocarbonyl" refers to NH2-C(O)-.

[0284] The term "alkylaminocarbonyl" refers to an aminocarbonyl group (NH2-C(O)-) in which one or both hydrogen atoms are replaced by an alkyl group, wherein the definition of alkyl is as described above.

[0285] The term "alkylamino" refers to an amino group in which one or both of the two hydrogen atoms are replaced by an alkyl group, as defined above.

[0286] The term "carbonyl" refers to the -C(O)-, -(CO)-, or -C(=O)- group. All designations are interchangeable in the specification.

[0287] The term "hydroxyl group" refers to the -OH group.

[0288] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0289] The term "amino" refers to -NH2.

[0290] The term "cyano" refers to -CN.

[0291] The term "nitro" refers to -NO2.

[0292] The term "carboxyl group" refers to -C(O)OH.

[0293] The term "acetyl" refers to -C(O)CH3.

[0294] The term "oxo" or "side oxygen" refers to =O.

[0295] The term "thiol" refers to -SH.

[0296] The term "hydrogen" includes protons ( 1 H), deuterium ( 2H), tritium ( 3 H) and / or mixtures thereof. In certain embodiments, one or more hydrogen-occupied sites in the compound may be enriched with deuterium and / or tritium. Such isotope-enriched analogs may be prepared from suitable isotopically labeled starting materials available from commercial sources or by known literature procedures, wherein the hydrogen or hydrogen atom described in this patent comprises its isotopes (H) and / or mixtures thereof. 1 H), deuterium ( 2 H), tritium ( 3 H) and / or mixtures thereof.

[0297] This invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms with different atomic weights or mass numbers. Examples of isotopes that can be included in the compounds of this invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, respectively as follows: 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Isotope-labeled compounds can be prepared using a general method, by replacing the non-isotope reagent with an readily available isotope-labeling reagent, as described in the examples.

[0298] The alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, arylene, heteroaryl, heteroarylene, heteroalkyl, alkoxy, alkylthio, hydroxyalkyl, alkenylcarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylamino, and alkylacyl groups may be substituted or unsubstituted. In one embodiment, the substituent is selected from one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, alkylacyl, halogen, mercapto, hydroxyl, nitro, cyano, azide, oxime, phosphate ester, oxo, thio, carboxyl, carboxylic acid ester, cycloalkyl, heterocyclic, aryl, heteroaryl, heterocycloalkoxy, cycloalkylthio, or heterocycloalkylthio.

[0299] In this invention, unless otherwise specified, the term "substituted or unsubstituted" indicates that the modified substituent may optionally be further substituted by one or more of the following substituents, selected from alkyl, deuteralkyl, haloalkyl, alkenyl, alkoxy, alkylthio, alkylamino, alkylacyl, halogen, mercapto, hydroxyl, nitro, cyano, azide, oxime, phosphate ester, oxo, thio, carboxyl, carboxylic acid ester, cycloalkyl, heterocyclic, aryl, heteroaryl, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, -(CH2) n -、-(CH2) n R aa -(CH2) n OR bb -O(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R bb -(CH2) n C(O)NR aa R bb -(CH2) n NR bb C(O)R cc -(CH2) n NR bb S(O) m R cc -OC(R) aa R bb ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NRbb C(O)NR aa R bb =N-OR bb or = CR aa R cc Preferred groups include deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 quinone heteroaryl, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, S(O)2C 1-6 Alkyl, COC 1-6 Alkyl, CONHC 1-6 Alkyl, CON(C) 1-6 Alkyl)2, SO2NHC 1-6 Alkyl, SO2N(C) 1-6 Alkyl)2, etc.

[0300] The different terms such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" all express the same meaning, that is, X can be any one or more of A, B, and C.

[0301] Unless otherwise specified, when a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-, and -CONH- is equivalent to -NHCO-.

[0302] In this application The symbol indicates the connection position of the group. Bonds extending into the ring. This refers to a connection at any available ring vertex, such as a group. Middle, key It can be connected to any connectable position of the parallel ring, and its substituent R c and / or R d It can replace any hydrogen atom on the ring, including any hydrogen atom on the carbon atom and any hydrogen atom on the nitrogen atom.

[0303] In some embodiments of the present invention, This represents a ring system in which rings C, D, and E are paired and fused, for example...

[0304] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0305] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0306] "Substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, provided that the valence state of the particular atom is normal and the substituted compound is stable in one embodiment and in another. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents can be arbitrary on a chemically feasible basis. It goes without saying that substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0307] Unless otherwise stated, the indefinite articles “a” and “an” and the definite article “the” in this specification and claims include both plural and singular forms.

[0308] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0309] "Medicinal salts" refer to the salts of the compounds of this invention, which are safe and effective when used in mammals and have the appropriate biological activity.

[0310] "Stereoisomers" encompass all enantiomers / non-corresponding isomers / stereoisomers of the present invention, as well as enantiomers / non-corresponding isomers / stereoisomers enriched in this invention.

[0311] "Stereoisopure" refers to a composition containing one stereoisomer of a compound but substantially lacking another stereoisomer of that compound. For example, a stereoisopure composition of a compound having one chiral center will substantially lack the opposing enantiomer of that compound. A stereoisopure composition of a compound having two chiral centers will substantially lack other diastereomers of that compound. A typical stereoisomeric pure compound comprises, by mass, more than about 80% of one stereoisomer of the compound and less than about 20% of another stereoisomer of the compound; more than about 90% of one stereoisomer of the compound and less than about 10% of another stereoisomer of the compound; more than about 95% of one stereoisomer of the compound and less than about 5% of another stereoisomer of the compound; more than about 97% of one stereoisomer of the compound and less than about 3% of another stereoisomer of the compound; or more than about 99% of one stereoisomer of the compound and less than about 1% of another stereoisomer of the compound.

[0312] "Stereoisomeric enrichment" refers to a composition containing a stereoisomer of a compound at a mass content greater than about 55%, about 60%, about 70%, or about 80%.

[0313] "Enantiomerically pure" refers to a stereoisomerically pure composition of a compound having a single chiral center. Similarly, the term "enantiomerically enriched" refers to a stereoisomerically enriched composition of a compound having a single chiral center.

[0314] "Optical activity" and "enantiomeric activity" refer to a molecular combination having an enantiomer excess of not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In a particular embodiment, the compound comprises about 95% or more of the desired enantiomer or diastereomer by weight of the racemic compound and about 5% or less of the subpreferred enantiomer or diastereomer.

[0315] In describing optically active compounds, the prefixes R and S are used to indicate the absolute configuration of the molecule relative to its chiral center. (+) and (-) are used to indicate the optical rotation of the compound, i.e., the direction of the plane of polarized light rotated by the optically active compound. The prefix (-) indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right or clockwise. However, the signs (+) and (-) for optical rotation are independent of the absolute configuration R and S of the molecule.

[0316] The compounds of this invention include all of their "stereoisomers", "stereoisomeric purity", "stereoisomeric enrichment", "enantiomeric purity", "optical activity", "enantiomeric activity" and "optical isomers". Detailed Implementation

[0317] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0318] Example

[0319] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0320] LC-MS analysis was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC analysis was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C). 18 (150×4.6mm chromatographic column).

[0321] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15mm to 0.20mm, while the standard size for separating and purifying products using TLC is 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0322] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0323] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius.

[0324] Example

[0325] Preparation of tert-butyl 6-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-carbonyl-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-carbonylisodihydroindole-5-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester (compound A-1)

[0326] Step 1: Preparation of methyl 5-bromo-2-(bromomethyl)-3-fluorobenzoate

[0327] Methyl 5-bromo-3-fluoro-2-methylbenzoate (5.5 g, 22.26 mmol) was dissolved in trifluorotoluene (50 mL), and N-bromosuccinimide (3.96 g, 22.26 mmol) and azobisisobutyronitrile (548 mg, 3.34 mmol) were added. The mixture was heated and stirred at 110 °C for 2 h. The reaction solution was diluted with ethyl acetate, washed successively with saturated sodium carbonate aqueous solution and saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by column chromatography to give the title compound (4.7 g, 65%). MS m / z (ESI): 326.9 [M+H] +

[0328] Step 2: Preparation of tert-butyl(2S)-2-(3-ethoxy-3-oxo-propionyl)pyrrolidine-1-carboxylic acid ester

[0329] Under ice bath cooling, Boc-L-proline (72 g, 334.50 mmol), Miescherichia coli (48.21 g, 334.50 mmol), and 4-dimethylaminopyridine (61.30 g, 501.75 mmol) were dissolved in dichloromethane (1 L), and N,N'-dicyclohexylcarbodiimide (69.02 g, 334.50 mmol) was slowly added. The mixture was stirred at room temperature for 48 h. The pH was adjusted to neutral with dilute hydrochloric acid, and the insoluble solids were removed by filtration. The filtrate was washed with saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in ethanol (500 mL), and the mixture was heated under reflux with stirring for 4 h. The solvent was removed under reduced pressure, and the residue was separated by column chromatography to give the title compound (71 g, overall yield of 74%). MS m / z (ESI): 286.2 [M+H] + .

[0330] Step 3: Preparation of ethyl 2-(3-thio-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl)

[0331] 36 g (126.17 mmol) of tert-butyl(2S)-2-(3-ethoxy-3-carbonyl-propionyl)pyrrolidine-1-carboxylic acid ester was dissolved in a mixture of dichloromethane (100 mL) and 4M HCl dioxane solution (100 mL). The mixture was heated and stirred at 45 °C for 1 h. The solvent was removed under reduced pressure. The residue was dissolved in ethanol (300 mL), and KSCN (25.54 g, 252.33 mmol) was added. The mixture was heated and stirred at 90 °C for 2 h. The solvent was removed by concentration under reduced pressure. The residue was slurried through methyl tert-butyl ether, filtered, and dried under reduced pressure to give the title compound (27 g, 95%). MS m / z (ESI): 227.1 [M+H] +

[0332] Step 4: Preparation of ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)

[0333] Under ice bath cooling, ethyl 2-(3-thio-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl) (27 g, 119.31 mmol) was dissolved in acetic acid (200 mL), and hydrogen peroxide solution (30 mL) was slowly added dropwise. After the addition was complete, the mixture was heated to room temperature and stirred for 1 h. The reaction was quenched by adding saturated sodium sulfite solution. The pH was adjusted to neutral by adding sodium hydroxide solution under ice bath cooling. The reaction solution was diluted with ethyl acetate, washed with saturated brine, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by column chromatography to give the title compound (18 g, 78%). MS m / z (ESI): 195.1 [M+H] +

[0334] Step 5: Preparation of ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(oxime)

[0335] Under ice bath cooling, ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (9 g, 46.34 mmol) was dissolved in ethanol (80 mL), sodium ethoxide (6.31 g, 92.67 mmol) was added, and amyl nitrite (10.86 g, 92.67 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 4 h, and then amyl nitrite (10.86 g, 92.67 mmol) was added again, and the mixture was stirred at room temperature for 12 h. The pH was adjusted to 6-7 with 4 M dioxane hydrochloride solution, and the insoluble solids were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to obtain the title compound (5.7 g, 55%). MS m / z (ESI): 224.1 [M+H] + .

[0336] Step 6: Preparation of ethyl 2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)

[0337] Ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(oxime)acetate (5.7 g, 25.53 mmol) was dissolved in ethanol (50 mL), and 10% Pd / C (5.43 g) was added. The mixture was purged with hydrogen three times and stirred at 50 °C for 12 h. After cooling to room temperature, the insoluble solids were removed by filtration, and the solvent was removed from the filtrate under reduced pressure to give the title compound (3.8 g, 71%), which was used directly in the next step. MS m / z (ESI): 210.1 [M+H] + .

[0338] Step 7: Preparation of ethyl acetate 2-(6-bromo-4-fluoro-1-carbonylisodihydroindole-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)

[0339] At room temperature, ethyl 2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl) and methyl 5-bromo-2-(bromomethyl)-3-fluorobenzoate (5.92 g, 18.16 mmol) were dissolved in N,N-dimethylformamide (50 mL), and N,N-diisopropylethylamine (7.04 g, 54.48 mmol, 9.49 mL) was added. The mixture was stirred at room temperature for 12 h. The reaction solution was diluted with ethyl acetate, washed successively with saturated aqueous sodium carbonate solution and saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by column chromatography to give the title compound (3.44 g, 45%). MS m / z (ESI): 422.0 [M+H] +

[0340] Step 8: Preparation of tert-butyl-6-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester

[0341] tert-Butyl-2,6-diazaspiro[3,3]heptane-2-carboxylic acid oxalate (6.3 g, 21.85 mmol), (4-bromophenyl)boronic acid (5.27 g, 26.22 mmol), and copper acetate (5.95 g, 32.78 mmol) were added to 100 mL of dry dichloromethane. 10 g of 4A molecular sieve was added, and the reaction mixture was replaced with dry oxygen. Triethylamine (22.11 g, 218.53 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The final product (5.6 g, 73%) was obtained by silica gel column chromatography. MS m / z (ESI): 353.1 [M+H] + .

[0342] Step 9: Preparation of tert-butyl-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester

[0343] tert-Butyl-6-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester (28.6 g, 80.96 mmol), pinacol diboronate (26.73 g, 105.25 mmol), Pd(dppf)Cl2 (5.92 g, 8.10 mmol), and potassium acetate (23.84 g, 242.89 mmol) were added to dioxane (500 mL). The reaction system was purged with dry nitrogen, transferred to 80 °C, stirred for 12 hours, cooled to room temperature, filtered through diatomaceous earth, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the title compound (19.3 g, 60%). MS m / z (ESI): 401.3 [M+H] + .

[0344] Step 10: Preparation of tert-butyl 6-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy-2-carbonylethyl)-7-fluoro-3-carbonylisodihydroindole-5-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester

[0345] Under nitrogen protection, ethyl acetate (10 g, 21 mmol) of 2-(6-bromo-4-fluoro-1-carbonylisodihydroindol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl) and tert-butyl-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester (12.6 g, 31.5 mmol) were dissolved in dioxane (200 mL), Pd(dppf)Cl2 (1.54 g, 2.10 mmol) and tBu-XPhos (1.78 g, 4.20 mmol) were added, and the mixture was stirred until homogeneous. Then, a solution of sodium carbonate (6.68 g, 63 mmol) in water (50 mL) was added, and the mixture was stirred at 80 °C for 4 h. The mixture was cooled to room temperature, concentrated under reduced pressure to remove most of the solvent, and the residue was extracted three times with ethyl acetate. The combined ethyl acetate phases were washed with saturated brine, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated by column chromatography to give the title compound (7.2 g, 56%). MS m / z (ESI): 616.3 [M+H] + .

[0346] Step 11: Preparation of tert-butyl 6-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-carbonyl-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-carbonylisodihydroindole-5-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester

[0347] 7.2 g (11.68 mmol) of tert-butyl 6-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy-2-carbonylethyl)-7-fluoro-3-carbonylisodihydroindol-5-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester was dissolved in tetrahydrofuran (60 mL), and a solution of lithium hydroxide (560 mg, 23.36 mmol) in water (20 mL) was added. The mixture was stirred at room temperature for 4 h, and the organic solvent was removed by concentration under reduced pressure. The remaining aqueous solution was then freeze-dried. The freeze-dried product was dissolved in dry N,N-dimethylformamide (50 mL), and 2-aminothiazole (2.34 g, 23.36 mmol) and N,N-diisopropylethylamine (239.30 mg, 1.85 mmol, 322.51 μL) were added. HATU (349.27 mg, 925.79 μmol) was added under ice-water bath cooling, and the mixture was transferred to room temperature and stirred for 30 minutes. The reaction solution was diluted with ethyl acetate, washed with saturated brine, and the organic phase was separated. The solution was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by column chromatography to give the title compound (6.4 g, overall yield of 82%). MS m / z (ESI): 670.3 [M+H] + .

[0348] Step 12: Preparation of the synthesis of 2-(6-(4-(2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-4-fluoro-1-carbonylisodihydroindole-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide (compound A-1).

[0349] 6.4 g (9.55 mmol) of tert-butyl-6-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-carbonyl-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-carbonylisodihydroindol-5-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester was dissolved in dichloromethane (20 mL), cooled to 0 °C in an ice-water bath, and then trifluoroacetic acid (20 mL) was added. The mixture was then transferred to room temperature and stirred for 1 hour. The solvent was removed by concentration under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with ice-cold saturated sodium bicarbonate solution and saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (4.9 g, 90%). MS m / z (ESI): 570.2 [M+H] + .

[0350] Synthesis of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-carbonyl-6-(4-piperazin-1-ylphenyl)isodihydroindol-2-yl]-N-thiazolyl-2-ylacetamide (compound A-2)

[0351] Step 1: Preparation of tert-butyl 4-[4-[2-[1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy-2-carbonyl-ethyl]-7-fluoro-3-carbonyl-isodihydroindole-5-yl]phenyl]piperazine-1-carboxylic acid ester

[0352] Under nitrogen protection, ethyl 2-(6-bromo-4-fluoro-1-carbonyl-isodihydroindole-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl) acetate (10 g, 23.68 mmol) and tert-butyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)phenyl]piperazine-1-carboxylic acid ester (13.79 g, 35.52 mmol) were prepared. Pd(dppf)Cl2 (1.73 g, 2.37 mmol) was added to dioxane (120 mL), followed by a 20 mL solution of sodium carbonate (7.53 g, 71.05 mmol) in water. The resulting reaction mixture was purged with nitrogen, transferred to 80 °C, and stirred for 6 hours. After cooling to room temperature, the solvent was removed by concentration under reduced pressure. The residue was separated by column chromatography to obtain the title compound (14.2 g, 99%). MS m / z (ESI): 604.3 [M+H] + .

[0353] Step 2: Preparation of lithium 2-[6-[4-(4-tert-butoxycarbonylpiperazin-1-yl)phenyl]-4-fluoro-1-carbonyl-isodihydroindole-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate

[0354] 14.2 g (23.52 mmol) of tert-butyl-4-[4-[2-[1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy-2-carbonyl-ethyl]-7-fluoro-3-carbonyl-isodihydroindol-5-yl]phenyl]piperazine-1-carboxylic acid ester was dissolved in tetrahydrofuran (210 mL), and a solution of lithium hydroxide (1.13 g, 47.04 mmol) in water (70 mL) was added. The resulting reaction mixture was stirred at room temperature for 8 hours, concentrated under reduced pressure to remove the organic solvent, and the residue was freeze-dried to obtain the crude lithium salt of the title compound, which was directly used in the next reaction. MS m / z (ESI): 576.3 [M+H] +.

[0355] Step 3: Preparation of tert-butyl 4-[4-[2-[1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-carbonyl-2-(thiazol-2-ylamino)ethyl]-7-fluoro-3-carbonyl-isodihydroindole-5-yl]phenyl]piperazine-1-carboxylic acid ester

[0356] 2-[6-[4-(4-tert-butoxycarbonylpiperazin-1-yl)phenyl]-4-fluoro-1-carbonyl-isodihydroindol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (13.54 g, 23.52 mmol) was dissolved in N,N-dimethylformamide (50 mL), followed by the addition of thiazol-2-amine (4.71 g, 47.04 mmol) and N,N-dimethylformamide. -Diisopropylethylamine (6.08 g, 47.04 mmol), the reaction solution was cooled to 0 °C, HATU (17.89 g, 47.04 mmol) was added, the mixture was transferred to room temperature and stirred for 30 min, the reaction solution was diluted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography to give the title compound (7.4 g, 11.25 mmol, overall yield of 48%). MS m / z (ESI): 658.3 [M+H] + .

[0357] Step 4: Synthesis of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-carbonyl-6-(4-piperazin-1-ylphenyl)isodihydroindol-2-yl]-N-thiazolyl-2-ylacetamide (compound A-2)

[0358] 7.4 g (11.25 mmol) of tert-butyl-4-[4-[2-[1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-carbonyl-2-(thiazol-2-ylamino)ethyl]-7-fluoro-3-carbonyl-isodihydroindol-5-yl]phenyl]piperazine-1-carboxylic acid ester was dispersed in 10 mL of dichloromethane. 100 mL of 4 M HCl dioxane solution was added with stirring, and the reaction was continued at room temperature for 1 hour. The solvent was removed by concentration under reduced pressure. The residue was dispersed in ethyl acetate, washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (5.6 g, 90%). MS m / z (ESI): 558.2 [M+H] + .

[0359] Preparation of 2-(6-bromo-4-fluoro-1-carbonyl-isodihydroindol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-pyridyl)acetamide (compound A-3)

[0360] Ethyl 2-(6-bromo-4-fluoro-1-carbonyl-isodihydroindol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (3.8 g, 9.00 mmol) was dissolved in tetrahydrofuran (30 mL), and an aqueous solution of lithium hydroxide (431 mg, 18.00 mmol) (10 mL) was added. The resulting reaction mixture was stirred at room temperature for 1 hour. The organic solvent was removed by concentration under reduced pressure, and the residue was freeze-dried to obtain the crude product.

[0361] Under dry nitrogen protection, the crude product from the previous step and pyridine-2-amine (1.70 g, 18.00 mmol) were dispersed in dry acetonitrile (30 mL). N-methylimidazole (738 mg, 9.00 mmol) and diisopropylethylamine (3.49 g, 27.00 mmol) were added sequentially, and the mixture was stirred until homogeneous. The mixture was cooled to 0°C in an ice-water bath. After removing the ice-water bath, N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (5.05 g, 18.00 mmol) was added, and stirring was continued for 1 hour. The organic solvent was removed by vacuum concentration. The residue was dissolved in ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography to obtain the title compound (4.02 g, 95% overall yield). MS m / z (ESI): 470.1 [M+H] + .

[0362] Preparation of (S)-2-(1-(4-(2,6-dicarbonylpiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-4-hydroxypiperidin-4-yl)acetic acid (compound B-1) and (R)-2-(1-(4-(2,6-dicarbonylpiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-4-hydroxypiperidin-4-yl)acetic acid (compound B-2)

[0363] Step 1: Preparation of benzyl 8-bromo-2,3-dihydro-1,4-benzoxazine-4-carboxylic acid ester

[0364] 8-Bromo-3,4-dihydro-2H-1,4-benzoxazine (10 g, 46.72 mmol) was dissolved in dichloromethane (100 mL) and cooled to 0 °C. Then, 4-dimethylaminopyridine (571 mg, 4.67 mmol), N,N-diisopropylethylamine (18.11 g, 140.15 mmol), and benzyl chloroformate (15.94 g, 93.43 mmol) were added sequentially. The mixture was transferred to room temperature and stirred for 12 hours. The solvent was removed by concentration under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate and sodium chloride solutions, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography to give the title compound (16 g, 98%). MS m / z (ESI): 348.1 [M+H] + .

[0365] Step 2: Preparation of benzyl 8-[4-(2-tert-butoxy-2-carbonyl-ethyl)-4-hydroxy-1-piperidinyl]-2,3-dihydro-1,4-benzoxazine-4-carboxylic acid ester

[0366] Benzyl 8-bromo-2,3-dihydro-1,4-benzoxazine-4-carboxylic acid ester (3.48 g, 9.99 mmol), tert-butyl-2-(4-hydroxy-4-piperidinyl)acetate (2.80 g, 12.99 mmol), Pd2(dba)3 (457.61 mg, 499.73 μmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (932.77 mg, 2.00 mmol), and cesium carbonate (9.77 g, 29.98 mmol) were added to toluene (50 mL). The reaction mixture was purged three times with dry nitrogen, and the mixture was stirred at 80 °C for 12 hours. After cooling to room temperature, the solvent was removed by concentration under reduced pressure. The residue was separated by silica gel column chromatography to obtain the title compound (4.38 g, 91%). MS m / z (ESI): 483.2 [M+H] + .

[0367] Step 3: Preparation of tert-butyl 2-[1-(3,4-dihydro-2H-1,4-benzoxazin-8-yl)-4-hydroxy-4-piperidinyl]acetate

[0368] 4.38 g (9.08 mmol) of benzyl 7-[4-(2-tert-butoxy-2-carbonyl-ethyl)-4-hydroxy-1-piperidinyl]-2,3-dihydro-1,4-benzoxazine-4-carboxylic acid ester was dispersed in methanol (100 mL). 10% palladium / carbon (300 mg) and palladium hydroxide / carbon (300 mg) were added. The reaction system was purged with hydrogen, heated to 40 °C, and stirred for 3 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the title compound (3 g, 95%). MS m / z (ESI): 349.2 [M+H] + .

[0369] Step 4: Preparation of tert-butyl(S)-2-(1-(4-(2,6-dicarbonylpiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-4-hydroxypiperidin-4-yl)acetate and tert-butyl(R)-2-(1-(4-(2,6-dicarbonylpiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-4-hydroxypiperidin-4-yl)acetate

[0370] tert-Butyl 2-[1-(3,4-dihydro-2H-1,4-benzoxazin-8-yl)-4-hydroxy-4-piperidinyl]acetate (3 g, 8.59 mmol) was dissolved in acetonitrile (30 mL), and 3-bromopiperidin-2,6-dione (4.35 g, 22.67 mmol), sodium bicarbonate (2.67 g, 31.74 mmol), and tetrabutylammonium iodide (335 mg, 906.91 μmol) were added sequentially. The mixture was heated to 85 °C and stirred for 72 hours under nitrogen protection. Cool to room temperature, dilute with ethyl acetate, wash with saturated ammonium chloride solution and saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate, and separate the residue by column chromatography to obtain tert-butyl 2-[1-[4-(2,6-dicarbonyl-3-piperidinyl)-2,3-dihydro-1,4-benzoxazin-8-yl]-4-hydroxy-4-piperidinyl]acetate (2.44 g, 62%), which is then chirally resolved to give tert-butyl(S)-2-(1 -(4-(2,6-dicarbonylpiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-4-hydroxypiperidin-4-yl)acetate (1.10 g) and tert-butyl(R)-2-(1-(4-(2,6-dicarbonylpiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-4-hydroxypiperidin-4-yl)acetate (1.05 g). MS m / z (ESI): 460.2 [M+H] + (Both enantiomers are identical)

[0371] Step 5: Synthesis of (S)-2-(1-(4-(2,6-dicarbonylpiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-4-hydroxypiperidin-4-yl)acetic acid (compound B-1)

[0372] 1.10 g (2.39 mmol) of tert-butyl(S)-2-(1-(4-(2,6-dicarbonylpiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-4-hydroxypiperidin-4-yl)acetate was dissolved in 10 mL of dichloromethane, cooled to 0 °C in an ice-water bath, and 10 mL of 4 M HCl dioxane solution was added. The mixture was then transferred to room temperature and stirred for 8 hours. The solvent was removed by concentration under reduced pressure to obtain the title compound (946 mg, 98%). MS m / z (ESI): 404.2 [M+H] + .

[0373] Step 6: Synthesis of (R)-2-(1-(4-(2,6-dicarbonylpiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-4-hydroxypiperidin-4-yl)acetic acid (compound B-2)

[0374] 1.05 g (2.28 mmol) of tert-butyl(S)-2-(1-(4-(2,6-dicarbonylpiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-4-hydroxypiperidin-4-yl)acetate was dissolved in 10 mL of dichloromethane, cooled to 0 °C in an ice-water bath, and 10 mL of 4 M HCl dioxane solution was added. The mixture was then transferred to room temperature and stirred for 8 hours. The solvent was removed by concentration under reduced pressure to give the title compound (893 mg, 98%). MS m / z (ESI): 404.2 [M+H] + .

[0375] Synthesis of (S)-2-(1-(1-(2,6-dicarbonylpiperidin-3-yl)dihydroindole-4-yl)-4-hydroxypiperidin-4-yl)acetic acid (compound B-3) and (R)-2-(1-(1-(2,6-dicarbonylpiperidin-3-yl)dihydroindole-4-yl)-4-hydroxypiperidin-4-yl)acetic acid (compound B-4)

[0376] Step 1: Preparation of benzyl 4-bromodihydroindole-1-carboxylic acid ester

[0377] 4-Bromodihydroindole (65 g, 328.18 mmol) and sodium carbonate (86.96 g, 820.46 mmol) were dissolved in water (1 L) and tetrahydrofuran (600 mL). Benzyl chloroformate (67.18 g, 393.82 mmol, 55.4 mL) was slowly added dropwise with stirring. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was extracted with ethyl acetate (500 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (1 L), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was added to 250 mL of petroleum ether and stirred. The residue was filtered, the solid was collected, concentrated under reduced pressure, and dried to give the title compound (98.9 g, 91%). MS m / z (ESI): 332.1 [M+H] +

[0378] Step 2: Preparation of benzyl 4-(4-(2-(tert-butoxy)-2-carbonylethyl)-4-hydroxypiperidin-1-yl)dihydroindole-1-carboxylic acid ester

[0379] Benzyl 4-bromodihydroindole-1-carboxylic acid ester (2 g, 6.02 mmol) and tert-butyl-2-(4-hydroxypiperidin-4-yl)acetate (1.62 g, 7.53 mmol) were dissolved in toluene (40 mL), and tris(dibenzylacetone)dipalladium (276 mg, 301.03 μmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (281 mg, 602.06 μmol), and cesium carbonate (3.92 g, 12.04 mmol) were added. The mixture was evacuated and purged with nitrogen, and this process was repeated three times. The reaction mixture was heated to 110 °C and stirred for 16 hours under a nitrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the title compound (2.56 g, 91%). MS m / z (ESI): 467.2 [M+H] + .

[0380] Step 3: Preparation of tert-butyl-2-(4-hydroxy-1-(dihydroindol-4-yl)piperidin-4-yl)acetate

[0381] Benzyl 4-(4-(2-(tert-butoxy)-2-carbonylethyl)-4-hydroxypiperidin-1-yl)dihydroindole-1-carboxylic acid ester (2.56 g, 5.49 mmol) was dissolved in methanol (50 mL) and tetrahydrofuran (50 mL), and palladium on carbon (292 mg, 274.34 μmol, 10% purity) and palladium hydroxide (385 mg, 274.34 μmol, 10% purity) were added. The mixture was evacuated and purged with hydrogen, and this process was repeated three times. The reaction solution was stirred in a hydrogen atmosphere (15 psi) for 16 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the title compound (1.8 g, 99%). MS m / z (ESI): 333.2 [M+H] + .

[0382] Step 4: Preparation of tert-butyl(S)-2-(1-(1-(2,6-dicarbonylpiperidin-3-yl)dihydroindole-4-yl)-4-hydroxypiperidin-4-yl)acetate and tert-butyl(R)-2-(1-(1-(2,6-dicarbonylpiperidin-3-yl)dihydroindole-4-yl)-4-hydroxypiperidin-4-yl)acetate

[0383] 1.8 g (5.41 mmol) of tert-butyl 2-(4-hydroxy-1-(dihydroindol-4-yl)piperidin-4-yl)acetate and 3-bromopiperidin-2,6-dione (3.12 g (16.24 mmol)) were dissolved in N,N-dimethylformamide (40 mL), and sodium bicarbonate (3.27 g (27.07 mmol) was added. The reaction mixture was heated to 65 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, poured into water (400 mL), and extracted with dichloromethane (100 mL × 2). The organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the title compound tert-butyl 2-(1-(1-(2,6-dicarbonylpiperidin-3-yl)dihydroindol-4-yl)acetate. The ester (2.35 g, 98%) was chirally resolved to yield tert-butyl(S)-2-(1-(1-(2,6-dicarbonylpiperidin-3-yl)dihydroindol-4-yl)-4-hydroxypiperidin-4-yl)acetate (1.1 g) and tert-butyl(R)-2-(1-(1-(2,6-dicarbonylpiperidin-3-yl)dihydroindol-4-yl)-4-hydroxypiperidin-4-yl)acetate (0.98 g). MS m / z (ESI): 444.2 [M+H] + .

[0384] Step 5: Preparation of (S)-2-(1-(1-(2,6-dicarbonylpiperidin-3-yl)dihydroindol-4-yl)-4-hydroxypiperidin-4-yl)acetic acid (compound B-3)

[0385] (S)-2-(1-(1-(2,6-dicarbonylpiperidin-3-yl)dihydroindol-4-yl)-4-hydroxypiperidin-4-yl)acetate (1.1 g, 2.48 mmol) was dissolved in dichloromethane (10 mL), and hydrochloric acid / dioxane solution (4 M, 6.8 mL) was added under ice bath conditions. The reaction mixture was heated to room temperature and stirred for 16 hours. The precipitated solid was collected by filtration, concentrated under reduced pressure, and dried to give the title compound (789 mg, 82%). MS m / z (ESI): 388.1 [M+H] + .

[0386] Step 6: Preparation of (R)-2-(1-(1-(2,6-dicarbonylpiperidin-3-yl)dihydroindole-4-yl)-4-hydroxypiperidin-4-yl)acetic acid (compound B-4)

[0387] (R)-2-(1-(1-(2,6-dicarbonylpiperidin-3-yl)dihydroindol-4-yl)-4-hydroxypiperidin-4-yl)acetate (0.98 g, 2.21 mmol) was dissolved in dichloromethane (10 mL), and hydrochloric acid / dioxane solution (4 M, 6.8 mL) was added under ice bath conditions. The reaction mixture was heated to room temperature and stirred for 16 hours. The precipitated solid was collected by filtration, concentrated under reduced pressure, and dried to give the title compound (700 mg, 82%). MS m / z (ESI): 388.1 [M+H] + .

[0388] Synthesis of (S)-2-(5-((2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindole-2-yl)acetic acid (compound B-5) and (S)-2-(5-((2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindole-2-yl)acetic acid (compound B-6)

[0389] Step 1: Synthesis of tert-butyl-2-(5-nitroisodihydroindole-2-yl)acetate

[0390] 5-Nitroisodihydroindole (20 g, 121.8 mmol), N,N-diisopropylethylamine (47 g, 364.3 mmol), and tert-butyl-2-bromoacetate (29 g, 148.7 mmol) were dissolved in N,N-dimethylformamide (200 mL) and reacted at 25 °C for 1 h. The mixture was then extracted three times with ethyl acetate after adding 250 mL of aqueous solution. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the title compound (30 g, 88%). MS m / z (ESI): 279.1 [M+H]+ .

[0391] Step 2: Synthesis of tert-butyl-2-(5-aminoisodihydroindole-2-yl)acetate

[0392] 30 g (108 mmol) of tert-butyl-2-(5-nitroisodihydroindole-2-yl)acetate was dissolved in 400 mL of ethanol, and 2 g of 10% palladium / carbon was added. The mixture was stirred at 25 °C for 12 hours under a hydrogen atmosphere. After filtration and concentration under reduced pressure, the solution was separated by silica gel column chromatography to obtain the title compound (17 g, 64%). MS m / z (ESI): 249.2 [M+H] + .

[0393] Step 3: Synthesis of tert-butyl(S)-2-(5-((2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindole-2-yl)acetate and tert-butyl(R)-2-(5-((2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindole-2-yl)acetate

[0394] tert-Butyl 2-(5-aminoisodihydroindol-2-yl)acetate (3.2 g, 12.88 mmol), sodium bicarbonate (3.8 g, 45.22 mmol), and 3-bromopiperidine-2,6-dione (6.2 g, 32.28 mmol) were dissolved in N,N-dimethylformamide (60 mL) and reacted at 75 °C for 12 hours. Add 50 mL of aqueous solution, extract three times with ethyl acetate, combine the organic phases, wash with saturated sodium chloride solution, dry to anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate by silica gel column chromatography to obtain tert-butyl(S)-2-(5-((2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindole-2-yl)acetate (2.4 g, 52%). Chiral resolution yielded tert-butyl(S)-2-(5-((2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindole-2-yl)acetate (1.1 g) and tert-butyl(R)-2-(5-((2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindole-2-yl)acetate (1.1 g). MS m / z (ESI): 360.2 [M+H] + .

[0395] Step 4: Synthesis of (S)-2-(5-((2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindol-2-yl)acetic acid (compound B-5)

[0396] 1.1 g (3.05 mmol) of tert-butyl 2-(5-((2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindol-2-yl)acetate was dissolved in 10 mL of dichloromethane, and 50 mL of 4 M dioxane hydrochloride solution was added. The reaction mixture was stirred at 30 °C for 60 min. The solvent was removed by concentration under reduced pressure to give the title compound (1.0 g, 97%). MS m / z (ESI): 304.1 [M+H] +

[0397] Step 5: Synthesis of (R)-2-(5-((2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindol-2-yl)acetic acid (compound B-6)

[0398] 1.1 g (3.05 mmol) of tert-butyl 2-(5-((2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindol-2-yl)acetate was dissolved in 10 mL of dichloromethane, and 50 mL of 4 M dioxane hydrochloride solution was added. The reaction mixture was stirred at 30 °C for 60 min. The solvent was removed by concentration under reduced pressure to give the title compound (1.0 g, 97%). MS m / z (ESI): 304.1 [M+H] +

[0399] Synthesis of (1S,3r)-3-(5-(((S)-2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindole-2-yl)cyclobutane-1-carboxylic acid (compound B-7), (1R,3r)-3-(5-(((R)-2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindole-2-yl)cyclobutane-1-carboxylic acid (compound B-8), (1R,3s)-3-(5-(((S)-2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindole-2-yl)cyclobutane-1-carboxylic acid (compound B-9), and (1S,3s)-3-(5-(((R)-2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindole-2-yl)cyclobutane-1-carboxylic acid (compound B-10)

[0400] Step 1: Synthesis of tert-butyl 3-(5-nitroisodihydroindol-2-yl)cyclobutane-1-carboxylic acid ester

[0401] 5-Nitroisodihydroindole hydrochloride (5 g, 25 mmol), tert-butyl-3-carbonylcyclobutane-1-carboxylic acid ester (11 g, 65 mmol), and triethylamine (7.7 g, 76 mmol) were dissolved in 1,2-dichloroethane (70 mL). After stirring at room temperature for 1 hour, acetic acid (6.4 g, 107 mmol) was added, and stirring continued at room temperature for 4 hours. Sodium triacetoxyborohydride (9.7 g, 46 mmol) was added, and stirring continued at room temperature for 1 hour. The mixture was quenched with water, extracted three times with ethyl acetate, and the combined organic phases were washed with saturated sodium bicarbonate and sodium chloride solutions, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by column chromatography to give the title compound (4.8 g, 61%). MS m / z (ESI): 319.2 [M+H] + .

[0402] Step 2: Synthesis of tert-butyl(1r,3r)-3-(5-aminoisodihydroindole-2-yl)cyclobutane-1-carboxylic acid ester and tert-butyl(1s,3s)-3-(5-aminoisodihydroindole-2-yl)cyclobutane-1-carboxylic acid ester

[0403] 4.8 g (15.1 mmol) of tert-butyl 3-(5-nitroisodihydroindole-2-yl)cyclobutane-1-carboxylic acid ester was dissolved in ethanol (40 mL), and palladium / carbon (1 g, 10%) was added. The mixture was stirred at 25 °C for 5 hours under a hydrogen atmosphere. The mixture was filtered and concentrated under reduced pressure. The residue was resolved to give 2.4 g (55%) of tert-butyl (1r,3r)-3-(5-aminoisodihydroindole-2-yl)cyclobutane-1-carboxylic acid ester and 0.74 g (17%) of tert-butyl (1s,3s)-3-(5-aminoisodihydroindole-2-yl)cyclobutane-1-carboxylic acid ester. MS m / z (ESI): 289.2 [M+H] + .

[0404] Step 3: Synthesis of tert-butyl(1S,3r)-3-(5-(((S)-2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindole-2-yl)cyclobutane-1-carboxylic acid ester and tert-butyl(1R,3r)-3-(5-(((R)-2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindole-2-yl)cyclobutane-1-carboxylic acid ester

[0405] tert-butyl(1r,3r)-3-(5-aminoisodihydroindol-2-yl)cyclobutane-1-carboxylic acid ester (2.4 g, 8.33 mmol), sodium bicarbonate (3.5 g, 41.66 mmol), and 3-bromopiperidine-2,6-dione (6.4 g, 33.33 mmol) were dissolved in N,N-dimethylformamide (30 mL) and reacted at 75 °C for 12 hours. The reaction was quenched with water, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain tert-butyl(1S,3r)-3-(5-(((2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindole-2-yl)cyclobutane-1-carboxylic acid ester (1.8 g, 54%). Chiral resolution yielded tert-butyl(1S,3r)-3-(5-(((S)-2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindole-2-yl)cyclobutane-1-carboxylic acid ester (780 mg) and tert-butyl(1R,3r)-3-(5-(((R)-2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindole-2-yl)cyclobutane-1-carboxylic acid ester (760 mg). MS m / z (ESI): 400.2 [M+H] + .

[0406] Step 4: Synthesis of (1S,3r)-3-(5-(((S)-2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindole-2-yl)cyclobutane-1-carboxylic acid (compound B-7)

[0407] 780 mg (1.95 mmol) of tert-butyl(1S,3r)-3-(5-(((S)-2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindol-2-yl)cyclobutane-1-carboxylic acid ester was dissolved in 10 mL of dichloromethane, and 30 mL of 4 M dioxane hydrochloride solution was added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed by concentration under reduced pressure to obtain the title compound (720 mg, 97%), which was used directly in the next step. MS m / z (ESI): 344.2 [M+H] + .

[0408] Step 5: Synthesis of (1R,3r)-3-(5-(((R)-2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindole-2-yl)cyclobutane-1-carboxylic acid (compound B-8)

[0409] 760 mg (1.90 mmol) of tert-butyl(1R,3r)-3-(5-(((R)-2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindol-2-yl)cyclobutane-1-carboxylic acid ester was dissolved in 10 mL of dichloromethane, and 30 mL of 4 M dioxane hydrochloride solution was added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed by concentration under reduced pressure to obtain the title compound (709 mg, 98%), which was used directly in the next step. MS m / z (ESI): 344.2 [M+H] + .

[0410] Step 6: Synthesis of tert-butyl(1R,3s)-3-(5-(((S)-2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindole-2-yl)cyclobutane-1-carboxylic acid ester and tert-butyl(1S,3s)-3-(5-((((R)-2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindole-2-yl)cyclobutane-1-carboxylic acid ester

[0411] 0.74 g (2.6 mmol) of tert-butyl(1s,3s)-3-(5-aminoisodihydroindol-2-yl)cyclobutane-1-carboxylic acid ester, 1.1 g (13.1 mmol) of sodium bicarbonate, and 2 g (10.4 mmol) of 3-bromopiperidine-2,6-dione were dissolved in N,N-dimethylformamide (25 mL) and reacted at 75 °C for 12 hours. The solution was quenched with water, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain tert-butyl(1S,3S)-3-(5-(((2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindole-2-yl)cyclobutane-1-carboxylic acid ester (0.6 g, 59%). Chiral resolution yielded tert-butyl(1R,3S)-3-(5-(((S)-2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindole-2-yl)cyclobutane-1-carboxylic acid ester (280 mg) and tert-butyl(1S,3S)-3-(5-(((R)-2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindole-2-yl)cyclobutane-1-carboxylic acid ester (240 mg). MS m / z (ESI): 400.2 [M+H] + .

[0412] Step 7: Synthesis of (1R,3s)-3-(5-(((S)-2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindole-2-yl)cyclobutane-1-carboxylic acid (compound B-9)

[0413] 280 mg (0.7 mmol) of tert-butyl(1R,3s)-3-(5-(((S)-2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindol-2-yl)cyclobutane-1-carboxylic acid ester was dissolved in dichloromethane (5 mL), and 15 mL of 4M dioxane hydrochloride solution was added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed by concentration under reduced pressure to obtain the title compound (263 mg, 99%), which was used directly in the next step. MS m / z (ESI): 344.2 [M+H] + .

[0414] Step 8: Synthesis of (1S,3S)-3-(5-(((R)-2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindole-2-yl)cyclobutane-1-carboxylic acid (compound B-10)

[0415] 240 mg (0.6 mmol) of tert-butyl(1R,3s)-3-(5-(((R)-2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindol-2-yl)cyclobutane-1-carboxylic acid ester was dissolved in dichloromethane (5 mL), and 15 mL of 4 M dioxane hydrochloride solution was added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed by concentration under reduced pressure to obtain the title compound (226 mg, 99%), which was used directly in the next step. MS m / z (ESI): 344.2 [M+H] + .

[0416] (S)-1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisodihydroindole-5-yl)acetidine-3-carboxaldehyde (compound B-)

[0417] Synthesis of 11)

[0418] Step 1: Preparation of methyl 2-cyano-5-(4-(hydroxymethyl)piperidin-1-yl)benzoate

[0419] Methyl 2-cyano-5-fluoro-phenyl ester (25 g, 139.55 mmol) and acridine-3-ylmethanol hydrochloride (17.5 g, 141.61 mmol) were dissolved in dimethyl sulfoxide (250 mL), and potassium carbonate (77 g, 557.14 mmol) was added. The reaction mixture was heated to 110 °C and stirred for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to give the title compound (18 g, 52%). MS m / z (ESI): 247.1 [M+H] +

[0420] Step 2: Preparation of methyl 2-formyl-5-(4-(hydroxymethyl)piperidin-1-yl)benzoate

[0421] Under dry nitrogen protection, methyl 2-cyano-5-(4-(hydroxymethyl)piperidin-1-yl)benzoate (10 g, 40.61 mmol) was dissolved in a mixed solvent of water (50 mL) / acetic acid (50 mL) / pyridine (100 mL). Sodium hypophosphite monohydrate (43.04 g, 406.07 mmol) and Raney nickel (3.34 g, 56.85 mmol) were added sequentially. The reaction mixture was heated to 70 °C and stirred for 16 hours. After cooling to room temperature, the mixture was filtered, the filtrate was diluted with water, and extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (10 g, 99%). MS m / z (ESI): 250.1 [M+H] + .

[0422] Step 3: Preparation of tert-butyl(4S)-5-amino-4-[5-[3-(hydroxymethyl)acetidin-1-yl]-1-carbonyl-isodihydroindole-2-yl]-5-carbonyl-valerate

[0423] Methyl 2-formyl-5-(4-(hydroxymethyl)piperidin-1-yl)benzoate (1.5 g, 6.02 mmol) and tert-butyl(S)-4,5-diamino-5-carbonylpentanoate hydrochloride (1.74 g, 7.29 mmol) were dissolved in dichloromethane (15 mL). N,N-diisopropylethylamine (950 mg, 7.35 mmol) and acetic acid (3 mL) were added sequentially. The reaction mixture was stirred at room temperature for 1 hour, cooled to 0 °C, and sodium borohydride acetate (3.83 g, 18.05 mmol) was added. The mixture was then stirred at room temperature for 16 hours. The solvent was removed by concentration under reduced pressure, and the residue was subjected to column chromatography to give the title compound (800 mg, 33%). MS m / z (ESI): 404.2 [M+H] + .

[0424] Step 4: Preparation of (S)-3-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-carbonylisodihydroindol-2-yl)piperidin-2,6-dione

[0425] tert-Butyl(4S)-5-amino-4-[5-[3-(hydroxymethyl)acetidin-1-yl]-1-carbonyl-isodihydroindol-2-yl]-5-carbonyl-valerate (800 mg, 1.98 mmol) was dissolved in acetonitrile (8 mL), and benzenesulfonic acid (640 mg, 4.05 mmol) was added. The reaction mixture was stirred at 85 °C for 2 hours, cooled to room temperature, and concentrated under reduced pressure to remove the solvent. The residue was then subjected to HPLC to prepare the title compound (200 mg, 31%). MS m / z (ESI): 330.1 [M+H] + .

[0426] Step 5: Preparation of (S)-1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisodihydroindol-5-yl)acetidine-3-carboxaldehyde (compound B-11)

[0427] (S)-3-(6-(3-(hydroxymethyl)acridin-1-yl)-1-carbonylisodihydroindol-2-yl)piperidin-2,6-dione (200 mg, 607.26 μmol) and triethylamine (620 mg, 6.13 mmol) were sequentially added to dimethyl sulfoxide (3 mL), cooled to 0 °C, and then pyridine trioxide (490 mg, 3.08 mmol) was added. The mixture was transferred to room temperature and stirred for 1 hour. The reaction mixture was purified by HPLC to give the title compound (160 mg, 80%). MS m / z (ESI): 328.1 [M+H] + .

[0428] Synthesis of (S)-1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisodihydroindole-5-yl)piperidin-4-carboxaldehyde (compound B-12)

[0429] Step 1: Preparation of methyl 2-cyano-5-(4-(hydroxymethyl)piperidin-1-yl)benzoate

[0430] Methyl 2-cyano-5-fluoro-phenyl ester (25 g, 139.55 mmol) and 4-piperidinylmethanol (21 g, 182.33 mmol) were dissolved in dimethyl sulfoxide (250 mL), and N,N-diisopropylethylamine (54.11 g, 418.65 mmol, 72.92 mL) was added. The reaction mixture was stirred at 110 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to give the title compound (34 g, 89%). MS m / z (ESI): 275.1 [M+H] + .

[0431] Step 2: Preparation of methyl 2-formyl-5-(4-(hydroxymethyl)piperidin-1-yl)benzoate

[0432] Under dry nitrogen protection, methyl 2-cyano-5-(4-(hydroxymethyl)piperidin-1-yl)benzoate (7 g, 25.52 mmol) was dissolved in a mixed solvent of water (35 mL) / acetic acid (35 mL) / pyridine (70 mL). Sodium hypophosphite monohydrate (27 g, 254.73 mmol) and Raney nickel (2.10 g, 35.73 mmol) were added sequentially. The reaction mixture was transferred to 70 °C and stirred for 16 hours. After cooling to room temperature, the mixture was filtered, the filtrate was diluted with water, and extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (7 g, 99%). MS m / z (ESI): 278.1 [M+H] + .

[0433] Step 3: Preparation of tert-butyl(S)-5-amino-4-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-carbonylisodihydroindole-2-yl)-5-carbonylpentanoate

[0434] Methyl 2-formyl-5-(4-(hydroxymethyl)piperidin-1-yl)benzoate (10 g, 36.06 mmol) and tert-butyl(S)-4,5-diamino-5-carbonylpentanoate hydrochloride (7.12 g, 43.26 mmol) were dissolved in dichloromethane (100 mL). N,N-diisopropylethylamine (5.59 g, 43.25 mmol, 7.53 mL) and acetic acid (20 mL) were added. The reaction mixture was stirred at 35 °C for 4 hours, then transferred to room temperature. Sodium borohydride acetate (22.93 g, 108.21 mmol) was added, and the mixture was stirred for another 3 hours at room temperature. The mixture was concentrated under reduced pressure, and the residue was separated by column chromatography to give the title compound (4 g, 31%). MS m / z (ESI): 432.2 [M+H] + .

[0435] Step 4: Preparation of (S)-3-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-carbonylisodihydroindol-2-yl)piperidin-2,6-dione

[0436] tert-Butyl(S)-5-amino-4-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-carbonylisodihydroindol-2-yl)-5-carbonylpentanoate (800 mg, 1.98 mmol) was dissolved in acetonitrile (8 mL), and benzenesulfonic acid (640 mg, 4.05 mmol) was added. The reaction mixture was stirred at 85 °C for 2 hours. The solution was concentrated under reduced pressure, and the residue was purified by HPLC to give the title compound (120 mg, 17%). MS m / z (ESI): 358.2 [M+H] + .

[0437] Step 5: Preparation of (S)-1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisodihydroindole-5-yl)piperidin-4-carboxaldehyde (compound B-12)

[0438] (S)-3-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-carbonylisodihydroindol-2-yl)piperidin-2,6-dione (220 mg, 615.55 μmol) and triethylamine (1.25 g, 12.31 mmol) were dissolved in dimethyl sulfoxide (4 mL), cooled to 0 °C, and pyridine sulfur trioxide (980 mg, 6.16 mmol) was added. The mixture was then transferred to room temperature and stirred for 1 hour. The reaction mixture was purified by HPLC to give the title compound (160 mg, 73%). MS m / z (ESI): 356.1 [M+H] + .

[0439] Preparation of 2-(4-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)dihydroindol-1-yl)piperidin-1-yl)acetic acid (compound B-13)

[0440] Step 1: Preparation of tert-butyl-4-(4-bromodihydroindol-1-yl)piperidine-1-carboxylic acid ester

[0441] 4-Bromodihydroindole (5 g, 25.24 mmol), N-tert-butoxycarbonyl-4-piperidinone (7.54 g, 37.87 mmol), and acetic acid (1.52 g, 25.24 mmol) were dissolved in 1,2-dichloroethane (100 mL) and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (16.05 g, 75.73 mmol) was added, and the reaction mixture was stirred at room temperature for another hour. The reaction mixture was poured into water and extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by column chromatography to give the title compound (9.06 g, 94%). MS m / z (ESI): 383.1 [M+H] + .

[0442] Step 2: Preparation of tert-butyl 4-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)dihydroindole-1-yl)piperidine-1-carboxylic acid ester

[0443] tert-Butyl 4-(4-bromodihydroindol-1-yl)piperidine-1-carboxylic acid ester (5.8 g, 15.21 mmol) and dihydrouracil (5.21 g, 45.63 mmol) were dissolved in 1,4-dioxane (100 mL), and bicyclohexyl(3-isopropoxy-2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphonane (814 mg, 1.52 mL) was added. The reaction mixture contained 1.40 g (1.52 mmol) of dicyclohexyl[3-isopropoxy-2′,4′,6′-triisopropyl-(1,1′-biphenyl)-2-yl]phosphonane}(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (ol), methanesulfonic acid {biscyclohexyl[3-isopropoxy-2′,4′,6′-triisopropyl-(1,1′-biphenyl)-2-yl]phosphonane}, and cesium carbonate (14.87 g, 45.63 mmol). The reaction solution was purged three times with dry nitrogen and heated to 110 °C with stirring for 16 hours. After cooling to room temperature, the reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give the title compound (2.04 g, 32%). MS m / z (ESI): 415.2 [M+H] + .

[0444] Step 3: Preparation of 1-(1-(piperidin-4-yl)dihydroindole-4-yl)dihydropyrimidine-2,4(1H,3H)-dione trifluoroacetate

[0445] 2.04 g (4.92 mmol) of tert-butyl 4-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)dihydroindol-1-yl)piperidin-1-carboxylic acid ester was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (10 mL) was added. The mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure to obtain crude trifluoroacetate of the title compound, which was used directly in the next reaction. MS m / z (ESI): 315.2 [M+H] + .

[0446] Step 4: Preparation of tert-butyl 2-(4-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)dihydroindol-1-yl)piperidin-1-yl)acetate

[0447] 1-(1-(piperidin-4-yl)dihydroindol-4-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.55 g, 4.93 mmol) was dissolved in N,N-dimethylformamide (10 mL), and diisopropylethylamine (3.19 g, 24.65 mmol) and tert-butyl bromoacetate (1.44 g, 7.40 mmol) were added. The reaction mixture was stirred for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by column chromatography to give the title compound (1.36 g, 64%). MS m / z (ESI): 429.3 [M+H] + .

[0448] Step 5: Preparation of 2-(4-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)dihydroindol-1-yl)piperidin-1-yl)acetic acid

[0449] 520 mg (1.21 mmol) of tert-butyl 2-(4-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)dihydroindol-1-yl)piperidin-1-yl)acetate was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (4 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. The solution was concentrated under reduced pressure, and the residue was purified by HPLC to give the title compound (428 mg, 95%). MS m / z (ESI): 373.2 [M+H] + .

[0450] Preparation of 2-((3S,4R)-4-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)dihydroindol-1-yl)-3-fluoropiperidin-1-yl)acetic acid (compound B-14)

[0451] Step 1: Preparation of tert-butyl(3S,4R)-4-(4-bromodihydroindol-1-yl)-3-fluoropiperidine-1-carboxylic acid ester

[0452] 4-Bromodihydroindole (0.3 g, 1.51 mmol) and tert-butyl(S)-3-fluoro-4-carbonylpiperidine-1-carboxylic acid ester (0.82 g, 3.79 mmol) were dissolved in a mixed solvent of acetic acid (6 mL) and 1,2-dichloroethane (2 mL). The mixture was heated to 40 °C and stirred for 3 hours. After cooling to room temperature, sodium triacetoxyborohydride (0.96 g, 4.54 mmol) was added in portions, and the mixture was stirred at room temperature for 9 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. After washing with saturated sodium bicarbonate solution and saturated sodium chloride solution, the residue was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography to give the title compound (0.51 g, 84%). MS m / z (ESI): 399.1 [M+H] + .

[0453] Step 2: Preparation of tert-butyl(3S,4R)-4-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)dihydroindole-1-yl)-3-fluoropiperidine-1-carboxylic acid ester

[0454] Under dry nitrogen protection, tert-butyl(3S,4R)-4-(4-bromodihydroindol-1-yl)-3-fluoropiperidine-1-carboxylic acid ester (580 mg, 1.45 mmol), dihydropyrimidine-2,4(1H,3H)-dione (497 mg, 4.36 mmol), and dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (118 mg, 0.22 mmol) were prepared. A mixture of methanesulfonate {dicyclohexyl[3-(1-methylethoxy)-2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine}(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (202 mg, 0.22 mmol) and cesium carbonate (1.42 g, 4.36 mmol) was placed in dioxane (30 mL), heated to 100 °C, and stirred for 12 hours. The mixture was then cooled to room temperature. The mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to obtain the title compound (290 mg, 46%). MS m / z (ESI): 433.2 [M+H] + .

[0455] Step 3: Preparation of 1-(1-((3S,4R)-3-fluoropiperidin-4-yl)dihydroindole-4-yl)dihydropyrimidine-2,4(1H,3H)-dione trifluoroacetate

[0456] 290 mg (0.67 mmol) of tert-butyl(3S,4R)-4-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)dihydroindol-1-yl)-3-fluoropiperidin-1-carboxylic acid ester was dissolved in a mixed solvent of dichloromethane (2 mL) and trifluoroacetic acid (1 mL) and stirred at room temperature for 1 hour. After concentrating the organic solvent under reduced pressure, crude 1-(1-((3S,4R)-3-fluoropiperidin-4-yl)dihydroindol-4-yl)dihydropyrimidin-2,4(1H,3H)-dione trifluoroacetate salt of the title compound was obtained and used directly in the next reaction. MS m / z (ESI): 333.2 [M+H] + .

[0457] Step 4: Preparation of tert-butyl 2-((3S,4R)-4-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)dihydroindol-1-yl)-3-fluoropiperidin-1-yl)acetate (compound B-14-A)

[0458] The crude product of 1-(1-((3S,4R)-3-fluoropiperidin-4-yl)dihydroindol-4-yl)dihydropyrimidine-2,4(1H,3H)-dione trifluoroacetate was dissolved in DMF (6 mL), followed by the addition of diisopropylethylamine (260 mg, 2.01 mmol) and tert-butyl-2-bromoacetate (156 mg, 0.80 mmol). The mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography to give the title compound (206 mg, 69% in two steps). MS m / z (ESI): 447.2 [M+H] + .

[0459] Step 5: Preparation of 2-((3S,4R)-4-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)dihydroindol-1-yl)-3-fluoropiperidin-1-yl)acetic acid

[0460] At room temperature, tert-butyl 2-((3S,4R)-4-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)dihydroindol-1-yl)-3-fluoropiperidin-1-yl)acetate (206 mg, 0.46 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 hour, and the organic solvent was concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (163 mg, 90%). MS m / z (ESI): 391.2 [M+H] + .

[0461] Preparation of 1-(1-((1r,4r)-4-(methylamino)cyclohexyl)dihydroindol-4-yl)dihydropyrimidine-2,4(1H,3H)-dione (compound B-15)

[0462] Step 1: Preparation of tert-butyl-4-(4-bromodihydroindol-1-yl)cyclohexyl(methyl)carbamate

[0463] 4-Bromodihydroindole (2 g, 10.10 mmol), tert-butylmethyl (4-carbonylcyclohexyl)carbamate (4.13 g, 18.18 mmol), and acetic acid (607 mg, 10.10 mmol) were dissolved in 1,2-dichloroethane (40 mL) and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (6.42 g, 30.29 mmol) was added, and stirring was continued at room temperature for another hour. The reaction mixture was poured into water, extracted with dichloromethane, and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the title compound (3.7 g, 90%). MS m / z (ESI): 409.1 [M+H] +

[0464] Step 2: Preparation of tert-butyl((1r,4r)-4-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)dihydroindole-1-yl)cyclohexyl(methyl)carbamate

[0465] The following substances were added: tert-butyl-4-(4-bromodihydroindol-1-yl)cyclohexyl(methyl)carbamate (3.7 g, 9.04 mmol), dihydrouracil (4.13 g, 36.15 mmol), bicyclohexyl(3-isopropoxy-2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphonate (484 mg, 903.85 μmol), and methanesulfonic acid {bicyclohexyl[3-isopropoxy-2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphonate. Oxy-2′,4′,6′-triisopropyl-(1,1′-biphenyl)-2-yl]phosphonane}(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II) (831 mg, 903.85 μmol) and cesium carbonate (5.89 g, 18.08 mmol) were added to 1,4-dioxane (150 mL). The reaction system was purged three times with dry nitrogen and heated to 110 °C with stirring for 16 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography and preparative high-performance liquid chromatography to obtain the title compound (585 mg, 17%). MS m / z (ESI): 443.3 [M+H] + .

[0466] Step 3: Preparation of 1-(1-((1r,4r)-4-(methylamino)cyclohexyl)dihydroindol-4-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0467] 500 mg (1.13 mmol) of tert-butyl((1r,4r)-4-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)dihydroindol-1-yl)cyclohexyl(methyl)carbamate was dissolved in a mixed solvent of dichloromethane (3 mL) and trifluoroacetic acid (3 mL) and stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure, and the residue was purified by HPLC to give the title compound (368 mg, 95%). MS m / z (ESI): 343.2 [M+H] + .

[0468] 1 H NMR (400MHz, DMSO-d6) δ10.29(s,1H),6.99(t,J=7.2Hz,1H),6.40(d,J=8.0Hz,1H ),6.33(d,J=8.0Hz,1H),3.66(t,J=6.6Hz,2H),3.40-3.38(m,1H),3.28(t,J=6.6 Hz,2H),2.76(t,J=6.2Hz,2H),2.67(t,J=6.2Hz,2H),2.26(s,3H),2.24-2.15(m, 1H),2.01-1.89(m,2H),1.75-1.66(m,2H),1.49-1.35(m,2H),1.16-1.05(m,2H).

[0469] (R)-3-(1-((3S,4R)-3-fluoropiperidin-4-yl)dihydroindol-4-yl)piperidin-2,6-dione (compound B-16)

[0470] Step 1: Preparation of tert-butyl(3S,4R)-4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)dihydroindol-1-yl)-3-fluoropiperidine-1-carboxylic acid ester

[0471] Under nitrogen protection, tert-butyl(3S,4R)-4-(4-bromodihydroindol-1-yl)-3-fluoropiperidine-1-carboxylic acid ester (6 g, 15.03 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine (8.15 g, 19.53 mmol) were dissolved in a mixed solvent of 1,4-dioxane (60 mL) and water (20 mL). Potassium phosphate (9.57 g, 45.08 mmol) and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloromethane complex (1.23 g, 1.5 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 2 hours, then cooled to room temperature. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give the title compound (8.1 g, 88%). MS m / z (ESI): 610.3 [M+H] + .

[0472] Step 2: Preparation of tert-butyl(3S,4R)-4-(4-((R)-2,6-dicarbonylpiperidin-3-yl)dihydroindole-1-yl)-3-fluoropiperidin-1-carboxylic acid ester

[0473] 8 g (13.12 mmol) of tert-butyl(3S,4R)-4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)dihydroindol-1-yl)-3-fluoropiperidine-1-carboxylic acid ester was dissolved in a mixed solvent of tetrahydrofuran (60 mL), ethanol (60 mL), and ethyl acetate (60 mL). Palladium / carbon (3.19 g, 5 wt.%) and platinum dioxide (1.49 g, 6.56 mmol) were added, and the reaction mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was separated by chiral column chromatography to obtain compound P1 (2.2 g, 39%) [Chiralpak IA 10 μm, 30 mm * 250 mm, acetonitrile 100%, F = 30 mL / min, T = room temperature, P1: 3.7 min]. MS m / z(ESI): 432.2 [M+H] + .

[0474] Step 3: Preparation of (R)-3-(1-((3S,4R)-3-fluoropiperidin-4-yl)dihydroindol-4-yl)piperidin-2,6-dione

[0475] 100 mg (0.23 mmol) of tert-butyl(3S,4R)-4-(4-((R)-2,6-dicarbonylpiperidin-3-yl)dihydroindol-1-yl)-3-fluoropiperidin-1-carboxylic acid ester was dissolved in a mixed solvent of dichloromethane (3 mL) and trifluoroacetic acid (3 mL). The mixture was stirred at room temperature for 0.5 hours, and the solvent was removed by concentration under reduced pressure. The residue was then subjected to HPLC to prepare the title compound (58 mg, 76%). MS m / z (ESI): 332.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.81 (s, 1H), 6.93 (t, J = 7.7Hz, 1H), 6.40 (d, J = 7.9Hz, 1H),6.33(d,J=7.6Hz,1H),4.81(d,J=51.0Hz,1H),3.77(dd,J=11.4,5.1Hz,1H) ,3.72-3.51(m,2H),3.46(q,J=8.9Hz,1H),3.14-2.96(m,2H),2.93-2.57(m,5H) ,2.50-2.40(m,2H),2.18-2.03(m,1H),2.02-1.79(m,2H),1.46(d,J=12.8,1H).

[0476] tert-Butyl 2-((3S,4R)-4-(4-((R)-2,6-dioxopiperidin-3-yl)dihydroindole-1-yl)-3-fluoropiperidin-1-

[0477] (B-17) Acetate (compound B-17)

[0478] (R)-3-(1-((3S,4R)-3-fluoropiperidin-4-yl)dihydroindol-4-yl)piperidin-2,6-dione (compound B-16) (230 mg, 694.06 μmol) was dissolved in N,N-dimethylformamide (5 mL), and diisopropylethylamine (449 mg, 3.47 mmol) and tert-butyl bromoacetate (203 mg, 1.04 mmol) were added. The reaction mixture was stirred for 2 hours. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate (30 mL × 2), the organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the title compound (273 mg, 88%). MS m / z (ESI): 446.2 [M+H] + .

[0479] (R)-3-(1-((3S,4S)-3-fluoropiperidin-4-yl)dihydroindol-4-yl)piperidin-2,6-dione (compound B-18)

[0480] Step 1: Preparation of tert-butyl(3S,4S)-4-(4-bromo-1H-indol-1-yl)-3-fluoropiperidine-1-carboxylic acid ester

[0481] 4-Bromo-1H-indole (7 g, 35.71 mmol) and tert-butyl(3S,4R)-3-fluoro-4-((methanesulfonyl)oxo)piperidine-1-carboxylic acid ester (21.23 g, 71.41 mmol) were dissolved in DMSO (140 mL), and cesium carbonate (34.90 g, 107.12 mmol) was added. The reaction mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the title compound (3.4 g, 24%). MS m / z (ESI): 397.1 [M+H] + .

[0482] Step 2: Preparation of tert-butyl(3S,4S)-4-(4-bromodihydroindol-1-yl)-3-fluoropiperidine-1-carboxylic acid ester

[0483] 3.5 g (8.81 mmol) of tert-butyl(3S,4S)-4-(4-bromo-1H-indol-1-yl)-3-fluoropiperidine-1-carboxylic acid ester was dissolved in acetic acid (20 mL), and sodium cyanoborohydride (1.66 g, 26.43 mmol) was added at 0 °C. The mixture was stirred at room temperature for 12 hours. The reaction solution was extracted three times with ethyl acetate, and the combined organic phases were washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the title compound (2.7 g, 77%). MS m / z (ESI): 399.1 [M+H] + .

[0484] Step 3: Preparation of tert-butyl(3S,4S)-4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)dihydroindole-1-yl)-3-fluoropiperidine-1-carboxylic acid ester

[0485] tert-Butyl(3S,4S)-4-(4-bromodihydroindol-1-yl)-3-fluoropiperidine-1-carboxylic acid ester (2.7 g, 6.76 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine (4.23 g, 10.14 mmol) were dissolved in 1,4-dioxane (60 mL) and water (20 mL), and Pd(dppf)Cl2 (495 mg, 676.51 μmol) and potassium carbonate (2.80 g, 20.29 mmol) were added. The mixture was evacuated and purged with nitrogen, and this process was repeated three times. The reaction mixture was heated to 100 °C and stirred for 1.5 hours under a nitrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the title compound (3.5 g, 85%). MS m / z (ESI): 610.3 [M+H] + .

[0486] Step 4: Preparation of tert-butyl(3S,4S)-4-(4-((R)-2,6-dioxopiperidin-3-yl)dihydroindol-1-yl)-3-fluoropiperidin-1-carboxylic acid ester

[0487] 3.5 g (5.74 mmol) of tert-butyl(3S,4S)-4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)dihydroindol-1-yl)-3-fluoropiperidine-1-carboxylic acid ester was dissolved in ethanol (15 mL), tetrahydrofuran (15 mL), and ethyl acetate (15 mL). Palladium on carbon (1.4 g, 10% purity) and platinum dioxide (700 mg, 3.08 mmol) were added. The mixture was evacuated and purged with hydrogen gas, and this process was repeated three times. The reaction mixture was stirred in a hydrogen atmosphere for 16 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain tert-butyl(3S,4S)-4-(4-(2,6-dioxopiridin-3-yl)dihydroindole-1-yl)-3-fluoropiperidin-1-carboxylic acid ester (2.4 g, 97%). Resolution was performed on a chiral column (CHIRALPAK IA, 30 × 150 mm, 10 μm, acetonitrile = 100%, F = 30.0 ml / min, T = room temperature, P1: 7.17 min) to give 560 mg of the title compound. MS m / z (ESI): 432.2 [M+H] + .

[0488] Step 5: Preparation of (R)-3-(1-((3S,4S)-3-fluoropiperidin-4-yl)dihydroindol-4-yl)piperidin-2,6-dione

[0489] 300 mg (695.25 μmol) of tert-butyl(3S,4S)-4-(4-((R)-2,6-dioxopiridine-3-yl)dihydroindol-1-yl)-3-fluoropiperidine-1-carboxylic acid ester was dissolved in a mixed solvent of dichloromethane (10 mL) and trifluoroacetic acid (10 mL) and stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure, and the residue was purified by HPLC to give the title compound (205 mg, 89%). MS m / z (ESI): 332.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.80(s,1H),6.91(t,J=7.8Hz,1H),6.40(d,J=7.9Hz,1H),6.30(d,J=7.6Hz,1H),4.70- 4.46(m,1H),3.76(dd,J=11.6,5.0Hz,1H),3.68-3.56(m,1H),3.54-3.45(m,1H),3.43-3.34(m,1H),3.27-3.17( 2.92-2.78 (m, 1H), 2.73-2.60 (m, 1H), 2.57-2.41 (m, 4H), 2.20-2.04 (m, 1H), 2.02-1.91 (m, 1H), 1.70-1.60 (m, 1H), 1.58-1.45 (m, 1H). tert-Butyl 2-((3S,4S)-4-(4-((R)-2,6-dioxopiperidin-3-yl)dihydroindol-1-yl)-3-fluoropiperidin-1-yl)acetate (compound B-19)

[0490] (R)-3-(1-((3S,4S)-3-fluoropiperidin-4-yl)dihydroindol-4-yl)piperidin-2,6-dione (compound B-18) (230 mg, 694.06 μmol) was dissolved in N,N-dimethylformamide (5 mL), and diisopropylethylamine (449 mg, 3.47 mmol) and tert-butyl bromoacetate (203 mg, 1.04 mmol) were added. The reaction mixture was stirred for 2 hours. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate (30 mL × 2), the organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the title compound (250 mg, 81%). MS m / z (ESI): 446.2 [M+H] + .

[0491] (R)-3-(1-((3R,4R)-3-fluoropiperidin-4-yl)dihydroindol-4-yl)piperidin-2,6-dione (compound B-20)

[0492] Step 1: Preparation of tert-butyl(3R,4S)-3-fluoro-4-((methanesulfonyl)oxo)piperidine-1-carboxylic acid ester

[0493] 65.78 g (300 mmol) of tert-butyl(3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylic acid ester and diisopropylethylamine (77.5 g (600 mmol)) were dissolved in dichloromethane (1 L), cooled to 0 °C, and methanesulfonic anhydride (78.39 g (450 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed by concentration under reduced pressure. The residue was washed successively with methyl tert-butyl ether solvent, saturated sodium bicarbonate solution, and saturated brine solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was slurried with petroleum ether:ethyl acetate (5:1) to give the title compound (88.57 g, 99%). MS m / z (ESI): 298.2 [M+H] + .

[0494] Step 2: Preparation of tert-butyl(3R,4R)-4-(4-bromo-1H-indol-1-yl)-3-fluoropiperidine-1-carboxylic acid ester

[0495] 4-Bromo-1H-indole (19.6 g, 100 mmol) and tert-butyl-tert-butyl-tert-butyl(3R,4S)-3-fluoro-4-((methanesulfonyl)oxo)piperidine-1-carboxylic acid ester (88.57 g, 297 mmol) were dissolved in DMSO (140 mL), and cesium carbonate (97.75 g, 300 mmol) was added. The reaction mixture was heated to 100 °C and stirred for 16 hours, then cooled to room temperature. The reaction mixture was quenched with water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the title compound (14 g, 35%). MS m / z (ESI): 397.1 [M+H] + .

[0496] Step 3: Tert-butyl(3R,4R)-4-(4-bromodihydroindol-1-yl)-3-fluoropiperidine-1-carboxylic acid ester

[0497] 14 g (35.24 mmol) of tert-butyl(3R,4R)-4-(4-bromo-1H-indol-1-yl)-3-fluoropiperidine-1-carboxylic acid ester was dissolved in acetic acid (50 mL). Sodium cyanoborohydride (6.64 g, 105.72 mmol) was added while cooling at 0 °C. The reaction mixture was transferred to room temperature and stirred for 12 hours. Most of the solvent was removed by concentration under reduced pressure. The residue was dispersed in water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate and sodium chloride solutions, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by column chromatography to give the title compound (10.5 g, 75%). MS m / z (ESI): 399.1 [M+H] + .

[0498] Step 4: Tert-butyl(3R,4R)-4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)dihydroindole-1-yl)-3-fluoropiperidine-1-carboxylic acid ester

[0499] Under nitrogen protection, tert-butyl(3R,4R)-4-(4-bromodihydroindol-1-yl)-3-fluoropiperidine-1-carboxylic acid ester (10.5 g, 26.31 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine (16.47 g, 39.46 mmol) were dissolved in a mixed solvent of 1,4-dioxane (120 mL) and water (40 mL). Pd(dppf)Cl2 (1.9 g, 2.6 mmol) and potassium carbonate (10.91 g, 78.93 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 2 hours, then cooled to room temperature. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the title compound (12.5 g, 78%). MS m / z (ESI): 610.3 [M+H] + .

[0500] Step 5: Preparation of tert-butyl(3R,4R)-4-(4-((R)-2,6-dicarbonylpiperidin-3-yl)dihydroindole-1-yl)-3-fluoropiperidin-1-carboxylic acid ester

[0501] 12.5 g (20.52 mmol) of tert-butyl(3R,4R)-4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)dihydroindol-1-yl)-3-fluoropiperidine-1-carboxylic acid ester was dissolved in a mixed solvent of ethanol (30 mL), tetrahydrofuran (30 mL), and ethyl acetate (30 mL). Palladium on carbon (2.8 g, 10% purity) and platinum dioxide (1.4 g, 6.16 mmol) were added, and the reaction mixture was stirred in a hydrogen atmosphere for 24 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give a mixture of the title compound (2.4 g, 97%), which was further resolved by chiral column chromatography (CHIRALPAK IA, 30 × 150 mm, 10 μm, acetonitrile = 100%, F = 30.0 mL / min, T = room temperature, P1: 6.57 min) to obtain the title compound. MS m / z(ESI): 432.2 [M+H] + .

[0502] Step 6: Preparation of (R)-3-(1-((3R,4R)-3-fluoropiperidin-4-yl)dihydroindol-4-yl)piperidin-2,6-dione

[0503] 300 mg (695.25 μmol) of tert-butyl(3R,4R)-4-(4-((R)-2,6-dicarbonylpiperidin-3-yl)dihydroindol-1-yl)-3-fluoropiperidin-1-carboxylic acid ester was dissolved in a mixed solvent of dichloromethane (10 mL) and trifluoroacetic acid (10 mL), and the reaction mixture was stirred for 1 hour. The solution was concentrated under reduced pressure and dried. The residue was purified by HPLC to give the title compound (180 mg, 78%). MS m / z (ESI): 332.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.80(s,1H),6.91(t,J=7.8Hz,1H),6.40(d,J=7.9Hz,1H),6.30(d ,J=7.6Hz,1H),4.70-4.46(m,1H),3.77(dd,J=11.6,5.0Hz,1H),3.68-3.56(m,1H),3.53-3. 45(m,1H),3.45-3.35(m,1H),3.27-3.17(m,1H),2.92-2.73(m,3H),2.71-2.58(m,1H),2.5 6-2.32(m,4H),2.20-2.04(m,1H),2.02-1.92(m,1H),1.70-1.60(m,1H),1.56-1.42(m,1H).

[0504] tert-Butyl 2-((3R,4R)-4-(4-((R)-2,6-dicarbonylpiperidin-3-yl)dihydroindol-1-yl)-3-fluoropiperidin-1-yl)acetate (compound B-21)

[0505] (R)-3-(1-((3R,4R)-3-fluoropiperidin-4-yl)dihydroindol-4-yl)piperidin-2,6-dione (230 mg, 694.06 μmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the sequential addition of diisopropylethylamine (449 mg, 3.47 mmol) and tert-butyl bromoacetate (203 mg, 1.04 mmol). The reaction mixture was stirred for 2 hours. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate (30 mL × 2), washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the title compound (235 mg, 76%). MS m / z (ESI): 446.2 [M+H] + .

[0506] (R)-3-(1-((1r,4R)-4-(methylamino)cyclohexyl)dihydroindol-4-yl)piperidine-2,6-dione (compound B-22)

[0507] Step 1: Preparation of tert-butyl((1r,4r)-4-(4-(2,6-di(benzyloxy)pyridin-3-yl)dihydroindole-1-yl)cyclohexyl)(methyl)carbamate

[0508] Tert-butyl((1r,4r)-4-(4-bromodihydroindol-1-yl)cyclohexyl)(methyl)carbamate (7 g, 17.10 mmol) and 2,6-di(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine (8.56 g, 20.52 mmol) were dissolved in 1,4-dioxane (110 mL) and water (20 mL), and Pd(dppf)Cl2 (1.25 g, 1.71 mmol) and potassium carbonate (7.08 g, 51.30 mmol) were added. The mixture was evacuated and purged with nitrogen, and this process was repeated three times. The reaction mixture was heated to 100 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the title compound (0.52 g, 60%). MS m / z (ESI): 620.3 [M+H] + .

[0509] Step 2: Preparation of tert-butyl((1R,4r)-4-(4-((R)-2,6-dicarbonylpiperidin-3-yl)dihydroindole-1-yl)cyclohexyl)(methyl)carbamate

[0510] 10.6 g (17.10 mmol) of tert-butyl((1r,4r)-4-(4-(2,6-di(benzyloxy)pyridin-3-yl)dihydroindol-1-yl)cyclohexyl)(methyl)carbamate was dissolved in ethanol (50 mL), tetrahydrofuran (50 mL), and ethyl acetate (50 mL). Palladium on carbon (4.24 g, 5% purity) and platinum dioxide (2.12 g, 9.34 mmol) were added. The mixture was evacuated and purged with hydrogen gas, and this process was repeated three times. The reaction mixture was stirred in a hydrogen atmosphere for 16 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give tert-butyl((1r,4r)-4-(4-(2,6-dicarbonylpiperidin-3-yl)dihydroindole-1-yl)cyclohexyl)(methyl)carbamate (7 g, 93%). Chiral resolution [CHIRALCEL AS-H, 4.6 × 150 mm, 5 μm, n-hexane:ethanol = 70:30, F = 1.0 ml / min, T = 35 °C, P1: 3.6 min] yielded the title compound P1 (2 g). MS m / z (ESI): 442.2 [M+H] + .

[0511] Step 3: Preparation of (R)-3-(1-((1r,4R)-4-(methylamino)cyclohexyl)dihydroindol-4-yl)piperidine-2,6-dione

[0512] 400 mg (905.88 μmol) of tert-butyl((1R,4r)-4-(4-((R)-2,6-dicarbonylpiperidin-3-yl)dihydroindole-1-yl)cyclohexyl)(methyl)carbamate was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (10 mL) was added. The reaction mixture was stirred for 1 hour. The solution was concentrated under reduced pressure and dried. The residue was purified by HPLC to give the title compound (279 mg, 90%). MS m / z (ESI): 342.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.79 (s, 1H), 6.92 (t, J = 7.7Hz, 1H), 6.38-6.24 (m ,2H),3.76(dd,J=11.4,5.1Hz,1H),3.46-3.31(m,3H),2.90-2.57(m,3H),2 .52-2.49(m,2H),2.48-2.40(m,1H),2.31-2.17(m,3H),2.16-2.02(m,1H), 2.01-1.88(m,3H),1.78-1.58(m,2H),1.49-1.33(m,2H),1.16-1.03m,2H).

[0513] (R)-3-(1-(piperidin-4-yl)dihydroindol-4-yl)piperidin-2,6-dione (compound B-23)

[0514] Step 1: Preparation of tert-butyl-4-(4-bromodihydroindol-1-yl)piperidine-1-carboxylic acid ester

[0515] 4-Bromodihydroindole (25 g, 126.22 mmol) and tert-butyl-4-carbonylpiperidin-1-carboxylic acid ester (37.72 g, 189.34 mmol) were dissolved in 1,2-dichloroethane (500 mL), and acetic acid (7.58 g, 126.22 mmol) was added. The mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (80.26 g, 378.67 mmol) was added to the reaction mixture, and the mixture was stirred for another hour. The reaction mixture was poured into water and extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the title compound (42.6 g, 88%). MS m / z (ESI): 381.1 [M+H] + .

[0516] Step 2: Preparation of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)dihydroindole-1-yl)piperidine-1-carboxylic acid ester

[0517] Under nitrogen protection, tert-butyl-4-(4-bromodihydroindol-1-yl)piperidine-1-carboxylic acid ester (42.6 g, 111.72 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine (51.28 g, 122.89 mmol) were dissolved in a mixed solvent of 1,4-dioxane (500 mL) and water (80 mL). 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (8.17 g, 11.17 μmol) and potassium carbonate (46.32 g, 335.16 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 6 hours, then cooled to room temperature. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the title compound (65.5 g, 99%). MS m / z (ESI): 592.3 [M+H] + .

[0518] Step 3: Preparation of tert-butyl(R)-4-(4-(2,6-dicarbonylpiperidin-3-yl)dihydroindole-1-yl)piperidin-1-carboxylic acid ester

[0519] 10.8 g (18.25 mmol) of tert-butyl-4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)dihydroindol-1-yl)piperidine-1-carboxylic acid ester was dissolved in a mixed solvent of tetrahydrofuran (50 mL), ethanol (50 mL), and ethyl acetate (50 mL). Palladium on carbon (7.77 g, 10%) and platinum dioxide (829 mg, 3.65 mmol) were added, and the reaction mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrates were combined, concentrated under reduced pressure, and dried to obtain a mixture of the title compounds (7.3 g, 97%). The title compound P1 (2.04 g) was separated by chiral chromatography (column type: CHIRALPAK IA, 30 mm ID × 250 mm L; mobile phase: acetonitrile; flow rate: 30 mL / min; column temperature: room temperature; P1 elution time: 9.38 min). MS m / z (ESI): 414.2 [M+H] + .

[0520] Step 4: Preparation of (R)-3-(1-(piperidin-4-yl)dihydroindol-4-yl)piperidin-2,6-dione

[0521] 100 mg (241.83 μmol) of tert-butyl(R)-4-(4-(2,6-dicarbonylpiperidin-3-yl)dihydroindol-1-yl)piperidin-1-carboxylic acid ester was dissolved in dichloromethane (1 mL), and 0.5 mL of trifluoroacetic acid was added. The reaction mixture was stirred for 0.5 hours. The solution was concentrated under reduced pressure, and the residue was purified by HPLC to give the title compound (61 mg, 81%). MS m / z(ESI):314.2[M+H]+.1H NMR (400MHz, DMSO-d6) δ = 10.81 (s, 1H), 6.93 (t, J = 7.6Hz, 1H), 6.36 (d, J = 8.0Hz, 1H), 6.31 (d, J = 7.6Hz, 1H), 3.83-3.68 (m, 2H), 3.44 (br s, 1H), 3.31 (br t,J=8.4Hz,2H),3.02(br s,2H),2.88-2.73(m,2H),2.73-2.52(m,3H),2.50-2.41(m,1H),2.17- 2.04(m,1H),2.03-1.92(m,1H),1.64-1.60(m,2H),1.56-1.39(m,2H).

[0522] 2-((3S,4R)-4-(4-((R)-2,6-dicarbonylpiperidin-3-yl)dihydroindol-1-yl)-3-fluoropiperidin-1-yl)acetic acid (compound B-24)

[0523] 45 mg (0.10 mmol) of tert-butyl 2-((3S,4R)-4-(4-((R)-2,6-dicarbonylpiperidin-3-yl)dihydroindol-1-yl)-3-fluoropiperidin-1-yl)acetate was dissolved in a mixed solution of dichloromethane (3 mL) and trifluoroacetic acid (3 mL). The mixture was stirred at room temperature for 30 minutes, and the solvent was removed by concentration under reduced pressure to obtain the title compound. MS m / z (ESI): 390.2 [M+H]+.

[0524] 1-(1-((3S,4S)-3-fluoropiperidin-4-yl)-1H-indazol-4-yl)dihydropyrimidine-2,4(1H,3H)-dione (compound B-25)

[0525] Step 1: Preparation of tert-butyl(3S,4R)-3-fluoro-4-((methanesulfonyl)oxo)piperidine-1-carboxylic acid ester

[0526] 25 g (114.02 mmol) of tert-butyl(3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylic acid ester and DIPEA (29.47 g, 228.05 mmol) were dissolved in 300 mL of dichloromethane and cooled to 0 °C. Methanesulfonic anhydride (29.79 g, 171.04 mmol) was added in portions. After addition, the mixture was transferred to room temperature and stirred for 2 hours. The solvent was removed by vacuum concentration. The residue was extracted three times with ethyl acetate. The combined ethyl acetate phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by column chromatography to give the title compound (33 g, 97%). MS m / z (ESI): 298.1 [M+H] + .

[0527] Step 2: Preparation of tert-butyl(3S,4S)-4-(4-bromo-1H-indazol-1-yl)-3-fluoropiperidine-1-carboxylic acid ester

[0528] 4-Bromo-1H-indazole (7 g, 35.72 mmol) and tert-butyl(3S,4R)-3-fluoro-4-((methanesulfonyl)oxo)piperidine-1-carboxylic acid ester (21.23 g, 71.41 mmol) were dissolved in DMSO (140 mL), and cesium carbonate (34.90 g, 107.11 mmol) was added. The reaction mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the title compound (3.4 g, 24%). MS m / z (ESI): 398.1 [M+H] + .

[0529] Step 3: Preparation of tert-butyl(3S,4S)-4-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)-1H-indazole-1-yl)-3-fluoropiperidine-1-carboxylic acid ester

[0530] Tert-butyl(3S,4S)-4-(4-bromo-1H-indazol-1-yl)-3-fluoropiperidine-1-carboxylic acid ester (3.4 g, 8.56 mmol) and dihydropyrimidine-2,4(1H,3H)-dione (3.9 g, 34.20 mmol) were dissolved in 1,4-dioxane (60 mL), and EPhos (916 mg, 1.71 mmol), EPhos Pd G4 (1.57 g, 1.71 mmol), and cesium carbonate (8.4 g, 25.78 mmol) were added. The mixture was evacuated and purged with nitrogen, and this process was repeated three times. The reaction mixture was heated to 110 °C and stirred for 16 hours under a nitrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the title compound (1 g, 27%). MS m / z (ESI): 432.2 [M+H] + .

[0531] Step 4: Preparation of 1-(1-((3S,4S)-3-fluoropiperidin-4-yl)-1H-indazol-4-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0532] 100 mg (0.23 mmol) of tert-butyl(3S,4S)-4-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)-1H-indazole-1-yl)-3-fluoropiperidine-1-carboxylic acid ester was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added. The reaction mixture was stirred for 1 hour. The solution was concentrated and dried under reduced pressure to obtain the crude product, which was then separated by high performance liquid chromatography to obtain the title compound (40 mg, 52%). MS m / z (ESI): 332.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.46(s,1H),8.09(s,1H),7.68(d,J=8.5Hz,1H),7.40(t,J=7.9Hz,1H),7.05(d,J=7.3Hz,1H),4.97-4.72(m,2H),3.8 9(t,J=6.6Hz,2H),3.37-3.27(m,2H),2.98(d,J=12.7Hz,1H),2.78(t, J=6.6Hz,2H),2.71-2.59(m,2H),2.16-2.05(m,1H),1.99-1.90(m,1H).

[0533] tert-Butyl 2-(4-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)-1H-indazol-1-yl)piperidin-1-yl)acetate (compound B-26)

[0534] The synthesis of compound B-26 references compound B-25. MS m / z (ESI): 428.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.46(s,1H),8.02(s,1H),7.66(d,J=8.5Hz,1H),7.39(t,J=7.3Hz,1H),7.04(d,J=7.3Hz,1H),4.617-4.55(m,1H),3.87( t,J=6.6Hz,2H),3.19(s,2H),2.98(d,J=11.4Hz,2H),2.78(t,J=6.6Hz,2 H),2.54-2.41(m,2H),2.20-2.05(m,2H),1.94-1.82(m,2H),1.44(s,9H).

[0535] 1-(1-(2-azaspiro[3.3]heptane-6-yl)dihydroindole-4-yl)dihydropyrimidine-2,4(1H,3H)-dione (compound B-27)

[0536] Step 1: Preparation of tert-butyl-6-(4-bromodihydroindol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid ester

[0537] 4-Bromodihydroindole (5 g, 25.38 mmol), tert-butyl-6-carbonyl-2-azaspiro[3.3]heptane-2-carboxylic acid ester (8 g, 37.90 mmol), and acetic acid (1.52 g, 25.31 mmol) were dissolved in 1,2-dichloroethane (100 mL), and the reaction mixture was stirred for 1 hour. Sodium triacetoxyborohydride (16.05 g, 75.73 mmol) was then added, and the reaction mixture was stirred for another 1 hour. The reaction mixture was poured into water (100 mL), extracted with dichloromethane (50 mL × 2), the organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the title compound (8 g, 80%). MS m / z (ESI): 393.1 [M+H] +

[0538] Step 2: Preparation of tert-butyl-6-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)dihydroindol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid ester

[0539] tert-Butyl-6-(4-bromodihydroindol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid ester (5 g, 12.75 mmol) and dihydropyrimidine-2,4(1H,3H)-dione (5.8 g, 50.86 mmol) were dissolved in 1,4-dioxane (150 mL), and EPhos (1.4 g, 2.62 mmol), EPhos Pd G4 (2.34 g, 2.55 mmol), and cesium carbonate (12.5 g, 38.36 mmol) were added. The mixture was evacuated and purged with nitrogen, and this process was repeated three times. The reaction mixture was heated to 110 °C and stirred for 16 hours under a nitrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the title compound (4 g, 74%). MS m / z (ESI): 427.2 [M+H] +

[0540] Step 3: Preparation of 1-(1-(2-azaspiro[3.3]heptane-6-yl)dihydroindole-4-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0541] 100 mg (0.23 mmol) of tert-butyl-6-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)dihydroindol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid ester was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added. The reaction mixture was stirred for 1 hour. The crude product was concentrated and dried under reduced pressure, and the title compound (40 mg, 52%) was prepared and separated by high performance liquid chromatography. MS m / z (ESI): 327.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.28(s,1H),6.99(t,J=7.2Hz,1H),6.49(d,J=8.0Hz,1H),6.35(d,J=8.0Hz,1H),3.75-3.69(m,1H),3.66(t,J=6.6 Hz,2H),3.55(s,2H),3.40(s,2H),3.26(t,J=6.6Hz,2H),2.76(t,J=6.2Hz,2H),2.67(t,J=6.2Hz,2H),2.42-2.32(m,2H),2.23-2.13(m,2H).

[0542] 1-(1-(2-azaspiro[3.5]nonane-7-yl)dihydroindole-4-yl)dihydropyrimidine-2,4(1H,3H)-dione (compound B-28)

[0543] Step 1: Preparation of tert-butyl-7-(4-bromodihydroindol-1-yl)-2-azaspiro[3.5]nonane-2-carboxylic acid ester

[0544] 4-Bromodihydroindole (5 g, 25.38 mmol), tert-butyl-7-carbonyl-2-azaspiro[3.5]nonane-2-carboxylic acid ester (9.1 g, 38.04 mmol), and acetic acid (1.52 g, 25.31 mmol) were dissolved in 1,2-dichloroethane (100 mL), and the reaction mixture was stirred for 1 hour. Sodium triacetoxyborohydride (16.05 g, 75.73 mmol) was then added, and the reaction mixture was stirred for another 1 hour. The reaction mixture was poured into water (100 mL), extracted with dichloromethane (50 mL × 2), the organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the title compound (9 g, 84%). MS m / z (ESI): 421.1 [M+H] +

[0545] Step 2: Preparation of tert-butyl-7-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)dihydroindole-1-yl)-2-azaspiro[3.5]nonane-2-carboxylic acid ester

[0546] tert-Butyl-7-(4-bromodihydroindol-1-yl)-2-azaspiro[3.5]nonane-2-carboxylic acid ester (5 g, 11.90 mmol) and dihydropyrimidine-2,4(1H,3H)-dione (5.4 g, 47.35 mmol) were dissolved in 1,4-dioxane (150 mL), and EPhos (1.3 g, 2.43 mmol), EPhos Pd G4 (2.2 g, 2.40 mmol), and cesium carbonate (11.6 g, 35.60 mmol) were added. The mixture was evacuated and purged with nitrogen, and this process was repeated three times. The reaction mixture was heated to 110 °C and stirred for 16 hours under a nitrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the title compound (3 g, 56%). MS m / z (ESI): 455.3 [M+H] +

[0547] Step 3: Preparation of 1-(1-(2-azaspiro[3.5]nonane-7-yl)dihydroindole-4-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0548] 100 mg (0.22 mmol) of tert-butyl-7-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)dihydroindol-1-yl)-2-azaspiro[3.5]nonane-2-carboxylic acid ester was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added. The reaction mixture was stirred for 1 hour. The crude product was concentrated and dried under reduced pressure, and the title compound (40 mg, 51%) was prepared and separated by high performance liquid chromatography. MS m / z (ESI): 355.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.28(s,1H),7.01(t,J=7.2Hz,1H),6.40(d,J=8.0Hz,1H),6.34(d,J=8.0Hz,1H),3.66(t,J=6.6Hz,2H),3.59-3.53(m,1H),3 .46(s,2H),3.17(s,2H),3.26(t,J=6.6Hz,2H),2.75(t,J=6.2Hz,2H),2.66 (t,J=6.2Hz,2H),2.10-1.85(m,2H),1.67-1.56(m,2H),1.55-1.22(m,4H).

[0549] 1-(1-((1r,4r)-4-(methylamino)cyclohexyl)-1H-indazol-4-yl)dihydropyrimidine-2,4(1H,3H)-dione (compound B-29)

[0550] Step 1: Preparation of (1s,4s)-4-((tert-butoxyoxo)(methyl)amino)cyclohexyl methanesulfonate

[0551] (cis)-tert-butyl N-(4-hydroxycyclohexyl)-N-methylcarbamate (1.7 g, 7.41 mmol) was dissolved in dichloromethane (20 mL), cooled to 0 °C, and then triethylamine (2.25 g, 22.24 mmol) and methanesulfonic anhydride (1.94 g, 11.12 mmol) were added sequentially. The reaction mixture was stirred at 20 °C for 2 hours, quenched with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (2.2 g, 97%). MS m / z (ESI): 252.2 [M-56+H] + .

[0552] Step 2: Preparation of tert-butyl N-[4-(4-bromoinzol-1-yl)cyclohexyl]-N-methyl-carbamate

[0553] 4-Bromo-1H-indazole (840 mg, 4.26 mmol) and (1s, 4s)-4-((tert-butoxyoxo)(methyl)amino)cyclohexyl methanesulfonate (1.1 g, 3.58 mmol) were dissolved in N,N-dimethylformamide (10 mL), and cesium carbonate (3.50 g, 10.74 mmol) was added. The reaction mixture was stirred at 100 °C for 3 hours. After cooling to room temperature, the reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography to give the title compound (750 mg, 51%). MS m / z (ESI): 408.2 [M+H] + .

[0554] Step 3: Preparation of tert-butylN-[4-[4-(2,4-dioxohexahydropyrimidin-1-yl)indazol-1-yl]cyclohexyl]-N-methylcarbamate

[0555] Under dry nitrogen protection, tert-butyl N-[4-(4-bromoinzol-1-yl)cyclohexyl]-N-methylcarbamate (750 mg, 1.84 mmol), hexahydropyrimidine-2,4-dione (840 mg, 7.36 mmol), cesium carbonate (1.80 g, 5.52 mmol), EPhos Pd G4 (254 mg, 276.52 μmol), and EPhos (148 mg, 276.74 μmol) were added to a dry 1,4-dioxane (22 mL). The reaction mixture was stirred at 100 °C for 16 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to column chromatography to give the title compound (500 mg, 61%). MS m / z (ESI): 442.2 [M+H] + .

[0556] Step 4: Preparation of 1-(1-((1r,4r)-4-(methylamino)cyclohexyl)-1H-indazol-4-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0557] tert-Butyl N-[4-[4-(2,4-dioxohexahydropyrimidin-1-yl)indazole-1-yl]cyclohexyl]-N-methyl-carbamate (300 mg, 679.47 μmol) was dissolved in a mixed solvent of dichloromethane (3 mL) and trifluoroacetic acid (3 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title compound, which was used directly in the next step without purification. (230 mg, 673.68 μmol, 99%). MS m / z (ESI): 342.2 [M+H] + . 1H NMR(400MHz, DMSO-d6)δ:10.45(s,1H),7.99(s,1H),7.66(d,J=8.0Hz,1H),7.38(t,J=7.2Hz,1H),7.03(d,J=8.0Hz,1H),4.67-4.56(m,1H ),3.87(t,J=6.2Hz,2H),2.77(t,J=6.2Hz,2H),2.45-2.35(m,1H),2.31(s,3H),2.07-1.97(m,3H),1.97-1.91(m,3H),1.35-1.22(m,2H).

[0558] 3-(dihydroindol-4-yl)piperidine-2,6-dione (compound B-30)

[0559] Step 1: Preparation of 4-(2,6-bis(benzyloxy)pyridin-3-yl)dihydroindole

[0560] 4-Bromodihydroindole (1 g, 5.05 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine (2.32 g, 5.55 mmol) were dissolved in 1,4-dioxane (25 mL) and water (4 mL). 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (369 mg, 504.9 μmol) and potassium carbonate (2.09 g, 15.15 mmol) were added. The mixture was evacuated and purged with nitrogen, and the process was repeated three times. The reaction mixture was heated to 100 °C and stirred for 6 hours under a nitrogen atmosphere. After cooling, the mixture was poured into water (20 mL) and extracted with ethyl acetate (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the title compound (2 g, 97%). MS m / z(ESI): 409.2[M+H]+.

[0561] Step 2: Preparation of 3-(dihydroindol-4-yl)piperidine-2,6-dione

[0562] 4-(2,6-Di(benzyloxy)pyridin-3-yl)dihydroindole (2 g, 4.90 mmol) was dissolved in tetrahydrofuran (15 mL), ethanol (8 mL), and ethyl acetate (15 mL). Wet palladium on carbon (2.38 g, 1.96 mmol, 10% purity) and platinum dioxide (222 mg, 979.21 μmol) were added. The mixture was evacuated and purged with hydrogen, and this process was repeated three times. The reaction mixture was stirred in a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrates were combined, concentrated under reduced pressure, dried, and then dissolved in 10 mL of acetonitrile. The solution was filtered through a microporous membrane, and the filtrate was subjected to HPLC to prepare and separate the title compound (35.8 mg, 3%). MS m / z (ESI): 231.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 10.5 (br s, 1H), 6.85 (t, J = 7.6Hz, 1H), 6.39 (d, J = 7.6Hz, 1H), 6.31 (d, J = 7.6Hz, 1H), 5.49 (s, 1H), 3.82-3.72 (m, 1H), 3.38 (br t,J=8.4Hz,2H),2.91-2.72(m,2H),2.71-2.60(m,1H),2.49-2.42(m,1H),2.17-2.04(m,1H),2.02-1.92(m,1H).

[0563] (R)-3-(1-((3R,4S)-3-fluoropiperidin-4-yl)dihydroindol-4-yl)piperidin-2,6-dione (compound B-31)

[0564] Compound B-31 was prepared from tert-butyl(R)-3-fluoro-4-carbonylpiperidine-1-carboxylic acid ester, using the same method as compound B-16. MS m / z (ESI): 332.2 [M+H] + .

[0565] tert-Butyl 2-((3R,4S)-4-(4-((R)-2,6-dicarbonylpiperidin-3-yl)dihydroindol-1-yl)-3-fluoropiperidin-1-yl)acetate (compound B-32)

[0566] Compound B-32 was prepared from compound B-31 using the same method as compound B-17. MS m / z (ESI): 446.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.80(s,1H),6.93(t,J=7.7Hz,1H),6.37(dd,J=22.4,7.8 Hz,2H),4.93(d,J=50.0Hz,1H),3.78(dd,J=11.6,5.0Hz,1H),3.61-3.52(m,1H),3. 51-3.41(m,1H),3.26-3.14(m,2H),3.12-3.03(m,1H),2.93(d,J=11.1Hz,1H),2.87 -.61(m,4H),2.58-2.42(m,3H),2.21-1.91(m,3H),1.58-1.47(m,1H),1.43(s,9H).

[0567] (R)-3-(1-((2S,4S)-2-methylpiperidin-4-yl)dihydroindol-4-yl)piperidin-2,6-dione (compound B-33)

[0568] Step 1: Preparation of tert-butyl(2S,4S)-4-(4-bromodihydroindol-1-yl)-2-methylpiperidine-1-carboxylic acid ester (P1) and tert-butyl(2S,4R)-4-(4-bromodihydroindol-1-yl)-2-methylpiperidine-1-carboxylic acid ester (P2)

[0569] Acetic acid (30 mL) was added to dichloroethane (300 mL) containing 4-bromodihydroindole (30 g, 151.47 mmol) and tert-butyl(2S)-2-methyl-4-carbonyl-piperidine-1-carboxylic acid ester (50 g, 234.44 mmol). The reaction mixture was stirred at 60 °C for 3 hours. The mixture was then cooled to room temperature, and sodium triacetoxyborohydride (64.21 g, 302.94 mmol) was added. Stirring was continued at room temperature for 1 hour. The reaction mixture was quenched with aqueous sodium bicarbonate solution, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, purified by silica gel column chromatography, and chiral resolution (method: CHIRALPAK OD, 4.6 × 150 mm, 5 μm; mobile phase: A for CO2 70%; B for EtOH). Compound P1 (38 g, 68%, retention time: 2.2 min) and compound P2 (18 g, 32%, retention time: 3.1 min) were obtained by flow rate: 2 ml / min (30%). P1 and P2 had the same molecular weight: MS m / z (ESI): 395.1 [M+H]. + .

[0570] Step 2: Preparation of tert-butyl(2S,4S)-4-(4-(2,6-di(benzyloxy)pyridin-3-yl)dihydroindole-1-yl)-2-methylpiperidine-1-carboxylic acid ester

[0571] At room temperature, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (655 mg, 895.17 μmol) and potassium carbonate (3.68 g, 26.60 mmol) were added to a solution of tert-butyl(2S,4S)-4-(4-bromodihydroindol-1-yl)-2-methylpiperidine-1-carboxylic acid ester (3.5 g, 8.85 mmol) and 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine (4.58 g, 10.98 mmol) in 1'4-dioxane (40 mL) and water (8 mL). The reaction solution was stirred at 100 °C for 16 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the target compound (5.3 g, 8.75 mmol, 98.83% yield). MS m / z (ESI): 606.2 [M+H] + .

[0572] Step 3: Preparation of tert-butyl(2S,4S)-4-(4-((R)-2,6-dicarbonylpiperidin-3-yl)dihydroindole-1-yl)-2-methylpiperidin-1-carboxylic acid ester

[0573] tert-Butyl(2S,4S)-4-(4-(2,6-di(benzyloxy)pyridin-3-yl)dihydroindol-1-yl)-2-methylpiperidin-1-carboxylic acid ester (5.3 g, 8.75 mmol) was dissolved in a mixed solvent of tetrahydrofuran (25 mL), ethanol (25 mL), and ethyl acetate (25 mL). Palladium on carbon (1.93 g, 10%) and platinum dioxide (973 mg, 4.28 mmol) were added. The reaction mixture was heated to 40 °C and stirred for 6 hours under a hydrogen atmosphere, and then cooled to room temperature. The reaction mixture was filtered, concentrated under reduced pressure, and chirally resolved (method: CHIRALPAK IA, 4.6 × 150 mm, 5 μm; mobile phase: A for CO2 60%; B for EtOH 30% & CAN 10%; flow rate: 2 mL / min; peak 1 retention time: 2.475 min) to give the target compound (1.5 g, 45%). MS m / z (ESI): 428.2 [M+H] + .

[0574] Step 4: Preparation of (R)-3-(1-((2S,4S)-2-methylpiperidin-4-yl)dihydroindol-4-yl)piperidin-2,6-dione

[0575] 750 mg (1.75 mmol) of tert-butyl(2S,4S)-4-(4-((R)-2,6-dicarbonylpiperidin-3-yl)dihydroindol-1-yl)-2-methylpiperidin-1-carboxylic acid ester was dissolved in a mixed solvent of dichloromethane (10 mL) and trifluoroacetic acid (5 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was subjected to HPLC to obtain the target compound (550 mg, 96%). MS m / z (ESI): 328.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=10.80(br s,1H),6.92(t,J=7.6Hz,1H),6.39-6.25(m,2H),3.81-3.71(m,1H),3.50-3.39(m,1H),3.32-3.22(m,3H),2.99(br d,J=11.2Hz,1H),2.86-2.56(m,5H),2.48-2.43(m,1H),2.16-1.92(m,2H),1.60(br t,J=12.8Hz,2H),1.46-1.33(m,1H),1.15-1.04(m,1H),1.00(d,J=6.4Hz,3H).

[0576] (R)-3-(1-((2S,4R)-2-methylpiperidin-4-yl)dihydroindol-4-yl)piperidin-2,6-dione (compound B-34)

[0577] Step 1: Preparation of tert-butyl(2S,4R)-4-(4-(2,6-di(benzyloxy)pyridin-3-yl)dihydroindole-1-yl)-2-methylpiperidine-1-carboxylic acid ester

[0578] tert-Butyl(2S,4R)-4-(4-bromodihydroindol-1-yl)-2-methylpiperidine-1-carboxylic acid ester (1.6 g, 4.05 mmol) and 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine (2.09 g, 5.02 mmol) were dissolved in a mixed solvent of 1,4-dioxane (15 mL) and water (3 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (299 mg, 408.64 μmol) and potassium carbonate (1.68 g, 12.16 mmol) were added. The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the target compound (2.4 g, 98%). MS m / z (ESI): 606.2 [M+H] + .

[0579] Step 2: Preparation of tert-butyl(2S,4R)-4-(4-((R)-2,6-dicarbonylpiperidin-3-yl)dihydroindole-1-yl)-2-methylpiperidin-1-carboxylic acid ester

[0580] 2.4 g (3.96 mmol) of tert-butyl(2S,4R)-4-(4-(2,6-di(benzyloxy)pyridin-3-yl)dihydroindol-1-yl)-2-methylpiperidin-1-carboxylic acid ester was dissolved in a mixed solvent of tetrahydrofuran (12 mL), ethanol (12 mL), and ethyl acetate (12 mL). Palladium / carbon (876 mg, 10%) and platinum dioxide (441 mg, 1.94 mmol) were added. The reaction mixture was heated to 40 °C and stirred for 6 hours under a hydrogen atmosphere and then cooled to room temperature. The mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was chirally resolved (method: CHIRALPAK IA, 4.6 × 150 mm, 5 μm; mobile phase: A for CO2 60%; B for EtOH 30% & CAN 10%; flow rate: 2 ml / min; peak 1 retention time: 2.586 min) to obtain the target compound (750 mg, 47%). MS m / z (ESI): 428.2 [M+H] + .

[0581] Step 3: Preparation of (R)-3-(1-((2S,4R)-2-methylpiperidin-4-yl)dihydroindol-4-yl)piperidin-2,6-dione

[0582] At room temperature, trifluoroacetic acid (1.5 mL) was added to a solution of tert-butyl(2S,4R)-4-(4-((R)-2,6-dicarbonylpiperidin-3-yl)dihydroindol-1-yl)-2-methylpiperidin-1-carboxylic acid ester (300 mg, 701.70 μmol) in dichloromethane (3 mL). The reaction mixture was stirred at 20 °C for 1 hour, concentrated under reduced pressure, and the residue was subjected to HPLC to prepare the target compound (200 mg, 87%). MS m / z (ESI): 328.2 [M+H] + .MS m / z(ESI):328.2[M+H] + . 1H NMR (400MHz, DMSO-d6) δ = 10.81 (br s, 1H), 6.94 (t, J = 7.6Hz, 1H), 6.39-6.30 (m, 2H), 3.81-3.73 (m, 1H), 3.68 (br t,J=9.6Hz,1H),3.37-3.28(m,3H),2.97-2.61(m,5H),2.48-2.43(m,1H),2. 17-2.04(m,1H),2.01-1.92(m,1H),1.82-1.43(m,4H),1.18(d,J=6.8Hz,3H).

[0583] (R)-3-(1-((2R,4R)-2-methylpiperidin-4-yl)dihydroindol-4-yl)piperidin-2,6-dione (compound B-35)

[0584] Starting from tert-butyl(2R)-2-methyl-4-carbonyl-piperidine-1-carboxylic acid ester, the preparation method was the same as for compound B-33. MS m / z (ESI): 328.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=10.80(br s,1H),6.93(t,J=7.6Hz,1H),6.41-6.25(m,2H),3.81-3.71(m,1H),3.51-3.40(m,1H),3.31-3.24(m,3H),3.00(br d,J=11.2Hz,1H),2.87-2.72(m,2H),2.71-2.56(m,3H),2.48-2.43(m,1H),2.18-2.04(m,1H),2.02-1.92(m,1H),1.61(br t,J=12.4Hz,2H),1.48-1.34(m,1H),1.18-1.06(m,1H),1.01(d,J=6.4Hz,3H).

[0585] (R)-3-(1-((2R,4S)-2-methylpiperidin-4-yl)dihydroindol-4-yl)piperidin-2,6-dione (compound B-36)

[0586] Starting from tert-butyl(2R)-2-methyl-4-carbonyl-piperidine-1-carboxylic acid ester, the preparation method is the same as that for compound B-34. MS m / z (ESI): 328.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ=10.80(br s,1H),6.93(t,J=7.6Hz,1H),6.32(t,J=7.2Hz,2H),3.81-3.73(m,1H),3.69-3.60(m,1H),3.38-3.34(m,2H),3.25-3.19(m ,1H),2.91-2.62(m,5H),2.48-2.43(m,1H),2.17-2.04(m,1H),2.02-1.93(m,1H),1.77-1.40(m,4H),1.14(d,J=6.8Hz,3H).

[0587] Preparation of 3-(1-(piperidin-4-yl)-1H-indazol-4-yl)piperidin-2,6-dione (Compound B-37)

[0588] Step 1: Preparation of tert-butyl((1r,4r)-4-(4-bromo-1H-indazol-1-yl)cyclohexyl)(methyl)carbamate

[0589] 4-Bromo-1H-indazole (7 g, 35.72 mmol) and (1s, 4s)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl methanesulfonate (20 g, 71.66 mmol) were dissolved in DMSO (100 mL), and cesium carbonate (34.90 g, 107.11 mmol) was added. The reaction mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the title compound (3 g, 27%). MS m / z (ESI): 380.1 [M+H] + .

[0590] Step 2: Preparation of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-1H-indazol-1-yl)piperidine-1-carboxylic acid ester

[0591] Tert-butyl((1r,4r)-4-(4-bromo-1H-indazol-1-yl)cyclohexyl)(methyl)carbamate (2.7 g, 7.12 mmol) and 2,6-di(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine (4.23 g, 10.14 mmol) were dissolved in 1,4-dioxane (60 mL) and water (20 mL), and Pd(dppf)Cl2 (495 mg, 676.51 μmol) and potassium carbonate (2.80 g, 20.29 mmol) were added. The mixture was evacuated and purged with nitrogen, and this process was repeated three times. The reaction mixture was heated to 100 °C and stirred for 1.5 hours under a nitrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the title compound (3.2 g, 89%). MS m / z (ESI): 591.3 [M+H] + .

[0592] Step 3: Preparation of tert-butyl 4-(4-(2,6-dicarbonylpiperidin-3-yl)-1H-indazole-1-yl)piperidin-1-carboxylic acid ester

[0593] 3.2 g (5.74 mmol) of tert-butyl-4-(4-(2,6-di(benzyloxy)pyridin-3-yl)-1H-indazol-1-yl)piperidine-1-carboxylic acid ester was dissolved in ethanol (15 mL), tetrahydrofuran (15 mL), and ethyl acetate (15 mL). Palladium on carbon (1.4 g, 10% purity) and platinum dioxide (700 mg, 3.08 mmol) were added. The mixture was evacuated and purged with hydrogen gas, and this process was repeated three times. The reaction mixture was stirred in a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the title compound (2 g, 90%). MS m / z (ESI): 413.2 [M+H] +

[0594] Step 4: Preparation of 3-(1-(piperidin-4-yl)-1H-indazol-4-yl)piperidin-2,6-dione

[0595] 100 mg (0.24 mmol) of tert-butyl 4-(4-(2,6-dicarbonylpiperidin-3-yl)-1H-indazole-1-yl)piperidin-1-carboxylic acid ester was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added. The reaction mixture was stirred for 1 hour. The solution was concentrated and dried under reduced pressure to obtain the crude product, which was then separated by high performance liquid chromatography to obtain the title compound (30 mg, 40%). MS m / z (ESI): 313.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.91(s,1H),8.05(s,1H),7.63(d,J=8.2Hz,1H),7.31(t,J=7.2Hz,1H),6.95(d,J=8.2Hz,1H),4.71-4.61(m,1H ),4.32-4.26(m,1H),3.12-3.05(m,2H),2.80-2.64(m,3H),2.58-2.53(m,1H),2.42-2.33(m,1H),2.13-1.92(m,3H),1.88-1.80(m,2H).

[0596] The following compounds were prepared by referring to the preparation methods of compounds B-1 to B-37 above.

[0597] Example 1-A

[0598] 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(4-(2-(1-(4-((S)-2,6-dicarbonylpiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-4-hydroxypiperidin-4-yl)acetyl)piperazin-1-yl)phenyl)-4-fluoro-1-carbonylisodihydroindole-2-yl)-N-(thiazolyl-2-yl)acetamide

[0599] Compound B-1 (51 mg, 127 μmol), HATU (48 mg, 126 μmol), and N,N-diisopropylethylamine (55 mg, 426 μmol) were sequentially added to N,N-dimethylformamide (5 mL), and stirred at room temperature for 15 minutes. Compound A-2 (50 mg, 89.8 μmol) was then added, and stirring continued at room temperature for 1 hour. The mixture was filtered through a microporous membrane, and the filtrate was separated by HPLC to obtain the title compound (43 mg, 51%). MS m / z (ESI): 943.4 [M+H] + .

[0600] Example 33

[0601] Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[4-[[1-[2-(2,6-dicarbonyl-3-piperidinyl)-3-carbonyl-isodihydroindole-5-yl]-4-piperidinyl]methyl]piperazin-1-yl]phenyl]-4-fluoro-1-carbonyl-isodihydroindole-2-yl]-N-thiazolyl-2-yl-acetamide

[0602] Compound A-2 (40 mg, 67.33 μmol) and compound B-12 (100 mg, 281.38 μmol) were dissolved in N,N-dimethylformamide (1 mL), and acetic acid (0.2 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes, cooled to 0 °C, and sodium triacetoxyborohydride (43 mg, 202.89 μmol) was added. The mixture was then transferred to room temperature and stirred for 30 minutes. The mixture was filtered through a microporous membrane, and the filtrate was purified by HPLC to obtain the title compound (25.7 mg, 43%). MS m / z (ESI): 897.4 [M+H] + .

[0603] Example 47

[0604] Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(4-((1-(2-((S)-2,6-dicarbonylpiperidin-3-yl)-3-carbonylisodihydroindole-5-yl)acetidin-3-yl)methyl)piperazin-1-yl)phenyl)-4-fluoro-1-carbonylisodihydroindole-2-yl)-N-(thiazol-2-yl)acetamide

[0605] Compounds A-2 (40 mg, 67.33 μmol) and B-11 (40 mg, 67.33 μmol) were dissolved in N,N-dimethylformamide (1 mL), and acetic acid (0.2 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes, cooled to 0 °C, and sodium triacetoxyborohydride (43 mg, 202.89 μmol) was added. The mixture was then transferred to room temperature and stirred for another 30 minutes. The reaction mixture was filtered, and the filtrate was purified by HPLC to obtain the title compound (15 mg, 25%). MS m / z (ESI): 869.3 [M+H] + .

[0606] Example 71-A

[0607] 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(4-((1R,3s)-3-(5-(((S)-2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindole-2-yl)cyclobutane-1-carbonyl)piperazin-1-yl)phenyl)-4-fluoro-1-carbonylisodihydroindole-2-yl)-N-(thiazolyl-2-yl)acetamide

[0608] Compound B-9 (48 mg, 127 μmol), HATU (48 mg, 126 μmol), and N,N-diisopropylethylamine (55 mg, 426 μmol) were sequentially added to N,N-dimethylformamide (5 mL), and stirred at room temperature for 15 minutes. Compound A-2 (50 mg, 89.8 μmol) was then added, and stirring continued at room temperature for 1 hour. The mixture was filtered through a microporous membrane, and the filtrate was separated by HPLC to obtain the title compound (17 mg, 21%). MS m / z (ESI): 883.3 [M+H] + .

[0609] Example 71-D

[0610] 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(4-((1S,3r)-3-(5-(((S)-2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindole-2-yl)cyclobutane-1-carbonyl)piperazin-1-yl)phenyl)-4-fluoro-1-carbonylisodihydroindole-2-yl)-N-(thiazolyl-2-yl)acetamide

[0611] Compound B-7 (48 mg, 127 μmol), HATU (48 mg, 126 μmol), and N,N-diisopropylethylamine (55 mg, 426 μmol) were dissolved in N,N-dimethylformamide (5 mL) and stirred at 25 °C for 15 min. Compound A-2 (50 mg, 89.8 μmol) was added, and the reaction was carried out at 25 °C for 1 h. Aqueous solution (25 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then preparatively isolated by liquid chromatography to obtain the title compound (13 mg, 16%). MS m / z (ESI): 883.3 [M+H] + .

[0612] Example 72-A

[0613] 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(4-(2-(5-((((S)-2,6-dicarbonylpiperidin-3-yl)amino)isodihydroindole-2-yl)acetyl)piperazin-1-yl)phenyl)-4-fluoro-1-carbonylisodihydroindole-2-yl)-

[0614] N-(thiazolyl-2-yl)acetamide

[0615] Compound B-5 (51 mg, 149.7 μmol), HATU (64 mg, 168.4 μmol), and N,N-diisopropylethylamine (86 mg, 666.7 μmol) were sequentially added to N,N-dimethylformamide (5 mL), and stirred at room temperature for 15 minutes. Compound A-2 (62 mg, 111.3 μmol) was then added, and stirring continued at room temperature for 1 hour. The mixture was filtered through a microporous membrane, and the filtrate was separated by HPLC to obtain the title compound (70 mg, 75%). MS m / z (ESI): 843.3 [M+H] + .

[0616] The preparation methods for other embodiments are the same as those in the above embodiments. The compounds of the present invention are summarized as follows:

[0617] Example 112 can also be prepared according to the following method

[0618] 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(4-(2-(4-(4-(2,4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)dihydroindole-1-yl)piperidin-1-yl)acetyl)piperazin-1-yl)phenyl)-4-fluoro-1-carbonylisodihydroindole-2-yl)-N-(thiazolyl-2-yl)acetamide

[0619] Compound A-2 (279 mg, 0.5 mmol) contains 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-1-carbonyl-6-(4-(piperazin-1-yl)phenyl)isodihydroindole-2-yl)-N-(thiazolyl-2-yl)acetamide (compound A-2) (279 mg, 0.5 mmol) and 2-(4-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)dihydroindole-1-yl) 1-(2-yl)piperidin-1-yl)acetic acid (compound B-13) (224 mg, 0.6 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the sequential addition of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (228 mg, 0.6 mmol) and diisopropylethylamine (646 mg, 5.00 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The solution was filtered through a microporous membrane, and the filtrate was preparatively separated by HPLC to obtain the title compound (118 mg, 26%). MS m / z (ESI): 912.3 [M+H] +

[0620] Example 118 can also be prepared according to the following method

[0621] 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(6-(2-(4-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)dihydroindole-1-yl)piperidin-1-yl)acetyl)-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-4-fluoro-1-carbonylisodihydroindole-2-yl)-N-(thiazolyl-2-yl)acetamide

[0622] 2-(6-(4-(2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-4-fluoro-1-carbonylisodihydroindole-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide (compound A-1) (285 mg, 0.5 mmol) and 2-(4-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl) Dihydroindol-1-yl)piperidin-1-yl)acetic acid (compound B-13) (224 mg, 0.6 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (228 mg, 0.6 mmol) and diisopropylethylamine (646 mg, 5.00 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The mixture was filtered through a microporous membrane, and the filtrate was preparatively separated by HPLC to obtain the title compound (148 mg, 32%). MS m / z (ESI): 924.3 [M+H] + .

[0623] Example 168 can also be prepared according to the following method

[0624] Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(6-((S)-4-(2-((3S,4R)-4-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)dihydroindole-1-yl)-3-fluoropiperidin-1-yl)acetyl)-3-methylpiperazin-1-yl)pyridin-3-yl)-4-fluoro-1-carbonylisodihydroindole-2-yl)-N-(pyridin-2-yl)acetamide

[0625] Step 1: Preparation of (S)-(6-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)pyridin-3-yl)boronic acid

[0626] 2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine (1.3 g, 5.83 mmol) and tert-butyl(S)-2-methylpiperazine-1-carboxylic acid ester (3.03 g, 15.15 mmol) were mixed in dimethyl sulfoxide (12 mL), bubbled under nitrogen for 5 minutes, and then potassium carbonate (4.03 g, 29.14 mmol) was added. The mixture was microwaved to 90 °C and stirred for 3 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was isolated by reverse-phase chromatography to give the title compound (269 mg, 14%). MS m / z (ESI): 322.2 [M+H] + .

[0627] Step 2: Preparation of tert-butyl(2S)-4-(5-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-carbonyl-2-(pyridin-2-ylamino)ethyl)-7-fluoro-3-carbonylisodihydroindole-5-yl)pyridin-2-yl)-2-methylpiperazine-1-carboxylic acid ester

[0628] 2-(6-bromo-4-fluoro-1-carbonylisodihydroindol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-yl)acetamide (compound A-3) (190 mg, 0.40 mmol) and (S)-(6-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)pyridin-3-yl)boronic acid (130 mg, 0.40 mmol) The compound was dissolved in dioxane / water (5 mL / 0.8 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (50 mg, 60.60 μmol), 2-di-tert-butylphosphine-2',4',6'-triisopropylbiphenyl (51.5 mg, 121.2 μmol), and sodium carbonate (163 mg, 1.54 mmol) were added. The mixture was purged with nitrogen three times, heated to 80 °C, and stirred for 3 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The residue was subjected to column chromatography to give the title compound (206 mg, 76%). MS m / z (ESI): 667.2 [M+H] + .

[0629] Step 3: Preparation of crude 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-(6-((S)-3-methylpiperazin-1-yl)pyridin-3-yl)-1-carbonylisodihydroindol-2-yl)-N-(pyridin-2-yl)acetamide trifluoroacetate

[0630] 50 mg (74.99 μmol) of tert-butyl(2S)-4-(5-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-carbonyl-2-(pyridin-2-ylamino)ethyl)-7-fluoro-3-carbonylisodihydroindol-5-yl)pyridin-2-yl)-2-methylpiperazine-1-carboxylic acid ester was dissolved in a mixed solvent of dichloromethane (2 mL) and trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 1 hour. After concentrating the organic solvent under reduced pressure, the crude trifluoroacetate of the title compound was obtained and used directly in the next reaction. MS m / z (ESI): 567.2 [M+H] + .

[0631] Step 4: Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(6-((S)-4-(2-((3S,4R)-4-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)dihydroindole-1-yl)-3-fluoropiperidin-1-yl)acetyl)-3-methylpiperazin-1-yl)pyridin-3-yl)-4-fluoro-1-carbonylisodihydroindole-2-yl)-N-(pyridin-2-yl)acetamide

[0632] 2-((3S,4R)-4-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)dihydroindol-1-yl)-3-fluoropiperidin-1-yl)acetic acid (compound B-14) (36 mg, 82.94 μmol) and 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-(6-((S)-3-methylpiperazin-1-yl)pyridin-3-yl)-1-carbonylisodihydroindol-2-yl)-N-(pyridin-2-yl)acetamide trifluoroacetate (crude product of step 3) were dissolved in DMF (2 mL), and HATU (38 mg, 99.5 μmol) and diisopropylethylamine (64 mg, 497.7 μmol) were added. The mixture was reacted at room temperature for 1 hour. The solution was filtered through a microporous membrane, and the filtrate was separated by HPLC to obtain the title compound (29 mg, overall yield of 41%). MS m / z (ESI): 939.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.89(s,1H),10.29(s,1H),8.56(d,J=2.6Hz,1H),8.33-8.30(m,1H),8.06(d,J=8.4Hz,1H),8.03-7.96(m,1H),7.82 -7.78(m,2H),7.77-7.75(m,1H),7.60(s,1H),7.14-7.09(m,1H),7.03 -6.90(m,2H),6.47-6.40(m,2H),6.19(s,1H),5.00-4.90(m,1H),4.80 (d,J=18.0Hz,1H),4.67-4.29(m,2H),4.28-4.10(m,3H),4.07-3.88(m ,3H),3.73-3.38(m,6H),3.29-3.01(m,5H),2.99-2.70(m,5H),2.66(t ,J=6.6Hz,2H),2.59-2.52(m,2H),2.41-2.27(m,1H),2.17-2.04(m,1H ),1.61-1.53(m,1H),1.25(d,J=6.0Hz,1.5H),1.10(d,J=6.0Hz,1.5H).

[0633] Example 188 can also be prepared according to the following method

[0634] 1-(5-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-carbonyl-2-(pyridin-2-ylamino)ethyl)-7-fluoro-3-carbonylisodihydroindole-5-yl)pyridin-2-yl)-N-((1r,4r)-4-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)dihydroindole-1-yl)cyclohexyl)-N-methylpiperidin-4-carboxamide

[0635] Step 1: Preparation of methyl 1-(5-bromopyridin-2-yl)piperidine-4-carboxylic acid ester

[0636] 4-Piperidincarnate (3 g, 20.95 mmol) and 5-bromo-2-fluoropyridine (4.42 g, 25.14 mmol) were dissolved in N,N-dimethylformamide (60 mL), and potassium carbonate (8.69 g, 62.86 mmol) was added. The reaction mixture was heated to 90 °C and stirred for 16 hours. After cooling to room temperature, the solution was poured into 600 mL of water, filtered, and the precipitated solid was collected. The solid was concentrated under reduced pressure and dried to give the title compound (4.86 g, 78%). MS m / z (ESI): 299.0 [M+H] + .

[0637] Step 2: Preparation of methyl 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridin-2-yl)piperidine-4-carboxylic acid ester

[0638] Methyl 1-(5-bromopyridin-2-yl)piperidine-4-carboxylic acid ester (2.86 g, 9.56 mmol), pinacol diborate ester (3.64 g, 14.34 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (700 mg, 956.00 μmol), and potassium acetate (2.81 g, 28.68 mmol) were added to 1,4-dioxane (75 mL). The reaction system was purged three times with dry nitrogen and heated to 100 °C with stirring for 16 hours. After cooling to room temperature, the reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the title compound (3 g, 91%). MS m / z (ESI): 347.2 [M+H] +

[0639] Step 3: Preparation of methyl 1-(5-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-carbonyl-2-(pyridin-2-ylamino)ethyl)-7-fluoro-3-carbonylisodihydroindole-5-yl)pyridin-2-yl)piperidine-4-carboxylic acid ester

[0640] 2-(6-bromo-4-fluoro-1-carbonylisodihydroindol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-yl)acetamide (compound A-3) (150 mg, 318.95 μmol), methyl 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridin-2-yl)piperidine-4-carboxylic acid ester (165.64 mg, 478.42 μmol), and tetra(triphenylphosphine)palladium (73.71 mg, 63.79 μmol) were added to 1,4-dioxane (10 mL), and sodium carbonate (101.42 mg, 956.85 μmol) in water (1.5 mL) were added. The reaction system was purged with nitrogen three times and heated to 110 °C with stirring for 16 hours. The solution was cooled to room temperature, filtered through diatomaceous earth, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the title compound (150 mg, 77%). MS m / z (ESI): 610.2 [M+H] +

[0641] Step 4: Preparation of 1-(5-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-carbonyl-2-(pyridin-2-ylamino)ethyl)-7-fluoro-3-carbonylisodihydroindole-5-yl)pyridin-2-yl)piperidine-4-carboxylic acid

[0642] Methyl 1-(5-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-carbonyl-2-(pyridin-2-ylamino)ethyl)-7-fluoro-3-carbonylisodihydroindol-5-yl)pyridin-2-yl)piperidine-4-carboxylic acid ester (150 mg, 246.04 μmol) was dissolved in tetrahydrofuran (5 mL), and lithium hydroxide aqueous solution (1 M, 1.23 mL) was added. The mixture was stirred at room temperature for 1 hour. The pH of the reaction solution was adjusted to 5-6 with 1N dilute hydrochloric acid, and then extracted with a dichloromethane / methanol mixture (50 mL × 2, v / v = 20 / 1). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (116 mg, 79%). MS m / z (ESI): 596.2 [M+H] +

[0643] Step 5: Preparation of 1-(5-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-carbonyl-2-(pyridin-2-ylamino)ethyl)-7-fluoro-3-carbonylisodihydroindole-5-yl)pyridin-2-yl)-N-((1r,4r)-4-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)dihydroindole-1-yl)cyclohexyl)-N-methylpiperidin-4-carboxamide

[0644] Dissolve 1-(5-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-carbonyl-2-(pyridin-2-ylamino)ethyl)-7-fluoro-3-carbonylisodihydroindol-5-yl)pyridin-2-yl)piperidine-4-carboxylic acid (67 mg, 110.97 μmol) in N,N-dimethylformamide (3 mL), and then add diisopropylethylamine (114.74 mg, 887.76 μmol, 154 μmol) sequentially. 0.63 μL) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (76 mg, 199.75 μmol) were added, and the mixture was stirred at room temperature for 10 minutes. Then, 1-(1-((1r,4r)-4-(methylamino)cyclohexyl)dihydroindol-4-yl)dihydropyrimidine-2,4(1H,3H)-dione (compound B-15) (38 mg, 110.97 μmol) was added, and the reaction mixture was stirred at room temperature for another 20 minutes. The reaction mixture was filtered through a microporous membrane, and the filtrate was subjected to high-performance liquid chromatography (HPLC) to prepare and separate the title compound (47.6 mg, 47%). MS m / z (ESI): 920.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 10.90 (s, 1H), 10.29 (d, J = 3.6Hz, 1H), 8.55 (d, J = 2.4Hz, 1H), 8.35-8.29 (m, 1H), 8.07 (br d,J=8.4Hz,1H),8.01-7.94(m,1H),7.84-7.74(m,3H),7.62(s,1H),7.16-7.09(m,1H),7.05-6.98(m,1H), 6.94(d,J=9.2Hz,1H),6.47-6.40(m,1H),6.39-6.33(m,1H),6.20(s,1H),4.80(d,J=17.6Hz,1H),4.40(br d,J=13.2Hz,2H),4.22(d,J=17.6Hz,1H),4.07-3.91(m,2H),3.71-3.62(m,2H),3.50-3.34(m,3H),3.31(br s,1H),3.09-2.96(m,2H),2.94(s,3H),2.89-2.72(m,4H),2.72(s,1H),2. 69-2.63(m,2H),2.58-2.51(m,2H),1.80-1.60(m,8H),1.59-1.45(m,4H).

[0645] Example 208

[0646] 1-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(pyridin-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindole-5-yl)-2-methoxyphenyl)-N-((1r,4r)-4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)dihydroindole-1-yl)cyclohexyl)-N-methylpiperidin-4-carboxamide

[0647] The preparation method of Example 208 can also be found in Example 188. MS m / z (ESI): 949.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),10.29(s,1H),8.32(dd,J=5.1,1.9Hz,1H),8.07(d,J=8.4Hz,1H),7.83(s,1H),7 .81-7.76(m,2H),7.63(s,1H),7.31(d,J=9.0Hz,2H),7.15-7.09(m,1H),7.03-6.92(m,2H),6.45-6.34(m,2H),6.21(s ,1H),4.82(d,J=17.8Hz,1H),4.24(d,J=17.8Hz,1H),4.06-3.99(m,2H),3.91(s,3H),3.67(t,J=6.7Hz,2H),3.51-3.4 1(m,2H),3.41-3.25(m,8H),2.92(s,2H),2.85-2.61(m,6H),2.51-2.42(m,5H),1.90-1,62(m,7H),1.60-1.42(m,2H).

[0648] Example 209 can also be prepared according to the following method

[0649] 1-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazo-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindole-5-yl)-2-methoxyphenyl)-N-((1r,4r)-4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)dihydroindole-1-yl)cyclohexyl)-N-methylpiperidin-4-carboxamide

[0650] Step 1: Preparation of tert-butyl-1-(4-bromo-2-methoxyphenyl)piperidine-4-carboxylic acid ester

[0651] Under dry nitrogen protection, tert-butylpiperidine-4-carboxylic acid ester (10 g, 53.98 mmol) and 4-bromo-1-iodo-2-methoxybenzene (17.74 g, 56.68 mmol) were dissolved in toluene (200 mL), followed by the addition of Pd₂(dba)₃ (2.97 g, 3.24 mmol), xantphos (3.75 g, 6.48 mmol), and sodium tert-butoxide (15.56 g, 161.93 mmol). The reaction mixture was heated to 60 °C and stirred for 6 hours, then cooled to room temperature. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give the title compound (18 g, 90%). MS m / z (ESI): 370.1 [M+H] + .

[0652] Step 2: Preparation of tert-butyl-1-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)phenyl)piperidine-4-carboxylic acid ester

[0653] Under dry nitrogen protection, tert-butyl-1-(4-bromo-2-methoxyphenyl)piperidine-4-carboxylic acid ester (10 g, 27.01 mmol), pinacol diboronate (20.58 g, 81.02 mmol), Pd(dppf)Cl2 (3.95 g, 5.40 mmol), and potassium acetate (10.60 g, 108.03 mmol) were added to dioxane (200 mL). The reaction mixture was heated to 100 °C and stirred for 4 hours, then cooled to room temperature. The mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to obtain the title compound (10 g, 89%). MS m / z (ESI): 418.3 [M+H] + .

[0654] Step 3: Preparation of tert-butyl 1-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindole-5-yl)-2-methoxyphenyl)piperidine-4-carboxylic acid ester

[0655] Under nitrogen protection, 2-(6-bromo-4-fluoro-1-oxoisodihydroindol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazo-2-yl)acetamide (0.6 g, 1.26 mmol) and tert-butyl-1-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)phenyl)piperidine-4-carboxylic acid ester (1.05 g, 2.52 mmol) were dissolved in 1,4-dioxane (25 mL) and water (8 mL). Pd(PPh3)4 (437 mg, 0.38 mmol) and sodium carbonate (401 mg, 3.78 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 3 hours, then cooled to room temperature. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to obtain the title compound (0.52 g, 60%). MS m / z (ESI): 687.3 [M+H] + .

[0656] Step 4: Preparation of 1-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindole-5-yl)-2-methoxyphenyl)piperidine-4-carboxylic acid trifluoroacetate

[0657] 520 mg (757.14 μmol) of tert-butyl-1-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindol-5-yl)-2-methoxyphenyl)piperidine-4-carboxylic acid ester was dissolved in a mixed solvent of dichloromethane (10 mL) and trifluoroacetic acid (10 mL) and stirred at room temperature for 1 hour. The solution was concentrated and dried under reduced pressure to obtain crude trifluoroacetate of the title compound, which was used directly in the next reaction without further purification. MS m / z (ESI): 631.2 [M+H] + .

[0658] Step 5: Preparation of 1-(1-((1r,4r)-4-(methylamino)cyclohexyl)dihydroindole-4-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0659] 336 mg (759.24 μmol) of tert-butyl((1r,4r)-4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)dihydroindole-1-yl)cyclohexyl)(methyl)carbamate was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (10 mL) was added. The reaction mixture was stirred for 1 hour. The solution was concentrated and dried under reduced pressure to obtain crude trifluoroacetate of the title compound, which was used directly in the next reaction without further purification. MS m / z (ESI): 343.2 [M+H] + .

[0660] Step 6: Preparation of 1-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindole-5-yl)-2-methoxyphenyl)-N-((1r,4r)-4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)dihydroindole-1-yl)cyclohexyl)-N-methylpiperidine-4-carboxamide

[0661] The crude trifluoroacetate of 1-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindol-5-yl)-2-methoxyphenyl)piperidine-4-carboxylic acid and the crude trifluoroacetate of 1-(1-((1r,4r)-4-(methylamino)cyclohexyl)dihydroindol-4-yl)dihydropyrimidine-2,4(1H,3H)-dione trifluoroacetate from step 5 were dissolved in N,N-dimethylformamide (10 mL), cooled to 0 °C, and DIPEA (489 mg, 3.78 mmol) and HATU (288 mg, 0.76 mmol) were added sequentially. The reaction mixture was stirred for 0.5 hours. The reaction solution was filtered through a microporous membrane, and the filtrate was subjected to HPLC to prepare and separate the title compound (318 mg, 44%). MS m / z (ESI): 955.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.52(s,1H),10.29(s,1H),7.84(s,1H),7.80(d,J=10.6H z,1H),7.61(s,1H),7.49(d,J=3.6Hz,1H),7.30(d,J=8.6Hz,2H),7.26(d,J=3.5Hz ,1H),7.05-6.94(m,2H),6.49–6.29(m,2H),6.16(s,1H),4.82(d,J=17.8Hz,1H),4 .24(d,J=17.7Hz,1H),4.08-3.94(m,2H),3.91(s,3H),3.67(t,J=6.6Hz,2H),3.52 -3.41(m,2H),3.32(s,8H),2.92(s,2H),2.88-2.59(m,8H),2.57-2.44(m,2H),1.93-1.61(m,8H),1.59-1.46(m,2H).

[0662] Example 210

[0663] 1-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazo-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindole-5-yl)-2-(methoxy-d3)phenyl)-N-((1r,4r)-4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)dihydroindole-1-yl)cyclohexyl)-N-methylpiperidin-4-carboxamide

[0664] The preparation method of Example 210 can also be found in Example 209. MS m / z (ESI): 958.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.52(s,1H),10.28(s,1H),7.84(s,1H),7.80(d,J=10.7Hz,1H),7.61(s,1H),7.49(d,J=3.6Hz,1H),7.31-7.29(m,2H ),7.26(d,J=3.6Hz,1H),7.02(t,J=8.0Hz,1H),6.97(d,J=7.5Hz,1H),6.48-6.40(m,1H),6.37(d,J=8.4Hz,1H),6.16(s,1H),4.81(d,J=17.7Hz ,1H),4.33-4.31(m,1H),4.24(d,J=17.7Hz,1H),4.02-3.98(m,2H),3.67(t,J=6.6Hz,2H),3.47(d,J=10.6Hz,2H),3.37(d,J=7.9Hz,1H),3.31 (s,1H),2.96-2.89(m,2H),2.79-2.71(m,5H),2.68-2.65(m,4H),2.57- 2.52(m,2H),2.49-2.46(m,2H),1.85-1.65(m,10H),1.60-1.47(m,3H).

[0665] Example 211

[0666] 1-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(pyridin-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindole-5-yl)-2-(methoxy-d3)phenyl)-N-((1r,4r)-4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)dihydroindole-1-yl)cyclohexyl)-N-methylpiperidin-4-carboxamide

[0667] The preparation method of Example 211 can also be found in Example 188. MS m / z (ESI): 952.5 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.89 (s, 1H), 10.28 (s, 1H), 8.32 (d, J = 4.8Hz, 1H), 8.07(d,J=8.6Hz,1H),7.84(s,1H),7.80(d,J=6.2Hz,1H),7.78(s,1H),7.6 1(s,1H),7.31-7.29(m,2H),7.16-7.08(m,1H),7.01(d,J=8.3Hz,1H),7.00 -6.97(m,1H),6.42(d,J=7.9Hz,1H),6.37(d,J=8.6Hz,1H),6.20(s,1H),4. 81(d,J=17.8Hz,1H),4.34-4.30(s,1H),4.25-4.21(m,1H),4.02-3.95(m,2 H),3.83-3.78(m,1H),3.66(d,J=7.0Hz,2H),3.48-3.43(m,2H),3.40-3.36 (m,2H),3.30(s,1H),2.92(s,1H),2.87-2.85(m,1H),2.80-2.74(m,5H),2. 68-2.64(m,5H),2.45-2.33(m,2H),1.79-1.68(m,10H),1.60-1.50(m,4H).

[0668] Example 212 can also be prepared according to the following method

[0669] 1-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazo-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindole-5-yl)-2-ethoxyphenyl)-N-((1r,4r)-4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)dihydroindole-1-yl)cyclohexyl)-N-methylpiperidin-4-carboxamide

[0670] Step 1: Preparation of tert-butyl-1-(4-bromo-2-ethoxyphenyl)piperidine-4-carboxylic acid ester

[0671] Under dry nitrogen protection, tert-butylpiperidine-4-carboxylic acid ester (12 g, 64.77 mmol), 4-bromo-2-ethoxy-1-iodobenzene (21.18 g, 64.77 mmol), XantPhos (3.75 g, 6.48 mmol), Pd2(dba)3 (1.78 g, 1.94 mmol), and sodium tert-butoxide (18.67 g, 194.32 mmol) were added to dry toluene (150 mL). The reaction mixture was heated to 60 °C and stirred for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to give the title compound (23 g, 92%). MS m / z (ESI): 384.2 [M+H] + .

[0672] Step 2: Preparation of tert-butyl-1-(2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)phenyl)piperidine-4-carboxylic acid ester

[0673] Under dry nitrogen protection, tert-butyl-1-(4-bromo-2-ethoxyphenyl)piperidine-4-carboxylic acid ester (23 g, 59.85 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-1,3,2-dioxoboropentane (19 g, 74.82 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (8.76 g, 11.97 mmol), and potassium acetate (17.62 g, 179.54 mmol) were added to 1,4-dioxane (230 mL). The reaction mixture was stirred at 90 °C for 2 hours and then cooled to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to give the title compound (19 g, 73%). MS m / z (ESI): 432.3 [M+H] + .

[0674] Step 3: Preparation of tert-butyl 1-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindole-5-yl)-2-ethoxyphenyl)piperidine-4-carboxylic acid ester

[0675] Under nitrogen protection, 2-(6-bromo-4-fluoro-1-oxo-isodihydroindol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazo-2-yl-acetamide (1 g, 2.10 mmol) and tert-butyl-1-(2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)phenyl)piperidine-4-carboxylic acid ester (1.8 g, 2.10 mmol) were reacted. 1 g (4.20 mmol) was dissolved in a mixed solution of 1,4-dioxane (15 mL) and water (3 mL). Tetra(triphenylphosphine)palladium (727 mg, 629.13 μmol) and sodium carbonate (668 mg, 6.30 mmol) were added sequentially. The reaction mixture was stirred at 100 °C for 5 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was then subjected to column chromatography to give the title compound (850 mg, 58%). MS m / z (ESI): 701.2 [M+H] + .

[0676] Step 4: Preparation of trifluoroacetate of 1-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindol-5-yl)-2-ethoxyphenyl)piperidine-4-carboxylic acid

[0677] 450 mg (642.10 μmol) of tert-butyl-1-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindol-5-yl)-2-ethoxyphenyl)piperidine-4-carboxylic acid ester was dissolved in a mixed solution of dichloromethane (6 mL) and trifluoroacetic acid (6 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain crude trifluoroacetate of the title compound, which was used directly in the next reaction without purification. MS m / z (ESI): 645.2 [M+H] + .

[0678] Step 5: Preparation of 1-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindole-5-yl)-2-ethoxyphenyl)-N-((1r,4r)-4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)dihydroindole-1-yl)cyclohexyl)-N-methylpiperidin-4-carboxamide

[0679] Under room temperature conditions, the crude product of trifluoroacetate of 1-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindol-5-yl)-2-ethoxyphenyl)piperidine-4-carboxylic acid trifluoroacetate from step four and 1-[1-[4-(methylamino)cyclohexyl]dihydroindol-4-yl] Hexahydropyrimidine-2,4-dione (222 mg, 648.30 μmol) was dissolved in N,N-dimethylformamide (6 mL), followed by the addition of triethylamine (207 mg, 2.05 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (242 mg, 641.45 μmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by HPLC to give the title compound (183 mg, 29%). MS m / z (ESI): 969.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.52(s,1H),10.28(s,1H),7.82(s,1H),7.79(d,J=10.6Hz,1H),7.62(s,1H),7.49(d,J=3.6Hz,1H),7.33-7.23(m,3 H),7.02(t,J=7.8Hz,1H),6.96(dd,J=8.2,4.6Hz,1H),6.42(d,J=8.0Hz,1H),6.37(d,J=8.9Hz,1H),6.16(s,1H),4.81(d,J=17.7Hz,1H),4.34 -4.30(m,1H),4.24(d,J=17.8Hz,1H),4.17(d,J=7.0Hz,2H),4.02-3.97(m,2H),3.8 6-3.79(m,1H),3.67(t,J=6.6Hz,2H),3.52(d,J=10.4Hz,2H),3.43-3.40(m,1H),3.3 8-3.36(m,2H),2.93(s,1H),2.84-2.70(m,5H),2.67(t,J=6.7Hz,3H),2.55-2.50(m, 2H),2.48-2.33(m,2H),1.92-1.61(m,8H),1.60-1.52(m,4H),1.39(t,J=6.9Hz,3H).

[0680] Example 213

[0681] 2-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazo-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindole-5-yl)-2-methoxyphenyl)-N-((1r,4r)-4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)dihydroindole-1-yl)cyclohexyl)-N-methyl-2-azaspiro[3.3]heptane-6-carboxamide

[0682] The preparation method of Example 213 can also be found in Example 188. MS m / z (ESI): 967.4 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ:12.51(s,1H),10.28(s,1H),7.78(s,1H),7.74(d,J=10.4Hz,1H),7.61(s,1H),7.48(d,J=3.6Hz ,1H),7.27-7.20(m,3H),7.01(t,J=7.9Hz,1H),6.42(d,J=8.0Hz,2H),6.37(t,J=7.5Hz,1H),6.15(s,1H),4.80(d,J=17.7 Hz,1H),4.22(d,J=17.7Hz,1H),4.05-3.90(m,4H),3.84(s,3H),3.76(d,J=2.7Hz,2H),3.67(t,J=6.7Hz,2H),3.19-3.44( s,6H),2.83-2.62(m,8H),2.55-2.43(m,1H),2.39-2.28(m,4H),1.83-1.72(m,3H),1.70-1.44(m,4H),1.29-1.21(m,2H).

[0683] Example 215

[0684] 1-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(pyridin-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindole-5-yl)-2-methoxyphenyl)-N-((1r,4r)-4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-indazole-1-yl)cyclohexyl)-N-methylpiperidin-4-carboxamide

[0685] The preparation method of Example 215 can also refer to Example 212. MS m / z (ESI): 948.4 [M+H] + .1 H NMR (400MHz, DMSO-d6) δ10.89(s,1H),10.45(d,J=2.7Hz,1H),8.32(d,J=4.9H z,1H),8.07(d,J=8.5Hz,1H),8.03(s,1H),7.84(s,1H),7.81(s,1H),7.80-7.7 7(m,1H),7.66(t,J=8.2Hz,1H),7.61(s,1H),7.40(d,J=6.7Hz,1H),7.32-7.3 0(m,2H),7.14-7.10(m,1H),7.05(d,J=7.3Hz,1H),7.00(t,J=8.6Hz,1H),6.21 (s,1H),4.82(d,J=17.8Hz,1H),4.72-4.66(m,1H),4.49-4.42(m,1H),4.23(d ,J=17.8Hz,1H),4.00-3.97(m,2H),3.92(s,3H),3.88(t,J=6.6Hz,2H),3.48(d ,J=10.6Hz,2H),3.32(s,1H),2.98(s,1H),2.95-2.90(m,1H),2.79-2.76(m,5H ),2.68-2.66(m,2H),2.27-2.23(m,2H),2.03-1.99(m,4H),1.84-1.65(m,8H).

[0686] Example 216

[0687] 11-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindole-5-yl)-2-methoxyphenyl)-N-((1r,4r)-4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-indazole-1-yl)cyclohexyl)-N-methylpiperidin-4-carboxamide

[0688] The preparation method of Example 216 can also refer to Example 212. MS m / z (ESI): 954.4 [M+H] +.1H NMR (400MHz, DMSO-d6)) δ12.52 (s, 1H), 10.45 (d, J = 2.8Hz, 1H), 8.03 (s, 1H) ,7.84(s,1H),7.81(d,J=10.6Hz,1H),7.67(d,J=8.2Hz,1H),7.63(d,J=7.9H z,1H),7.49(d,J=3.6Hz,1H),7.41(t,J=7.8Hz,1H),7.32-7.30(m,2H),7.26 (d,J=3.6Hz,1H),7.05(d,J=7.3Hz,1H),7.00(t,J=8.7Hz,1H),6.16(s,1H), 4.82(d,J=17.8Hz,1H),4.72-4.66(m,1H),4.50-4.42(m,1H),4.24(d,J=17. 8Hz,1H),4.02-3.98(m,2H),3.92(s,3H),3.88(t,J=6.6Hz,2H),3.48(d,J=1 0.6Hz,2H),3.31(s,1H),2.98(s,1H),2.94-2.90(m,1H),2.82-2.74(m,5H), 2.69-2.67(m,2H),2.26-2.23(m,2H),2.03-1.99(m,4H),1.84-1.65(m,8H).

[0689] Example 234

[0690] 1-(5-(7-chloro-2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazo-2-ylamino)ethyl)-3-oxoisodihydroindole-5-yl)pyridin-2-yl)-N-((1r,4r)-4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)dihydroindole-1-yl)cyclohexyl)-N-methylpiperidin-4-carboxamide

[0691] The preparation method of Example 234 can also be found in Example 212. MS m / z (ESI): 942.4 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.52(br s,1H),10.28(s,1H),8.55(s,1H),7.98(s,2H),7.90(s,1H),7.61(s,1H),7.48(d,J=3.6Hz,1H),7.25(d, J=3.6Hz,1H),7.01(s,1H),6.94(d,J=9.0Hz,1H),6.46-6.33(m,2H),6.16(s,1H),4.76(d,J=18.0Hz,1H) ,4.40(d,J=12.4Hz,2H),4.28(s,1H),4.16(d,J=18.0Hz,1H),4.02-3.96(m,2H),3.85-3.78(m,1H),3.66 (s,2H),3.48-3.42(m,4H),3.22-3.18(m,3H),3.03-2.94(m,4H),2.72-2.65(m,6H),1.77-1.53(m,11H).

[0692] Example 250

[0693] 1-(5-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazo-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindole-5-yl)-3-methoxypyridin-2-yl)-N-((1r,4r)-4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)dihydroindole-1-yl)cyclohexyl)-N-methylpiperidin-4-carboxamide

[0694] The preparation method of Example 250 can also be found in Example 212. MS m / z (ESI): 956.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.52(s,1H),10.29(d,J=1.8Hz,1H),8.21(s,1H),7.91(s,1H),7.87(d,J=10.2Hz,1H),7.61(s,1H),7 .58(d,J=3.6Hz,1H),7.49(d,J=3.5Hz,1H),7.26(d,J=3.6Hz,1H),7.02(t,J=7.8Hz,1H),6.47-6.32(m,2H),6.16(s,1H),4.82 (d,J=17.8Hz,1H),4.24(d,J=17.8Hz,1H),4.08(d,J=12.2Hz,2H),4.02-3.95(m,2H),3.93(s,3H),3.67(t,J=6.0Hz,2H),3.48 -3.27(m,8H),2.93(s,2H),2.88-2.71(m,4H),2.67(t,J=6.6Hz,2H),2.57-2.42(m,4H),1.88-1.60(m,9H),1.59-1.46(m,1H).

[0695] Example 259

[0696] 1-(5-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazo-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindole-5-yl)-3-methoxypyridin-2-yl)-N-((1r,4r)-4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)dihydroindole-1-yl)cyclohexyl)-N-methoxypiperidine-4-carboxamide

[0697] The preparation method of Example 259 can also be found in Example 212. MS m / z (ESI): 972.4 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.52(br s,1H),10.28(s,1H),8.21(d,J=1.6Hz,1H),7.91(s,1H),7.87(d,J=10.4Hz,1H),7.63-7.56(m,2H),7.48(d,J=3.6Hz,1H),7.26 (d,J=3.6Hz,1H),7.01(t,J=8.0Hz,1H),6.45-6.37(m,2H),6.16(s,1H),4.82(d,J=17.6Hz,1H),4.24(d,J=17.6Hz,1H),4.10(br d,J=12.0Hz,3H),4.04-3.95(m,2H),3.93(s,3H),3.79(br s,3H),3.66(br t,J=6.4Hz,2H),3.43(br t,J=11.6Hz,1H),3.38-3.32(m,2H),2.85(br t,J=10.4Hz,3H),2.77(br t,J=8.4Hz,3H),2.66(t,J=6.4Hz,2H),2.55(br s,1H),2.47-2.31(m,1H),2.06-1.86(m,1H),1.83-1.75(m,6H),1.74-1.62(m,4H),1.61-1.46(m,2H).

[0698] Example 260

[0699] 1-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(pyridin-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindole-5-yl)-2-hydroxyphenyl)-N-((1r,4r)-4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)dihydroindole-1-yl)cyclohexyl)-N-methylpiperidin-4-carboxamide

[0700] The preparation method of Example 260 can also be found in Example 212. MS m / z (ESI): 935.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.90(s,1H),10.29(s,1H),9.17(s,1H),8.32(dd,J=5.0,1.9Hz,1H),8.07(d,J=8.4Hz,1H),7.84-7.75(m,1H),7.69(s, 1H),7.65(d,J=10.6Hz,1H),7.61(s,1H),7.21-7.08(m,3H),7.04-6.92 (m,2H),6.47-6.40(m,1H),6.41-6.33(m,1H),6.19(s,1H),4.81(d,J=17 .8Hz,1H),4.31(d,J=11.7Hz,1H),4.22(d,J=17.8Hz,1H),3.98(dtt,J= 13.7,10.1,6.0Hz,2H),3.88-3.76(m,1H),3.67(t,J=6.6Hz,2H),3.45-3 .40(m,3H),3.37(d,J=8.4Hz,2H),2.93(s,2H),2.79-2.74(m,5H),2.69 -2.63(m,4H),2.53-2.51(m,2H),1.87-1.68(m,10H),1.58-1.52(m,3H).

[0701] Example 261

[0702] 1-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(pyridin-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindole-5-yl)-2-methoxyphenyl)-N-((1r,4r)-4-(4-(2,6-dioxopiperidin-3-yl)dihydroindole-1-yl)cyclohexyl)-N-methylpiperidin-4-carboxamide

[0703] The preparation method of Example 261 can also be found in Example 212. MS m / z (ESI): 948.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.89(s,1H),10.80(s,1H),8.36-8.29(m,1H),8.07(d,J=8.4Hz,1H),7.88-7.74(m,3H),7. 61(s,1H),7.31(d,J=8.8Hz,2H),7.17-7.06(m,1H),7.02-6.90(m,2H),6.41-6.27(m,2H),6.21(s,1H),4.82(d,J=17 .8Hz,1H),4.23(d,J=17.8Hz,1H),4.07-3.95(m,2H),3.92(s,3H),3.81-3.71(m,1H),3.55-3.39(m,2H),3.32-3.21( m,8H),2.92(s,2H),2.86-2.59(m,5H),2.56-2.38(m,2H),2.19-1.92(m,2H),1.90-1.38(m,12H),1.34-1.12(m,1H).

[0704] Example 262

[0705] 1-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazo-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindole-5-yl)-2-fluoro-6-methoxyphenyl)-N-((1r,4r)-4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)dihydroindole-1-yl)cyclohexyl)-N-methylpiperidin-4-carboxamide

[0706] The preparation method of Example 262 can also be found in Example 212. MS m / z (ESI): 973.4 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.51(br s,1H),10.28(s,1H),7.78(s,1H),7.74(d,J=10.4Hz,1H),7.69(d,J=8.8H z,2H),7.61(s,1H),7.48(d,J=3.6Hz,1H),7.25(d,J=3.6Hz,1H),7.07(br d,J=8.8Hz,2H),7.00(t,J=8.0Hz,1H),6.42(d,J=8.0Hz,1H),6.37(d,J=8.0Hz,1H),6 .15(s,1H),4.80(d,J=17.6Hz,1H),4.22(d,J=17.6Hz,1H),4.06-3.93(m,2H),3.73(br s,2H),3.68-3.57(m,4H),3.43-3.34(m,3H),3.29(br s,3H),3.21(br s,4H),2.93(br d,J=10.8Hz,2H),2.77(br t,J=8.4Hz,3H),2.65(t,J=6.4Hz,2H),2.58-2.52(m,1H),2.52-2.51(m,2H),2.49-2.48(m,2H),2.47-2.32(m,1H),2.15(br t,J=10.0Hz,2H),1.71-1.58(m,4H).

[0707] Example 275

[0708] 4'-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazo-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindole-5-yl)-N-((1r,4r)-4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)dihydroindole-1-yl)cyclohexyl)-2'-methoxy-N-methyl-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-carboxamide

[0709] The preparation method of Example 275 can also be found in Example 212. MS m / z (ESI): 952.4 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.52(s,1H),10.28(s,1H),7.89(s,1H),7.86(br d,J=10.4Hz,1H),7.61(s,1H),7.49(d,J=3.6Hz,1H),7.35-7.30(m,2H),7.26(d,J=3.6Hz,1H),7.21(br t,J=8.0Hz,1H),7.02(t,J=8.0Hz,1H),6.42(d,J=8.0Hz,1H),6.38(t,J=8.0Hz,1H),6.16(s,1H),5.82(br s,1H),4.83(d,J=17.6Hz,1H),4.25(d,J=17.6Hz,1H),4.04-3.93(m,2H),3.89(d,J=2.0Hz,3H),3.71-3.62(m,2H),3.37(br d,J=6.0Hz,3H),3.29(br s,1H),2.94(s,2H),2.83-2.72(m,5H),2.69-2.64(m,2H),2.60-2.55(m ,1H),2.40-2.17(m,5H),2.04-1.96(m,1H),1.87-1.64(m,8H),1.57(br d,J=11.6Hz,2H).

[0710] Example 537 can also be prepared according to the following method

[0711] (1r,4R)-4-(2-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazo-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindole-5-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-yl)-N-((1r,4R)-4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)dihydroindole-1-yl)cyclohexyl)-N-methylcyclohexane-1-carboxamide

[0712] Step 1: Preparation of tert-butyl 2-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy-2-oxoethyl)-7-fluoro-3-oxoisodihydroindol-5-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylic acid ester

[0713] Under dry nitrogen protection, ethyl 2-(6-bromo-4-fluoro-1-oxoisodihydroindol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl) acetate (5 g, 11.84 mmol) and tert-butyl 2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylic acid ester (4.21 g, 20.13 mmol) were dissolved in 1,4-dioxane (150 mL), followed by the addition of (1R,2R)-cyclohexane-1,2-diamine (2.16 g, 18.95 mmol), cuprous iodide (1.80 g, 9.47 mmol), and potassium phosphate (5.03 g, 23.68 mmol). The reaction mixture was heated to 105 °C and stirred for 25 hours, then cooled to room temperature. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to obtain the title compound (18 g, 90%). MS m / z (ESI): 551.2 [M+H] + .

[0714] Step 2: Preparation of tert-butyl 2-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindole-5-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylic acid ester

[0715] 5.5 g (9.99 mmol) of tert-butyl 2-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy-2-oxoethyl)-7-fluoro-3-oxoisodihydroindol-5-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylic acid ester was dissolved in tetrahydrofuran (50 mL), and a solution of lithium hydroxide (480 mg, 20.04 mmol) in water (20 mL) was added. The mixture was stirred at room temperature for 1 hour, and the organic solvent was removed by concentration under reduced pressure. The remaining aqueous solution was then freeze-dried. The freeze-dried product was dissolved in dry N,N-dimethylformamide (50 mL), and 2-aminothiazole (1.49 g, 14.93 mmol) and N,N-diisopropylethylamine (3.86 g, 29.85 mmol) were added. HATU (5.67 g, 14.93 mmol) was added under ice-water bath cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, and the organic phase was separated. The solution was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by column chromatography to give the title compound (2.3 g, overall yield of 38%). MS m / z (ESI): 605.2 [M+H] + .

[0716] Step 3: Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(5,6-dihydropyrrolo[3,4-c]pyrrolo-2(4H)-yl)-4-fluoro-1-oxoisodihydroindole-2-yl)-N-(thiazol-2-yl)acetamide

[0717] 2.3 g (3.80 mmol) of tert-butyl 2-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindol-5-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylic acid ester was dissolved in dichloromethane (25 mL), and trifluoroacetic acid (25 mL) was added. The reaction mixture was stirred for 1 hour. The solution was concentrated and dried under reduced pressure to obtain crude trifluoroacetate of the title compound, which was used directly in the next reaction without purification. MS m / z (ESI): 505.2 [M+H] + .

[0718] Step 4: Preparation of tert-butyl(1r,4r)-4-(2-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindol-5-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-yl)cyclohexane-1-carboxylic acid ester

[0719] In step three, crude 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-yl)-4-fluoro-1-oxoisodihydroindol-2-yl)-N-(thiazol-2-yl)acetamide trifluoroacetate, tert-butyl-4-oxocyclohexane-1-carboxylic acid ester (2.26 g, 11.42 mmol), and triethylamine (1.54 g, 15.22 mmol) were dissolved in 1,2-dichloroethane (50 mL). After stirring at room temperature for 1 hour, acetic acid (1.37 g, 22.83 mmol) was added, and stirring was continued at room temperature for 1 hour. Sodium triacetoxyborohydride (2.42 g, 11.42 mmol) was added, and stirring was continued at room temperature for 1 hour. The reaction solution was quenched with water, extracted three times with dichloromethane, and the combined organic phases were washed with saturated sodium bicarbonate and sodium chloride solutions, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by column chromatography to obtain a mixture of cis-trans isomers of the title compound (2.3 g, 88%). The title compound (0.68 g) was then prepared by HPLC. MS m / z (ESI): 687.3 [M+H] + .

[0720] Step 5: Preparation of (1r,4r)-4-(2-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindol-5-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-yl)cyclohexane-1-carboxylic acid

[0721] 30 mg (43.68 μmol) of tert-butyl(1r,4r)-4-(2-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindol-5-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-yl)cyclohexane-1-carboxylic acid ester was dissolved in a mixed solvent of dichloromethane (5 mL) and trifluoroacetic acid (5 mL) and stirred at room temperature for 1 hour. The solution was concentrated and dried under reduced pressure to obtain crude trifluoroacetate of the title compound, which was used directly in the next reaction without purification. MS m / z (ESI): 631.2 [M+H] + .

[0722] Step 6: Preparation of (1r,4R)-4-(2-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindole-5-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-yl)-N-((1r,4R)-4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)dihydroindole-1-yl)cyclohexyl)-N-methylcyclohexane-1-carboxamide

[0723] The crude trifluoroacetate of (1r,4r)-4-(2-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindole-5-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-yl)cyclohexane-1-carboxylic acid trifluoroacetate from step 5 and 1-(1-((1r) 4,4-(methylamino)cyclohexyl)dihydroindol-4-yl)dihydropyrimidine-2,4(1H,3H)-dione (15 mg, 43.83 μmol) was dissolved in N,N-dimethylformamide (10 mL), cooled to 0 °C, and then DIPEA (29 mg, 224.37 μmol) and HATU (17 mg, 44.71 μmol) were added sequentially, with stirring continued for 0.5 hours. The reaction solution was filtered through a microporous membrane, and the filtrate was subjected to HPLC to prepare and separate the title compound (24 mg, overall yield of 59%). MS m / z (ESI): 955.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.53(s,1H),10.29(s,1H),8.40(s,1H),8.10-7.87(m,2H),7.61(s,1H),7.49(d,J= 3.6Hz,1H),7.26(d,J=3.6Hz,1H),7.01(t,J=7.8Hz,1H),6.44-6.32(m,2H),6.15(s,1H),4.81(d,J=17.8,1H ),4.35-4.16(m,2H),4.04-3.91(m,2H),3.79(d,J=8.1Hz,4H),3.67(t,J=6.6Hz,2H),3.49-3.27(m,5H),2.8 9(s,2H),2.84-2.62(m,6H),2.58-2.40(m,7H),2.04(d,J=11.3Hz,2H),1.90-1.60(m,7H),1.58-1.15(m,3H).

[0724] Example 538 can also be prepared by the following method: (1r,4R)-4-(2-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindole-5-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-yl)-N-((1R,4R)-4-(4-((R)-2,6-dioxopiperidin-3-yl)dihydroindole-1-yl)cyclohexyl)-N-methylcyclohexane-1-carboxamide. Step 1: Preparation of (R)-3-(1-((1r,4R)-4-(methylamino)cyclohexyl)dihydroindole-4-yl)piperidin-2,6-dione.

[0725] 400 mg (905.88 μmol) of tert-butyl((1R,4r)-4-(4-((R)-2,6-dioxoperidin-3-yl)dihydroindole-1-yl)cyclohexyl)(methyl)carbamate was dissolved in a mixed solvent of dichloromethane (5 mL) and trifluoroacetic acid (10 mL) and stirred at room temperature for 1 hour. The organic solvent was concentrated under reduced pressure to obtain crude trifluoroacetate of the title compound, which was used directly in the next reaction without purification. MS m / z (ESI): 342.2 [M+H] + .

[0726] Step 2: Preparation of (1r,4R)-4-(2-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindole-5-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-yl)-N-((1R,4R)-4-(4-((R)-2,6-dioxopiperidin-3-yl)dihydroindole-1-yl)cyclohexyl)-N-methylcyclohexane-1-carboxamide

[0727] (1r,4r)-4-(2-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindole-5-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-yl)cyclohexane-1-carboxylic acid (0.6 g, 951.34 μmol) and Step 1: Crude (R)-3-(1-((1r,4R)-4-(methylamino)cyclohexyl)dihydroindol-4-yl)piperidine-2,6-dione trifluoroacetate was dissolved in N,N-dimethylformamide (10 mL), cooled to 0 °C, and DIPEA (615 mg, 4.76 mmol) and HATU (362 mg, 952.03 μmol) were added sequentially. Stirring was continued for 0.5 hours. The reaction solution was filtered through a microporous membrane, and the filtrate was subjected to HPLC to prepare and separate the title compound (500 mg, overall yield of two steps: 55%). MS m / z (ESI): 954.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.53(s,1H),10.80(s,1H),8.40(s,1H),7.98(d,J=1.7Hz,1H),7.94(dd,J=10.3,1.8 Hz,1H),7.61(s,1H),7.48(d,J=3.5Hz,1H),7.26(d,J=3.6Hz,1H),6.94(t,J=7.7Hz,1H),6.41-6.27(m,2H),6 .14(s,1H),4.81(d,J=17.7Hz,1H),4.33-4.15(m,2H),4.05-3.92(m,2H),3.82-3.72(m,5H),3.46-3.30(m,5H ),2.89(s,2H),2.84-2.59(m,6H),2.57-2.41(m,8H),2.18-1.92(m,4H),1.85-1.59(m,5H),1.58-1.10(m,4H).

[0728] Example 540 can also be prepared according to the following method

[0729] (1r,4R)-4-(2-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazo-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindole-5-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-yl)-N-((1r,4R)-4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-indazole-1-yl)cyclohexyl)-N-methylcyclohexane-1-carboxamide

[0730] (1r,4r)-4-(2-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindole-5-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-yl)cyclohexane-1-carboxylic acid (27 mg, 42.84 μmol) and 1-(1-( 1,4r)-4-(methylamino)cyclohexyl)-1H-indazol-4-yl)dihydropyrimidine-2,4(1H,3H)-dione (15 mg, 43.96 μmol) was dissolved in N,N-dimethylformamide (10 mL), cooled to 0 °C, and then DIPEA (28 mg, 216.63 mmol) and HATU (17 mg, 44.71 μmol) were added sequentially. The mixture was stirred for 0.5 hours. The reaction solution was filtered through a microporous membrane, and the filtrate was preparatively separated by HPLC to obtain the title compound (24 mg, 59%). MS m / z (ESI): 954.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.54(s,1H),10.46(d,J=2.7Hz,1H),8.40(s,1H),8.02(d,J=3.6Hz,1H),7.99(s,1H),7.94(d,J=10.5Hz,1H),7.6 6(t,J=9.4Hz,1H),7.61(s,1H),7.49(d,J=3.5Hz,1H),7.44-7.36(m,1H),7.26(d,J=3.5Hz,1H),7.05(d,J=7.3Hz,1H),6.15(s,1H),4.82( d,J=17.7,1H),4.73-4.62(m,1H),4.49-4.38(m,1H),4.24(d,J=17.6,,1H),4.05-3.92(m,2H),3.88(t,J=6.6Hz,2H),3.83-3.71(m,4H),3 .30(s,3H),2.94(s,2H),2.82-2.70(m,5H),2.61-2.42(m,2H),2.29- 2.15(m,1H),2.12-1.93(m,7H),1.91-1.58(m,4H),1.56-1.16(m,3H).

[0731] Example 585

[0732] 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(5-(1-(2-((1R,4r)-4-(4-(((R)-2,6-dioxopiperidin-3-yl)dihydroindole-1-yl)cyclohexyl)acetyl)piperidin-4-yl)-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-yl)-4-fluoro-1-oxoisodihydroindole-2-yl)-N-(thiazolyl-2-yl)acetamide

[0733] The synthesis of Example 585 can also be described with reference to Example 538. MS m / z (ESI): 940.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.53(s,1H),10.79(s,1H),8.42(s,1H),7.99(d,J=1.7Hz,1H),7.94(dd,J=10.4,1.8Hz,1H),7.61(s,1H),7 .49(d,J=3.5Hz,1H),7.26(d,J=3.5Hz,1H),6.92(t,J=7.7Hz,1H),6.30(t,J=7.1Hz,2H),6.14(s,1H),4.81(d,J=17.8,1H),4.23(d,J =17.8Hz,1H),4.19–4.10(m,1H),4.07-3.92(m,2H),3.88-3.67(m,5H),3.37-3.27(m,4H),3.15(t,J=11.8Hz,1H),2.92-2.62(m,5H), 2.56-2.41(m,9H),2.27-2.18(m,2H),2.14-2.04(m,1H),2.02-1.76(m,2H),1.74-1.61(m,2H),1.51-1.21(m,4H),1.18-1.04(m,2H).

[0734] Example 619 can also be prepared according to the following method

[0735] 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(2-(4-(2-((3S,4R)-4-(4-(((R)-2,6-dioxopiperidin-3-yl)dihydroindole-1-yl)-3-fluoropiperidin-1-yl)acetyl)piperazin-1-yl)pyrimidin-5-yl)-4-fluoro-1-oxoisodihydroindole-2-yl)-N-(pyridin-2-yl)acetamide

[0736] Step 1: Preparation of tert-butyl 4-(5-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(pyridin-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindol-5-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid ester

[0737] Under nitrogen protection, 2-(6-bromo-4-fluoro-1-oxoisodihydroindol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-yl)acetamide (1.5 g, 3.19 mmol) and tert-butyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid ester (1.87 g, 4.78 mmol) were dissolved in a mixed solvent of 1,4-dioxane (60 mL) and water (20 mL). Pd(PPh3)4 (1.11 g, 956.85 μmol) and sodium carbonate (1.01 g, 9.57 mmol) were added sequentially. The reaction mixture was heated to 100 °C and stirred for 1.5 hours, then cooled to room temperature. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to obtain the title compound (1.7 g, 82%). MS m / z (ESI): 654.3 [M+H] + .

[0738] Step 2: Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-1-oxo-6-(2-(piperazin-1-yl)pyrimidin-5-yl)isodihydroindole-2-yl)-N-(pyridin-2-yl)acetamide

[0739] 830 mg (1.27 mmol) of tert-butyl 4-(5-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(pyridin-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindol-5-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid ester was dissolved in a mixed solvent of dichloromethane (10 mL) and trifluoroacetic acid (10 mL) and stirred at room temperature for 0.5 hours. The solution was concentrated and dried under reduced pressure to obtain the crude trifluoroacetate of the title compound. MS m / z (ESI): 554.3 [M+H] + .

[0740] Step 3: Preparation of 2-((3S,4R)-4-(4-((R)-2,6-dioxopiperidin-3-yl)dihydroindole-1-yl)-3-fluoropiperidin-1-yl)acetic acid

[0741] 565 mg (1.27 mmol) of tert-butyl 2-((3S,4R)-4-(4-((R)-2,6-dioxopiridin-3-yl)dihydroindol-1-yl)-3-fluoropiperidin-1-yl)acetate was dissolved in a mixed solvent of dichloromethane (10 mL) and trifluoroacetic acid (10 mL) and stirred at room temperature for 1 hour. The solution was concentrated and dried under reduced pressure to obtain the crude trifluoroacetate of the title compound. MS m / z (ESI): 390.2 [M+H] + .

[0742] Step 4: Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(2-(4-(2-((3S,4R)-4-(4-((R)-2,6-dioxopiperidin-3-yl)dihydroindole-1-yl)-3-fluoropiperidin-1-yl)acetyl)piperazin-1-yl)pyrimidin-5-yl)-4-fluoro-1-oxoisodihydroindole-2-yl)-N-(pyridin-2-yl)acetamide

[0743] The crude products of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-1-oxo-6-(2-(piperazin-1-yl)pyrimidin-5-yl)isodihydroindol-2-yl)-N-(pyridin-2-yl)acetamide from step two and crude products of 2-((3S,4R)-4-(4-((R)-2,6-dioxopiperidin-3-yl)dihydroindol-1-yl)-3-fluoropiperidin-1-yl)acetic acid from step three were dissolved in N,N-dimethylformamide (10 mL), cooled to 0 °C, and DIPEA (817 mg, 6.32 mmol) and HATU (481 mg, 1.26 mmol) were added sequentially, and stirring was continued for 0.5 hours. The reaction solution was filtered through a microporous membrane, and the filtrate was subjected to HPLC to prepare and separate the title compound (400 mg, overall yield of 34% over three steps). MS m / z (ESI): 925.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.89(s,1H),10.80(s,1H),8.87(s,2H),8.34-8.29(m,1H),8.07(d,J=8.4Hz,1H),7.89(s,1H),7.87-7.77(m ,2H),7.61(s,1H),7.14-7.09(m,1H),6.94(t,J=7.8Hz,1H),6.40(d,J=7.9Hz,1H),6.34(d,J=7.7Hz,1H),6.20(s,1H),4.95(d,J=50. 0Hz,1H),4.82(d,J=17.9Hz,1H),4.23(d,J=17.9Hz,1H),4.07-3.93(m,1H),3.91-3.73(m,3H),3.70-3.44(m,7H),3.31-3.23(m,3H), 3.11(t,J=11.9Hz,1H),2.98(d,J=10.8Hz,1H),2.86-2.72(m,3H),2.69-2.60(m,1H),2.59-2.41(m,7H),2.37(t,J=11.8Hz,1H),2.18 -2.03(m,2H),2.02-1.86(m,1H),1.62-1.52(m,1H).

[0744] Example 623 can also be prepared according to the following method

[0745] 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(2-(4-(2-((3S,4R)-4-(4-(((R)-2,6-dicarbonylpiperidin-3-yl)dihydroindole-1-yl)-3-fluoropiperidin-1-yl)acetyl)piperidin-1-yl)pyrimidin-5-yl)-4-fluoro-1-carbonylisodihydroindole-2-yl)-N-(pyridin-2-yl)acetamide

[0746] Step 1: Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-(2-fluoropyrimidin-5-yl)-1-oxoisodihydroindole-2-yl)-N-(pyridin-2-yl)acetamide

[0747] Under nitrogen protection, 2-(6-bromo-4-fluoro-1-oxoisodihydroindol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-yl)acetamide (3 g, 6.38 mmol) and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrimidine (2.86 g, 12.76 mmol) were reacted. The compound was dissolved in a mixed solvent of 1,4-dioxane (60 mL) and water (20 mL), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (467 mg, 637.90 μmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (542 mg, 1.28 mmol), and sodium carbonate (2.03 g, 19.14 mmol) were added. The reaction mixture was heated to 85 °C and stirred for 2 hours. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give the title compound (1.6 g, 51%). MS m / z (ESI): 488.2 [M+H] + .

[0748] Step 2: Preparation of (R)-3-(1-((3S,4R)-3-fluoropiperidin-4-yl)dihydroindol-4-yl)piperidin-2,6-dione trifluoroacetate

[0749] 400 mg (927.00 μmol) of tert-butyl(3S,4R)-4-(4-((R)-2,6-dicarbonylpiperidin-3-yl)dihydroindol-1-yl)-3-fluoropiperidin-1-carboxylic acid ester was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure to obtain crude trifluoroacetate of the title compound, which was used directly in the next reaction without purification. MS m / z (ESI): 332.2 [M+H] + .

[0750] Step 3: Preparation of tert-butyl 4-(2-((3S,4R)-4-(4-((R)-2,6-dicarbonylpiperidin-3-yl)dihydroindol-1-yl)-3-fluoropiperidin-1-yl)acetyl)piperidin-1-carboxylic acid ester

[0751] At 0 °C, the trifluoroacetate salt of (R)-3-(1-((3S,4R)-3-fluoropiperidin-4-yl)dihydroindol-4-yl)piperidin-2,6-dione obtained in step 2 was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of diisopropylethylamine (1.2 g, 9.27 mmol) and tert-butyl-4-(2-bromoacetyl)piperidin-1-carboxylic acid ester (426 mg, 1.39 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solution was slowly poured into water (30 mL), and the precipitated solid was collected by filtration, concentrated under reduced pressure, and dried to give the title compound (360 mg, 70% yield in two steps). MS m / z (ESI): 557.3 [M+H] + .

[0752] Step 4: Preparation of (R)-3-(1-((3S,4R)-3-fluoro-1-(2-carbonyl-2-(piperidin-4-yl)ethyl)piperidin-4-yl)dihydroindol-4-yl)piperidin-2,6-dione trifluoroacetate

[0753] 240 mg (431.13 μmol) of tert-butyl-4-(2-((3S,4R)-4-(4-((R)-2,6-dicarbonylpiperidin-3-yl)dihydroindol-1-yl)-3-fluoropiperidin-1-yl)acetyl)piperidin-1-carboxylic acid ester was dissolved in a mixed solvent of dichloromethane (6 mL) and trifluoroacetic acid (3 mL). The reaction mixture was stirred at room temperature for 0.5 hours, and the solution was concentrated under reduced pressure to obtain crude trifluoroacetate of the title compound. This crude product was used directly in the next reaction without purification. MS m / z (ESI): 457.3 [M+H] + .

[0754] Step 5: Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(2-(4-(2-((3S,4R)-4-(4-((R)-2,6-dicarbonylpiperidin-3-yl)dihydroindole-1-yl)-3-fluoropiperidin-1-yl)acetyl)piperidin-1-yl)pyrimidin-5-yl)-4-fluoro-1-carbonylisodihydroindole-2-yl)-N-(pyridin-2-yl)acetamide

[0755] The crude trifluoroacetate of (R)-3-(1-((3S,4R)-3-fluoro-1-(2-carbonyl-2-(piperidin-4-yl)ethyl)piperidin-4-yl)dihydroindole-4-yl)piperidin-2,6-dione trifluoroacetate obtained in step 4 was dissolved in dimethyl sulfoxide (5 mL), and diisopropylethylamine (557 mg, 4.31 mmol) and 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-(2-fluoropyrimidin-5-yl)-1-carbonylisodihydroindole-2-yl)-N-(pyridin-2-yl)acetamide (210 mg, 430.80 μmol) were added sequentially. The reaction solution was heated to 85 °C and stirred for 2 hours. The solution was cooled to room temperature, filtered through a microporous membrane, and the filtrate was separated by HPLC to obtain the title compound (196 mg, overall yield of 49%). MS m / z (ESI): 924.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.89(s,1H),10.80(s,1H),8.82(s,2H),8.32(d,J=4.0Hz,1H),8.07(d,J=8.4Hz,1H),7.87(s,1H),7.84-7.76(m,2H),7. 61(s,1H),7.15-7.09(m,1H),6.93(t,J=7.8Hz,1H),6.39(d,J=8.2Hz,1H ),6.33(d,J=8.2Hz,1H),6.20(s,1H),5.05-4.84(m,1H),4.81(d,J=18.0H z,1H),4.74-4.65(m,2H),4.23(d,J=17.8Hz,1H),4.04-3.91(m,2H),3.8 0-3.75(m,1H),3.63-3.43(m,3H),3.39(s,2H),3.16-2.97(m,3H),2.96- 2.72(m,5H),2.71-2.56(m,2H),2.54-2.51(m,2H),2.49-2.35(m,3H),2. 16-1.93(m,3H),1.92-1.83(m,2H),1.58-1.49(m,1H),1.48-1.33(m,2H).

[0756] Example 629

[0757] 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(2-(6-(2-((3S,4R)-4-(4-(((R)-2,6-dioxopiperidin-3-yl)dihydroindole-1-yl)-3-fluoropiperidin-1-yl)acetyl)-2,6-diazaspiro[3.3]heptane-2-yl)pyrimidin-5-yl)-4-fluoro-1-oxoisodihydroindole-2-yl)-N-(pyridin-2-yl)acetamide

[0758] The synthesis method of Example 629 can also be found in Example 631. MS m / z (ESI): 937.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.89(s,1H),10.80(s,1H),8.82(s,2H),8.35-8.29(m, 1H),8.07(d,J=8.3Hz,1H),7.86(s,1H),7.85-7.74(m,2H),7.61(s,1H),7.12(dd ,J=7.3,4.9Hz,1H),6.94(t,J=7.7Hz,1H),6.39(d,J=7.9Hz,1H),6.34(d,J=7.7 Hz,1H),6.20(s,1H),4.94(d,J=50.1Hz,1H),4.82(d,J=17.9Hz,1H),4.51-4.39( m,2H),4.33-4.19(m,5H),4.10(s,2H),3.99(tq,J=10.9,5.4Hz,2H),3.78(dd,J =11.4,5.1Hz,1H),3.60-3.45(m,3H),3.14-3.05(m,3H),2.94(d,J=10.3Hz,1H), 2.86-2.75(m,3H),2.70-2.63(m,1H),2.57-2.51(m,3H),2.48-2.43(m,2H),2.36 (t,J=11.4Hz,1H),2.18-2.04(m,2H),2.04-1.93(m,1H),1.55(d,J=11.9Hz,1H).

[0759] Example 631 can also be prepared according to the following method

[0760] 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(2-(5-(2-((3S,4R)-4-(4-(((R)-2,6-dioxopiperidin-3-yl)dihydroindole-1-yl)-3-fluoropiperidin-1-yl)acetyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)pyrimidin-5-yl)-4-fluoro-1-oxoisodihydroindole-2-yl)-N-(pyridin-2-yl)acetamide

[0761] Step 1: Preparation of tert-butyl 5-(5-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(pyridin-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindol-5-yl)pyrimidin-2-yl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid ester

[0762] 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-(2-fluoropyrimidin-5-yl)-1-oxoisodihydroindol-2-yl)-N-(pyridin-2-yl)acetamide (1.6 g, 3.28 mmol) and tert-butyl-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylic acid ester (1.38 g, 6.56 mmol) were dissolved in dimethyl sulfoxide (20 mL), and diisopropylethylamine (3.39 g, 26.26 mmol, 4.57 mL) was added. The reaction mixture was heated to 100 °C and stirred for 1 hour, and then cooled to room temperature. The reaction mixture was poured into water (100 mL), filtered, and the precipitated solid was collected. The residue was washed with water, collected, and dried under reduced pressure to give the title compound (1.82 g, 81%). MS m / z (ESI): 678.3 [M+H] + .

[0763] Step 2: Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-1-oxo-6-(2-(3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)pyrimidin-5-yl)isodihydroindol-2-yl)-N-(pyridin-2-yl)acetamide

[0764] 650 mg (959.09 μmol) of tert-butyl 5-(5-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(pyridin-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindol-5-yl)pyrimidin-2-yl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid ester was dissolved in a mixed solution of dichloromethane (5 mL) and trifluoroacetic acid (5 mL), and the reaction mixture was stirred at room temperature for 0.5 hours. The organic solvent was concentrated under reduced pressure to obtain the title compound, which was used directly in the next reaction without further purification. MS m / z (ESI): 578.2 [M+H] + .

[0765] Step 3: Preparation of 2-((3S,4R)-4-(4-((R)-2,6-dioxopiperidin-3-yl)dihydroindole-1-yl)-3-fluoropiperidin-1-yl)acetic acid

[0766] 400 mg (897.82 μmol) of tert-butyl 2-((3S,4R)-4-(4-((R)-2,6-dioxopiridin-3-yl)dihydroindol-1-yl)-3-fluoropiperidin-1-yl)acetate was dissolved in 10 mL of dichloromethane, and trifluoroacetic acid (51.18 g, 448.91 mmol) was added. The reaction mixture was stirred for 1 hour. The organic solvent was concentrated under reduced pressure to obtain the trifluoroacetate of the title compound, which was used directly in the next reaction without further purification. MS m / z (ESI): 390.2 [M+H] + .

[0767] Step 4: Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(2-(5-(2-((3S,4R)-4-(4-(((R)-2,6-dioxopiperidin-3-yl)dihydroindole-1-yl)-3-fluoropiperidin-1-yl)acetyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)pyrimidin-5-yl)-4-fluoro-1-oxoisodihydroindole-2-yl)-N-(pyridin-2-yl)acetamide

[0768] The crude product of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-1-oxo-6-(2-(3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)pyrimidin-5-yl)isodihydroindol-2-yl)-N-(pyridin-2-yl)acetamide trifluoroacetate from the second step and the crude product of 2-((3S,4R)-4-(4-((R)-2,6-dioxopiperidine-) from the third step were combined. Crude 3-yl)dihydroindol-1-yl)-3-fluoropiperidin-1-yl)acetic acid trifluoroacetate was dissolved in N,N-dimethylformamide (10 mL) and cooled to 0 °C in an ice-water bath. Diisopropylethylamine (1.16 g, 8.96 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (372 mg, 985.83 μmol) were added sequentially with stirring. The reaction mixture was stirred for 0.5 h. The reaction mixture was filtered through a microporous membrane, and the filtrate was purified by HPLC to obtain the title compound (349 mg, total yield 41%). MS m / z (ESI): 949.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.89(s,1H),10.80(s,1H),8.87(s,2H),8.32(br d,J=4.0Hz,1H),8.07(br d,J=8.4Hz,1H),7.88(s,1H),7.86-7.74(m,2H),7.61(s,1H),7.15-7.08(m,1H),6.94(t,J=8.0Hz,1H),6. 40(d,J=8.0Hz,1H),6.34(d,J=8.0Hz,1H),6.20(s,1H),5.05-4.87(m,1H),4.81(d,J=18.0Hz,1H),4.47(br s,2H),4.37(br s,4H),4.27-4.15(m,3H),4.06-3.91(m,2H),3.82-3.73(m,1H),3.65-3.44(m,3H),3.30(br s,1H),3.24(s,2H),3.13(br t,J=11.6Hz,1H),3.00(br d,J=10.8Hz,1H),2.87-2.74(m,3H),2.74-2.59(m,2H),2.58-2.51(m,2H),2.48-2.40(m,2H),2.18-2.04(m,2H),2.02-1.92(m,1H),1.56(br d, J = 10.4 Hz, 1H).

[0769] Example 633

[0770] 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(2-((S)-4-(2-((3S,4R)-4-(4-(((R)-2,6-dicarbonylpiperidin-3-yl)dihydroindole-1-yl)-3-fluoropiperidin-1-yl)acetyl)-3-methylpiperazin-1-yl)pyrimidin-5-yl)-4-fluoro-1-carbonylisodihydroindole-2-yl)-N-(pyridin-2-yl)acetamide

[0771] The synthesis method of Example 633 can also be found in Example 631. MS m / z (ESI): 939.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.89(s,1H),10.80(s,1H),8.85(s,2H),8.38 -8.27(m,1H),8.07(d,J=8.4Hz,1H),7.88(s,1H),7.86-7.76(m,2H),7.6 1(s,1H),7.14-7.08(m,1H),6.94(t,J=7.8Hz,1H),6.40(d,J=7.9Hz,1H) ,6.34(d,J=7.7Hz,1H),6.20(s,1H),4.94(d,J=49.9Hz,1H),4.81(d,J=1 7.9Hz,1H),4.76-4.60(m,1H),4.59-4.41(m,2H),4.23(d,J=17.9Hz,1H) ,3.99-3.90(m,3H),3.78(dd,J=11.4,5.1Hz,1H),3.64-3.37(m,2H),3.3 3-3.00(m,6H),2.98-2.89(m,1H),2.87-2.72(m,2H),2.70-2.60(m,1H), 2.57-2.41(m,6H),2.38-2.31(m,1H),2.20-2.04(m,2H),2.03-1.88(m,1 H), 1.57 (d, J = 11.6Hz, 1H), 1.21 (d, J = 6.4Hz, 2H), 1.07 (d, J = 6.7Hz, 2H).

[0772] Example 647

[0773] 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(2-(3-(2-((3S,4R)-4-(4-(((R)-2,6-dioxopiperidin-3-yl)dihydroindole-1-yl)-3-fluoropiperidin-1-yl)acetyl)-3,8-diazabicyclo[3.2.1]octane-8-yl)pyrimidin-5-yl)-4-fluoro-1-oxoisodihydroindole-2-yl)-N-(pyridin-2-yl)acetamide

[0774] The synthesis method of Example 647 can also be found in Example 631. MS m / z (ESI): 965.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.89(s,1H),10.80(s,1H),8.88(s,2H),8.35-8.29(m,1H),8.07(br d,J=8.4Hz,1H),7.89(s,1H),7.84(d,J=10.4Hz,1H),7.82-7.75(m,1H),7.61(s,1H),7.15-7.09(m,1H),6.94(t,J=8.0Hz,1H), 6.40(d,J=8.0Hz,1H),6.34(d,J=8.0Hz,1H),6.20(s,1H),5.06-4.86(m,1H),4.85-4.72(m,3H),4.23(d,J=17.6Hz,1H),4.14(br d,J=14.4Hz,1H),4.05-3.90(m,3H),3.82-3.74(m,1H),3.64-3.43(m,3H),3.34(br s,1H),3.30(br s,1H),3.18-2.92(m,3H),2.88-2.74(m,4H),2.70-2.61(m,1H),2.59-2.52(m,2H),2.48- 2.39(m,2H),2.37-2.30(m,1H),2.20-2.04(m,3H),2.04-1.84(m,4H),1.68-1.51(m,2H).

[0775] Example 707 can also be prepared according to the following method

[0776] 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(2-(5-(2-((3S,4R)-4-(4-(((R)-2,6-dioxopiperidin-3-yl)dihydroindole-1-yl)-3-fluoropiperidin-1-yl)acetyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)pyrimidin-5-yl)-4-fluoro-1-oxoisodihydroindole-2-yl)-N-(thiazolyl-2-yl)acetamide

[0777] Step 1: Preparation of tert-butyl 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrimidin-2-yl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid ester

[0778] 2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyrimidine (1 g, 4.46 mmol) was dissolved in dimethyl sulfoxide (15 mL), and diisopropylethylamine (4.61 g, 35.71 mmol, 6.22 mL) and tert-butyl-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylic acid ester (1.41 g, 6.70 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 1 hour. The reaction mixture was cooled to room temperature, poured into water (75 mL), filtered, and the precipitated solid was collected, concentrated under reduced pressure, and dried to give the title compound (1.7 g, 92%). MS m / z (ESI): 415.2 [M+H] + .

[0779] Step 2: Preparation of tert-butyl 5-(5-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindol-5-yl)pyrimidin-2-yl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid ester

[0780] Under nitrogen protection, 2-(6-bromo-4-fluoro-1-oxoisodihydroindol-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazo-2-yl)acetamide (500 mg, 1.05 mmol) and tert-butyl5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)pyrimidin-2-yl)-3,4,5,6-tetrahydropyrrolo[3, [4-C]pyrrole-2(1H)-carboxylic acid ester (522 mg, 1.26 mmol) was dissolved in 1,4-dioxane (15 mL) and water (3 mL), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (77 mg, 104.97 μmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (89 mg, 209.94 μmol), and sodium carbonate (334 mg, 3.15 mmol) were added. The reaction mixture was heated to 85 °C and stirred for 2 hours. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give the title compound (680 mg, 94%). MS m / z (ESI): 684.2 [M+H] + .

[0781] Step 3: Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-1-oxo-6-(2-(3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)pyrimidin-5-yl)isodihydroindol-2-yl)-N-(thiazolyl-2-yl)acetamide trifluoroacetate

[0782] 615 mg (899.45 μmol) of tert-butyl 5-(5-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindol-5-yl)pyrimidin-2-yl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid ester was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2.05 g, 17.99 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 hours. The solution was concentrated under reduced pressure to obtain crude trifluoroacetate of the title compound, which was used directly in the next reaction without purification. MS m / z (ESI): 584.2 [M+H] + .

[0783] Step 4: Preparation of 2-((3S,4R)-4-(4-((R)-2,6-dioxopiperidin-3-yl)dihydroindol-1-yl)-3-fluoropiperidin-1-yl)acetic acid trifluoroacetate

[0784] 400 mg (897.82 μmol) of tert-butyl 2-((3S,4R)-4-(4-((R)-2,6-dioxopiridin-3-yl)dihydroindol-1-yl)-3-fluoropiperidin-1-yl)acetate was dissolved in 10 mL of dichloromethane, and 51.18 g (448.91 mmol) of trifluoroacetic acid was added. The reaction mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure to obtain crude trifluoroacetate of the title compound, which was used directly in the next reaction without purification. MS m / z (ESI): 390.2 [M+H] + .

[0785] Step 5: Preparation of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(2-(5-(2-((3S,4R)-4-(4-(((R)-2,6-dioxopiperidin-3-yl)dihydroindole-1-yl)-3-fluoropiperidin-1-yl)acetyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)pyrimidin-5-yl)-4-fluoro-1-oxoisodihydroindole-2-yl)-N-(thiazolyl-2-yl)acetamide

[0786] The crude 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-1-oxo-6-(2-(3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)pyrimidin-5-yl)isodihydroindol-2-yl)-N-(thiazo-2-yl)acetamide trifluoroacetate obtained in step 3 and the crude 2-((3S,4R)-4-(4-((R)-2,6-dioxo)acetamide trifluoroacetate obtained in step 4 were combined with the crude 2-((3S,4R)-4-(4-((R)-2,6-dioxo)acetamide trifluoroacetate obtained in step 4. Crude piperidin-3-yl)dihydroindol-1-yl)-3-fluoropiperidin-1-yl)acetic acid trifluoroacetate was dissolved in N,N-dimethylformamide (10 mL), cooled to 0 °C in an ice-water bath, and diisopropylethylamine (1.14 g, 8.86 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (368 mg, 974.53 μmol) were added sequentially with stirring. The reaction mixture was stirred for 0.5 h. The reaction mixture was filtered through a microporous membrane, and the filtrate was purified by HPLC to obtain the title compound (377 mg, overall yield of 44%). MS m / z (ESI): 955.4 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.65-12.35(m,1H),10.80(s,1H),8.87(s,2H),7.88(s,1H),7.84(br d,J=10.4Hz,1H),7.61(s,1H),7.48(d,J=3.6Hz,1H),7.26(d,J=3.6Hz,1H),6.94(t,J=8.0H z,1H),6.40(d,J=8.0Hz,1H),6.34(d,J=7.6Hz,1H),6.15(s,1H),5.04-4.87(m,1H),4.81(br d,J=18.0Hz,1H),4.47(br s,2H),4.36(br s,4H),4.27-4.17(m,3H),4.04-3.93(m,2H),3.82-3.74(m,1H),3.65-3.43(m,3H),3.30(br s,1H),3.24(s,2H),3.13(br t,J=11.2Hz,1H),3.00(br d,J=10.4Hz,1H),2.88-2.74(m,3H),2.73-2.61(m,2H),2.60-2.52(m,2H),2.48-2.42(m,2H),2.18-2.03(m,2H),2.02-1.93(m,1H),1.56(br d,J=9.2Hz,1H).

[0787] Example 661 can also be prepared according to the following method

[0788] 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(2-(4-(2-((3S,4R)-4-(4-(((R)-2,6-dioxopiperidin-3-yl)dihydroindole-1-yl)-3-fluoropiperidin-1-yl)acetyl)piperazin-1-yl)pyrimidin-5-yl)-4-fluoro-1-oxoisodihydroindole-2-yl)-N-(thiazolyl-2-yl)acetamide

[0789] Step 1: Preparation of tert-butyl 4-(5-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisodihydroindol-5-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid ester

[0790] Under nitrogen protection, 2-(6-bromo-4-fluoro-1-oxoisodihydroindol-2-yl)-2-(6,7-dihydro-5H-pyrrolo...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in: Ar1 is a 5-14 member heteroaryl group; Ar2 is selected from 5-10-membered heteroaryl, 5-10-membered heteroaryl with 5-8-membered heterocyclic, or 5-10-membered heteroaryl with C 5-8 cycloalkyl; L1 is selected from either NHCO or NHCO; L2 is selected from the bond, C 2-6 imidene group, C 2-6 alkynyl, 5-10 methyl aryl, phenylene, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, phenyl-C 5-8 cycloalkyl, 5-10-membered heteroaryl benzo[C] 5-8 Cycloalkyl, 5-10-membered heteroaryl, or phenyl 5-8-membered heterocyclic, wherein the C 2-6 imidene group, C 2-6 alkynyl, 5-10 methyl aryl, phenylene, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, phenyl-C 5- 8-cycloalkyl, 5-10-membered heteroaryl benzo[C] 5-8 Cycloalkyl, 5-10-membered heteroaryl, and phenyl 5-8-membered heterocyclic groups may be further substituted with 1-4 R4 groups; L3, L4, L5, L6, and L7 are each independently selected from the bond, -(CH2). n7 O(CH2) n8 -、-(CH2) n7 C=O(CH2) n8 -、-(CH2) n7 C = S(CH2) n8 -、-(CH2) n7 C = OO(CH2) n8 -、-(CH2) n7 NR bb (CH2) n8 -、-(CH2) n7 S(CH2) n8 -、-(CH2) n7 CONH(CH2) n8 -、(CH2) n7 NHCONH(CH2) n8 -、(CH2) n7 NHC(=NH)NH(CH2) n8 -、(CH2) n7 POR bb (CH2) n8 -、O(CH2) n7 POR bb (CH2) n8 -、C 1-6 Alkylene, C 2-6 imidene group, C 2-6 alkynyl, 5-10 methyl aryl, phenylene, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, phenyl-C 5-8 cycloalkyl, 5-10-membered heteroaryl benzo[C] 5-8 Cycloalkyl, 5-10-membered heteroaryl, or phenyl-5-8-membered heterocyclic; wherein the -(CH2) group... n7 O(CH2) n8 -、-(CH2) n7 C=O(CH2) n8 -、-(CH2) n7 C = S(CH2) n8 -、-(CH2) n7 C = OO(CH2) n8 -、-(CH2) n7 NR bb (CH2) n8 -、-(CH2) n7 S(CH2) n8 -、-(CH2) n7 CONH(CH2) n8 -、(CH2) n7 NHCONH(CH2) n8 -、(CH2) n7 NHC(=NH)NH(CH2) n8 -、(CH2) n7 POR bb (CH2) n8 -、O(CH2) n7 POR bb (CH2) n8 -、C 1-6 Alkylene, C 2-6 imidene group, C 2-6 alkynyl, 5-10 methyl aryl, phenylene, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, phenyl-C 5- 8-cycloalkyl, 5-10-membered heteroaryl benzo[C] 5-8 Cycloalkyl, 5-10-membered heteroaryl, and phenyl 5-8-membered heterocyclic groups may be further modified by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2). n R aa -(CH2) n OR dd -O(CH2) n R aa -(CH2) n SR dd -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R dd -(CH2) n C(O)NR aa R dd -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R dd -(CH2) n P(O)R aa R dd -O(CH2) n P(O)R aa R dd -(CH2) n NR cc C(=NH)NR aa R dd (CH2) n NR dd S(O) m R cc -OC(R) aa R dd ) n (CH2) m R aa -NR dd (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R dd -CH=CH(CH2) n NR dd C(O)R cc -CH=CH(CH2) n NR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1- 6-alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; The constraint is that L3, L4, L5, L6, and L7 cannot all be keys simultaneously; M is selected from Preferably, M is selected from M1 and M2 are each independently selected from N or CH; M3 is selected from bond, NH, O or CONH; X1 is selected from N or CH; M9, M 10 M 11 and M 12 Each is independently selected from C, N, or CH; M 13 and M 14 Each is independently selected from C, N, or CH; Y0, Y1, and Y2 are each independently selected from bonds, NH, O, S, or -(CH2). v -; Lx is -(CH2) n 、-(CH2) n O、-(CH2) n S、-(CH2) n C(O)、-(CH2) n C(O)O、-(CH2) n S(O) m 、-(CH2) n NR ee -、-(CH2) n C(O)NR ee -、-(CH2) n NR ee C(O)-、-(CH2) n NR ee C(O)NR ff -; R1, R2, R3, R4, R5, and R6 are each independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n R aa -(CH2) n OR dd -O(CH2) n R aa -(CH2) n SR dd -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R dd -(CH2) n C(O)NR aa R dd -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R dd -(CH2) n P(O)R aa R dd -O(CH2) n P(O)R aa R dd -(CH2) n NR cc C(=NH)NR aa R dd (CH2) n NR dd S(O) m R cc -OC(R) aa R dd ) n (CH2) m R aa -NR dd (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R dd -CH=CH(CH2) n NR dd C(O)R cc -CH=CH(CH2) n NR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc The C mentioned therein 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3- 12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl and 5-14 heteroaryl groups may be further substituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or unsubstituted C groups. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1- 6-alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; R7 is selected from H or D; R aa R bb R cc R dd R ee and R ff Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl and 5-14 heteroaryl groups may be further substituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or unsubstituted C groups. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; v, n, n1, n2, n3, n5, n6, n7, and n8 are each independently 0, 1, 2, 3, 4, 5, or 6; m is 1 or 2; Constraints: When M is At that time; L2 is selected from C 2-6 imidene group, C 2-6 alkynyl, 5-10 methyl methacrylate, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, phenyl-C 5-8 cycloalkyl, 5-10-membered heteroaryl benzo[C] 5-8 Cycloalkyl, 5-10-membered heteroaryl, or phenyl 5-8-membered heterocyclic, wherein the C 2-6 imidene group, C 2-6 alkynyl, 5-10 methyl aryl, phenylene, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, phenyl-C 5-8 cycloalkyl, 5-10-membered heteroaryl benzo[C] 5-8 The cycloalkyl, 5-10-membered heteroaryl, 5-8-membered heterocyclic and phenyl 5-8-membered heterocyclic groups may be further substituted with 1-4 R4 groups.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, M is selected from Preferably, M is selected from More preferably, Selected from 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, L2 is selected from the following group, either substituted or unsubstituted: C 2-3 alkynyl, 5-6 quinone heteroaryl, phenylene, C 5-8 Cycloalkylene, 5-8 membered heterocyclic alkylene, phenyl-C 5-8 cycloalkyl, 5-6-membered heteroaryl benzo[C] 5-8 Cycloalkyl, 5-6-membered heteroaryl, or phenyl 5-8-membered heterocyclic group; Preferred substituted or unsubstituted groups include: ethynyl, phenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxadiazole, oxazolyl, thiophene, furanyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, and others. The substitution refers to being replaced by 1-4 R4 atoms; More preferably, L2 is selected from More preferably, L2 is selected from Among them, M4 is selected from N or CH; M5 is selected from N or CH; M6 is selected from N or CH; M7 is selected from N or CH; M8 is selected from N or CH; n9 and n10 are each independently selected from 0, 1, 2 or 3; n4 is 0, 1, 2, 3, or 4; R4 is defined as described in claim 1.

4. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-3, characterized in that, Ar2 is selected from 5-6 N-containing heteroaryl groups or 5-6 N-containing heteroaryl groups with 5-8 heterocyclic groups, preferably. Cy1 is selected from non-existent or 5-8 membered heterocyclic groups; preferably 5-6 membered heterocyclic groups.

5. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-4, characterized in that, The compound is shown in formula (IB). Preferably, the compound is as shown in formula (IA). in, Cy1 is selected from non-existent or 5-8 membered heterocyclic groups; preferably 5-6 membered heterocyclic groups; n'3 is 0, 1, 2, 3, 4 or 5; The definitions of n1, n2, n3, n6, Ar1, R1, R2, R3, R4, R6, R7, L1, L3, L4, L5, L6, L7 and X1 are as described in claim 1.

6. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-5, characterized in that, The compounds are shown in formulas (I-3-1), (I-4-1) to (I-9-1). Preferably, the compounds are as shown in formulas (I-3-1-1)-(I-3-1-2), (I-4-1-1)-(I-4-1-5), to (I-9-1-1)-(I-9-1-2). Among them, M4 is selected from N or CH; M5 is selected from N or CH; M6 is selected from N or CH; M7 is selected from N or CH; M8 is selected from N or CH; M 16 Selected from N, O, S, CH, NH or CH2; M 17 Selected from N, O, S, CH, NH or CH2; It can be a single bond or a double bond; Y4, Y5, Y7, Y9 and Y 10 Each is independently selected from bonds, NH, N, O, CH, S, or -(CH2). u -; Y6, Y8 and Y 11 Each is independently selected from N, C, or CH; n9 and n10 are each independently selected from 0, 1, 2 or 3; n21, n22, n23, and n24 are each independently selected from 0, 1, 2, or 3; n4 can be 0, 1, 2, 3 or 4; n4' is 0, 1, 2 or 3; "n4" can be 0, 1, 2, 3 or 4; u can be 0, 1, 2, 3 or 4; Cy1 is selected from non-existent or 5-8 membered heterocyclic groups; preferably 5-6 membered heterocyclic groups; n'3 is 0, 1, 2, 3, 4 or 5; R1, R2, R3, R4, R 4-1 R5 and R6 are each independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n R aa -(CH2) n OR dd -O(CH2) n R aa -(CH2) n SR dd -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R dd -(CH2) n C(O)NR aa R dd -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R dd -(CH2) n P(O)R aa R dd -O(CH2) n P(O)R aa R dd -(CH2) n NR cc C(=NH)NR aa R dd (CH2) n NR dd S(O) m R cc -OC(R) aa R dd ) n (CH2) m R aa -NR dd (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R dd -CH=CH(CH2) n NR dd C(O)R cc -CH=CH(CH2) n NR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc The C mentioned therein 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3- 12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl and 5-14 heteroaryl groups may be further substituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or unsubstituted C groups. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1- 6-alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Cy2 is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups; The definitions of n1, n2, n3, n6, M9, Ar1, R7, L1, L3, L4, L5, L6, L7 and X1 are as described in claim 1.

7. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-6, characterized in that, Ar1 is a 5-10 membered heteroaryl, preferably a 5-9 membered heteroaryl, more preferably a 5 membered heteroaryl or a 5 membered heteroaryl-6 membered heteroaryl, and even more preferably a 5 membered heteroaryl or More preferably, indole, thiazolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxadiazole, oxazolyl, thiophene, furanyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, and more preferably... Ar3 is selected from 6-membered heteroaryl groups, preferably pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl. Ar4 is selected from 5-membered heteroaryl groups, preferably pyrrole, thiazolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxadiazole, oxazolyl, thiophene, and furanyl.

8. The compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-7, characterized in that, The compounds are shown as those of formula (I-4-1-1-1)-(I-4-1-1-4) or (I-6-1-1-1). in, Cy1 is selected from non-existent or 5-8 membered heterocyclic groups; preferably 5-6 membered heterocyclic groups; n'3 is 0, 1, 2, 3, 4 or 5; n4 can be 0, 1, 2, 3 or 4; M4 is selected from N or CH; M5 is selected from N or CH; M6 is selected from N or CH; n4' is 0, 1, 2 or 3; "n4" is 0, 1, 2, 3, or 4; n1, n2, n3, n6, R1, R2, R3, R4, R 4-1 The definitions of R6, R7, L1, L3, L4, L5, L6, L7 and X1 are as described in claim 1 or 6.

9. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-8, characterized in that, L3 and L5 are each independently selected from the following group of substituted or unsubstituted groups: CH2, 4-6 membered monocyclic heterocyclic groups, 7-11 membered spirocyclic heterocyclic groups, 5-8 membered bridged heterocyclic groups, 8-10 membered fused heterocyclic groups, or C 4-6 Monocyclic cycloalkyl, C 7-11 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 8-10 Fused cycloalkyl groups; preferably substituted or unsubstituted groups from the following group: More preferably, the following groups are substituted or unsubstituted: Alternatively, L3 can be selected from NH or NC. 1-3 Alkyl, CO, COCH2, C 1-3 Alkylene, C 1-3 Halogenated alkylene oxides, CONH, CONC 1-3 Alkyl, CONHCH2, CONC 1-3 Alkyl group CH2; or L5 bond; Wherein, substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2). n R aa -(CH2) n OR dd -O(CH2) n R aa -(CH2) n SR dd -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R dd -(CH2) n C(O)NR aa R dd -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R dd -(CH2) n P(O)R aa R dd -O(CH2) n P(O)R aa R dd -(CH2) n NR cc C(=NH)NR aa R dd (CH2) n NR dd S(O) m R cc -OC(R) aa R dd ) n (CH2) m R aa -NR dd (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R dd -CH=CH(CH2) n NR dd C(O)R cc -CH=CH(CH2) n NR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1- 6-alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents from a group consisting of aryl and substituted or unsubstituted 5-14 heteroaryl groups; preferably, the substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2)R. aa -(CH2)OR dd -(CH2)2OR dd C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-6 The substance is substituted by one or more substituents selected from cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; n21, n22, n23, and n24 are each independently selected from 0, 1, 2, or 3; n11, n12, n13, and n14 are each independently selected from 0, 1, 2, or 3; R aa R cc R dd The definitions of m and n are as described above.

10. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-9, characterized in that, L4 is selected from C 1-6 Alkylene, -(CH2) n7 C=O, C=O(CH2) n8 -、-(CH2) n7 CONH, CONH(CH2) n8 -、-(CH2) n7 S(O)2, S(O)2(CH2) n8 -、-(CH2) n7 S(O)2NR bb S(O)2NR bb (CH2) n8 -、-(CH2) n7 S(=NH)(=O) or S(=NH)(=O)(CH2) n8 -, wherein C 1-6 Alkylene, -(CH2) n7 C=O, C=O(CH2) n8 -、-(CH2) n7 CONH, CONH(CH2) n8 -、-(CH2) n7 S(O)2, S(O)2(CH2) n8 -、-(CH2) n7 S(O)2NR bb S(O)2NR bb (CH2) n8 -、-(CH2) n7 S(=NH)(=O) or S(=NH)(=O)(CH2) n8 -Optionally controlled by one or more R bb Replacement; preferably, R bb Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy group; wherein n7 and n8 are each independently 0, 1 or 2; preferably, L4 is selected from COCH2, COCH2CH2, CH2, CO, NR bb CONR bb ; And / or, L6 is selected from the following group of groups: bonded, substituted, or unsubstituted: 4-6 membered monocyclic heterocyclic groups, 7-11 membered spirocyclic heterocyclic groups, 5-8 membered bridged ring heterocyclic groups, 8-10 membered fused ring heterocyclic groups, or C 4-6 Monocyclic cycloalkyl, C 7-11 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 8-10 Fused cycloalkyl groups; more preferably, bonded or substituted or unsubstituted groups of the following: Wherein, substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2). n R aa -(CH2) n OR dd -O(CH2) n R aa -(CH2) n SR dd -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R dd -(CH2) n C(O)NR aa R dd -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R dd -(CH2) n P(O)R aa R dd -O(CH2) n P(O)R aa R dd -(CH2) n NR cc C(=NH)NR aa R dd (CH2) n NR dd S(O) m R cc -OC(R) aa R dd ) n (CH2) m R aa -NR dd (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R dd -CH=CH(CH2) n NR dd C(O)R cc -CH=CH(CH2) n NR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1- 6-alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents from a group consisting of aryl and substituted or unsubstituted 5-14 heteroaryl groups; preferably, the substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2)R. aa -(CH2)OR dd -(CH2)2OR dd C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-6 The substance is substituted by one or more substituents selected from cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; n11, n12, n13, and n14 are each independently selected from 0, 1, 2, or 3; R aa R bb R cc R dd The definitions of m and n are as described above.

11. The compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-10, characterized in that, L7 is selected from key; or L6 is selected from key; Alternatively, L6 is selected from the key and L7 is selected from the key.

12. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-11, characterized in that, Selected from 13. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-12, characterized in that, for or for or for In this group, ring A and ring B are each independently selected from the following group of substituted or unsubstituted groups: 4-6 membered monocyclic heterocyclic groups, 7-11 membered spirocyclic heterocyclic groups, 5-8 membered bridged ring heterocyclic groups, 8-10 membered fused ring heterocyclic groups, or C 4-6 Monocyclic cycloalkyl, C 7-11 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 8-10 Fused cycloalkyl groups; The heterocyclic group preferably contains 1-3 heteroatoms, wherein the heteroatoms are N, O or S; more preferably, the heteroatoms are 1 or 2 nitrogen atoms; Preferably, ring A and ring B are each independently selected from the following group of substituted or unsubstituted groups: Each can be a single bond or a double bond independently; Z1, Z4, Z8, Z 10 Z 12 Z 14 Z 15 and Z 16 Each is independently selected from N, C, or CH; Z 25 Z 26 Z 27 and Z 28 Each is independently selected from N or CH; Z2, Z3, Z5, Z6, Z7, Z9, Z 11 Z 13 Z 17 -Z 24 Z 29 -Z 36 Each is independently selected from bonds, O, S, N, NH, CH, CH2 or CH2CH2; Preferably, ring A and ring B are each independently selected from the following group: substituted or unsubstituted. More preferably, ring A and ring B are each independently selected from the group consisting of substituted or unsubstituted groups: Wherein, substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2). n R aa -(CH2) n OR dd -O(CH2) n R aa -(CH2) n SR dd -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R dd -(CH2) n C(O)NR aa R dd -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R dd -(CH2) n P(O)R aa R dd -O(CH2) n P(O)R aa R dd -(CH2) n NR cc C(=NH)NR aa R dd (CH2) n NR dd S(O) m R cc -OC(R) aa R dd ) n (CH2) m R aa -NR dd (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R dd -CH=CH(CH2) n NR dd C(O)R cc -CH=CH(CH2) n NR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1- 6-alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents from a group consisting of aryl and substituted or unsubstituted 5-14 heteroaryl groups; preferably, the substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2)R. aa -(CH2)OR dd -(CH2)2OR dd C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-6 The substance is substituted by one or more substituents selected from cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; L3 is selected from NH and NC. 1-3 Alkyl, CO, COCH2, C 1-3 Alkylene, C 1-3 Halogenated alkylene oxides, CONH, CONC 1-3 Alkyl, CONHCH2, CONC 1-3 Alkyl CH2; L 4' L4 and L4 are each independently selected from C 1-6 Alkylene, -(CH2) n7 C=O, C=O(CH2) n8 -、-(CH2) n7 CONH, CONH(CH2) n8 -、-(CH2) n7 S(O)2, S(O)2(CH2) n8 -、-(CH2) n7 S(O)2NR bb S(O)2NR bb (CH2) n8 -、-(CH2) n7 S(=NH)(=O) or S(=NH)(=O)(CH2) n8 -, wherein C 1- 6-alkylene group, -(CH2) n7 C=O, C=O(CH2) n8 -、-(CH2) n7 CONH, CONH(CH2) n8 -、-(CH2) n7 S(O)2, S(O)2(CH2) n8 -、-(CH2) n7 S(O)2NR bb S(O)2NR bb (CH2) n8 -、-(CH2) n7 S(=NH)(=O) or S(=NH)(=O)(CH2) n8 -Optionally controlled by one or more R bb Replacement; preferably, R bb Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy; wherein n7 and n8 are each independently 0, 1 or 2; Preferably, L 4' L4 and L4 are each independently selected from COCH2, COCH2CH2, CH2, CO, NR bb CONR bb ; n21, n22, n23, n24, n11, n12, n13, n14, R aa R bb R cc R dd The definitions of m and n are as described above; Preferably Selected from the following group of groups, whether substituted or unsubstituted: Preferably, Selected from the following group of groups, whether substituted or unsubstituted: or Selected from the following group of groups, whether substituted or unsubstituted: Preferably, Selected from the following group of groups, whether substituted or unsubstituted: Preferably Selected from the following group of groups, whether substituted or unsubstituted: Preferably, Selected from the following group of groups, whether substituted or unsubstituted: Wherein, substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2). n R aa -(CH2) n OR dd -O(CH2) n R aa -(CH2) n SR dd -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R dd -(CH2) n C(O)NR aa R dd -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R dd -(CH2) n P(O)R aa R dd -O(CH2) n P(O)R aa R dd -(CH2) n NR cc C(=NH)NR aa R dd (CH2) n NR dd S(O) m R cc -OC(R) aa R dd ) n (CH2) m R aa -NR dd (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R dd -CH=CH(CH2) n NR dd C(O)R cc -CH=CH(CH2) n NR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1- 6-alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents from a group consisting of aryl and substituted or unsubstituted 5-14 heteroaryl groups; preferably, the substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2)R. aa -(CH2)OR dd -(CH2)2OR dd C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-6 The substance is substituted by one or more substituents selected from cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; n11, n12, n13, n14, R aa R bb R cc R dd The definitions of m and n are as described above; Preferably, Selected from 14. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-13, characterized in that, The compounds are shown in formulas (I-3-1-1-1), (I-3-1-2-1), (I-4-1-1-1), (I-4-1-5-1), and (I-9-1-1-1), (I-9-1-2-1). The definitions of L4, ring A, and ring B are as described in claim 13; The definitions of other groups are as described in claims 1-13.

15. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, characterized in that, The compounds are shown in formulas (I-3-1-1-1-1), (I-3-1-2-1-1), (I-4-1-1-1-1), (I-4-2-1-1-1), and (I-9-1-1-1-1), (I-9-1-2-1-1). M b Selected from N or CH; R L Each group is independently selected from hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and -(CH2). n R aa -(CH2) n OR dd -O(CH2) n R aa -(CH2) n SR dd -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R dd -(CH2) n C(O)NR aa R dd -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R dd -(CH2) n P(O)R aa R dd -O(CH2) n P(O)R aa R dd -(CH2) n NR cc C(=NH)NR aa R dd (CH2) n NR dd S(O) m R cc -OC(R) aa R dd ) n (CH2) m R aa -NR dd (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R dd -CH=CH(CH2) n NR dd C(O)R cc -CH=CH(CH2) n NR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1- 6-alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents from a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; preferably, R L Each is independently selected from hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -(CH2)R aa -(CH2)OR dd -(CH2)2OR dd C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; j can be 0, 1, 2, 3, 4, 5 or 6.

16. The compound or a pharmaceutically acceptable salt thereof according to claim 14 or 15, characterized in that, The compounds are shown in formulas (I-3-1-1-1-1)-(I-3-1-2-1-1-1), (I-4-1-1-1-1)-(I-4-2-1-1-1) to (I-9-1-1-1-1-1)-(I-9-1-2-1-1-1). Where * indicates R or S configuration.

17. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 14-16, characterized in that, Ring A and ring B are each independently selected from the following group of substituted or unsubstituted groups: 4-6 membered monocyclic heterocyclic groups, 7-11 membered spirocyclic heterocyclic groups, 5-8 membered bridged ring heterocyclic groups, 8-10 membered fused ring heterocyclic groups, or C. 4-6 Monocyclic cycloalkyl, C 7-11 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 8-10 Fused cycloalkyl groups; The heterocyclic group preferably contains 1-3 heteroatoms, wherein the heteroatoms are N, O or S; more preferably, the heteroatoms are 1 or 2 nitrogen atoms; Preferably, ring A and ring B are each independently selected from the following group of substituted or unsubstituted groups: Each can be a single bond or a double bond independently; Z1, Z4, Z8, Z 10 Z 12 Z 14 Z 15 and Z 16 Each is independently selected from N, C, or CH; Z 25 Z 26 Z 27 and Z 28 Each is independently selected from N or CH; Z2, Z3, Z5, Z6, Z7, Z9, Z 11 Z 13 Z 17 -Z 24 Z 29 -Z 36 Each is independently selected from bonds, O, S, N, NH, CH, CH2 or CH2CH2; Preferably, ring A and ring B are each independently selected from the following group of substituted or unsubstituted groups: Wherein, substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2). n R aa -(CH2) n OR dd -O(CH2) n R aa -(CH2) n SR dd -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R dd -(CH2) n C(O)NR aa R dd -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R dd -(CH2) n P(O)R aa R dd -O(CH2) n P(O)R aa R dd -(CH2) n NR cc C(=NH)NR aa R dd (CH2) n NR dd S(O) m R cc -OC(R) aa R dd ) n (CH2) m R aa -NR dd (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R dd -CH=CH(CH2) n NR dd C(O)R cc -CH=CH(CH2) n NR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1- 6-alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents from a group consisting of aryl and substituted or unsubstituted 5-14 heteroaryl groups; preferably, the substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2)R. aa -(CH2)OR dd -(CH2)2OR dd C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-6 The substance is substituted by one or more substituents selected from cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; Preferably, L4 is selected from C 1-6 Alkylene, -(CH2) n7 C=O, C=O(CH2) n8 -、-(CH2) n7 CONH, CONH(CH2) n8 -、-(CH2) n7 S(O)2, S(O)2(CH2) n8 -、-(CH2) n7 S(O)2NR bb S(O)2NR bb (CH2) n8 -、-(CH2) n7 S(=NH)(=O) or S(=NH)(=O)(CH2) n8 -, wherein C 1- 6-alkylene group, -(CH2) n7 C=O, C=O(CH2) n8 -、-(CH2) n7 CONH, CONH(CH2) n8 -、-(CH2) n7 S(O)2, S(O)2(CH2) n8 -、-(CH2) n7 S(O)2NR bb S(O)2NR bb (CH2) n8 -、-(CH2) n7 S(=NH)(=O) or S(=NH)(=O)(CH2) n8 -Optionally controlled by one or more R bb Replacement; preferably, R bb Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy group; wherein n7 and n8 are each independently 0, 1 or 2; more preferably, L4 is selected from COCH2, COCH2CH2, CH2, CO, NH, NCH3, CONH, CON(CH3), SO2, SO2CH2, COCHCH3, CH(CH3)CH2, C(CH3)(OH)CH2, CHFCH2, CHFCHF, CF2CH2, CF2CF2, CH2NHCO, NHCOCH2, CH2N(CH3)CO, N(CH3)COCH2 or COCH(CH3)CH2.

18. A compound or a pharmaceutically acceptable salt thereof, comprising a structural unit represented by formula (I'). in, M is selected from The definitions of X1, R6, and n6 are as described in claim 1; Preferably, the structural unit has the structure shown in formula (I'-1) or (I'-2). in, M9, M 10 M 11 M 13 M 14 The definitions of Y0, Y1, Y2, X1, R5, n5, R6 and n6 are as described in claim 1.

19. The compound of claim 18 or a pharmaceutically acceptable salt thereof, characterized in that, The structural unit described herein has a structural unit as shown in formula (I'-1-1) or (I'-2-1). Preferably, the structural unit has the structural unit shown in formula (I'-1-1-1)-(I'-1-1-2) or (I'-2-1-1)-(I'-2-1-2). Where * indicates R or S configuration.

20. The compound of claim 18 or a pharmaceutically acceptable salt thereof, characterized in that, The compound further comprises the structural unit shown in formula (I'-3). Wherein, ring B is selected from the following group, either substituted or unsubstituted: 4-6 membered monocyclic heterocyclic group, 7-11 membered spirocyclic heterocyclic group, 5-8 membered bridged ring heterocyclic group, 8-10 membered fused ring heterocyclic group, or C. 4-6 Monocyclic cycloalkyl, C 7-11 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 8-10 Fused cycloalkyl groups; The heterocyclic group preferably contains 1-3 heteroatoms, wherein the heteroatoms are N, O or S; more preferably, the heteroatoms are 1 or 2 nitrogen atoms; Preferably, each ring B is independently selected from the following group, either substituted or unsubstituted: Each can be a single bond or a double bond independently; Z1, Z4, Z8, Z 10 Z 12 Z 14 Z 15 and Z 16 Each is independently selected from N, C, or CH; Z 25 Z 26 Z 27 and Z 28 Each is independently selected from N or CH; Z2, Z3, Z5, Z6, Z7, Z9, Z 11 Z 13 Z 17 -Z 24 Z 29 -Z 36 Each is independently selected from bonds, O, S, N, NH, CH, CH2 or CH2CH2; Preferably, ring B is selected from the following group: substituted or unsubstituted groups. Wherein, substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2). n R aa -(CH2) n OR dd -O(CH2) n R aa -(CH2) n SR dd -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R dd -(CH2) n C(O)NR aa R dd -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R dd -(CH2) n P(O)R aa R dd -O(CH2) n P(O)R aa R dd -(CH2) n NR cc C(=NH)NR aa R dd (CH2) n NR dd S(O) m R cc -OC(R) aa R dd ) n (CH2) m R aa -NR dd (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R dd -CH=CH(CH2) n NR dd C(O)R cc -CH=CH(CH2) n NR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1- 6-alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents from a group consisting of aryl and substituted or unsubstituted 5-14 heteroaryl groups; preferably, the substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2)R. aa -(CH2)OR dd -(CH2)2OR dd C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-6 It is substituted by one or more substituents selected from cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl.

21. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 18-20, characterized in that, The compound further comprises structural units represented by formulas (I'-3-3) to (I'-3-12). Preferably, the compound further comprises structural units represented by formula (I'-3-1) or formula (I'-3-2). Among them, M b Selected from N or CH; R L Each group is independently selected from hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and -(CH2). n R aa -(CH2) n OR dd -O(CH2) n R aa -(CH2) n SR dd -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R dd -(CH2) n C(O)NR aa R dd -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R dd -(CH2) n P(O)R aa R dd -O(CH2) n P(O)R aa R dd -(CH2) n NR cc C(=NH)NR aa R dd (CH2) n NR dd S(O) m R cc -OC(R) aa R dd ) n (CH2) m R aa -NR dd (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R dd -CH=CH(CH2) n NR dd C(O)R cc -CH=CH(CH2) n NR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1- 6-alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents from a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; preferably, R L Each is independently selected from hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -(CH2)R aa -(CH2)OR dd -(CH2)2OR dd C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; j is 0, 1, 2, 3, 4, 5 or 6; R aa R cc R dd The definitions of m and n are as described in claim 1; Preferably, the compound further comprises structural units represented by formula (I'-3-1-1)-(I'-3-1-2) or formula (I'-3-2-1)-(I'-3-2-2). Where * indicates R or S configuration.

22. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 18-21, characterized in that, The compound further comprises the structural unit shown in formula (I'-4). Preferably, the compound further comprises structural units as shown in formulas (I'-4-1)-(I'-4-3). Preferably, the compound further comprises structural units represented by the formula (I'-4-1-1)-(I'-4-1-3). The definitions of ring A, ring B, and L4 are as described in claim 13.

23. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 18-22, characterized in that, The compound is a PROTAC compound, further comprising a target protein binding unit; preferably, the compound has the following structure. Preferably, the compound further comprises structural units as shown in formulas (I'-5-1)-(I'-5-3). Preferably, the compound further comprises structural units represented by formulas (I'-5-1-1) to (I'-5-1-12). Among them, P, P-L2-, P-L2-L3-, P-L2-L3-L4-, P-L2-L3-L4-L5-, For target protein binding units; R L-2 The definition is the same as R L ; j1 is 0, 1, 2, 3, 4, 5 or 6; Preferably, the target protein is selected from EGFR, AR, BRD9, BCL6, or BTK; the target protein further comprises one or more of the following structural units: thiazolyl, pyridyl, indolyl, pyrimidinyl, phenyl, pyridonel, oxadiazolyl, pyrazolyl, quinolinyl, piperidinyl, piperazinyl, cyclobutyl, cyclopentyl, cyclohexylbenzopyridine, benzopyrimidine, benzopyrazole, pyrimidopyrrole, pyridopyridone, benzopyridone, isodihydroindolyl, furan, triazole, and analogues. EGFR inhibitors are preferred; the EGFR is further preferably mutated and / or overexpressed EGFR, particularly EGFR with single or multiple mutations associated with the L858R mutation.

24. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-23, characterized in that, The compound is selected from the following compounds:

25. A compound of formula (I”) or (I”’) or a pharmaceutically acceptable salt thereof: in, Ring B is selected from the following group, either substituted or unsubstituted: 4-6 membered monocyclic heterocyclic groups, 7-11 membered spirocyclic heterocyclic groups, 5-8 membered bridged ring heterocyclic groups, 8-10 membered fused ring heterocyclic groups, or C. 4-6 Monocyclic cycloalkyl, C 7-11 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 8-10 Fused cycloalkyl groups; The heterocyclic group preferably contains 1-3 heteroatoms, wherein the heteroatoms are N, O or S; more preferably, the heteroatoms are 1 or 2 nitrogen atoms; Preferably, each ring B is independently selected from the following group, either substituted or unsubstituted: Each can be a single bond or a double bond independently; Z1, Z4, Z8, Z 10 Z 12 Z 14 Z 15 and Z 16 Each is independently selected from N, C, or CH; Z 25 Z 26 Z 27 and Z 28 Each is independently selected from N or CH; Z2, Z3, Z5, Z6, Z7, Z9, Z 11 Z 13 Z 17 -Z 24 Z 29 -Z 36 Each is independently selected from bonds, O, S, N, NH, CH, CH2 or CH2CH2; Preferably, ring B is selected from the following group: substituted or unsubstituted groups. Among them, the sulfur substitution group refers to - being substituted by (C₁H₂) n halogen R aa element, -(substituted C₁H₂) or n O unsubstituted R dd - substituted O(amino C₁H₂) n R nitro aa group, -(hydroxy C₁H₂), n S cyano R d group d - substituted (mercapto C₁H₂) n C oxygen (substituted O) group R c , c , -(C₁H₂) n C(O)OR cc , -(C₁H₂) n S(O) m R cc , -(C₁H₂) n NR aa R dd , -(C₁H₂) n C(O)NR aa R dd , -(C₁H₂) n NR bb C(O)R cc , -(C₁H₂) n NR cc C(O)NR aa R dd , -(C₁H₂) n P(O)R aa R dd , -O(C₁H₂) n P(O)R aa R dd , -(C₁H₂) n NR cc C(=NH)NR aa R dd , (C₁H₂) n NR dd S(O) m R cc , -OC(R aa R dd ) n (C₁H₂) m R aa , -NR dd (C₁H₂) n R aa , -CH=CH(C₁H₂) n R aa , -CH=CH(C₁H₂) n NR aa R dd -CH=CH(CH2) n NR dd C(O)R cc -CH=CH(CH2) n NR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3- 12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents from a group consisting of aryl and substituted or unsubstituted 5-14 heteroaryl groups; preferably, the substitution refers to the substitution by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or -(CH2)R. aa -(CH2)OR dd -(CH2)2OR dd C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1- 6-alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 The substance is substituted by one or more substituents selected from cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; M9, M 10 M 11 X1, R5, n5, R6, n6, R aa R cc R dd The definitions of m and n are as described in claim 1.

26. The compound of claim 25 or a pharmaceutically acceptable salt thereof, characterized in that, The compound has the structures shown in formulas (I”’-2) to (I”’-11). Preferably, the compound has the structure shown in formula (I”’-1). Among them, M b Selected from N or CH; R L-1 The definition is the same as R L ; R L Each group is independently selected from hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and -(CH2). n R aa -(CH2) n OR dd -O(CH2) n R aa -(CH2) n SR dd -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R dd -(CH2) n C(O)NR aa R dd -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R dd -(CH2) n P(O)R aa R dd -O(CH2) n P(O)R aa R dd -(CH2) n NR cc C(=NH)NR aa R dd (CH2) n NR dd S(O) m R cc -OC(R) aa R dd ) n (CH2) m R aa -NR dd (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R dd -CH=CH(CH2) n NR dd C(O)R cc -CH=CH(CH2) n NR cc C(O)NR aa R dd =N-OR dd or = CR aa R cc C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1- 6-alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents from a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; preferably, R L Each is independently selected from hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -(CH2)R aa -(CH2)OR dd -(CH2)2OR dd C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; j is 0, 1, 2, 3, 4, 5 or 6; R aa R cc R dd The definitions of m and n are as described in claim 1; Preferably, the compound has the structure shown in formula (I”’-1-1)-(I”’-1-2). Where * indicates R or S configuration.

27. The compound of claim 25 or 26, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is selected from 28. A pharmaceutical composition comprising a therapeutically effective dose of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

29. The use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-27, or the pharmaceutical composition of claim 28, in the preparation of an EGFR, AR, BRD9, BCL6, or BTK inhibitor medicament; preferably an EGFR inhibitor; wherein the EGFR is further preferably a mutated and / or overexpressed EGFR, preferably a single or multiple mutated EGFR associated with the L858R mutation.

30. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-27, or the pharmaceutical composition of claim 28, for the treatment of abnormal cell proliferation, tumors, immune diseases, diabetes, cardiovascular diseases, infectious diseases, and inflammatory diseases; preferably tumors and infectious diseases; preferably, the tumor is cancer; preferably breast cancer, endometrial cancer, uterine cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, fallopian tube tumors, ovarian tumors, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, renal cell carcinoma, bladder cancer, colon cancer, etc. Application in drugs for rectal cancer, esophageal cancer, head cancer, kidney cancer, hepatocellular carcinoma, lung cancer, cervical cancer, pancreatic cancer, gastric cancer, lymphoma, non-Hodgkin's lymphoma, melanoma, myeloproliferative disorders, sarcoma, angiosarcoma, peripheral neuroepithelial tumor, astrocytoma, glioma, ependymoma, neuroblastoma, gangliocytoma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, schwannoma, cholangiocarcinoma, myeloma, mesothelioma, gastrointestinal stromal tumor, thyroid cancer, esophageal cancer, Hodgkin's tumor, Wilms' tumor, and teratoma; Preferably, the application is in the preparation of a medicament for treating cancer; wherein the cancer is selected from ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, renal cancer, anaplastic large cell lymphoma, multiple myeloma, or mesothelioma; more preferably, the cancer is non-small cell lung cancer; even more preferably, the cancer is non-small cell lung cancer with EGFR L858R, EGFR L858R / T790M, L858R / C797S, or L858R / T790M / C797S mutations.

31. The pharmaceutically acceptable salt of the compound according to any one of claims 1-27, characterized in that, The compound includes its stereoisomers.

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