Tricyclic scaffold compound and use thereof in preparation of antitumor drugs

Abstract

Disclosed in the present invention are a tricyclic scaffold compound and a use thereof in the preparation of antitumor drugs. Specifically, the present invention provides a compound as shown in formula (IA) or a pharmaceutically acceptable salt thereof. The tricyclic scaffold compound of the present invention can effectively inhibit the proliferation of tumor cells.

Description

Tricyclic skeleton compounds and their application in the preparation of anti-tumor drugs

[0001] This application claims the benefit of priority to Chinese Patent Application No. 2024103339139 filed on March 22, 2024, and Chinese Patent Application No. 2024118381355 filed on December 13, 2024. The entire contents of the aforementioned Chinese patent applications are incorporated herein by reference. Technical Field

[0002] The present invention relates to a tricyclic skeleton compound and application thereof in the preparation of anti-tumor drugs. Background Art

[0003] Cancer is a persistent global public health challenge. As the second most common cause of death worldwide, cancer is projected to be the primary obstacle to increasing life expectancy in the 21st century. The burden of cancer is steadily increasing globally. Cancer is the leading cause of death in my country, and the burden of malignant tumors in China is on the rise. Cancer is also a major contributor to premature mortality from major chronic diseases and life expectancy. Therefore, identifying effective diagnostic and therapeutic targets will help achieve breakthroughs in cancer treatment.

[0004] With the advancement of research, our understanding of cancer has deepened. Since the 21st century, 14 hallmark characteristics of cancer have been identified. These characteristics have led to the study of numerous related signaling and metabolic pathways, which have led to the discovery of relevant targets and the development of new drugs.

[0005] The mitogen-activated protein kinase (MAPK) signaling pathway is an important pathway for tumor generation and development. The MAPK pathway performs signal transduction based on a three-stage kinase phosphorylation model (such as Raf-MEK-ERK). Ras kinase inhibitor KSR family proteins are important scaffold proteins of the MAPK pathway and have a positive regulatory effect on this signaling pathway. KSR2 is a member of this family. As a scaffold protein, it binds to RAF, MEK, and ERK to form a complex and participate in the regulation of the MAPK signaling pathway. In the crystal structure study of the KSR2 kinase domain, it was found that KSR2 is a key molecule for the phosphorylation of MEK by Raf (see BRENNAN DF, DAR AC, HERTZ NT, et al. A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK [J]. Nature, 2011, 472(7343): 366-9). KSR2 can directly phosphorylate AMPK, regulating metabolic processes such as glucose uptake and fatty acid oxidation mediated by the energy sensor AMPK and insulin sensitivity (see COSTANZO-GARVEY DL, PFLUGER PT, DOUGHERTY MK, et al. KSR2 is an essential regulator of AMP kinase, energy expenditure, and insulin sensitivity [J]. Cell Metab, 2009, 10(5): 366-78). We have confirmed the carcinogenic effect of KSR2 at the cellular, molecular and animal levels (reference FERNANDEZ MR, HENRY MD, LEWIS R E. Kinase suppressor of Ras 2 (KSR2) regulates tumor cell transformation via AMPK[J]. Mol Cell Biol, 2012, 32(18): 3718-31, GAO C, WANG SW, LU JC, et al. KSR2-14-3-3zeta complex serves as a biomarker and potential therapeutic target in sorafenib-resistant hepatocellular carcinoma[J]. Biomark Res, 2022, 10(1): 25); and explained the key mechanism by which it activates AMPK to participate in oxidative phosphorylation and acquires stemness to achieve targeted drug resistance.Currently, no KSR2 inhibitors have entered clinical trials. Based on this, we are developing small molecule inhibitors of the KSR2-AMPK pathway for the treatment of tumors associated with the KSR2 protein. Summary of the Invention

[0006] The technical problem to be solved by the present invention is the singleness of existing drugs for targeted cancer treatment, and a tricyclic skeleton compound and its application in the preparation of anti-tumor drugs are provided. The tricyclic skeleton compound can effectively inhibit the proliferation of tumor cells.

[0007] The present invention provides a compound represented by formula (IA) or a pharmaceutically acceptable salt thereof,

[0008] wherein Ring C is a benzene ring or a "5- to 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from N, O and S";

[0009] Each R1 is independently halogen, cyano, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Alkoxy, C substituted by one or more halogen 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkoxy, "heteroatoms selected from 1, 2 or 3 of N, O, S, 5-10 membered heteroaryl with 1, 2 or 3 heteroatoms" or one or more R 1-1 Substituted "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0010] Each R 1-1 C 1-6 alkyl;

[0011] m and k are each independently 0, 1 or 2;

[0012] X1 is -CH2-, -O-, -S-, -NH- or -S(=O)2-;

[0013] X2 is -C(R a R b )-or-O-;

[0014] R a and R b are independently hydrogen, deuterium or C 1-6 Alkyl, or R a 、R b and their common carbon atoms are connected to form a 3-10 membered saturated carbocyclic ring;

[0015] n is 0 or 1;

[0016] each Each independently represents a single bond or a double bond;

[0017] X3 and X4 are independently C or N;

[0018] Ring A is a pyrazole ring;

[0019] Each R2 is independently H, halogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl with 1, 2 or 3 heteroatoms selected from N, O and S", C 6-10 Aryl, one or more R 2-1 Substituted C 1-6 Alkyl or one or more R 2-2 Substituted "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0020] Each R 2-1 and R 2-2 are independently halogen, hydroxyl, C 1-6 Alkyl, -N(R 2a R 2b ), C 3-10 Cycloalkyl, C 1-6 Alkoxy, "heteroatoms selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 3-membered heterocycloalkyl", C 6-10 Aryl or "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0021] R 2a and R 2b are independently H or C 1-6 alkyl;

[0022] E is -N(R3)- or n1 is 1, 2 or 3; # represents the end connected to -C(O)- in formula (IA);

[0023] R3 is hydrogen, C 1-6 Alkyl or C 3-10 Cycloalkyl;

[0024] L is C 1-6 Alkylene, one or more R L Substituted C 1-6 Alkylene, "-(C 1-6 Alkylene)-L A -*" or -L A -;

[0025] Each R L Deuterium, C 1-6 Alkoxy, C 3-10 Cycloalkyl, hydroxy, halogen or oxo (=O), or when two R L When substituted on the same carbon atom, two R L and their common carbon atoms are connected to form a 3-10 membered saturated carbocyclic ring or a 3-10 membered saturated heterocyclic ring in which the heteroatoms are selected from 1, 2 or 3 of N, O and S and the number of heteroatoms is 1, 2 or 3;

[0026] L A -C(O)NH-, -O-, -N(R LA )-, vinylidene, ethynylene, 3-10 membered saturated carbocyclic ring or "a 3-10 membered saturated heterocyclic ring in which the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3";

[0027] R LA H, C 1-6 Alkyl, C 3-10 Cycloalkyl or "3-10 membered heterocycloalkyl group wherein the heteroatoms are 1, 2 or 3 selected from N, O and S";

[0028] Ring B is a 3-10 membered saturated or unsaturated carbon ring, surrounded by one or more R B-1 Substituted 3-10 membered saturated or unsaturated carbon ring, "heteroatoms selected from 1, 2 or 3 of N, O, S, 3-10 membered saturated or unsaturated heterocyclic ring with 1, 2 or 3 heteroatoms" or one or more R B-2 Substituted "3-10 membered saturated or unsaturated heterocyclic ring having 1, 2 or 3 heteroatoms selected from N, O and S";

[0029] Each R B-1 and R B-2 are independently hydroxy, halogen, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy or C substituted by one or more hydroxyl groups 1-6 alkyl;

[0030] When U is absent, ring B is

[0031] U does not exist, -N(R')(R''), C 3-6 Alkyl, one or more R U-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, one or more RU-2 Substituted C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl with 1, 2 or 3 heteroatoms selected from N, O and S", "heteroatoms selected from 1, 2 or 3 heteroatoms selected from N, O and S", "heteroatoms selected from 1, 2 or 3 heteroatoms" U-3 Substituted "3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S", C 6-10 Aryl, one or more R U-4 Substituted C 6-10 Aryl, "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S", one or more R U-5 Substituted "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S" or -XR U-6 ;

[0032] X is -C(O)-, -SO2- or -O-;

[0033] Each R' and R" are independently hydrogen, C 1-6 Alkyl, -C(O)-C 3-10 Cycloalkyl or C substituted by one or more R" 1-6 Alkyl; R'" is independently C 6-10 aryl;

[0034] Each R U-1 are independently -N(R')(R''), halogen, C 3-10 Cycloalkyl, C 6-10 Aryl, "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S" or "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms ... U-1-1 Substituted "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0035] Each R U-1-1 C 1-6 alkyl;

[0036] Each R U-2 、R U-3 、R U-4 and R U-5 are independently halogen, cyano, hydroxyl, -SO2-C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -C(O)NH-C 1-6 Alkyl, C 1-6 Alkyl, one or more RU-3-1 Substituted C 1-6 Alkyl, C 1-6 Alkoxy, one or more R U-3-2 Substituted C 1-6 Alkoxy, C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl wherein the heteroatoms are 1, 2 or 3 selected from the group consisting of N, O and S, and the number of heteroatoms is 1, 2 or 3" or -O- "3-10 membered heterocycloalkyl wherein the heteroatoms are 1, 2 or 3 selected from the group consisting of N, O and S, and the number of heteroatoms is 1, 2 or 3";

[0037] Each R U-3-1 and R U-3-2 are independently halogen, C 3-10 Cycloalkyl, C 6-10 Aryl, C 1-6 Alkoxy, hydroxy, cyano or heteroatoms selected from 1, 2 or 3 of N, O and S, and a 3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms;

[0038] Each R U-6 C 6-10 Aryl or "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0039] The compound represented by formula (I) is not any of the following compounds:

[0040] The present invention provides a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof,

[0041] wherein Ring C is a benzene ring or a "5- to 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from N, O and S";

[0042] Each R1 is independently halogen, cyano, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Alkoxy, C substituted by one or more halogen 1-6 Alkyl or C substituted by one or more halogen 1-6 alkoxy;

[0043] m and k are each independently 0, 1 or 2;

[0044] X1 is -CH2-, -O-, -S-, -NH- or -S(=O)2-;

[0045] X2 is -C(R a R b )-or-O-;

[0046] R a and R b are independently hydrogen, deuterium or C 1-6 Alkyl, or R a 、R b and their common carbon atoms are connected to form a 3-10 membered saturated carbocyclic ring;

[0047] n is 0 or 1;

[0048] each Each independently represents a single bond or a double bond;

[0049] X3 and X4 are independently C or N;

[0050] Ring A is a pyrazole ring;

[0051] Each R2 is independently halogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl with 1, 2 or 3 heteroatoms selected from N, O and S", C 6-10 Aryl, one or more R 2-1 Substituted C 1-6 Alkyl or one or more R 2-2 Substituted "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0052] Each R 2-1 and R 2-2 are independently halogen, hydroxyl, C 1-6 Alkyl, -N(R 2a R 2b ), C 3-10 Cycloalkyl, C 1-6 Alkoxy, "heteroatoms selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 3-membered heterocycloalkyl", C 6-10 Aryl or "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0053] R 2a and R 2b are independently H or C 1-6 alkyl;

[0054] R3 is hydrogen, C 1-6 Alkyl or C 3-10 Cycloalkyl;

[0055] L is C 1-6 Alkylene, one or more R LSubstituted C 1-6 Alkylene, "-(C 1-6 Alkylene)-L A -*" or -L A -(*indicates the end connected to ring B);

[0056] Each R L Deuterium, C 1-6 Alkoxy, C 3-10 Cycloalkyl, hydroxy, halogen or oxo (=O), or when two R L When substituted on the same carbon atom, two R L and their common carbon atoms are connected to form a 3-10 membered saturated carbocyclic ring or a 3-10 membered saturated heterocyclic ring in which the heteroatoms are selected from 1, 2 or 3 of N, O and S and the number of heteroatoms is 1, 2 or 3;

[0057] L A -C(O)NH-, -O-, -N(R LA )-, vinylidene, ethynylene, 3-10 membered saturated carbocyclic ring or "a 3-10 membered saturated heterocyclic ring in which the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3";

[0058] R LA H, C 1-6 Alkyl, C 3-10 Cycloalkyl or "3-10 membered heterocycloalkyl group wherein the heteroatoms are 1, 2 or 3 selected from N, O and S";

[0059] Ring B is a 3-10 membered saturated or unsaturated carbon ring, surrounded by one or more R B-1 Substituted 3-10 membered saturated or unsaturated carbon ring, "heteroatoms selected from 1, 2 or 3 of N, O, S, 3-10 membered saturated or unsaturated heterocyclic ring with 1, 2 or 3 heteroatoms" or one or more R B-2 Substituted "3-10 membered saturated or unsaturated heterocyclic ring having 1, 2 or 3 heteroatoms selected from N, O and S";

[0060] Each R B-1 and R B-2 are independently hydroxy, halogen, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy or C substituted by one or more hydroxyl groups 1-6 alkyl;

[0061] U is C 3-6 Alkyl, one or more R U-1 Substituted C 1-6 Alkyl, C3-10 Cycloalkyl, one or more R U-2 Substituted C 3- 10 Cycloalkyl, "3-10 membered heterocycloalkyl with 1, 2 or 3 heteroatoms selected from N, O and S", "heteroatoms selected from 1, 2 or 3 heteroatoms selected from N, O and S", "heteroatoms selected from 1, 2 or 3 heteroatoms" U-3 Substituted "3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S", C 6-10 Aryl, one or more R U-4 Substituted C 6-10 Aryl, "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S", one or more R U-5 Substituted "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S" or -XR U-6 ;

[0062] X is -C(O)-, -SO2- or -O-;

[0063] Each R U-1 are independently halogen, C 3-10 Cycloalkyl, C 6-10 Aryl, "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S" or "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms ... U-1-1 Substituted "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0064] Each R U-1-1 C 1-6 alkyl;

[0065] Each R U-2 、R U-3 、R U-4 and R U-5 are independently halogen, cyano, hydroxyl, -SO2-C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -C(O)NH-C 1-6 Alkyl, C 1-6 Alkyl, one or more R U-3-1 Substituted C 1-6 Alkyl, C 1-6 Alkoxy, one or more R U- 3-2 Substituted C 1-6 Alkoxy, C 3-10Cycloalkyl, "3-10 membered heterocycloalkyl wherein the heteroatoms are 1, 2 or 3 selected from the group consisting of N, O and S, and the number of heteroatoms is 1, 2 or 3" or -O- "3-10 membered heterocycloalkyl wherein the heteroatoms are 1, 2 or 3 selected from the group consisting of N, O and S, and the number of heteroatoms is 1, 2 or 3";

[0066] Each R U-3-1 and R U-3-2 are independently halogen, C 3-10 Cycloalkyl or cyano;

[0067] Each R U-6 C 6-10 Aryl or "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0068] The compound represented by formula (I) is not any of the following compounds:

[0069] In some embodiments, the compound represented by formula (IA) is a compound represented by formula (IIA):

[0070] Each R1 is independently halogen, cyano, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Alkoxy, C substituted by one or more halogen 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkoxy, "heteroatoms selected from 1, 2 or 3 of N, O, S, 5-10 membered heteroaryl with 1, 2 or 3 heteroatoms" or one or more R 1-1 Substituted "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0071] Each R 1-1 C 1-6 alkyl;

[0072] m and k are each independently 0, 1 or 2;

[0073] X1 is -CH2-, -O-, -S- or -S(=O)2-;

[0074] Each R2 is independently H, C 1-6 Alkyl, one or more R 2-1 Substituted C 1-6 Alkyl or "3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0075] Each R 2-1 are independently hydroxyl or C 3-10 Cycloalkyl;

[0076] each Each independently represents a single bond or a double bond;

[0077] E is -N(R3)- or n1 is 1, 2 or 3; # represents the end connected to -C(O)- in formula (IA);

[0078] R3 is hydrogen or C 1-6 alkyl;

[0079] L is C 1-6 Alkylene, one or more R L Substituted C 1-6 Alkylene or "-(C 1-6 Alkylene)-L A -*”;

[0080] Each R L are independently hydroxy or halogen, or when two R L When substituted on the same carbon atom, two R L and their common carbon atoms are connected to form a 3-10 membered saturated carbocyclic ring;

[0081] L A -NH-, -N(C 1-6 alkyl)- or 3-10 membered saturated carbocyclic ring;

[0082] Ring B is a "3-10 membered saturated or unsaturated heterocyclic ring with 1, 2 or 3 heteroatoms selected from N, O and S" or is replaced by one or more R B-2 Substituted "3-10 membered saturated or unsaturated heterocyclic ring having 1, 2 or 3 heteroatoms selected from N, O and S";

[0083] Each R B-2 are independently hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C substituted by one or more hydroxyl groups 1-6 alkyl;

[0084] When U is absent, ring B is

[0085] U does not exist, -N(R')(R''), C 3-6 Alkyl, one or more R U-1 Substituted C 1-6 Alkyl, C3-10 Cycloalkyl, one or more R U-2 Substituted C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl with 1, 2 or 3 heteroatoms selected from N, O and S", "heteroatoms selected from 1, 2 or 3 heteroatoms selected from N, O and S", "heteroatoms selected from 1, 2 or 3 heteroatoms" U-3 Substituted "3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S", C 6-10 Aryl, one or more R U-4 Substituted C 6-10 Aryl, "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S" or "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms ... U-5 Substituted "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0086] Each R' and R" are independently hydrogen, C 1-6 Alkyl, -C(O)-C 3-10 Cycloalkyl or C substituted by one or more R" 1-6 Alkyl; R'" is independently C 6-10 aryl;

[0087] Each R U-1 are independently -N(R')(R''), C 3-10 Cycloalkyl or C 6-10 aryl;

[0088] Each R U-2 、R U-3 、R U-4 and R U-5 are independently halogen, -SO2-C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S", cyano, hydroxyl, C 1-6 Alkyl, one or more R U-3-1 Substituted C 1-6 Alkyl, C 1-6 Alkoxy or one or more R U-3-2 Substituted C 1-6 alkoxy;

[0089] Each R U-3-1 and R U-3-2 are independently halogen, C 3-10 Cycloalkyl, C 6-10 Aryl, C 1-6Alkoxy, hydroxy, cyano or heteroatoms selected from 1, 2 or 3 of N, O and S, and a 3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms.

[0090] In some embodiments, the compound represented by formula (I) is a compound represented by the following formula (II):

[0091] Each R1 is independently halogen;

[0092] m and k are each independently 0, 1 or 2;

[0093] X1 is -CH2-, -O-, -S- or -S(=O)2-;

[0094] Each R2 is independently C 1-6 Alkyl or one or more R 2-1 Substituted C 1-6 alkyl;

[0095] Each R 2-1 C 3-10 Cycloalkyl;

[0096] each Each independently represents a single bond or a double bond;

[0097] R3 is hydrogen or C 1-6 alkyl;

[0098] L is C 1-6 Alkylene, one or more R L Substituted C 1-6 Alkylene or "-(C 1-6 Alkylene)-L A -*”;

[0099] Each R L are independently hydroxy or halogen, or when two R L When substituted on the same carbon atom, two R L and their common carbon atoms are connected to form a 3-10 membered saturated carbocyclic ring;

[0100] L A -NH- or -N(C 1-6 alkyl)-;

[0101] Ring B is a "3-10 membered saturated or unsaturated heterocyclic ring with 1, 2 or 3 heteroatoms selected from N, O and S" or is replaced by one or more R B-2 Substituted "3-10 membered saturated or unsaturated heterocyclic ring having 1, 2 or 3 heteroatoms selected from N, O and S";

[0102] Each R B-2 are independently hydroxyl, halogen, C 1-6 Alkoxy or C substituted by one or more hydroxyl groups 1-6 alkyl;

[0103] U is C 3-6 Alkyl, one or more R U-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, one or more R U-2 Substituted C 3- 10 Cycloalkyl, "3-10 membered heterocycloalkyl with 1, 2 or 3 heteroatoms selected from N, O and S", "heteroatoms selected from 1, 2 or 3 heteroatoms selected from N, O and S", "heteroatoms selected from 1, 2 or 3 heteroatoms" U-3 Substituted "3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S", C 6-10 Aryl, one or more R U-4 Substituted C 6-10 Aryl, "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S" or "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms ... U-5 Substituted "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0104] Each R U-1 C 3-10 Cycloalkyl or C 6-10 aryl;

[0105] Each R U-2 、R U-3 、R U-4 and R U-5 are independently halogen, C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S", cyano, hydroxyl, C 1-6 Alkyl, one or more R U-3-1 Substituted C 1-6 Alkyl, C 1-6 Alkoxy or one or more R U-3-2 Substituted C 1-6 alkoxy;

[0106] Each R U-3-1 and R U-3-2 are independently halogen or C 3-10 Cycloalkyl.

[0107] In some embodiments, the compound represented by formula (IA) is a compound represented by formula (IIIA) or formula (IIIB):

[0108]

[0109] Each R1 is independently halogen, cyano, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Alkoxy, C substituted by one or more halogen 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkoxy, "heteroatoms selected from 1, 2 or 3 of N, O, S, 5-10 membered heteroaryl with 1, 2 or 3 heteroatoms" or one or more R 1-1 Substituted "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0110] Each R 1-1 C 1-6 alkyl;

[0111] m is 0, 1, or 2;

[0112] X1 is -CH2-, -O-, -S- or -S(=O)2-;

[0113] Each R2 is independently H, C 1-6 Alkyl, one or more R 2-1 Substituted C 1-6 Alkyl or "3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0114] Each R 2-1 are independently hydroxyl or C 3-10 Cycloalkyl;

[0115] E is -N(R3)- or n1 is 1, 2 or 3; # represents the end connected to -C(O)- in formula (IA);

[0116] R3 is hydrogen or C 1-6 alkyl;

[0117] L is C 1-6 Alkylene, one or more R L Substituted C 1-6 Alkylene or "-(C 1-6 Alkylene)-L A -*;

[0118] Each R Lare independently hydroxy or halogen, or when two R L When substituted on the same carbon atom, two R L and their common carbon atoms are connected to form a 3-10 membered saturated carbocyclic ring;

[0119] L A is a 3-10 membered saturated carbon ring;

[0120] Ring B is a "3-10 membered saturated or unsaturated heterocyclic ring with 1, 2 or 3 heteroatoms selected from N, O and S" or is replaced by one or more R B-2 Substituted "3-10 membered saturated or unsaturated heterocyclic ring having 1, 2 or 3 heteroatoms selected from N, O and S";

[0121] Each R B-2 are independently halogen or C 1-6 alkyl;

[0122] When U is absent, ring B is

[0123] U is absent, -N(R')(R''), or is replaced by one or more R U-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, one or more R U-2 Substituted C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl with 1, 2 or 3 heteroatoms selected from N, O and S", "heteroatoms selected from 1, 2 or 3 heteroatoms selected from N, O and S", "heteroatoms selected from 1, 2 or 3 heteroatoms" U-3 Substituted "3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S", C 6-10 Aryl, one or more R U-4 Substituted C 6-10 Aryl or "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0124] Each R' and R" are independently hydrogen, C 1-6 Alkyl, -C(O)-C 3-10 Cycloalkyl or C substituted by one or more R' 1-6 Alkyl; R'" is independently C 6-10 aryl;

[0125] Each R U-1 C 3-10 Cycloalkyl or C 6-10 aryl;

[0126] Each RU-2 、R U-3 and R U-4 are independently halogen, hydroxyl, -SO2-C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl with 1, 2 or 3 heteroatoms selected from N, O and S", C 1-6 Alkoxy or one or more R U-3-1 Substituted C 1-6 alkyl;

[0127] Each R U-3-1 are independently halogen, C 3-10 Cycloalkyl, C 6-10 Aryl, C 1-6 Alkoxy, hydroxy, cyano or heteroatoms selected from 1, 2 or 3 of N, O and S, and a 3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms.

[0128] In some embodiments, the compound represented by formula (I) is a compound represented by formula (III):

[0129] Each R1 is independently halogen;

[0130] m is 0 or 1;

[0131] X1 is -CH2-, -O-, -S- or -S(=O)2-;

[0132] Each R2 is independently C 1-6 Alkyl or one or more R 2-1 Substituted C 1-6 alkyl;

[0133] Each R 2-1 C 3-10 Cycloalkyl;

[0134] R3 is hydrogen or C 1-6 alkyl;

[0135] L is C 1-6 Alkylene or one or more R L Substituted C 1-6 alkylene;

[0136] Each R L are independently hydroxy or halogen;

[0137] Ring B is a "3-10 membered saturated or unsaturated heterocyclic ring with 1, 2 or 3 heteroatoms selected from N, O and S" or is replaced by one or more R B-2 Substituted "3-10 membered saturated or unsaturated heterocyclic ring having 1, 2 or 3 heteroatoms selected from N, O and S";

[0138] Each R B-2 are each independently halogen;

[0139] U is one or more R U-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, one or more R U-2 Substituted C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl with 1, 2 or 3 heteroatoms selected from N, O and S", C 6-10 Aryl, one or more R U-4 Substituted C 6-10 Aryl or "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0140] Each R U-1 C 3-10 Cycloalkyl or C 6-10 aryl;

[0141] Each R U-2 and R U-4 are independently halogen, C 1-6 Alkoxy or one or more R U-3-1 Substituted C 1-6 alkyl;

[0142] Each R U-3-1 are each independently halogen.

[0143] In some embodiments, each R1 is independently halogen, cyano, C 1-6 Alkyl, C 3-10 Cycloalkyl, C substituted by one or more halogen 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkoxy, "heteroatoms selected from 1, 2 or 3 of N, O, S, 5-10 membered heteroaryl with 1, 2 or 3 heteroatoms" or one or more R 1-1 Substituted "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0144] Each R 1-1 C1-6 alkyl.

[0145] In some embodiments, each R1 is independently halogen.

[0146] In some embodiments, m and k are each independently 0 or 1.

[0147] In some embodiments, each R2 is independently H, C 1-6 Alkyl, one or more R 2-1 Substituted C 1-6 Alkyl or "3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0148] Each R 2-1 are independently hydroxyl or C 3-10 Cycloalkyl.

[0149] In some embodiments, each R2 is independently C 1-6 Alkyl or one or more R 2-1 Substituted C 1-6 alkyl;

[0150] Each R 2-1 C 3-10 Cycloalkyl.

[0151] In some embodiments, E is -N(R3)-.

[0152] In some embodiments, R3 is hydrogen or C 1-6 alkyl.

[0153] In some embodiments, R3 is hydrogen.

[0154] In some embodiments, L is C 1-6 Alkylene, one or more R L Substituted C 1-6 Alkylene or "-(C 1-6 Alkylene)-L A -*”;

[0155] Each R L are independently hydroxy or halogen, or when two R L When substituted on the same carbon atom, two R L and their common carbon atoms are connected to form a 3-10 membered saturated carbocyclic ring;

[0156] L A -NH-, -N(C 1-6 alkyl)- or a 3-10 membered saturated carbocyclic ring; preferably a 3-10 membered saturated carbocyclic ring.

[0157] In some embodiments, L is C 1-6 Alkylene, one or more R L Substituted C 1-6 Alkylene or "-(C 1-6 Alkylene)-L A -*”:

[0158] Each R L are independently hydroxy or halogen, or when two R L When substituted on the same carbon atom, two R L and their common carbon atoms are connected to form a 3-10 membered saturated carbocyclic ring;

[0159] L A -NH- or -N(C 1-6 alkyl)-.

[0160] In some embodiments, L is C 1-6 Alkylene, one or more R L Substituted C 1-6 Alkylene or "-(C 1-6 Alkylene)-L A -*”;

[0161] Each R L are independently hydroxy or halogen, or when two R L When substituted on the same carbon atom, two R L and their common carbon atoms are connected to form a 3-10 membered saturated carbocyclic ring;

[0162] L A It is -NH-.

[0163] In some embodiments, L is C 1-6 Alkylene or one or more R L Substituted C 1-6 alkylene;

[0164] Each R L are each independently hydroxy or halogen.

[0165] In some embodiments, L is C 1-6 Alkylene or one or more R L Substituted C 1-6 alkylene;

[0166] Each R L are each independently a hydroxyl group.

[0167] In some embodiments, ring B is a "3-10 membered saturated or unsaturated heterocyclic ring with 1, 2 or 3 heteroatoms selected from N, O and S" or is replaced by one or more R B-2 Substituted "3-10 membered saturated or unsaturated heterocyclic ring having 1, 2 or 3 heteroatoms selected from N, O and S";

[0168] Each R B-2 are independently hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C substituted by one or more hydroxyl groups 1-6 Alkyl; preferably halogen or C 1-6 alkyl.

[0169] In some embodiments, ring B is a "3-10 membered saturated or unsaturated heterocyclic ring with 1, 2 or 3 heteroatoms selected from N, O and S" or is replaced by one or more R B-2 Substituted "3-10 membered saturated or unsaturated heterocyclic ring having 1, 2 or 3 heteroatoms selected from N, O and S";

[0170] Each R B-2 are independently hydroxyl, halogen, C 1-6 Alkoxy or C substituted by one or more hydroxyl groups 1-6 Alkyl; preferably halogen.

[0171] In some embodiments, Ring B is a "3-10 membered saturated or unsaturated heterocyclic ring having 1, 2 or 3 heteroatoms selected from N, O and S".

[0172] In some embodiments, U is absent, -N(R')(R"), C 3-6 Alkyl, one or more R U-1 Substituted C 1-6 Alkyl, C 3- 10 Cycloalkyl, one or more R U-2 Substituted C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl with 1, 2 or 3 heteroatoms selected from N, O and S", "heteroatoms selected from 1, 2 or 3 heteroatoms selected from N, O and S", "heteroatoms selected from 1, 2 or 3 heteroatoms" U-3 Substituted "3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S", C 6-10 Aryl, one or more R U-4 Substituted C 6-10Aryl, "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S" or "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms ... U-5 Substituted "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0173] Each R' and R" are independently hydrogen, C 1-6 Alkyl, -C(O)-C 3-10 Cycloalkyl or C substituted by one or more R' 1-6 Alkyl; R'" is independently C 6-10 aryl;

[0174] Each R U-1 are independently -N(R')(R"), C 3-10 Cycloalkyl or C 6-10 aryl;

[0175] Each R U-2 、R U-3 、R U-4 and R U-5 are independently halogen, -SO2-C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S", cyano, hydroxyl, C 1-6 Alkyl, one or more R U-3-1 Substituted C 1-6 Alkyl, C 1-6 Alkoxy or one or more R U-3-2 Substituted C 1-6 alkoxy;

[0176] Each R U-3-1 and R U-3-2 are independently halogen, C 3-10 Cycloalkyl, C 6-10 Aryl, C 1-6 Alkoxy, hydroxy, cyano or heteroatoms selected from 1, 2 or 3 of N, O and S, and a 3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms.

[0177] In some embodiments, U is absent, -N(R')(R"), replaced by one or more R U-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, one or more R U-2 Substituted C 3-10Cycloalkyl, "3-10 membered heterocycloalkyl with 1, 2 or 3 heteroatoms selected from N, O and S", "heteroatoms selected from 1, 2 or 3 heteroatoms selected from N, O and S", "heteroatoms selected from 1, 2 or 3 heteroatoms" U-3 Substituted "3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S", C 6-10 Aryl, one or more R U-4 Substituted C 6-10 Aryl or "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0178] Each R' and R" are independently hydrogen, C 1-6 Alkyl, -C(O)-C 3-10 Cycloalkyl or C substituted by one or more R' 1-6 Alkyl; R'" is independently C 6-10 aryl;

[0179] Each R U-1 C 3-10 Cycloalkyl or C 6-10 aryl;

[0180] Each R U-2 、R U-3 and R U-4 are independently halogen, hydroxyl, -SO2-C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl with 1, 2 or 3 heteroatoms selected from N, O and S", C 1-6 Alkoxy or one or more R U-3-1 Substituted C 1-6 alkyl;

[0181] Each R U-3-1 are independently halogen, C 3-10 Cycloalkyl, C 6-10 Aryl, C 1-6 Alkoxy, hydroxy, cyano or heteroatoms selected from 1, 2 or 3 of N, O and S, and a 3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms.

[0182] In some embodiments, U is C 3-6 Alkyl, one or more R U-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, one or more R U-2 Substituted C 3-10Cycloalkyl, "3-10 membered heterocycloalkyl with 1, 2 or 3 heteroatoms selected from N, O and S", "heteroatoms selected from 1, 2 or 3 heteroatoms selected from N, O and S", "heteroatoms selected from 1, 2 or 3 heteroatoms" U-3 Substituted "3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S", C 6-10 Aryl, one or more R U-4 Substituted C 6-10 Aryl, "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S" or "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms ... U-5 Substituted "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0183] Each R U-1 C 3-10 Cycloalkyl or C 6-10 aryl;

[0184] Each R U-2 、R U-3 、R U-4 and R U-5 are independently halogen, C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S", cyano, hydroxyl, C 1-6 Alkyl, one or more R U-3-1 Substituted C 1-6 Alkyl, C 1-6 Alkoxy or one or more R U-3-2 Substituted C 1-6 alkoxy;

[0185] Each R U-3-1 and R U-3-2 are independently halogen or C 3-10 Cycloalkyl.

[0186] In some embodiments, U is replaced by one or more R U-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, one or more R U-2 Substituted C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl with 1, 2 or 3 heteroatoms selected from N, O and S", C 6-10 Aryl, one or more R U-4 Substituted C 6-10Aryl or "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0187] Each R U-1 C 3-10 Cycloalkyl or C 6-10 aryl;

[0188] Each R U-2 and R U-4 are independently halogen, C 1-6 Alkoxy or one or more R U-3-1 Substituted C 1-6 alkyl;

[0189] Each R U-3-1 are each independently halogen.

[0190] In some embodiments, in ring C, the “5-6 membered heteroaromatic ring wherein the heteroatom is 1, 2 or 3 selected from N, O and S, and the number of heteroatoms is 1, 2 or 3” is a “5-6 membered heteroaromatic ring wherein the heteroatom is N, and the number of heteroatoms is 1 or 2”, such as a pyridine ring or a pyrimidine ring.

[0191] In some embodiments, each "C1-C6 alkyl" is independently a C1-C4 alkyl, which may be methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, preferably methyl or ethyl.

[0192] In some embodiments, each "C1-C6 alkoxy" is independently a C1-C4 alkoxy group, which may be a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a tert-butoxy group, an isobutoxy group or a sec-butoxy group, preferably a methoxy group.

[0193] In some embodiments, each "halogen" is independently fluorine, chlorine, bromine, or iodine, preferably fluorine or chlorine.

[0194] In some embodiments, each "halogen" is independently fluorine, chlorine, or bromine, preferably fluorine.

[0195] In some embodiments, when R a 、R b and their common carbon atoms are connected to form a 3-10 membered saturated carbocyclic ring, the "3-10 membered saturated carbocyclic ring" is a 3-membered saturated carbocyclic ring, for example ( represents a bond to the rest of the molecule).

[0196] In some embodiments, each "C3-C 10 "Cycloalkyl" is independently a C3-C6 monocyclic cycloalkyl or a C5-C 10Polycyclic (for example, spirocyclic, fused or bridged) cycloalkyl, the C3-C6 monocyclic cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, the C5-C 10 The polycyclic cycloalkyl group is preferably C5-C 10 Spirocyclic cycloalkyl, further preferably

[0197] In some embodiments, each "heteroatom selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 3-membered heterocycloalkyl" is independently a 4-6 membered monocyclic heterocycloalkyl or a 5-10 membered polycyclic (e.g., spirocyclic, cyclic or bridged) heterocycloalkyl, and the 4-6 membered monocyclic heterocycloalkyl is preferably a 4-6 membered monocyclic heterocycloalkyl selected from 1 or 2 of N and O, and the number of heteroatoms is 1 or 2, more preferably The 5-10 membered polycyclic heterocycloalkyl may be a 5-10 membered spiro heterocycloalkyl, preferably a 6 membered spiro 3 membered heterocycloalkyl, more preferably Alternatively, the 5-10 membered polycyclic heterocycloalkyl group may be a 5-10 membered bridged heterocycloalkyl group, preferably

[0198] In some embodiments, each "heteroatom selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 3-membered heterocycloalkyl" is independently a 4-6 membered monocyclic heterocycloalkyl or a 5-10 membered polycyclic (e.g., spirocyclic, cyclic or bridged) heterocycloalkyl, and the 4-6 membered monocyclic heterocycloalkyl is preferably a 6 membered heterocycloalkyl with 1 or 2 heteroatoms selected from N and O, and the number of heteroatoms is 1 or 2, more preferably The 5-10 membered polycyclic heterocycloalkyl may be a 5-10 membered spiro heterocycloalkyl, preferably a 6 membered spiro 3 membered heterocycloalkyl, more preferably

[0199] In some embodiments, each "C6-C 10 "Aryl" is independently phenyl or naphthyl, preferably phenyl.

[0200] In some embodiments, each "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S, and having 1, 2 or 3 heteroatoms" can independently be a 5-6 membered monocyclic heteroaryl group, and the 5-6 membered monocyclic heteroaryl group is preferably a 5-6 membered monocyclic heteroaryl group having N as the heteroatom and 1, 2 or 3 heteroatoms, for example

[0201] In some embodiments, each "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S, and having 1, 2 or 3 heteroatoms" can independently be a 5-6 membered monocyclic heteroaryl group, wherein the 5-6 membered monocyclic heteroaryl group preferably has N as the heteroatom and 1 or 2 heteroatoms, and more preferably

[0202] In some embodiments, each "C 1-6 "Alkylene" is independently C1-C4 alkylene, preferably methylene,

[0203] In some embodiments, each "C 1-6 "Alkylene" is independently C1-C4 alkylene, preferably

[0204] In some embodiments, when two R L When substituted on the same carbon atom, two R L and their common carbon atoms are connected to form a "3-10 membered saturated carbocyclic ring" is a 3-membered saturated carbocyclic ring, for example ( represents a bond to the rest of the molecule).

[0205] In some embodiments, when L A When is a 3-10 membered saturated carbocyclic ring, the “3-10 membered saturated carbocyclic ring” is a 4-6 membered saturated carbocyclic ring, for example

[0206] In some embodiments, each "heteroatom selected from 1, 2 or 3 of N, O and S, and a 3-10 membered saturated or unsaturated heterocyclic ring having 1, 2 or 3 heteroatoms" is independently "a 4-8 membered saturated or unsaturated heterocyclic ring having 1 or 2 heteroatoms selected from N and O, for example

[0207] In some embodiments, each "heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 3-membered saturated or unsaturated heterocyclic ring" is independently "a heteroatom is N, and the number of heteroatoms is 1 or 2 5-6 membered saturated or unsaturated heterocyclic ring", for example ( represents a bond to the rest of the molecule).

[0208] In some embodiments, Ring C is a benzene ring.

[0209] In some embodiments, each R1 is independently fluoro, chloro, bromo, cyano, trifluoromethyl, cyclopropyl, trifluoromethoxy, methyl, m is 0, 1 or 2.

[0210] In some embodiments, each R1 is independently fluoro or chloro; and m is 0 or 1.

[0211] In some embodiments, X1 is -CH2-, -O-, -S-, or -S(=O)2-; X2 is -CH2-; n is 0; and X3 and X4 are C.

[0212] In some embodiments, R2 is H, methyl, ethyl, k is 0 or 1.

[0213] In some embodiments, R2 is methyl, ethyl or k is 1.

[0214] In some embodiments, the structural fragment for

[0215] In some embodiments, R3 is hydrogen or methyl.

[0216] In some embodiments, L is methylene,

[0217] In some embodiments, Ring B is

[0218] In some embodiments, U is

[0219] In some embodiments, E is -NH-, -N(CH3)- or

[0220] The present invention also provides the following compounds or pharmaceutically acceptable salts thereof:

[0221] The present invention also provides a pharmaceutical composition comprising substance A and a pharmaceutically acceptable excipient, wherein the substance A is a compound represented by formula (XA) or a pharmaceutically acceptable salt thereof;

[0222] wherein Ring A, Ring B, Ring C, X1, X2, X3, X4, R1, R2, E, m, n, k, L, B and U are as defined above.

[0223] The present invention also provides a pharmaceutical composition comprising (a therapeutically effective amount of) substance A and a pharmaceutically acceptable excipient, wherein the substance A is a compound represented by formula (X) or a pharmaceutically acceptable salt thereof;

[0224] wherein Ring A, Ring B, Ring C, X1, X2, X3, X4, R1, R2, R3, m, n, k, L, B and U are as defined above.

[0225] In some embodiments, the pharmaceutical composition is used to treat and / or prevent a KSR2-AMPK-related disease or disorder, such as cancer, for example, liver cancer.

[0226] The present invention also provides the use of a substance A or the aforementioned pharmaceutical composition in the preparation of a KSR2-AMPK inhibitor, wherein the substance A is a compound represented by formula (XA) or a pharmaceutically acceptable salt thereof. In such use, the KSR2-AMPK inhibitor can be used in vivo in mammals; it can also be used in vitro, primarily for experimental purposes, for example, as a standard or control sample for comparison, or prepared into a kit according to conventional methods in the art to provide rapid detection of KSR2-AMPK inhibition effects.

[0227] The present invention also provides a use of a substance A or the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the drug is used to treat and / or prevent diseases or disorders related to KSR2-AMPK; the substance A is the compound represented by formula (XA) or a pharmaceutically acceptable salt thereof; the substance A is in a therapeutically effective amount; the disease or disorder related to KSR2-AMPK is preferably cancer, such as liver cancer.

[0228] The present invention also provides a use of a substance A or the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the drug is used to treat and / or prevent cancer (e.g., liver cancer); the substance A is the above-mentioned compound represented by formula (XA) or a pharmaceutically acceptable salt thereof; and the substance A is in a therapeutically effective amount.

[0229] The present invention also provides a use of a substance A or the above-mentioned pharmaceutical composition in inhibiting KSR2-AMPK, wherein the substance A is the above-mentioned compound represented by formula (XA) or a pharmaceutically acceptable salt thereof.

[0230] The present invention also provides a use of a substance A or the aforementioned pharmaceutical composition in the preparation of a KSR2-AMPK inhibitor, wherein the substance A is a compound represented by formula (X) or a pharmaceutically acceptable salt thereof. In such use, the KSR2-AMPK inhibitor can be used in mammals in vivo or in vitro, primarily for experimental purposes, for example, as a standard or control sample for comparison, or prepared as a kit according to conventional methods in the art to provide rapid detection of KSR2-AMPK inhibition effects.

[0231] The present invention also provides a use of a substance A or the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the drug is used to treat and / or prevent diseases or disorders related to KSR2-AMPK; the substance A is the compound represented by formula (X) or a pharmaceutically acceptable salt thereof; the substance A is in a therapeutically effective amount; the disease or disorder related to KSR2-AMPK is preferably cancer, such as liver cancer.

[0232] The present invention also provides a use of a substance A or the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the drug is used to treat and / or prevent cancer (e.g., liver cancer); the substance A is the compound represented by formula (X) or a pharmaceutically acceptable salt thereof; and the substance A is in a therapeutically effective amount.

[0233] The present invention also provides a use of a substance A or the above-mentioned pharmaceutical composition in inhibiting KSR2-AMPK, wherein the substance A is the above-mentioned compound represented by formula (X) or a pharmaceutically acceptable salt thereof.

[0234] In addition to the foregoing, when used in this application, the following terms have the meanings indicated below unless otherwise specifically stated.

[0235] The term "plurality" refers to 2, 3, 4 or 5.

[0236] It will be understood by those skilled in the art that the structural formulas used in the present invention to describe groups are based on the conventions used in the art. It means that the corresponding group R is connected to other fragments and groups in the compound through this site.

[0237] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention with a relatively nontoxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acid includes inorganic acids and organic acids. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0238] The term "pharmaceutical composition" refers to a formulation comprising a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, thereby facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0239] The term "pharmaceutically acceptable excipients" refers to excipients and additives used in the production of drugs and the preparation of prescriptions. They are all substances contained in pharmaceutical preparations in addition to the active ingredients. Please refer to the Pharmacopoeia of the People's Republic of China (2015 Edition) Part IV, or the Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition). Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition. They can also provide methods to dissolve the active ingredient at a desired rate after the subject receives the drug, or to promote the effective absorption of the active ingredient after the subject receives the composition. The pharmaceutical excipients can be inert fillers, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

[0240] The term "treat" refers to therapeutic treatment or palliative measures. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition, or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition. "Treatment" may also mean prolonging survival as compared to expected survival if not receiving treatment.

[0241] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0242] The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat a disease or condition described herein. The "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as needed by those skilled in the art.

[0243] The term "substituted" or "substituent" means that a hydrogen atom in a group is replaced by a specified group. When the position of substitution is not specified, the substitution can be at any position, but only if a stable or chemically feasible compound is formed. Examples are as follows: The structure shows that the hydrogen atoms on ring A are replaced by p R4.

[0244] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with one or more R, then the group may be optionally substituted with at least one R, and each occurrence of R is an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0245] The term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon group. 1-6 Alkyl refers to an alkyl group having 1 to 6 carbon atoms, preferably an alkyl group having 1 to 4 carbon atoms. 1-4 The alkyl group is specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0246] The term "alkylene" is a divalent group that is attached to the rest of the molecule by two single bonds, and the rest of the definition is the same as the term "alkyl".

[0247] The term "alkoxy" refers to -OC 1-6 Alkyl, where "C 1-6 "Alkyl" is as defined above. Preferably it is an alkoxy group having 1 to 4 carbon atoms, such as methoxy or ethoxy.

[0248] The term "cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more cyclic bridged ring, fused ring or spirocyclic) carbocyclic substituent, which can be connected to the rest of the molecule by a single bond via any suitable carbon atom. For example, a 3-10 membered cycloalkyl having 3 to 10 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wait.

[0249] The term "carbocycle" refers to a ring having a specified number of carbon atoms (e.g., C3 to C 10 ) cyclic, saturated or unsaturated cyclic group, which is a monocyclic or polycyclic ring (e.g., a bicyclic, tricyclic or more cyclic bridged ring, a fused ring (condensed ring) or a spirocyclic ring system), preferably a 3-membered saturated carbocyclic ring; which satisfies any of the following conditions: (1) is connected to the rest of the molecule by two or more single bonds, for example ( indicates a bond to the rest of the molecule) or (2) shares two atoms and a bond with the rest of the molecule.

[0250] The term "heterocycle" refers to a saturated or unsaturated cyclic group having a specified number of ring atoms (e.g., 3-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatom (one or more of N, O, and S), which is monocyclic or polycyclic (e.g., bicyclic, tricyclic, or more cyclic bridged, fused, or spirocyclic systems); preferably a 5-6 membered saturated monocyclic heterocycle; which satisfies any of the following conditions: (1) is connected to the rest of the molecule by two or more single bonds, for example ( indicates a bond to the rest of the molecule) or (2) shares two atoms and a bond with the rest of the molecule.

[0251] The term "heterocycloalkyl" refers to a saturated monovalent group having a specified number of ring atoms (e.g., 3-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified heteroatom type (one or more of N, O, and S), a monocyclic or polycyclic ring (e.g., a bicyclic, tricyclic, or more cyclic bridged, fused, or spirocyclic ring system), which is attached to the rest of the molecule through a carbon atom or a heteroatom. Examples of heterocycloalkyl include, but are not limited to, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, or azaspiro[2.5]octyl, for example

[0252] The term "aryl" refers to a radical having the specified number of carbon atoms (e.g., C 6-10 ) is a cyclic, unsaturated, monovalent hydrocarbon group, which may be monocyclic or polycyclic (e.g., two or three). In the case of polycyclic rings, the individual rings share two atoms and one bond, and at least one ring is aromatic. The aryl group is attached to the rest of the molecule through either an aromatic or non-aromatic ring. Examples of aryl groups include, but are not limited to, phenyl and naphthyl.

[0253] The term "heteroaryl" refers to a cyclic, unsaturated, monovalent group having a specified number of ring atoms (e.g., 5-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatom (one or more of N, O, and S), which is monocyclic or polycyclic; when polycyclic, two atoms and one bond are shared between each two monocyclic rings, and at least one ring is aromatic. A heteroaryl group is attached to the rest of the molecule through a carbon atom or a heteroatom; a heteroaryl group is attached to the rest of the molecule through a ring with heteroatoms or a ring without heteroatoms; a heteroaryl group is attached to the rest of the molecule through a ring with aromatic properties or a ring without aromatic properties. Heteroaryl groups include, but are not limited to, pyridyl or pyrimidinyl, for example wait.

[0254] The term "heteroaromatic ring" refers to a cyclic, unsaturated group having a specified number of ring atoms (e.g., 5-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3 members), and a specified type of heteroatom (one or more of N, O, and S), which is monocyclic or polycyclic; in the case of polycyclic, two atoms and one bond are shared between each two monocyclic rings, and at least one ring is aromatic; preferably a 5-6 membered monocyclic heteroaromatic ring; which satisfies any of the following conditions: (1) is connected to the rest of the molecule by two or more bonds; (2) shares two atoms and one bond with the rest of the molecule.

[0255] The term "halogen" refers to fluorine, chlorine, bromine or iodine, in particular to F or Cl.

[0256] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0257] The reagents and raw materials used in the present invention are commercially available.

[0258] The positive improvement effect of the present invention is that the compound of the present invention can effectively inhibit the proliferation of cancer cells. DETAILED DESCRIPTION

[0259] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0260] Example 1

[0261] Step 1: Ethanol (120 mL) and a 20% sodium ethoxide ethanol solution (83 g, 243.58 mmol) were added to a 500 mL three-necked flask in sequence. Diethyl oxalate (26.7 g, 182.69 mmol) and compound 1-1 (20 g, 121.79 mmol) were added at 0°C under nitrogen protection and stirred at room temperature for 16 hours. The pH of the reaction solution was adjusted to 6-7 with dilute hydrochloric acid, and the ethanol was removed by concentration under reduced pressure. Water and ethyl acetate were added, and the mixture was separated and extracted. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed twice with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product compound 1-2 (29 g, yield: 90%), which was used directly in the next step.

[0262] ESI (m / z) = 263.1 [M-1]

[0263] Step 2: Dissolve compound 1-2 (7 g, 26.49 mmol) in dioxane (70 mL) and add methylhydrazine sulfate (7.64 g, 52.98 mmol) with stirring. The mixture was reacted at 105°C for 16 h and monitored by LCMS. The reaction mixture was added to water (200 mL) and extracted with ethyl acetate (2 x 500 mL). The organic phase was washed once with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 1-3 (2.65 g, 36% yield) was isolated by column chromatography.

[0264] ESI (m / z) = 275.2 [M+H] + , RT = 3.657 min.

[0265] 1 H NMR (400MHz, DMSO-d6) δ7.88-7.84 (m, 1H), 7.52 (dd, J=7.3, 1.8Hz, 1H), 7.33 (pd, J=7. 4, 1.6Hz, 2H), 4.30 (q, J=7.1Hz, 2H), 4.16 (s, 3H), 4.15 (s, 2H), 1.31 (t, J=7.1Hz, 3H).

[0266] Step 3: Dissolve compound 1-3 (2.65 g, 9.66 mmol) in ethanol (30 mL) and water (10 mL), and add sodium hydroxide (1.16 g, 29 mmol) with stirring. The reaction mixture was stirred at 20°C for 16 h. The reaction was monitored by LCMS. The reaction solution was concentrated to remove ethanol, and 4N hydrochloric acid was added to adjust the pH to 4. The mixture was slurried in water for 30 minutes, filtered, and the filter cake was dried to obtain compound 1-4 (2.25 g, 95% yield).

[0267] ESI (m / z) = 247.1 [M+H] + , RT = 3.005 min.

[0268] 1 H NMR (400MHz, DMSO-d6) δ7.85 (dd, J=7.4, 1.7Hz, 1H), 7.51 (dd, J=7.4, 1.7Hz, 1H), 7.37-7.28 (m, 2H), 4.14 (s, 5H).

[0269] Step 4: Compound 1-4 (150 mg, 0.61 mmol), tert-butyl 4-(3-aminopropyl)-piperazine-1-carboxylate (160 mg, 0.66 mmol), and NMI (150 mg, 1.83 mmol) were dissolved in DMF (12 mL). TCFH (200 mg, 0.71 mmol) was added at 0°C, and the reaction mixture was stirred at 20°C for 1 hr. Completion of the reaction was monitored by LCMS. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain compound 1-5 (245 mg, 85%) as a white solid.

[0270] ESI (m / z) = 472.4 [M+H] + , RT = 2.803 min.

[0271] 1 H NMR (400MHz, Chloroform-d) δ8.20 (s, 1H), 7.60-7.54 (m, 1H), 7.52-7.47 (m, 1H), 7.26-7.19 (m, 2H), 4.29 (s, 2H), 4.08 (s, 3H), 3.58-3.50 (m, 6H), 2.54 (t, J=6.2Hz, 2H), 2.45 (t, J=5.0Hz, 4H), 1.78 (p, J=6.2Hz, 2H), 1.47 (s, 9H).

[0272] Step 5: Compound 1-5 (245 mg, 0.52 mmol), HCl / Dioxane (2 mL, 4 mmol / mL), and methanol (2 mL) were added to a reaction flask and allowed to react at 20°C for 1 h. The reaction was monitored by LCMS. The reaction mixture was added dropwise to a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and spun down to afford compound 1-6 (60 mg, 31%).

[0273] ESI (m / z) = 372.3 [M+H] + , RT = 2.281 min.

[0274] Step 6: Dissolve compound 1-6 (60 mg, 0.16 mmol) and 4,4-difluorocyclohexanone (40 mg, 0.30 mmol) in dichloromethane (5 mL) and sodium acetate borohydride (70 mg, 0.33 mmol). Stir the reaction mixture at 20°C for 16 h. Completion of the reaction was monitored by LCMS. The reaction mixture was quenched by adding saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and lyophilized after column chromatography to obtain compound 1 (38.9 mg, 49%).

[0275] ESI (m / z) = 490.4 [M+H] + , RT = 6.364 min.

[0276] 1 H NMR (400MHz, DMSO-d6) δ8.34 (t, J=5.7Hz, 1H), 7.84 (dd, J=7.6, 1.6Hz, 1H), 7.50 (dd, J=7.4, 1.6Hz, 1H), 7.37-7.27 (m, 2H) , 4.18(s, 2H), 4.13(s, 3H), 3.32-3.17(m, 6H), 2.47-2.23(m, 6H), 1.99(t, J=10.9Hz, 2H), 1.91(s, 1H), 1.88-1.38(m, 8H).

[0277] Example 2

[0278] Step 1: Ethanol (120 mL) and a 20% sodium ethoxide ethanol solution (83 g, 243.58 mmol) were added to a 500 mL three-necked flask in sequence. Diethyl oxalate (26.7 g, 182.69 mmol) and compound 1-1 (20 g, 121.79 mmol) were added at 0°C under nitrogen protection and stirred at room temperature for 16 hours. The pH of the reaction solution was adjusted to 6-7 with dilute hydrochloric acid, and the ethanol was removed by concentration under reduced pressure. Water and ethyl acetate were added, and the mixture was separated and extracted. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed twice with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product compound 1-2 (29 g, yield: 90%), which was used directly in the next step.

[0279] ESI (m / z) = 263.1 [M-1]

[0280] Step 2: Compound 1-2 (14 g, 52.97 mmol), ethanol (200 mL), and methylhydrazine sulfate (11.45 g, 79.45 mmol) were added sequentially to a 500 mL single-necked flask and stirred at 80°C for 6 hours. The reaction mixture was returned to room temperature and concentrated under reduced pressure to remove ethanol. Water and ethyl acetate were added and separated for extraction. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and washed twice with aqueous sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Column chromatography gave the product compound 1-3 (11 g, yield: 75.7%).

[0281] ESI (m / z) = 275.1 [M+H] +

[0282] 1H NMR (400MHz, DMSO-d6) δ7.88-7.84 (m, 1H), 7.52 (dd, J=7.3, 1.8Hz, 1H), 7.33 (pd, J=7. 4, 1.6Hz, 2H), 4.30 (q, J=7.1Hz, 2H), 4.16 (s, 3H), 4.15 (s, 2H), 1.31 (t, J=7.1Hz, 3H).

[0283] Step 3: Compound 1-3 (5 g, 18.23 mmol), tetrahydrofuran (25 mL), methanol (25 mL), water (50 mL), and sodium hydroxide (0.88 g, 21.88 mmol) were added sequentially to a 250 mL single-necked flask. Stir at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to remove the organic solvent, diluted with water, and the pH was adjusted to 2-3 with dilute hydrochloric acid. The mixture was stirred for 30 minutes and filtered to obtain a filter cake. The filter cake was dried to obtain the product compound 1-4 (4.1 g, yield: 91%).

[0284] ESI (m / z) = 247.1 [M+H] +

[0285] Step 4: Compound 1-4 (1 g, 4.06 mmol), tert-butyl 4-(3-aminopropyl)-piperazine-1-carboxylate (1.48 g, 6.09 mmol), N,N-dimethylformamide (15 mL), N-methylimidazole (0.83 g, 10.15 mmol) and N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (1.37 g, 4.87 mmol) were added to a 100 mL single-necked flask in sequence and stirred at room temperature for 16 hours. Water and ethyl acetate were added to the reaction solution, and the mixture was separated and extracted. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and washed twice with brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product compound 1-5 (1.4 g, yield: 73.11%) was obtained by column chromatography.

[0286] ESI (m / z) = 472.3 [M+H] +

[0287] Step 5: Compound 1-5 (1.4 g, 2.97 mmol) and a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 15 mL) were added sequentially to a 100 mL single-necked flask and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to afford compound 2-1 (1.2 g, yield: 99%), which was used directly in the next step.

[0288] ESI (m / z) = 372.3 [M+H] +

[0289] Step 6: Compound 2-1 (55 mg, 0.13 mmol), dichloromethane (1 mL) and triethylamine (17 mg, 0.17 mmol) were added to a 25 mL single-necked flask in sequence and stirred at room temperature for 2 minutes. Tetrahydropyrone (26 mg, 0.26 mmol) and acetic acid (20 mg, 0.33 mmol) were added and stirred at room temperature for 5 minutes. Sodium triacetoxyborohydride (55 mg, 0.26 mmol) was then added and stirred at 35°C for 6 hours. Water and ethyl acetate were added to the reaction solution and separated for extraction. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and washed twice with brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product compound 2 (16.2 mg, yield: 26.37%) was prepared by reverse phase.

[0290] ESI (m / z) = 456.4 [M+H] +

[0291] 1 H NMR (400MHz,) δ8.35 (t, J=5.7Hz, 1H), 8.23 ​​(s, 1H), 7.84 (dd, J=7.5, 1.7Hz, 1H), 7.50 (dd, J=7.4, 1.7Hz, 1H), 7.37-7.27 (m, 2H), 4.19 (s, 2H), 4.14 (s, 3 H), 3.90-3.82(m, 2H), 3.33-3.20(m, 4H), 2.51(s, 3H), 2.49(s, 2H), 2.32(q , J=6.8Hz, 6H), 1.68 (tt, J=13.5, 9.5Hz, 4H), 1.36 (qd, J=12.2, 4.5Hz, 2H).

[0292] Example 3

[0293] Compound 2-1 (100 mg, 0.25 mmol), dichloromethane (2 mL) and triethylamine (33 mg, 0.33 mmol) were added to a 25 mL single-necked flask in sequence and stirred at room temperature for 2 minutes. Cyclopentanone (42 mg, 0.50 mmol) and acetic acid (38 mg, 0.63 mmol) were added and stirred at room temperature for 5 minutes. Sodium triacetoxyborohydride (110 mg, 0.50 mmol) was then added and stirred at 35°C for 6 hours. Water and ethyl acetate were added to the reaction solution and separated for extraction. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and washed twice with brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product compound 3 (38.8 mg, yield: 32.6%) was prepared by reverse phase.

[0294] ESI (m / z) = 440.4 [M+H] +

[0295] 1 H NMR (400MHz,) δ8.37 (t, J=5.7Hz, 1H), 8.20 (s, 1H), 7.87-7.80 (m, 1H), 7.50 (dd, J=7.3, 1.7Hz, 1H), 7.37-7.26(m, 2H), 4.18(s, 2H), 4.14(s, 3H), 3.95(s , 3H), 3.28 (q, J=6.5Hz, 2H), 2.64-2.52 (m, 3H), 2.47-2.27 (m, 5H), 1.78 (dq, J=11.3, 6.5Hz, 2H), 1.71-1.42 (m, 6H), 1.33 (ddd, J=16.7, 13.5, 8.4Hz, 2H).

[0296] Example 4

[0297] Compound 2-1 (100 mg, 0.25 mmol), dichloromethane (2 mL) and triethylamine (33 mg, 0.33 mmol) were added to a 25 mL single-necked flask in sequence and stirred at room temperature for 2 minutes. Spiro[3.3]heptan-2-one (55 mg, 0.50 mmol) and acetic acid (38 mg, 0.63 mmol) were added and stirred at room temperature for 5 minutes. Sodium triacetoxyborohydride (110 mg, 0.50 mmol) was then added and stirred at 35°C for 6 hours. Water and ethyl acetate were added to the reaction solution and separated for extraction. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and washed twice with brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product compound 4 (54.6 mg, yield: 43.53%) was prepared by reverse phase.

[0298] ESI (m / z) = 466.4 [M+H] +

[0299] 1 H NMR (400MHz,) δ8.36 (t, J=5.7Hz, 1H), 8.20 (s, 1H), 7.84 (dd, J=7.6, 1.6Hz, 1H) , 7.50 (dd, J=7.4, 1.7Hz, 1H), 7.32 (dtd, J=16.7, 7.4, 1.6Hz, 2H), 4.25 (s, 5H), 4.18(s, 2H), 4.14(s, 3H), 3.27(q, J=6.4Hz, 2H), 2.76(p, J=7.8Hz, 1H), 2.38(p , J=12.9, 11.8Hz, 9H), 2.02-1.88(m, 2H), 1.86-1.71(m, 2H), 1.72-1.52(m, 4H).

[0300] Example 5

[0301] Compound 2-1 (100 mg, 0.25 mmol), acetonitrile (2 mL), triethylamine (76 mg, 0.75 mmol), and bromomethylcyclopropane (51 mg, 0.38 mmol) were added sequentially to a 50 mL single-necked flask and stirred at 60°C for 4 hours. The reaction mixture was returned to room temperature, filtered, and the filtrate was reversed to obtain the product compound 5 (24.1 mg, yield: 23.1%).

[0302] ESI (m / z) = 426.3 [M+H] +

[0303] 1 H NMR (400MHz,) δ8.38 (t, J=5.7Hz, 1H), 8.20 (s, 1H), 7.83 (dd, J=7.6, 1.7Hz, 1H), 7.50 ( dd, J=7.3, 1.8Hz, 1H), 7.37-7.26 (m, 2H), 4.18 (s, 2H), 4.13 (s, 3H), 3.28 (q, J=6.5Hz, 2H), 2.53 (d, J=12.5Hz, 4H), 2.50-2.30 (m, 6H), 2.24 (d, J=6.6Hz, 2H), 1.66 (p, J=6.8H z, 2H), 0.83 (dddd, J=12.6, 9.6, 4.6, 3.2Hz, 1H), 0.50-0.43 (m, 2H), 0.12-0.05 (m, 2H).

[0304] Example 6

[0305] Compound 2-1 (100 mg, 0.25 mmol), dichloromethane (2 mL) and triethylamine (33 mg, 0.33 mmol) were added to a 25 mL single-necked flask in sequence and stirred at room temperature for 2 minutes. Cyclobutanone (35 mg, 0.50 mmol) and acetic acid (38 mg, 0.63 mmol) were added and stirred at room temperature for 5 minutes. Sodium triacetoxyborohydride (110 mg, 0.50 mmol) was then added and stirred at 35°C for 6 hours. Water and ethyl acetate were added to the reaction solution and separated for extraction. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and washed twice with brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product compound 6 (45.7 mg, yield: 39.53%) was prepared by reverse phase.

[0306] ESI (m / z) = 426.4 [M+H] +

[0307] 1H NMR (400MHz, DMSO-d6) δ8.35 (t, J=5.7Hz, 1H), 8.17 (s, 1H), 7.84 (dd, J=7.6, 1.6Hz, 1 H), 7.50 (dd, J=7.4, 1.7Hz, 1H), 7.37-7.27 (m, 2H), 4.18 (s, 2H), 4.14 (s, 3H), 3.27 (q, J=6.5Hz, 2H), 2.59-2.52(m, 1H), 2.39-2.22(m, 6H), 2.07(ddd, J=9.4, 7.0, 3.0Hz, 2H ), 1.96 (t, J=7.1Hz, 2H), 1.80 (dddd, J=21.9, 8.9, 6.3, 2.2Hz, 4H), 1.73-1.60 (m, 4H).

[0308] Example 7

[0309] Step 1: Compound 1-3 (200 mg, 0.73 mmol), dichloromethane (3 mL), and m-chloroperbenzoic acid (370 mg, 1.82 mmol) were added sequentially to a 50 mL single-necked flask and stirred at room temperature for 4 hours. Aqueous sodium sulfite solution and ethyl acetate were added to the reaction solution, and the mixture was separated and extracted. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and washed twice with aqueous sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product compound 7-1 (185 mg, yield: 83%).

[0310] ESI (m / z) = 307.1 [M+H] +

[0311] Step 2: Compound 7-1 (185 mg, 0.60 mmol), tetrahydrofuran (1 mL), methanol (1 mL), water (2 mL), and sodium hydroxide (29 mg, 0.72 mmol) were added sequentially to a 50 mL single-necked flask. Stir at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to remove the organic solvent, diluted with water, and the pH was adjusted to 2-3 with dilute hydrochloric acid. The mixture was stirred for 30 minutes and filtered to obtain a filter cake. The filter cake was dried to obtain the product compound 7-2 (150 mg, yield: 89%).

[0312] ESI (m / z) = 279.0 [M+H] +

[0313] Step 3: Compound 7-2 (100 mg, 0.36 mmol), compound 7-3 (120 mg, 0.54 mmol), N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (140 mg, 1.08 mmol), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (210 mg, 0.54 mmol) were added sequentially to a 50 mL single-necked vial and stirred at room temperature for 16 hours. The reaction mixture was filtered and purified by reverse phase preparative and TLC to give the product compound 7 (42.1 mg, yield: 24.12%).

[0314] ESI (m / z) = 486.3 [M+H] +

[0315] 1 H NMR (400MHz,) δ8.51 (t, J=5.9Hz, 1H), 8.08-7.99 (m, 2H), 7.89 (td, J=7.7, 1.4Hz, 1H), 7.73 (td, J=7.7, 1.1Hz, 1H), 4.92 (s, 2H), 4.2 7 (s, 3H), 3.28 (t, J=6.4Hz, 6H), 2.84-2.54 (m, 3H), 2.36 (d, J=24.3Hz, 3H), 1.69 (ddd, J=51.8, 41.2, 20.9Hz, 7H), 1.35-0.96 (m, 6H).

[0316] Example 8

[0317] Step 1: Compound 1-2 (14 g, 52.97 mmol), ethanol (200 mL), and methylhydrazine sulfate (11.45 g, 79.45 mmol) were added sequentially to a 500 mL single-necked flask and stirred at 80°C for 6 hours. The reaction mixture was returned to room temperature and concentrated under reduced pressure to remove ethanol. Water and ethyl acetate were added and separated for extraction. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and washed twice with aqueous sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Column chromatography afforded the product, compound 8-1 (1.2 g, yield: 8.26%).

[0318] ESI (m / z) = 275.1 [M+H] +

[0319] Step 2: Compound 8-1 (200 mg, 0.73 mmol), tetrahydrofuran (1 mL), methanol (1 mL), water (2 mL), and sodium hydroxide (35 mg, 0.88 mmol) were added sequentially to a 100 mL single-necked flask. Stir at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to remove the organic solvent, diluted with water, and the pH was adjusted to 2-3 with dilute hydrochloric acid. The mixture was stirred for 30 minutes and filtered to obtain a filter cake. The filter cake was dried to obtain the product, compound 8-2 (160 mg, yield: 89%).

[0320] ESI (m / z) = 247.1 [M+H] +

[0321] Step 3: Compound 8-2 (100 mg, 0.41 mmol), compound 7-3 (140 mg, 0.61 mmol), N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (160 mg, 1.23 mmol), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (230 mg, 0.61 mmol) were added sequentially to a 50 mL single-necked bottle and stirred at room temperature for 16 hours. The reaction mixture was filtered and reversed to obtain the product compound 8 (43.1 mg, yield: 21.24%).

[0322] ESI (m / z) = 454.3 [M+H] +

[0323] 1 H NMR (400MHz, DMSO-d6) δ8.40 (t, J=5.6Hz, 1H), 8.23 ​​(s, 1H), 7.81-7.73 (m, 1H), 7.37-7.29 (m, 1H), 7.26-7.17 (m, 2H), 4.07 (s, 2H), 3.95 (s, 3H), 3.28 (q, J=6.6Hz, 2H), 2.58 (s, 4H), 2.49-2.21 (m, 7H), 1.84-1.62 (m, 6H), 1.55 (d, J=12.3Hz, 1H), 1.27-0.97 (m, 5H).

[0324] Example 9

[0325] Step 1: Dissolve compound 9-1 (0.8 g, 4.93 mmol), N-Boc-3-chloropropylamine (0.95 g, 4.93 mmol), K2CO3 (1.7 g, 12.32 mmol), and potassium iodide (0.41 g, 2.46 mmol) in acetonitrile (8 mL) and heat at 80°C for 6 hours. LCMS showed completion, and the mixture was directly concentrated and subjected to dry-phase column chromatography to obtain compound 9-2 (0.8 g, yield: 50.79%). m / z [M+H]+ =220

[0326] Step 2: Compound 9-2 (0.8 g, 2.50 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at 25°C for 1 hour. LCMS showed the reaction was complete. The reaction solution was concentrated and loaded onto a column for chromatography to obtain compound 9-3 (0.4 g, yield: 72.82%). m / z [M+H] + =220.3

[0327] Step 3: Compound 1-4 (0.1 g, 0.41 mmol), compound 9-3 (0.1 g, 0.45 mmol), and HATU (0.23 g, 0.61 mmol) were dissolved in DMF (1 mL) and DIPEA (0.16 g, 1.23 mmol) was added. The reaction solution was stirred at 25°C for 3 hours. LCMS showed the reaction was complete. The reaction solution was directly purified by reverse phase C18 column (0.5% formic acid in water and acetonitrile) to obtain compound 9 (23.2 mg, yield: 12.5%). m / z [M+H] + =448.4.

[0328] 1 H NMR(400MHz, DMSO-d6)1H NMR (400MHz, DMSO-d6) δ8.52 (d, J=5.5Hz, 1H), 8.15 (s, 0H), 7.79 (dd, J=7.6, 1.5Hz, 1 H), 7.50 (dd, J=7.4, 1.6Hz, 1H), 7.31 (pd, J=7.4, 1.5Hz, 2H), 7.23-7.17 (m, 2H), 6.94 ( d, J=8.0Hz, 2H), 6.77 (t, J=7.2Hz, 1H), 4.19 (s, 2H), 4.01 (s, 3H), 3.33 (d, J=6.0Hz, 2H ), 3.21-3.18 (m, 4H), 2.58-2.53 (m, 4H), 2.45 (t, J=6.6Hz, 2H), 1.72 (p, J=6.5Hz, 2H).

[0329] Example 10

[0330] Compound 2-1 (0.15 g, 0.37 mmol), benzyl bromide (0.063 g, 0.37 mmol), and TEA (0.19 g, 1.85 mmol) were dissolved in DCM (2 mL) and heated at 25°C for 3 hours. LCMS showed completion, and the mixture was directly concentrated and subjected to dry-bed chromatography to afford compound 10 (58.8 mg, yield: 34.64%). m / z [M+H]+ =462.3

[0331] 1 H NMR(400MHz, DMSO-d6)1H NMR (400MHz, DMSO-d6) δ8.39 (t, J=5.6Hz, 1H), 7.84 (dd, J=7.6, 1.7Hz, 1H), 7.50 (dd, J=7.5, 1.7Hz, 1H), 7.35-7.28 (m, 6H), 7.24 (ddd, J=8.6, 5.3, 2.2Hz, 1H), 4.18 (s, 2H), 4.16 (s, 3H), 3.47 (s, 2H), 3.28 (q, J=6.4Hz, 2H) , 2.51 (s, 1H), 2.43 (s, 5H), 2.38 (t, J = 6.8Hz, 4H), 1.66 (p, J = 6.6Hz, 2H).

[0332] Example 11

[0333] Step 1: Compound 11-1 (0.8 g, 3.15 mmol), compound 11-4 (0.53 g, 3.15 mmol), and K2CO3 (0.87 g, 6.3 mmol) were dissolved in DMF (8 mL) and heated at 100°C for 3 hours. LCMS showed completion, followed by extraction, concentration, and column chromatography to afford compound 11-2 (0.8 g, yield: 74.41%). m / z [M+H] + =342.2

[0334] Step 2: Dissolve compound 11-2 (0.8 g, 2.34 mmol) in ethanol (8 mL), then add hydrazine hydrate (0.31 g, 4.91 mmol). The reaction mixture was stirred at 80°C for 15 hours. LCMS showed the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated to obtain compound 11-3 (0.3 g, yield: 60.58%). m / z [M+H] + =222.3.

[0335] Step 3: Compound 1-4 (0.1 g, 0.41 mmol), compound 11-3 (0.14 g, 0.49 mmol), and HATU (0.23 g, 0.61 mmol) were dissolved in DMF (1 mL) and DIPEA (0.16 g, 1.23 mmol) was added. The reaction mixture was stirred at 25°C for 3 hours. LCMS showed the reaction was complete, and the reaction mixture was directly purified by reverse phase C18 column (0.5% formic acid in water and acetonitrile) to obtain compound 11 (31.6 mg, yield: 17.7%). m / z [M+H] + =440.4.

[0336] 1 H NMR(400MHz, DMSO-d6)1H NMR (400MHz, DMSO-d6) δ8.07 (s, 1H), 7.84 (dd, J = 7.5, 1.6 Hz, 1H), 7.51 (dd, J = 7.4 , 1.6Hz, 1H), 7.32 (dtd, J = 16.9, 7.4, 1.6Hz, 2H), 4.18 (s, 2H), 4.13 (s, 3H), 3.23 (d d, J=10.5, 2.7Hz, 4H), 2.89-2.59 (m, 5H), 2.52 (s, 3H), 1.94-1.81 (m, 2H), 1.79-1. 69 (m, 2H), 1.57 (d, J=11.4Hz, 1H), 1.22 (q, J=10.3, 8.2Hz, 5H), 1.14-1.01 (m, 1H).

[0337] Example 12

[0338] Step 1: Compound 1-4 (0.2 g, 0.81 mmol), compound 12-1 (0.1 g, 0.97 mmol), and HATU (0.4 g, 1.05 mmol) were dissolved in DMF (2 mL). DIPEA (0.31 g, 2.43 mmol) was then added. The reaction mixture was stirred at 25°C for 3 hours. LCMS indicated the reaction was complete. The reaction mixture was concentrated by extraction and column chromatography to afford compound 12-2 (0.2 g, yield: 73.33%). m / z [M+H] + = 336.2.

[0339] Step 2: Compound 12-2 (0.1 g, 0.24 mmol), compound 11-4 (0.04 g, 0.24 mmol), K2CO3 (0.083 g, 0.6 mmol), and potassium iodide (0.02 g, 0.12 mmol) were dissolved in acetonitrile (2 mL) and heated at 80°C for 6 hours. LCMS showed completion, and the reaction solution was concentrated and then directly purified by reverse phase C18 column (0.5% formic acid in water and acetonitrile) to obtain compound 12 (22 mg, yield: 19.75%). m / z [M+H] + =468.4

[0340] 1H NMR(400MHz, DMSO-d6)1H NMR (400MHz, DMSO-d6) δ7.62-7.57 (m, 1H), 7.49 (dd, J=7.2, 1.9Hz, 1H), 7.26-7.18 ( m, 2H), 4.12 (d, J=3.7Hz, 3H), 4.09 (d, J=4.6Hz, 2H), 3.81 (t, J=7.4Hz, 1H), 3.55 (t, J =7.4Hz, 1H), 3.36 (s, 1H), 3.07 (s, 2H), 2.67 (d, J = 35.8Hz, 7H), 2.44 (dt, J = 43.9, 7. 2Hz, 4H), 2.07-1.76 (m, 7H), 1.64 (s, 1H), 1.37-1.27 (m, 2H), 1.11 (d, J=12.1Hz, 2H).

[0341] Example 13

[0342] Step 1: Compound 13-1 (0.5 g, 1.86 mmol), compound 11-4 (0.31 g, 1.86 mmol), and K2CO3 (0.51 g, 3.72 mmol) were dissolved in DMF (5 mL) and heated at 100°C for 3 hours. LCMS showed completion, followed by extraction, concentration, and column chromatography to afford compound 13-2 (0.4 g, yield: 60.34%). m / z [M+H] + =342.2

[0343] Step 2: Compound 13-2 (0.4 g, 1.13 mmol) was dissolved in ethanol (5 mL), followed by the addition of hydrazine hydrate (0.15 g, 2.37 mmol). The reaction mixture was stirred at 80°C for 15 hours. LCMS showed the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated to obtain compound 13-3 (0.9 g, yield: 74.92%). m / z [M+H] + =226.3

[0344] Step 3: Compound 1-4 (0.13 g, 0.53 mmol), compound 13-3 (0.19 g, 1.21 mmol), and HATU (0.26 g, 0.69 mmol) were dissolved in DMF (2 mL) and DIPEA (0.21 g, 1.59 mmol) was added. The reaction mixture was stirred at 25°C for 3 hours. LCMS showed the reaction was complete, and the reaction mixture was directly purified by reverse phase C18 column (0.5% formic acid in water and acetonitrile) to obtain compound 13 (14.2 mg, yield: 5.93%). m / z [M+H] + =440.4.

[0345] 1 H NMR(400MHz, DMSO-d6)1H NMR (400MHz, DMSO-d6) δ8.29 (s, 1H), 7.84 (dd, J=7.6, 1.6Hz, 1H), 7.51 (dd, J=7.4, 1.6Hz, 1H), 7.33 (dtd, J=16.9, 7.4, 1.6Hz, 2H), 4.19 (s, 2H), 4.14(s, 3H), 3.27(q, J=6.5Hz, 5H), 3.19-3.08(m, 2H), 3.04-2.91(m, 3H ), 2.23-2.00(m, 2H), 2.00-1.91(m, 2H), 1.83-1.56(m, 9H), 1.48(s, 2H)

[0346] Example 14

[0347] Step 1: Compound 1-2 (1 g, 3.78 mmol) and ethylhydrazine hydrochloride (0.23 g, 3.78 mmol) were dissolved in ethanol (10 mL). The reaction mixture was stirred at 80°C for 1 hour. LCMS showed completion. The reaction mixture was concentrated, extracted, and subjected to dry-type column chromatography to obtain compound 14-1 (0.6 g, yield: 44%). m / z [MH] + =289.1

[0348] Step 2: Compound 14-1 (0.2 g, 0.69 mmol) and NaOH (0.055 g, 1.38 mmol) were dissolved in a THF / H2O = 4 / 1 solution (2 mL). The reaction mixture was stirred at 60°C for 1 hour. LCMS indicated the reaction was complete. The reaction mixture was adjusted to pH 5 and filtered. The filter cake contained the product, compound 14-2 (0.15 g, yield: 83.03%). m / z [M+H] + =261.1.

[0349] Step 3: Compound 14-2 (0.12 g, 0.46 mmol), compound 7-3 (0.12 g, 0.55 mmol), and HATU (0.26 g, 0.69 mmol) were dissolved in DMF (1 mL) and DIPEA (0.18 g, 1.38 mmol) was added. The reaction mixture was stirred at 25°C for 3 hours. LCMS showed the reaction was complete, and the reaction mixture was directly purified by reverse phase C18 column (0.5% formic acid in water and acetonitrile) to obtain compound 14 (22.2 mg, yield: 10.30%). m / z [M+H] + =468.4

[0350] 1H NMR(400MHz, DMSO-d6)1H NMR (400MHz, DMSO-d6) δ8.28 (t, J=5.8Hz, 1H), 7.72 (dd, J=7.8, 1.5Hz, 1H), 7.51 (dd, J=7.6, 1.5Hz, 1 H), 7.35 (td, J=7.6, 1.6Hz, 1H), 7.30 (td, J=7.5, 1.5Hz, 1H), 4.46 (q, J=7.2Hz, 2H), 4.17 (s, 2H), 3.28 (q, J=6.6Hz, 4H), 2.71 (s, 4H), 2.59-2.51 (m, 2H), 2.42 (s, 3H), 1.90-1.77 (m, 2H), 1.71 (dp, J=20.6, 6.9, 4.9Hz, 4H), 1.56 (d, J=12.4Hz, 1H), 1.44 (t, J=7.2Hz, 3H), 1.25-1.16 (m, 4H), 1.15-1.00 (m, 1H).

[0351] Example 15

[0352] Step 1: Compound 1-2 (0.8 g, 3.03 mmol) and cyclopropylhydrazine hydrochloride (0.31 g, 3.64 mmol) were dissolved in ethanol (8 mL). The reaction mixture was stirred at 80°C for 1 hour. LCMS showed completion. The reaction mixture was concentrated, extracted, and subjected to dry-type column chromatography to obtain compound 15-1 (0.6 g, yield: 63.05%). m / z [MH] + =315.2

[0353] Step 2: Compound 15-1 (0.23 g, 0.73 mmol) and NaOH (0.058 g, 1.46 mmol) were dissolved in a THF / H2O = 4 / 1 solution (3 mL). The reaction mixture was stirred at 60°C for 1 hour. LCMS indicated the reaction was complete. The reaction mixture was adjusted to pH 5 and filtered. The filter cake contained the product, compound 15-2 (0.13 g, yield: 62.06%). m / z [M+H] + =287.1.

[0354] Step 3: Compound 15-2 (0.1 g, 0.35 mmol), compound 7-3 (0.13 g, 0.42 mmol), and HATU (0.17 g, 0.45 mmol) were dissolved in DMF (1 mL) and DIPEA (0.14 g, 1.05 mmol) was added. The reaction solution was stirred at 25°C for 3 hours. LCMS showed the reaction was complete, and the reaction solution was directly purified by reverse phase C18 column (0.5% formic acid in water and acetonitrile) to obtain compound 15 (59.3 mg, yield: 34.39%). m / z [M+H] + =468.4

[0355] 1 H NMR (400MHz, DMSO-d6) δ8.26 (d, J = 5.6Hz, 1H), 7.83 (d, J = 7.8Hz, 1H), 7.51 (dd, J = 7.7, 1.5Hz, 1H), 7.32 (dtd, J = 23. 5, 7.5, 1.4Hz, 2H), 4.35 (d, J=6.6Hz, 2H), 4.17 (s, 2H), 3.28 (q, J=6.5Hz, 2H), 2.56 (s, 4H), 2.44 (d, J=21.5Hz, 3H), 2 .35 (t, J=6.6Hz, 3H), 2.29-2.18 (m, 1H), 1.77 (d, J=7.3Hz, 2H), 1.68 (dt, J=13.3, 7.7Hz, 4H), 1.55 (d, J=11.6Hz, 1H ), 1.33-1.24 (m, 1H), 1.16 (d, J=10.2Hz, 4H), 1.05 (d, J=11.6Hz, 1H), 0.54-0.47 (m, 2H), 0.35 (q, J=6.0, 5.3Hz, 2H).

[0356] Example 16

[0357] Step 1: Compound 16-1 (1 g, 6.75 mmol) and sodium ethoxide (0.51 g, 7.43 mmol) were dissolved in ethanol (15 mL) and stirred at 0°C for 0.5 h. Diethyl oxalate (0.99 g, 6.75 mmol) was then added and stirred at 40°C for 1 h. LCMS showed completion. The reaction solution was concentrated, extracted, and subjected to dry-type column chromatography to obtain compound 16-2 (1 g, yield: 35.81%). m / z [MH] + =247.0

[0358] Step 2: Compound 16-2 (1 g, 4.03 mmol) and methylhydrazine sulfate (0.7 g, 4.84 mmol) were dissolved in ethanol (10 mL). The reaction mixture was stirred at 80°C for 1 hour. LCMS showed the reaction was complete. The reaction mixture was concentrated and loaded onto a column for chromatography to obtain compound 16-3 (0.6 g, yield: 57.67%). m / z [M+H] + =259.3.

[0359] Step 3: Compound 16-3 (0.2 g, 0.77 mmol) and NaOH (0.062 g, 1.54 mmol) were dissolved in a THF / H2O = 4 / 1 solution (2 mL). The reaction mixture was stirred at 60°C for 1 hour. LCMS indicated the reaction was complete. The reaction mixture was adjusted to pH 5 and filtered. The filter cake contained the product, compound 16-4 (0.1 g, yield: 56.09%). m / z [M+H] + =231.1.

[0360] Step 4: Compound 16-4 (0.12 g, 0.52 mmol), compound 7-3 (0.14 g, 0.62 mmol), and HATU (0.3 g, 0.78 mmol) were dissolved in DMF (1 mL) and DIPEA (0.2 g, 1.56 mmol) was added. The reaction mixture was stirred at 25°C for 3 hours. LCMS showed the reaction was complete, and the reaction mixture was directly purified by reverse phase C18 column (0.5% formic acid in water and acetonitrile) to obtain compound 16 (63 mg, yield: 27.62%). m / z [M+H] + =438.4

[0361] 1 H NMR (400MHz, DMSO-d6) δ8.36-8.30 (m, 1H), 7.72 (d, J=7.7Hz, 1H), 7.28 (t, J=7.7Hz, 1H), 7.0 7(t, J=7.4Hz, 1H), 7.01 (d, J=6.5Hz, 1H), 5.39 (d, J=1.8Hz, 2H), 4.15 (d, J=2.4Hz, 3H), 3.26 (q, J=5.7Hz, 2H), 2.60 (s, 4H), 2.43 (s, 3H), 2.34 (q, J=14.8, 10.8Hz, 4H), 1.79 (s, 2H), 1.71 (s, 2H), 1.68-1.61 (m, 2H), 1.55 (d, J=11.9Hz, 1H), 1.18 (t, J=8.9Hz, 4H), 1.11-1.00 (m, 1H).

[0362] Example 17

[0363] Step 1: Compound 17-1 (5 g, 34.2 mmol) and sodium ethoxide (2.44 g, 35.91 mmol) were dissolved in ethanol (100 mL) and stirred at 0°C for 0.5 h. Diethyl oxalate (5 g, 34.2 mmol) was then added and stirred at 40°C for 1 h. LCMS showed completion. The reaction solution was concentrated, extracted, and subjected to dry-type column chromatography to obtain compound 17-2 (8.5 g, yield: 86.35%). m / z [MH] + =247.2

[0364] Step 2: Compound 17-2 (2 g, 5.69 mmol) and methylhydrazine sulfate (1.64 g, 11.38 mmol) were dissolved in ethanol (10 mL). The reaction mixture was stirred at 25°C for 16 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated and loaded onto a column chromatography column to obtain compound 17-3 (0.55 g, yield: 37.75%). m / z [M+H] + =257.2.

[0365] Step 3: Compound 17-3 (0.25 g, 0.98 mmol) and KOH (0.33 g, 5.88 mmol) were dissolved in a 4 / 1 MeOH / H2O solution (2 mL). The reaction mixture was stirred at 60°C for 1 hour. LCMS indicated the reaction was complete. The reaction mixture was adjusted to pH 5 and filtered. The filter cake contained the product, compound 17-4 (0.1 g, yield: 56.09%). m / z [M+H] + =229.2.

[0366] Step 4: Compound 17-4 (0.12 g, 0.52 mmol), compound 7-3 (0.14 g, 0.62 mmol), and HATU (0.3 g, 0.78 mmol) were dissolved in DMF (1 mL) and DIPEA (0.2 g, 1.56 mmol) was added. The reaction mixture was stirred at 25°C for 3 hours. LCMS showed the reaction was complete, and the reaction mixture was directly purified by reverse phase C18 column (0.5% formic acid in water and acetonitrile) to obtain compound 17 (50.8 mg, yield: 28.62%, formate salt). m / z [M+H] + =436.4

[0367] 1H NMR (400MHz, DMSO-d6) 8.25 (s, 1H), 8.16 (t, J = 5.5Hz, 1H), 7.72 (d, J = 7.6Hz, 1H ), 7.39-7.32 (m, 2H), 7.28 (t, J = 7.3Hz, 1H), 4.15 (s, 3H), 3.26 (q, J = 6.2Hz, 2H) , 2.89 (d, J = 6.9Hz, 2H), 2.84 (d, J = 6.7Hz, 2H), 2.65 (s, 4H), 2.48 (s, 2H), 2.38 ( t, J=6.7Hz, 4H), 1.85-1.50 (m, 8H), 1.19 (p, J=11.7Hz, 4H), 1.11-0.99 (m, 1H).

[0368] Example 18

[0369] Step 1: Compound 1-4 (0.14 g, 0.57 mmol), compound 18-1 (0.075 g, 0.68 mmol), and HATU (0.28 g, 0.74 mmol) were dissolved in DMF (2 mL) and DIPEA (0.22 g, 1.71 mmol) was added. The reaction mixture was stirred at 25°C for 3 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated and purified by column chromatography to obtain compound 18-2 (0.18 g, yield: 92.3%). m / z [M+H] + =338.1.

[0370] Step 2: Compound 18-2 (0.18 g, 0.53 mmol), N-phenylpiperazine (0.086 g, 0.53 mmol), K2CO3 (0.18 g, 1.33 mmol), and potassium iodide (0.044 g, 0.27 mmol) were dissolved in acetonitrile (2 mL) and heated at 80°C for 6 hours. LCMS showed completion, and the reaction solution was concentrated and then directly purified by reverse phase C18 column (0.5 / 1000 formic acid in water and acetonitrile) to obtain compound 18 (63 mg, yield: 25.5%). m / z [M+H] + =464.3

[0371] 1H NMR (400MHz, DMSO-d6) δ8.26 (t, J=5.6Hz, 1H), 7.80 (dd, J=7.4, 1.8Hz, 1H), 7.50 (dd, J=7.1, 1.8Hz, 1H), 7.31 (pd, J=7.4, 1.6Hz, 2H), 7.20 (t, J=7.7Hz, 2H), 6.93 (d, J=8.2Hz, 2H), 6.76 (t, J=7.2Hz, 1H ), 4.94 (s, 1H), 4.19 (s, 2H), 4.02 (s, 3H), 3.84 (t, J=6.1Hz, 1H), 3.34-3.29 (m, 2H), 3.18 (t, J=5.0H z, 4H), 2.63 (dt, J=10.2, 5.0Hz, 2H), 2.57 (q, J=5.8, 5.4Hz, 2H), 2.42 (td, J=12.5, 10.9, 6.2Hz, 2H).

[0372] Example 19

[0373] Compound 1-6 (0.1 g, 0.27 mmol), 2-bromopyridine (0.043 g, 0.27 mmol), palladium acetate (6 mg, 0.027 mmol), BINAP (34 mg, 0.054 mmol), and sodium tert-butoxide (78 mg, 0.81 mmol) were dissolved in dioxane (2 mL) and heated at 110°C for 4 hours. LCMS showed completion, and the mixture was then directly concentrated and purified directly on a reverse phase C18 column (0.5% formic acid aqueous solution and acetonitrile) to obtain compound 19 (33.5 mg, yield: 27.74%). m / z [M+H] + =449.3

[0374] 1 H NMR (400MHz, DMSO-d6) δ8.55 (t, J=5.6Hz, 1H), 8.11 (dd, J=5.0, 1.9Hz, 1H), 7.80 (d d, J=7.3, 1.9Hz, 1H), 7.55-7.47 (m, 2H), 7.31 (pd, J=7.4, 1.7Hz, 2H), 6.82 (d, J=8. 6Hz, 1H), 6.63 (dd, J=7.1, 4.9Hz, 1H), 4.19 (s, 2H), 4.03 (s, 3H), 3.53 (t, J=5.0Hz, 5H), 3.32-3.30 (m, 3H), 2.48 (s, 2H), 2.43 (t, J=6.6Hz, 2H), 1.72 (p, J=6.7Hz, 2H).

[0375] Example 20

[0376] Compound 1-6 (0.1 g, 0.27 mmol), 3-bromopyridine (0.043 g, 0.27 mmol), palladium acetate (6 mg, 0.027 mmol), BINAP (34 mg, 0.054 mmol), and sodium tert-butoxide (78 mg, 0.81 mmol) were dissolved in dioxane (2 mL) and heated at 110°C for 15 hours. LCMS showed completion, and the mixture was then directly concentrated and purified directly on a reverse phase C18 column (0.5% formic acid aqueous solution and acetonitrile) to obtain compound 20 (9.9 mg, yield: 8.2%). m / z [M+H] + =449.3

[0377] 1 H NMR (400MHz, DMSO-d6) δ8.51 (t, J=5.6Hz, 1H), 8.31 (d, J=2.9Hz, 1H), 8.01- 7.97 (m, 1H), 7.82-7.77 (m, 1H), 7.50 (dd, J=7.4, 1.7Hz, 1H), 7.34-7.28 (m, 3 H), 7.20 (dd, J=8.5, 4.5Hz, 1H), 4.19 (s, 2H), 4.02 (s, 3H), 3.32-3.29 (m, 3H ), 3.29-3.22(m, 4H), 2.55(s, 3H), 2.48-2.40(m, 2H), 1.72(p, J=6.3Hz, 2H).

[0378] Example 21

[0379] Compound 1-6 (0.1 g, 0.27 mmol), 4-bromopyridine (0.043 g, 0.27 mmol), palladium acetate (6 mg, 0.027 mmol), BINAP (34 mg, 0.054 mmol), and sodium tert-butoxide (78 mg, 0.81 mmol) were dissolved in dioxane (2 mL) and heated at 110°C for 15 hours. LCMS showed completion, and the mixture was then directly concentrated and purified by Pre-TLC to give compound 21 (29.8 mg, yield: 27.1%). m / z [M+H] + =449.3

[0380] 1H NMR (400MHz, DMSO-d6) δ8.50 (t, J=5.6Hz, 1H), 8.16 (d, J=5.9Hz, 2H), 7.80 (dd, J=7.4, 1.8Hz, 1H), 7.50 (dd, J=7.3, 1.9Hz, 1H), 7.35-7.27 (m, 2H), 6 .88 (d, J=6.0Hz, 2H), 4.19 (s, 2H), 4.03 (s, 3H), 3.43 (d, J=4.7Hz, 3H), 3.3 4-3.29 (m, 4H), 2.52 (s, 3H), 2.43 (t, J=6.7Hz, 2H), 1.70 (q, J=6.7Hz, 2H).

[0381] Example 22

[0382] Compound 1-6 (0.1 g, 0.27 mmol), 2-bromochlorobenzene (0.043 g, 0.27 mmol), palladium acetate (6 mg, 0.027 mmol), BINAP (34 mg, 0.054 mmol), and sodium tert-butoxide (78 mg, 0.81 mmol) were dissolved in dioxane (2 mL) and heated at 110°C for 15 hours. LCMS showed completion, and the mixture was then directly concentrated and purified directly on a reverse phase C18 column (0.5% formic acid aqueous solution and acetonitrile) to obtain compound 22 (27 mg, yield: 20.77%). m / z [M+H] + =449.3

[0383] 1 H NMR (400MHz, DMSO-d6) δ8.49 (t, J=5.6Hz, 1H), 7.83 (dd, J=7.6, 1.7Hz, 1H), 7.50 (dd, J= 7.4, 1.7Hz, 1H), 7.40 (dd, J=7.9, 1.5Hz, 1H), 7.31 (dddd, J=16.0, 8.9, 7.4, 1.6Hz, 3H), 7 .17(dd, J=8.1, 1.6Hz, 1H), 7.03(td,J=7.6, 1.5Hz, 1H), 4.19(s, 2H), 4.11(s, 3H), 3.33( s, 3H), 3.05 (d, J=4.8Hz, 4H), 2.59 (s, 3H), 2.47 (d, J=6.6Hz, 2H), 1.72 (t, J=6.6Hz, 2H).

[0384] Example 23

[0385] Step 1: Compound 1-4 (0.15 g, 0.61 mmol), compound 23-1 (0.086 g, 0.73 mmol), and HATU (0.3 g, 0.79 mmol) were dissolved in DCM (2 mL) and DIPEA (0.24 g, 1.83 mmol) was added. The reaction mixture was stirred at 25°C for 3 hours. LCMS showed the reaction was complete. The reaction mixture was extracted, concentrated, and subjected to dryness column chromatography to obtain compound 23-2 (0.18 g, yield: 87.09%). m / z [M+H] + =340.1.

[0386] Step 2: Compound 23-2 (0.27 g, 0.8 mmol), MsCl (0.11 g, 0.96 mmol) and TEA (0.16 g, 1.6 mmol) were added. LCMS showed completion. The reaction solution was concentrated and purified by column chromatography to obtain compound 23-3 (0.25 g, yield: 75.27%). m / z [M+H] + =418.2.

[0387] Step 3: Compound 23-3 (0.15 g, 0.36 mmol), N-phenylpiperazine (0.088 g, 0.54 mmol), K2CO3 (0.15 g, 1.08 mmol), and potassium iodide (0.048 g, 0.29 mmol) were dissolved in dioxane (3 mL) and heated at 105°C for 5 days. LCMS showed completion, and the reaction solution was concentrated and then directly purified by reverse phase C18 column (0.5% formic acid in water and acetonitrile) to obtain compound 23 (5.2 mg, yield: 2.99%). m / z [M+H] + =484.3.

[0388] 1 H NMR (400MHz, DMSO-d6) δ8.42 (t, J=6.2Hz, 1H), 7.84-7.78 (m, 1H), 7.51 (dd, J =7.5, 1.7Hz, 1H), 7.32 (pd, J=7.4, 1.7Hz, 2H), 7.24-7.17 (m, 2H), 6.94 (d, J= 7.9Hz, 2H), 6.80-6.75 (m, 1H), 4.19 (s, 2H), 4.05 (s, 3H), 3.86 (td, J=14.4, 6 .3Hz, 2H), 3.22-3.16 (m, 4H), 2.92 (t, J=14.0Hz, 2H), 2.73 (t, J=4.9Hz, 4H).

[0389] Example 24

[0390] Compound 1-6 (0.1 g, 0.27 mmol), m-chlorobromobenzene (0.062 g, 0.32 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), RuPhos (25 mg, 0.054 mmol), and potassium tert-butoxide (91 mg, 0.81 mmol) were dissolved in dioxane (2 mL) and heated at 110°C for 5 hours. LCMS showed completion, and the mixture was then directly concentrated and purified directly on a reverse phase C18 column (0.5% formic acid aqueous solution and acetonitrile) to obtain compound 24 (32 mg, yield: 24.66%). m / z [M+H] + =482.3.

[0391] 1 H NMR (400MHz, DMSO-d6) δ8.50 (t, J=5.6Hz, 1H), 7.80 (dd, J=7.4, 1.8Hz, 1H), 7.50 (d d, J=7.3, 1.8Hz, 1H), 7.31 (pd, J=7.4, 1.6Hz, 2H), 7.20 (t, J=8.1Hz, 1H), 6.95 (t, J= 2.2Hz, 1H), 6.90 (dd, J=8.4, 2.4Hz, 1H), 6.78 (dd, J=7.8, 1.8Hz, 1H), 4.19 (s, 2H), 4 .03 (s, 3H), 3.23 (d, J = 5.4Hz, 8H), 2.55 (s, 3H), 2.46 (s, 1H), 1.72 (p, J = 6.8Hz, 2H).

[0392] Example 25

[0393] To an 8 mL single-necked flask were added compound 2-1 (100 mg, 0.25 mmol), p-chlorobromobenzene (57 mg, 0.3 mmol), 1,4-dioxane (2 mL), and potassium tert-butoxide (93 mg, 0.82 mmol). Under nitrogen protection, 2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl (12 mg, 0.025 mmol) and tris(dibenzylideneacetone)palladium (11 mg, 0.013 mmol) were added. The mixture was stirred at 105°C under nitrogen protection for 16 hours. The reaction mixture was returned to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The product compound 25 (42.8 mg, yield: 36.22%) was obtained by reverse phase reaction. ESI (m / z) = 482.3 [M+H] + .

[0394] 1H NMR (400MHz, DMSO-d6) δ8.53 (t, J=5.6Hz, 1H), 7.84-7.76 (m, 1H), 7.53-7.47 (m, 1H), 7.31 (pd, J=7.4, 1.7Hz, 2H), 7.25-7.18 (m, 2H), 7 .00-6.90 (m, 2H), 4.19 (s, 2H), 4.02 (s, 3H), 3.19 (t, J=5.0Hz, 6H), 2.53 (t, J=5.0Hz, 4H), 2.44 (t, J=6.6Hz, 2H), 1.71 (p, J=6.6Hz, 2H).

[0395] Example 26

[0396] Compound 2-1 (100 mg, 0.25 mmol), p-bromotrifluorobenzoyl (68 mg, 0.3 mmol), 1,4-dioxane (2 mL), and potassium tert-butoxide (93 mg, 0.82 mmol) were added sequentially to an 8 mL single-necked flask. 2-Dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl (12 mg, 0.025 mmol) and tris(dibenzylideneacetone)palladium (11 mg, 0.013 mmol) were then added under nitrogen. The mixture was stirred at 105°C for 16 hours under nitrogen. The reaction mixture was returned to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The product, compound 26 (36.2 mg, yield: 28.6%), was obtained by reverse phase chromatography. ESI (m / z) = 516.3 [M+H] + .

[0397] 1 H NMR (400MHz, DMSO-d6) δ8.50 (t, J=5.6Hz, 1H), 7.80 (dd, J=7.3, 1.9Hz, 1H), 7.54-7.44 (m, 3H), 7.31 (pd, J=7.4, 1.7Hz, 2H), 7.0 7 (d, J=8.6Hz, 2H), 4.19 (s, 2H), 4.03 (s, 3H), 3.31 (s, 6H), 2.53 (t, J=5.1Hz, 4H), 2.43 (t, J=6.6Hz, 2H), 1.72 (p, J=6.7Hz, 2H).

[0398] Example 27

[0399] The synthetic method of reference example 26, with Instead of p-bromotrifluorotoluene, compound 27 was synthesized.

[0400] 1H NMR (400MHz, DMSO-d6) δ8.54 (t, J=5.6Hz, 1H), 8.18 (s, 0.42H), 7.83 (dd, J=7.3, 1 .9Hz, 1H), 7.53 (dd, J=7.2, 1.9Hz, 1H), 7.41-7.27 (m, 2H), 6.98-6.88 (m, 2H), 6.87 -6.77 (m, 2H), 4.22 (s, 2H), 4.06 (s, 3H), 3.71 (s, 3H), 3.35 (d, J=6.0Hz, 2H), 3.11 (t, J=4.9Hz, 4H), 2.59 (d, J=4.8Hz, 4H), 2.48 (t, J=6.6Hz, 2H), 1.79-1.67 (m, 2H).

[0401] Example 28

[0402] The synthetic method of reference example 26, with Instead of p-bromotrifluorotoluene, compound 28 was synthesized.

[0403] 1 H NMR (400MHz, DMSO-d6) δ8.56 (t, J=5.7Hz, 1H), 8.39 (d, J=4.7Hz, 2H), 7.85 (d, J=7.5Hz, 1H), 7.53 (dd, J=7.0, 1.8Hz, 1H), 7.40-7.26 (m, 2H), 6.66 (t, J=4.7Hz, 1H), 4.22 (s, 2H), 4.10 (s, 3H), 3.80 (s, 4H), 3.34 (d, J=8.2Hz, 2H), 2.48 (s, 4H), 1.75 (s, 2H), 1.26 (s, 2H).

[0404] Example 29

[0405] The synthetic method of reference example 26, with Instead of p-bromotrifluorotoluene, compound 29 was synthesized.

[0406] 1H NMR (400MHz, DMSO-d6) δ8.52 (t, J=5.6Hz, 1H), 7.81 (dd, J=7.4, 1.9Hz, 1H), 7.60-7.56 (m, 2H), 7.50 (dd, J=7.2, 1.9Hz, 1H), 7.31 (pd, J=7.4, 1 .7Hz, 2H), 7.08-7.01(m, 2H), 4.19(s, 2H), 4.03(s, 3H), 3.43-3.36(m, 5H), 3.30 (s, 3H), 2.55 (s, 3H), 2.46 (s, 1H), 1.72 (p, J=6.2, 5.8Hz, 2H).

[0407] Example 30

[0408] The synthetic method of reference example 13, with Instead of 11-4, compound 30 was synthesized.

[0409] 1 H NMR (400MHz, DMSO-d6) δ8.47 (t, J=6.1Hz, 1H), 7.88 (dd, J=7.6, 1.6Hz, 1H), 7.54 (dd, J=7.5, 1.6Hz, 1H), 7.43-7.32 (m, 2H), 4.22 (s, 2H), 4. 18(s, 3H), 3.62-3.40(m, 6H), 3.36-3.30(m, 2H), 3.22-2.91(m, 8H), 2 .81(s, 3H), 2.49(s, 1H), 2.40(s, 1H), 1.93(s, 4H), 1.61-1.51(m, 1H).

[0410] Example 31

[0411] The synthetic method of reference example 13, with Instead of 11-4, compound 31 was synthesized.

[0412] 1 H NMR (400MHz, DMSO-d6) δ8.45 (t, J=5.9Hz, 1H), 7.84 (dd, J=7.6, 1.6Hz, 1H), 7.51 (dd, J=7.4, 1.7Hz, 1H), 7.37-7. 29(m, 4H), 7.26-7.20(m, 3H), 4.20(s, 2H), 4.11(s, 3H), 3.34-3.28(m, 6H), 2.76-2.59(m, 2H), 2.04-1.68(m, 7H).

[0413] Example 32

[0414] The synthetic method of reference example 13, with Instead of 11-4, compound 32 was synthesized.

[0415] 1 H NMR (400MHz, DMSO-d6) δ8.46 (t, J=5.9Hz, 1H), 7.84 (dd, J=7.6, 1.6Hz, 1H), 7.53-7.45 (m, 3H), 7.40-7.30 (m, 4H), 7.29-7.24 ( m, 1H), 4.20 (s, 2H), 4.13 (s, 3H), 3.32 (d, J=6.4Hz, 4H), 3.08 (s, 4H), 2.17 (d, J=14.2Hz, 2H), 1.92 (s, 2H), 1.83-1.75 (m, 2H).

[0416] Example 33

[0417] The synthetic method of reference example 23, with replace Compound 33 was synthesized.

[0418] 1 H NMR (400MHz,) δ8.42 (t, J=6.1Hz, 1H), 8.20 (s, 1H), 7.86 (dd, J=7.5, 1.6Hz, 1H), 7.51 (dd, J=7.4, 1.7Hz, 1H), 7.33 (dtd, J=16.8, 7.4, 1.6Hz, 2H), 4.19 (s, 2H), 4.1 7 (s, 3H), 3.81 (td, J=14.2, 6.1Hz, 4H), 2.98 (d, J=11.3Hz, 2H), 2.82 (t, J=13.9Hz , 2H), 2.34(s, 6H), 2.21-2.04(m, 6H), 1.74(d, J=11.7Hz, 2H), 1.59-1.42(m, 2H).

[0419] Example 34

[0420] The synthetic method of reference example 23, with replace Compound 34 was synthesized.

[0421] 1H NMR (400MHz, DMSO-d6) δ8.36 (t, J=6.3Hz, 1H), 8.24 (s, 1H), 7.86 (dd, J=7.5, 1.7Hz, 1H), 7.51 (dd, J=7.4, 1.7Hz, 1H), 7.39-7.27 (m, 2H), 4.17 (s, 3H), 3.80 (d, J=6.3Hz, 2H), 2.99 ( d, J=11.2Hz, 2H), 2.81 (t, J=14.0Hz, 2H), 2.56 (t, J=5.2Hz, 4H), 2.37-2.26 (m, 1H), 2.22- 2.11 (m, 2H), 1.74 (d, J=12.4Hz, 2H), 1.53 (tt, J=11.2, 4.6Hz, 6H), 1.39 (t, J=5.9Hz, 2H).

[0422] Example 35

[0423] The synthetic method of reference example 23, with replace Compound 35 was synthesized.

[0424] 1 H NMR (400MHz, DMSO-d6) δ8.46 (t, J=6.1Hz, 1H), 8.18 (s, 0H), 7.86 (dd, J=7.5, 1.6Hz, 1H), 7.51 (dd, J=7.4, 1.7Hz, 1H), 7.38-7.27 (m, 2H), 4.19 (s, 5H), 3.81 (td, J=14.1, 6.0Hz, 2H), 3.55 (t, J=4.6Hz, 4H), 2.99 (d, J=11.4Hz, 2H), 2.83 (t, J=13.9Hz, 2H), 2.43 (t, J=4.6Hz, 4H), 2.23-2. 12 (m, 2H), 2.04 (tt, J=11.1, 3.8Hz, 1H), 1.77 (d, J=11.8Hz, 2H), 1.50 (qd, J=12.1, 3.7Hz, 2H).

[0425] Example 36

[0426] The synthetic method of reference example 13, with Instead of 11-4, compound 36 was synthesized.

[0427] 1H NMR (400MHz, DMSO-d6) δ8.27 (s, 1H), 7.84 (dd, J=7.7, 1.5Hz, 1H), 7.51 (dd, J=7.5, 1.6Hz, 1H), 7.33 (dtd, J=16.6, 7.4, 1.5Hz, 2H ), 4.18(s, 2H), 4.14(s, 3H), 3.33-3.10(m, 10H), 2.66(s, 1H), 2.37(s, 2H), 2.13(s, 1H), 1.86(s, 1H), 1.75(s, 6H), 1.47(s, 2H).

[0428] Example 37

[0429] The synthetic method of reference example 23, with replace Compound 37 was synthesized.

[0430] 1 H NMR (400MHz,) δ8.36 (t, J=6.2Hz, 1H), 7.86 (dd, J=7.5, 1.7Hz, 1H), 7.51 (dd, J=7.4, 1.7 Hz, 1H), 7.39-7.27 (m, 2H), 4.19 (s, 2H), 4.16 (s, 3H), 3.81 (td, J=14.3, 6.2Hz, 2H), 2.98 (d, J=10.8Hz, 2H), 2.81 (t, J=14.0Hz, 2H), 2.57 (t, J=5.6Hz, 4H), 2.35-2.09 (m, 3H), 1. 90 (ddt, J=20.0, 13.7, 5.6Hz, 4H), 1.69 (d, J=12.1Hz, 2H), 1.52 (qd, J=11.9, 3.7Hz, 2H).

[0431] Example 38

[0432] Step 1: Dissolve compound 1-4 (150 mg, 0.61 mmol, 1.0 eq), HATU (325 mg, 0.85 mmol, 1.4 eq), and DIEA (315 mg, 2.44 mmol, 4.0 eq) in DMF (3 mL). Add 1-amino-3,3-diethoxypropane (90 mg, 0.61 mmol, 1.0 eq) to the reaction mixture. Stir the reaction mixture at room temperature overnight. After completion of the reaction, dilute the reaction mixture with water (40 mL) and extract with ethyl acetate (3 × 20 mL). The combined organic phases are washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain crude product 100-1 (300 mg, crude).

[0433] Step 2: Dissolve 100-1 (100 mg, crude, 0.27 mmol, 1.0 eq) in acetone / water (v / v = 10 / 1, 2 mL / 0.2 mL) and add TsOH (56 mg, 0.29 mmol, 1.1 eq) to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude 100-2 (57 mg, crude). LCMS: m / z = 302.1 [M+H] +

[0434] Step 3: 100-2 (53 mg, crude, 0.18 mmol, 1.5 eq) and 100-3 (40 mg, 0.12 mmol, 1.0 eq) were dissolved in MeOH (1 mL), and NaBH3CN (14 mg, 0.22 mmol, 2.0 eq) was added to the reaction solution. The reaction solution was stirred at room temperature overnight. After the reaction was completed, the reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (3×10 mL). The organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by preparative thin-layer chromatography to obtain the free product. The free product was dissolved in methanol and formic acid was added to form a salt. The resulting solution was concentrated under reduced pressure to obtain compound 100 (17 mg, 37%) as a colorless oil. LCMS: m / z = 412.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.27 (t, J=5.8Hz, 1H), 8.19 (s, 1H), 7.83 (dd, J=7.6, 1.7Hz, 1H), 7.50 (dd, J=7.4, 1.7Hz, 1H), 7.38-7.27 (m, 2H), 4.18 (s, 2H), 4.13(s, 3H), 3.32-3.24(m, 4H), 3.18-3.12(m, 2H), 2.62-2.53(m, 4H ), 2.36(s, 3H), 2.09-2.01(m, 2H), 1.69-1.60(m, 2H), 1.60-1.51(m, 2H).

[0435] Referring to the synthesis method of compound 100, the corresponding amine was used instead of 100-3 to synthesize the following compounds.

[0436] Example 39

[0437] Step 1: Potassium phthalimide (0.6 g, 3.24 mmol), 1,1-bis-bromomethylcyclopropane (0.96 g, 4.21 mmol), and potassium carbonate (1.57 g, 11.34 mmol) were dissolved in acetonitrile (10 mL), followed by the addition of N-phenylpiperazine (0.53 g, 3.24 mmol). The mixture was heated at 60°C for 8 hours. LCMS indicated completion, and the mixture was filtered, concentrated, and dry-phase column chromatography using PE / EA (50%) afforded 39-1 (0.61 g, yield: 50.15%). m / z [M+H] + =376.4

[0438] Step 2: Dissolve 39-1 (0.61 g, 1.62 mmol) and hydrazine hydrate (80% by weight, 0.2 g, 3.24 mmol) in ethanol (10 mL). Heat to 80°C and react overnight. LCMS indicates completion. The reaction is then filtered and the filtrate is concentrated to obtain a solid. The solid is slurried with petroleum ether, filtered again, and the filtrate is concentrated to obtain 39-2 (0.35 g, yield: 87.8%).

[0439] Step 3: Compound 1-4 (0.106 g, 0.43 mmol), 39-2 (0.21 g, 0.52 mmol), and HATU (0.25 g, 0.62 mmol) were added to a DMF (2 mL) solution, followed by DIPEA (0.17 g, 1.29 mmol). The reaction was allowed to proceed at room temperature for 3 h. LCMS indicated completion, and product 39 (0.065 g, yield: 31.89%) was obtained by direct reverse-phase column chromatography. m / z [M+H] + =474.4. 1 H NMR (400MHz, DMSO-d6) δ8.74 (t, J=5.5Hz, 1H), 7.75 (dd, J=6.7, 2.4Hz, 1H), 7.49 (dd, J= 6.5, 2.4Hz, 1H), 7.29 (dt, J=6.3, 2.6Hz, 2H), 7.21 (t, J=7.8Hz, 2H), 6.96 (d, J=8.2Hz, 2 H), 6.78 (t, J=7.2Hz, 1H), 4.18 (s, 2H), 3.88 (s, 3H), 3.33 (d, J=5.4Hz, 3H), 3.31-3.27 ( m, 4H), 2.64 (t, J=4.8Hz, 3H), 2.43 (s, 2H), 0.52 (d, J=4.7Hz, 2H), 0.38 (d, J=4.8Hz, 2H).

[0440] Example 40

[0441] Referring to the synthesis method of Example 39, 1,1-dibromo-2-methylpropane was used instead of 1,1-bis-bromomethylcyclopropane to synthesize Compound 40. 1 H NMR (400MHz, DMSO-d6) δ8.86 (d, J=4.1Hz, 1H), 7.78-7.72 (m, 1H), 7.48 (dd, J=7.2, 1.9Hz, 1H), 7. 28 (tt, J=7.4, 5.6Hz, 2H), 7.23-7.16 (m, 2H), 6.94 (d, J=8.1Hz, 2H), 6.76 (t, J=7.2Hz, 1H), 4.17 ( s, 2H), 3.91 (s, 3H), 3.41 (dd, J=13.5, 7.3Hz, 2H), 3.22 (s, 4H), 3.02 (dd, J=12.7, 8.6Hz, 1H), 2.6 4(s, 2H), 2.39(t, J=10.9Hz, 2H), 2.28-2.20(m, 1H), 2.04(s, 1H), 0.86(d, J=6.6Hz, 3H).m / z[M+H] + =462.4

[0442] Example 41

[0443] Step 1: To a 50 mL single-necked flask, 49-1 (450 mg, 1.50 mmol), 49-2 (280 mg, 1.80 mmol), and N,N-dimethylformamide (4 mL) were added sequentially, followed by potassium carbonate (510 mg, 3.75 mmol) and stirred at 60°C for 16 hours. Water and ethyl acetate were added to the reaction mixture, and the mixture was separated and extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Column chromatography afforded 49-3 (420 mg, yield: 85.7%). LCMS m / z [M+H] + =324.3

[0444] Step 2: To a 50 mL single-necked flask, 49-3 (320 mg, 0.99 mmol), methanol (1 mL), and a 1,4-dioxane solution of HCl (4 M, 4 mL) were added sequentially and stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure to afford 49-4 (200 mg, yield: 61%), which was used directly in the next step.

[0445] Step 3: To a 50 mL single-necked vial were added 1-4 (100 mg, 0.41 mmol), 49-4 (160 mg, 0.49 mmol), and N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (320 mg, 2.46 mmol) and (7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (180 mg, 0.47 mmol) were then added. The mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered, and the filtrate was directly purified by reverse-phase column chromatography to afford 49 (50.4 mg, 27.5% yield). 1 H NMR (400MHz, DMSO-d6) δ7.83 (dd, J=7.6, 1.7Hz, 1H), 7.50 (dd, J=7.4, 1.7Hz, 1H), 7.37-7.26 (m, 2H), 4.56 (t, J=9.0Hz, 1H), 4.16 (s, 2H), 4.1 5-4.04 (m, 5H), 3.63 (dd, J=9.9, 5.5Hz, 1H), 2.96-2.51 (m, 9H), 2.04-1.80 (m, 4H), 1.74 (s, 4H), 1.45 (s, 2H), 1.24 (d, J=5.9Hz, 1H).m / z[M+H] + =452.3

[0446] Example 42

[0447] Referring to the synthesis method of Example 30, compound 50 was synthesized by replacing 1-4 with 16-4. 1 HNMR (400MHz, DMSO-d6) δ 8.56 (t, J = 5.6 Hz, 1H), 7.73 (dd, J = 7.8, 1.5 Hz, 1H), 7.28 (td, J = 7.8, 1. 6Hz, 1H), 7.08(td,J=7.6, 1.2Hz, 1H), 7.01(dd,J=8.2, 1.2Hz, 1H), 5.39(s, 2H), 4.17(s, 3H), 3. 28(q, J=6.3Hz, 4H), 3.01(d, J=11.2Hz, 2H), 2.58(s, 2H), 2.46(s, 6H), 2.22(s, 3H), 2.18(s, 1H) , 1.96 (s, 2H), 1.79 (d, J=11.3Hz, 2H), 1.68 (p, J=6.6Hz, 2H), 1.54 (tt, J=12.1, 6.1Hz, 2H).LCMS m / z[M+H] + =453.3

[0448] Example 43

[0449] Referring to the synthetic method of Example 13, the corresponding amine fragment was used instead of 11-4 to synthesize the following compound.

[0450] Example 44

[0451] Step 1: 38-2 (700 mg, 2.32 mmol) and (720 mg, 2.67 mmol) and dichloromethane (15 mL) were added, followed by sodium triacetoxyborohydride (1.08 g, 5.10 mmol) and acetic acid (6 mg, 0.1 mmol), and stirred at room temperature for 2 hours. Water and dichloromethane were added to the reaction solution, and the pH was adjusted to 8-9 with dilute aqueous sodium hydroxide solution. The mixture was separated and extracted twice with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Purification by column chromatography gave 41-1 (700 mg, yield: 54.3%). LCMS m / z [M+H] + =555.4

[0452] Step 2: To a 25 mL single-necked vial were added 41-1 (200 mg, 0.36 mmol), methanol (1 mL), and a 1,4-dioxane solution of HCl (4 M, 4 mL) in sequence and stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness under reduced pressure and purified by reverse phase column to afford 41 (125.7 mg, yield: 76.6%) as the hydrochloride salt. 1 H NMR (400MHz, DMSO-d6) δ8.48 (t, J=5.8Hz, 1H), 8.18 (s, 1H), 7.84 (dd, J=7.6, 1.6Hz, 1H ), 7.50 (dd, J=7.5, 1.6Hz, 1H), 7.32 (dtd, J=17.6, 7.4, 1.6Hz, 2H), 4.19 (s, 2H), 4.15 ( s, 3H), 3.29 (q, J=6.3Hz, 2H), 3.16 (d, J=11.7Hz, 2H), 3.02 (t, J=4.9Hz, 4H), 2.73-2.5 9 (m, 6H), 2.41-2.26 (m, 3H), 1.79 (dt, J=13.9, 8.9Hz, 4H), 1.65 (q, J=11.2Hz, 2H).LCMS m / z[M+H] + =455.4

[0453] Reference is made to the synthesis of compound 41, using replace Compound 55 was synthesized. 1HNMR (400MHz, DMSO-d6) δ8.47 (s, 2H), 8.39 (t, J=6.0Hz, 1H), 7.84 (dd, J=7.6, 1.6 Hz, 1H), 7.50 (dd, J=7.5, 1.6Hz, 1H), 7.32 (dtd, J=16.9, 7.4, 1.6Hz, 2H), 4.19 (d, J=2.1Hz, 2H), 4.14(s, 3H), 3.51(d, J=12.3Hz, 2H), 3.30(q, J=6.5Hz, 3H), 3.00(q , J=11.6, 11.1Hz, 4H), 2.12 (d, J=13.1Hz, 2H), 1.97 (dd, J=14.8, 9.0Hz, 4H).LCMS m / z[M+H] + =386.2

[0454] Example 45

[0455] 1 HNMR (400MHz, DMSO-d6) δ8.38 (t, J=5.7Hz, 1H), 8.20 (HCOOH, 0.53H), 7.95 (d, J=7.4Hz, 1H), 7.83 (dd, J=7.7, 1.6Hz, 1H), 7.50 (dd, J=7.4, 1.7Hz, 1H), 7.37-7.26 (m, 2H), 4.19 (s, 2H), 4. 14(s, 3H), 3.28(q, J=6.5Hz, 3H), 2.85(d, J=11.5Hz, 2H), 2.38(t, J=6.8Hz, 2H), 2.06-1.96( m, 2H), 1.80-1.71 (m, 2H), 1.66 (q, J=6.8Hz, 2H), 1.56-1.43 (m, 3H), 0.66-0.58 (m, 4H).LCMS m / z[M+H] + =454.2

[0456] Example 46

[0457] Step 1: (679.6 mg, 4.0 mmol, 1.0 eq) and 80-1 (800 mg, 4.0 mmol, 1.0 eq) were dissolved in DCE (10 mL), and 2 drops of acetic acid were added. The reaction was stirred at room temperature for 0.5 h and then cooled to 0°C. NaBH(OAc)3 (1.69 g, 8.0 mmol, 2.0 eq) was then added portionwise to the reaction. The reaction was stirred at 0°C for 5 min, then brought to room temperature and stirred overnight. After completion of the reaction, the reaction solution was diluted with water (50 mL), the pH was adjusted to alkaline with saturated NaHCO3 solution, and extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 10:1) to obtain compound 80-2 (640 mg, 45%) as a yellow oil. LCMS m / z=353.3[M+H] +

[0458] Step 2: Dissolve compound 80-2 (640 mg, 1.81 mmol, 1.0 eq) in DCM (7 mL) and add HCl solution (4-Mindioxane, 7 mL) dropwise to the reaction mixture. Stir the reaction mixture at room temperature for 3 h. After completion of the reaction, concentrate the reaction mixture under reduced pressure to obtain compound 80-3 (630 mg, 100%) as a white solid. LCMS m / z = 253.3 [M+H] +

[0459] Step 3: Referring to the synthesis method of compound 13, 61-3 was used instead of 13-3 to synthesize compound 80. 1 HNMR (400MHz, DMSO-d6) δ8.32 (q, J=5.6Hz, 1H), 8.14 (HCOOH, H0.45), 7.87-7.81 (m, 1H), 7.51 (dd, J=7. 5, 1.7Hz, 1H), 7.38-7.27 (m, 2H), 4.18 (d, J=1.7Hz, 2H), 4.14 (s, 3H), 3.91-3.85 (m, 2H), 3.78-3.72 (m, 1 H), 3.65-3.61(m, 3H), 3.34-3.25(m, 4H), 3.17(dd,J=9.9, 5.9Hz, 2H), 2.83-2.74(m, 4H), 2.46-2.32(m, 2H), 2.21 (dt, J=28.0, 7.7Hz, 2H), 2.02 (t, J=7.2Hz, 2H), 1.80-1.70 (m, 1H), 1.10 (q, J=7.5Hz, 3H).LCMS m / z[M+H] + =481.3

[0460] Example 47

[0461] Refer to the synthesis method of compound 80, replacing The following compounds were synthesized by replacing 1-4 with the corresponding acid fragments.

[0462] Example 48

[0463] Step 1: Under nitrogen, compound 68-1 (923 mg, 5.05 mmol, 1.0 eq) was dissolved in THF (9 mL) and cooled to -78°C. NaHMDS (2 M THF, 5.1 mL, 10.11 mmol, 2.0 eq) was added dropwise to the reaction mixture, and stirred at -78°C for 0.5 h. Diethyl oxalate (1.48 g, 10.11 mmol, 2.0 eq) was dissolved in THF (4.5 mL) and added dropwise to the reaction mixture. The reaction mixture was stirred at -78°C for 10 min, then brought to room temperature and stirred at room temperature for 1.5 h. After completion of the reaction, the reaction mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate (3 x 40 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 68-2 (1.9 g, 100%) as a white solid. LCMS m / z=283.1[M+H] + .

[0464] Step 2: Dissolve compound 68-2 (1.8 g, 6.37 mmol) in EtOH (45 mL) and add methylhydrazine (293.4 mg, 6.37 mmol) to the reaction mixture. Stir the reaction mixture at room temperature for 4 h. After completion of the reaction, concentrate the reaction mixture. The crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to obtain white solid compounds 68-3a (350 mg, 19%) and 68-3b (405 mg, 21.7%). 68-3a: LCMS m / z = 293.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ7.43 (d, J=8.3Hz, 1H), 7.04 (d, J=2.1Hz, 1H), 7.01 (dd, J=8.3, 2.1H z, 1H), 5.49 (s, 2H), 4.42 (q, J=7.1Hz, 2H), 4.20 (s, 3H), 1.41 (t, J=7.1Hz, 3H).68-3b: LCMS m / z=293.1[M+H] + ; 1H NMR (400MHz, CDCl3) δ7.59 (d, J=8.1Hz, 1H), 6.94 (dd, J=8.1, 2.0Hz, 1H), 6.91 (d, J= 2.0Hz, 1H), 5.41 (s, 2H), 4.34 (q, J=7.1Hz, 2H), 4.18 (s, 3H), 1.38 (t, J=7.1Hz, 3H).

[0465] Step 3: Dissolve 68-3a (200 mg, 0.68 mmol, 1.0 eq) in THF (1.5 mL) and slowly add NaOH solution (NaOH (54.7 mg, 1.37 mmol, 2.0 eq) dissolved in H2O (0.5 mL)). The reaction mixture was stirred at 60°C for 3 h. After completion of the reaction, the pH of the reaction mixture was adjusted to 3-4 with 2N HCl solution and extracted with DCM (3×20 mL). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 68-4a (200 mg, 100%) as a white solid. LCMS m / z=265.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ7.73 (d, J=8.2Hz, 1H), 7.16-7.09 (m, 2H), 5.42 (s, 2H), 4.16 (s, 3H).

[0466] Step 4: Dissolve 68-4a (100 mg, 0.38 mmol, 1.0 eq), HATU (186.8 mg, 0.50 mmol, 1.3 eq), and DIEA (146.4 mg, 1.14 mmol, 3.0 eq) in DMF (2 mL), and stir the reaction at room temperature for 0.5 h. Dissolve compound 68-5 (170.4 mg, 0.76 mmol, 2.0 eq) in DMF (1 mL) and add dropwise to the reaction. Stir the reaction at room temperature for 2.5 h. After completion of the reaction, the reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by preparative column chromatography to obtain compound 68 (26 mg, 28%) as a white solid. LCMS m / z = 487.3 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ8.72-8.59 (m, 1H), 7.74 (d, J=8.3Hz, 1H), 7.16-7. 06 (m, 2H), 5.44 (s, 2H), 4.17 (s, 3H), 3.27-3.23 (m, 2H), 2.96-2.89 (m, 2H) , 2.49-2.41(m, 5H), 2.39-2.26(m, 5H), 2.14(s, 3H), 2.10-1.94(m, 1H), 1. 90-1.80(m, 2H), 1.80-1.70(m, 2H), 1.69-1.57(m, 2H), 1.57-1.43(m, 2H).

[0467] Referring to the synthetic procedure of compound 68, compound 117 was synthesized by substituting 68-3b for 68-3a in step 3. 1 H NMR (400MHz, DMSO-d6) δ8.32 (t, J=5.6Hz, 1H), 8.18 (s, HCOOH, 1.27H), 7.60 (d, J=8.7Hz, 1H), 7.14-7.00 (m, 2H), 5.40 (s, 2H), 3.98 (s, 3H), 3.30-3.24 (m, 2H), 3 .02(d, J=11.4Hz, 2H), 2.58-2.51(m, 4H), 2.48-2.43(m, 4H), 2.31-2.26(m, 1H), 2.25(s, 3H), 2.08(t, J=11.5Hz, 2H), 1.80-1.68(m, 4H), 1.49-1.39(m, 2H).LCMS m / z=487.3[M+H] +

[0468] Example 49

[0469] Referring to the synthetic methods of compounds 68 and 117, the following compounds were synthesized by replacing 68-1 with the corresponding ketone fragment and replacing 68-5 with the corresponding amine fragment.

[0470] Example 50

[0471] Step 1: (200 mg, 0.59 mmol, 1.0 eq) and 1-methylpyrazole-4-boronic acid naphthalene ester (370 mg, 1.78 mmol, 3.0 eq) were mixed in dioxane (4 mL) and water (1 mL), and Pd(dppf)2Cl2 (45 mg, 0.059 mmol, 0.1 eq) and potassium carbonate (244.6 mg, 1.78 mmol, 3.0 eq) were added. The reaction solution was replaced with nitrogen three times and stirred at 90°C under nitrogen protection for 2 hours. After the reaction was completed, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3×30 mL). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography to obtain compound 95-1 (190 mg, 94.6%) as a yellow solid. LCMS m / z=339.1[M+H] +

[0472] Step 2: Referring to the synthesis method of compound 68, 95-1 was used instead of 68-3a to synthesize compound 95. LCMS m / z = 533.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.45 (t, J=5.8Hz, 1H), 8.20 (s, 1H), 8.15 (s, HCOOH, 3.5H), 7 .92 (s, 1H), 7.69 (d, J = 8.1Hz, 1H), 7.28 (dd, J = 8.0, 1.8Hz, 1H), 7.24 (d, J = 1.8Hz, 1H) ,5.41(s,2H),4.16(s,3H),3.86(s,3H),3.30-3.26(m,2H),3.18-3.15(m,2H),2.73- 2.60(m, 10H), 2.40(s, 3H), 2.38-2.31(m, 3H), 1.89-1.76(m, 4H), 1.66-1.54(m, 2H).

[0473] Example 51

[0474] Refer to the synthesis method of compound 95, using the corresponding boronic acid or boronic ester instead Replace with the corresponding bromo fragment The following compounds were synthesized by replacing 68-5 with the corresponding amine fragment.

[0475] Example 52

[0476] Step 1: Under nitrogen protection, (300 mg, 0.89 mmol, 1.0 eq) was dissolved in DMF (10 mL), and Zn(CN)2 (209 mg, 1.78 mmol, 2.0 eq) and Pd(pph3)4 (205.6 mg, 0.178 mmol, 0.2 eq) were added to the reaction solution. The reaction solution was purged with nitrogen three times and stirred at 130°C under nitrogen protection for 2 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was diluted with water (100 mL), and extracted with ethyl acetate (3×30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:1) to obtain 94-1 (140 mg, 55%) as a yellow solid. LCMS: m / z = 284.1 [M+H] +

[0477] Step 2: Referring to the synthesis method of compound 68, 94-1 was used instead of 68-3a to synthesize compound 94. LCMS: m / z = 478.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.69 (t, J=5.4Hz, 1H), 8.20 (s, 2H), 7.90 (d, J=8.1Hz, 1H ), 7.57-7.46 (m, 2H), 5.50 (s, 2H), 4.21 (s, 3H), 3.28 (q, J=6.2Hz, 2H), 2.96 (d, J =11.2Hz, 2H), 2.50-2.46(m, 4H), 2.43-2.30(m, 6H), 2.17(s, 3H), 2.14-2.07(m, 1H), 1.94-1.85(m, 2H), 1.80-1.74(m, 2H), 1.69-1.61(m, 2H), 1.55-1.45(m, 2H).

[0478] Example 53

[0479] Referring to the synthesis method of compound 30, 7-2 was used instead of 1-4 to synthesize compound 75. LCMS m / z = 501.3 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ8.75-8.63 (s, 1H), 8.04 (t, J=7.8Hz, 2H), 7.90 (t, J =7.8Hz, 1H), 7.73 (t, J = 7.7Hz, 1H), 4.92 (s, 2H), 4.29 (s, 3H), 3.24-3.18 (m, 2H), 3.15-3.07(m, 2H), 3.06-2.82(m, 2H), 2.77-2.51(m, 10H), 2.32(s, 3H), 2.04-1.94(m, 1H), 1.90-1.80(m, 2H), 1.79-1.67(m, 2H), 1.62-1.46(m, 2H).

[0480] Example 54

[0481] Compound 41 (0.13 g, 0.25 mmol), 3-bromopropionitrile (0.12 g, 0.88 mmol), and potassium carbonate (0.17 g, 1.25 mmol) were added to an acetonitrile (2 mL) solution and reacted overnight at room temperature. LCMS indicated completion. The product was extracted, concentrated, and purified by preparative thin-layer chromatography to afford compound 79 (0.03 g, yield: 23.98%). 1 HNMR (400MHz, DMSO-d6) δ8.55 (t, J=5.6Hz, 1H), 7.84 (dd,J=7.6, 1.6Hz, 1H), 7.50 (dd,J=7.5, 1. 6Hz, 1H), 7.32 (dtd, J = 17.0, 7.5, 1.5Hz, 2H), 4.18 (s, 2H), 4.15 (s, 3H), 3.26 (m, 6H), 2.97 (m, 2H ), 2.64 (t, J=6.7Hz, 2H), 2.52 (m, 3H), 2.39 (m, 4H), 2.14 (dd, J=13.3, 5.6Hz, 1H), 2.05-1.87 (m, 2H), 1.79 (d, J=11.3Hz, 2H), 1.72-1.63 (m, 2H), 1.59-1.44 (m, 2H), 1.27 (d, J=16.0Hz, 1H)..LCMS m / z[M+H] + =508.3.

[0482] Example 55

[0483] Refer to the synthesis method of compound 94, replacing the corresponding bromine fragment The following compounds were synthesized by replacing 68-5 with the corresponding amine fragment. Prepared by referring to the synthetic method of intermediate 83-2.

[0484] Example 56

[0485] Step 1: Dissolve compound 1-2 (6.0 g, 22.7 mmol, 1.0 eq) in EtOH (60 mL) and add hydrazine hydrate (1.42 g, 22.7 mmol, 1.0 eq). Stir the reaction mixture at room temperature overnight. After completion of the reaction, concentrate the reaction mixture. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 8:1) to obtain compound 83-1 (4.45 g, 75.39%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ14.06 (s, 1H), 7.87-7.71 (m, 1H), 7.43-7.32 (m, 1H), 7. 28-7.21(m, 2H), 4.38-4.27(m, 2H), 4.27-4.21(m, 2H), 1.36-1.29(m, 3H).LCMS m / z=261.1[M+H] +

[0486] Step 2: Referring to the synthesis method of compound 14, use 83-1 instead of 14-1, and use 68-5 instead of 7-3 to synthesize compound 83. 1 H NMR (400MHz, DMSO-d6) δ8.41-8.37(m, 1H), 7.73-7.69(m, 1H), 7.37-7.35(m, 1H), 7.25-7.23(m, 2H), 4.24(s, 2H), 3.25-3.21(m, 2H), 2.78-2.66(m, 10H), 2.64-2.62(m, 2H), 2.46-2.43(m, 1H), 2.40(s, 3H), 1.97-1.93(m, 2H), 1.85-1.79(m, 4H), 1.62-1.52(m, 2H).LCMS m / z=455.2[M+H] +

[0487] Example 57

[0488] Step 1: Dissolve compound 83-1 (2.0 g, 7.69 mmol) in DMF (30 mL). Add cesium carbonate (3.76 g, 11.53 mmol) and 3-iodooxetane (1.7 g, 9.23 mmol) to the reaction mixture. Stir the reaction mixture at 110°C for 1 h. After completion of the reaction, dilute the reaction mixture with water (200 mL) and extract with ethyl acetate (3 × 80 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain compound 88-1a (170 mg, 2.88%) and compound 88-1b (1.3 g, 53.43%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ7.55-7.52(m, 1H), 7.50-7.47(m, 1H), 7.36-7.32(m, 2H), 6.01-5.9 2 (m, 1H), 5.03-4.97 (m, 4H), 4.35 (q, J=7.1Hz, 2H), 4.14 (s, 2H), 1.33 (d, J=7.1Hz, 3H).LCMS m / z=317.1[M+H] +

[0489] Step 2: Compound 88-1a (63 mg, 0.199 mmol, 1.0 eq) was dissolved in MeOH (1 mL) and THF (1 mL), and NaOH solution (25.32 mg, 0.633 mmol, 2.0 eq) dissolved in H2O (1 mL) was slowly added. The reaction mixture was stirred at 60°C for 2 h. After completion of the reaction, the pH of the reaction mixture was adjusted to 3-4 with 2N HCl solution and extracted with DCM (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 88-2a (57 mg, 100%) as a yellow solid. LCMS m / z = 289.0 [M+H] +

[0490] Step 3: Dissolve compound 88-2a (57 mg, 0.198 mmol), HATU (112.93 mg, 0.297 mmol), and DIEA (76.77 mg, 0.594 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature for 0.5 h. Compound 68-5 (118.82 mg, 0.494 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was diluted with water (40 mL), extracted with ethyl acetate (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by preparative column chromatography to obtain compound 88 (20.6 mg, 20.4%). 1 H NMR (400MHz, DMSO-d6) δ8.46 (t, J=6.1Hz, 1H), 8.17 (s, 1H), 7.53-7.44 (m, 2H), 7.35-7.30 (m, 2H), 5.99-5.88 (m, 1H), 5.12-5.01 (m, 4H), 4.17 (s, 2H), 3.33-3.31(m, 2H), 3.23-3.19(m, 2H), 2.75-2.63(m, 10H), 2.47-2. 32(m, 7H), 2.11-1.94(m, 1H), 1.92-1.84(m, 4H), 1.72-1.64(m, 2H).LCMS m / z=511.2[M+H] +

[0491] Referring to the synthesis method of compound 88, compound 89 was synthesized by replacing 88-1a with 88-1b. 1 HNMR (400 MHz, DMSO-d6) δ8.51-8.41(m, 1H), 8.22(s, HCOOH, 1H), 7.98-7.83(m, 1H), 7.43-7.19(m, 3H), 5.88-5.73(m, 1H), 5.05-4.83(m, 4H), 4.09(s, 2H), 3.3 2-3.10(m, 2H), 3.04-2.90(m, 2H), 2.72-2.58(m, 1H), 2.41-2.28(m, 10H), 2.17(s, 3H), 2.04-1.89(m, 2H), 1.80-1.66(m, 4H), 1.48-1.33(m, 2H).LCMS m / z=511.2[M+H] +

[0492] Example 58

[0493] Referring to the synthesis method of compound 88, 1-chloro-2-methyl-2-propanol was used instead of 3-iodooxetane to synthesize compound 90. 1 H NMR (400MHz, DMSO-d6) δ8.33 (t, J=6.2Hz, 1H), 8.23 ​​(dd, J=7.6, 1.6Hz, 1H), 7.51 (dd, J=7.4, 1.6Hz, 1H), 7.35-7.26 (m, 2H), 4.92 (s, 1H), 4.30 (s, 2H), 4.16 (s, 2H), 3.33-3.28 (m, 2H), 3.17-2.54 (m, 16H), 1.90-1.72 (m, 6H), 1.19 (s, 6H). LCMS: m / z=527.3[M+H] +

[0494] Example 59

[0495] Reference is made to the synthesis method of compound 83, using Substituting 1-2 and replacing 68-5 with the appropriate amine fragment, the following compounds were synthesized.

[0496] Example 60

[0497] Step 1: Compound (300 mg, 0.89 mmol, 1.0 eq), 1,2,3-triazole (74 mg, 1.07 mmol, 1.2 eq), and K3PO4 (380 mg, 1.78 mmol, 2.0 eq) were mixed in toluene (5 mL). 4MetBuXPhos (85 mg, 0.18 mmol, 0.2 eq) and Pd2(dba)3 (80 mg, 0.09 mmol, 0.1 eq) were added to the mixture. The reaction mixture was purged with nitrogen three times and stirred at 120°C under nitrogen for 5 hours. After completion, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain compound 124-1 (100 mg, 34.6%) as a white solid. LCMS m / z=326.1[M+H] + ; 1H NMR (400MHz, DMSO-d6) δ8.13 (s, 2H), 7.77 (d, J=8.3Hz, 1H), 7.68 (dd, J=8.4, 2.1Hz, 1H), 7 .55-7.50 (m, 1H), 5.51 (s, 2H), 4.31 (q, J=7.1Hz, 2H), 4.14 (s, 3H), 1.33 (t, J=7.0Hz, 3H).

[0498] Step 2: Referring to the synthetic route of compound 95, 124-1 was used instead of 95-1 to synthesize compound 124. LCMS m / z = 520.4 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.34 (t, J=5.6Hz, 1H), 8.13 (s, 2H), 7.78 (d, J=8.3Hz, 1H), 7.69 (dd, J=8.3, 2.1Hz, 1H), 7.56 (d, J=2.0Hz, 1H), 5.46 (s, 2H), 4.00 (s, 3H), 3.30 -3.36 (m, 2H), 3.00 (d, J=11.2Hz, 2H), 2.55-2.51 (m, 4H), 2.48-2.32 (m, 6H), 2.28- 2.22(m, 1H), 2.20(s, 3H), 2.06-1.97(m, 2H), 1.78-1.68(m, 4H), 1.48-1.39(m, 2H).

[0499] Effect embodiment

[0500] Cell IC50 assay

[0501] (1) Cell preparation: Prepare well-grown hepatocellular carcinoma cells (PLC / PRF / 5, from the Chinese Academy of Sciences; MHCC97H, from our institute), digest and dilute them, plate them into 96-well cell culture plates, add 1000-3000 cells per well, and then culture them in a cell culture incubator at 37°C and 5% CO2. After 24 hours of cell attachment, add drugs.

[0502] (2) Dosing: The drug is diluted in a gradient, generally with 9 concentrations, and a control group containing a medium without drug and a medium containing only drug solvent is set up; the diluted drug is added to the cell culture plate where cells were plated the day before, and cultured in an incubator for 72 hours;

[0503] (3) CCK8 detection of cell activity: CCK8 was mixed with culture medium at a ratio of 1:10, added to the cell culture plate, 100 μL per well, and allowed to stand for 2-4 hours before reading the OD value using a microplate reader;

[0504] (4) Data analysis: According to the corresponding OD values, organize the data, draw the IC50 curve, and obtain the IC50 value;

[0505] (5) Verify IC50: Find the theoretical IC50 value based on the IC50 curve, and take 1 / 2 times, 1 times and 2 times the theoretical value to verify the drug concentration.

[0506] “\” means not tested.

[0507] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound represented by formula (IA) or a pharmaceutically acceptable salt thereof, in, Ring C is a benzene ring or a 5- to 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from N, O and S; Each R1 is independently halogen, cyano, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Alkoxy, C substituted by one or more halogen 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkoxy, "heteroatoms selected from 1, 2 or 3 of N, O, S, 5-10 membered heteroaryl with 1, 2 or 3 heteroatoms" or one or more R 1-1 Substituted "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S"; Each R 1-1 C 1-6 alkyl; m and k are each independently 0, 1 or 2; X1 is -CH2-, -O-, -S-, -NH- or -S(=O)2-; X2 is -C(R a R b )-or-O-; R a and R b are independently hydrogen, deuterium or C 1-6 Alkyl, or R a 、R b and their common carbon atoms are connected to form a 3-10 membered saturated carbocyclic ring; n is 0 or 1; each Each independently represents a single bond or a double bond; X3 and X4 are independently C or N; Ring A is a pyrazole ring; Each R2 is independently H, halogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S", C 6-10 Aryl, one or more R 2-1 Substituted C 1-6 Alkyl or one or more R 2-2 Substituted "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S"; Each R 2-1 and R 2-2 are independently halogen, hydroxyl, C 1-6 Alkyl, -N(R 2a R 2b ), C 3-10 Cycloalkyl, C 1-6 Alkoxy, "a 3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S", C 6-10 Aryl or "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S"; R 2a and R 2b are independently H or C 1-6 alkyl; E is -N(R3)- or n1 is 1, 2 or 3; # represents the end connected to -C(O)- in formula (IA); R3 is hydrogen, C 1-6 Alkyl or C 3-10 Cycloalkyl; L is C 1-6 Alkylene, one or more R L Substituted C 1-6 Alkylene, "-(C 1-6 Alkylene)-L A -*" or -L A -; Each R L Deuterium, C 1-6 Alkoxy, C 3-10 Cycloalkyl, hydroxy, halogen or oxo (=O), or when two R L When substituted on the same carbon atom, two R L and their common carbon atoms are connected to form a 3-10 membered saturated carbocyclic ring or a 3-10 membered saturated heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O and S; L A -C(O)NH-, -O-, -N(R LA )-, vinylene, ethynylene, 3-10 membered saturated carbocyclic ring or "a 3-10 membered saturated heterocyclic ring in which the heteroatoms are 1, 2 or 3 selected from N, O and S, and the number of heteroatoms is 1, 2 or 3"; R LA H, C 1-6 Alkyl, C 3-10 Cycloalkyl or "3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S"; Ring B is a 3-10 membered saturated or unsaturated carbon ring, surrounded by one or more R B-1 Substituted 3-10 membered saturated or unsaturated carbon ring, "heteroatoms selected from 1, 2 or 3 of N, O, S, 3-10 membered saturated or unsaturated heterocyclic ring with 1, 2 or 3 heteroatoms" or one or more R B-2 Substituted "3-10 membered saturated or unsaturated heterocyclic ring having 1, 2 or 3 heteroatoms selected from N, O and S"; Each R B-1 and R B-2 are independently hydroxy, halogen, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy or C substituted by one or more hydroxyl groups 1-6 alkyl; When U is absent, ring B is U is absent, -N(R')(R"), C 3-6 Alkyl, one or more R U-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, one or more R U-2 Substituted C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl with 1, 2 or 3 heteroatoms selected from N, O and S", "heteroatoms selected from 1, 2 or 3 heteroatoms selected from N, O and S", "heteroatoms selected from 1, 2 or 3 heteroatoms" U-3 Substituted "3-10 membered heterocycloalkyl group with 1, 2 or 3 heteroatoms selected from N, O and S", C 6-10 Aryl, one or more R U-4 Substituted C 6-10 Aryl, "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S", one or more R U-5 Substituted "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S" or -XR U-6 ; X is -C(O)-, -SO2- or -O-; Each R' and R" are independently hydrogen, C 1-6 Alkyl, -C(O)-C 3-10 Cycloalkyl or C substituted by one or more R" 1-6 Alkyl; R"' is independently C 6-10 aryl; Each R U-1 are independently -N(R')(R"), halogen, C 3-10 Cycloalkyl, C 6-10 Aryl, "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S" or "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms ... U-1-1 Substituted "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S"; Each R U-1-1 C 1-6 alkyl; Each R U-2 、R U-3 、R U-4 and R U-5 are independently halogen, cyano, hydroxyl, -SO2-C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -C(O)NH-C 1-6 Alkyl, C 1-6 Alkyl, one or more R U-3-1 Substituted C 1-6 Alkyl, C 1-6 Alkoxy, one or more R U-3-2 Substituted C 1-6 Alkoxy, C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S" or -O- "3-10 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S"; Each R U-3-1 and R U-3-2 are independently halogen, C 3-10 Cycloalkyl, C 6-10 Aryl, C 1-6 Alkoxy, hydroxy, cyano or heteroatoms selected from 1, 2 or 3 of N, O and S, and a 3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms; Each R U-6 C 6-10 Aryl or "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S"; The compound represented by formula (I) is not any of the following compounds:

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The compound represented by formula (IA) is a compound represented by the following formula (IIA): Each R1 is independently halogen, cyano, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Alkoxy, C substituted by one or more halogen 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkoxy, "heteroatoms selected from 1, 2 or 3 of N, O, S, 5-10 membered heteroaryl with 1, 2 or 3 heteroatoms" or one or more R 1-1 Substituted "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S"; Each R 1-1 C 1-6 alkyl; m and k are each independently 0, 1 or 2; X1 is -CH2-, -O-, -S- or -S(=O)2-; Each R2 is independently H, C 1-6 Alkyl, one or more R 2-1 Substituted C 1-6 Alkyl or "3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S"; Each R 2-1 are independently hydroxyl or C 3-10 Cycloalkyl; each Each independently represents a single bond or a double bond; E is -N(R3)- or n1 is 1, 2 or 3; # represents the end connected to -C(O)- in formula (IA); R3 is hydrogen or C 1-6 alkyl; L is C 1-6 Alkylene, one or more R L Substituted C 1-6 Alkylene or "-(C 1-6 Alkylene)-L A -*”; Each R L are independently hydroxy or halogen, or when two R L When substituted on the same carbon atom, two R L and their common carbon atoms are connected to form a 3-10 membered saturated carbocyclic ring; L A -NH-, -N(C 1-6 alkyl)- or 3-10 membered saturated carbocyclic ring; Ring B is a "3-10 membered saturated or unsaturated heterocyclic ring with 1, 2 or 3 heteroatoms selected from N, O and S" or is replaced by one or more R B-2 Substituted "3-10 membered saturated or unsaturated heterocyclic ring having 1, 2 or 3 heteroatoms selected from N, O and S"; Each R B-2 are independently hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C substituted by one or more hydroxyl groups 1-6 alkyl; When U is absent, ring B is U is absent, -N(R')(R"), C 3-6 Alkyl, one or more R U-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, one or more R U-2 Substituted C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl with 1, 2 or 3 heteroatoms selected from N, O and S", "heteroatoms selected from 1, 2 or 3 heteroatoms selected from N, O and S", "heteroatoms selected from 1, 2 or 3 heteroatoms" U-3 Substituted "3-10 membered heterocycloalkyl group with 1, 2 or 3 heteroatoms selected from N, O and S", C 6-10 Aryl, one or more R U-4 Substituted C 6-10 Aryl, "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S" or "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms ... U-5 Substituted "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S"; Each R' and R" are independently hydrogen, C 1-6 Alkyl, -C(O)-C 3-10 Cycloalkyl or C substituted by one or more R" 1-6 Alkyl; R"' is independently C 6-10 aryl; Each R U-1 are independently -N(R')(R"), C 3-10 Cycloalkyl or C 6-10 aryl; Each R U-2 、R U-3 、R U-4 and R U-5 are independently halogen, -SO2-C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S", cyano, hydroxyl, C 1-6 Alkyl, one or more R U-3-1 Substituted C 1-6 Alkyl, C 1-6 Alkoxy or one or more R U-3-2 Substituted C 1-6 alkoxy; Each R U-3-1 and R U-3-2 are independently halogen, C 3-10 Cycloalkyl, C 6-10 Aryl, C 1-6 Alkoxy, hydroxy, cyano or heteroatoms selected from 1, 2 or 3 of N, O and S, and a 3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The compound represented by formula (IA) is a compound represented by formula (IIIA) or formula (IIIB): Each R1 is independently halogen, cyano, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Alkoxy, C substituted by one or more halogen 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkoxy, "heteroatoms selected from 1, 2 or 3 of N, O, S, 5-10 membered heteroaryl with 1, 2 or 3 heteroatoms" or one or more R 1-1 Substituted "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S"; Each R 1-1 C 1-6 alkyl; m is 0, 1, or 2; X1 is -CH2-, -O-, -S- or -S(=O)2-; Each R2 is independently H, C 1-6 Alkyl, one or more R 2-1 Substituted C 1-6 Alkyl or "3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S"; Each R 2-1 are independently hydroxyl or C 3-10 Cycloalkyl; E is -N(R3)- or n1 is 1, 2 or 3; # represents the end connected to -C(O)- in formula (IA); R3 is hydrogen or C 1-6 alkyl; L is C 1-6 Alkylene, one or more R L Substituted C 1-6 Alkylene or "-(C 1-6 Alkylene)-L A -*; Each R L are independently hydroxy or halogen, or when two R L When substituted on the same carbon atom, two R L and their common carbon atoms are connected to form a 3-10 membered saturated carbocyclic ring; L A is a 3-10 membered saturated carbon ring; Ring B is a "3-10 membered saturated or unsaturated heterocyclic ring with 1, 2 or 3 heteroatoms selected from N, O and S" or is replaced by one or more R B-2 Substituted "3-10 membered saturated or unsaturated heterocyclic ring having 1, 2 or 3 heteroatoms selected from N, O and S"; Each R B-2 are independently halogen or C 1-6 alkyl; When U is absent, ring B is U is absent, -N(R')(R"), or replaced by one or more R U-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, one or more R U-2 Substituted C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl with 1, 2 or 3 heteroatoms selected from N, O and S", "heteroatoms selected from 1, 2 or 3 heteroatoms selected from N, O and S", "heteroatoms selected from 1, 2 or 3 heteroatoms" U-3 Substituted "3-10 membered heterocycloalkyl group with 1, 2 or 3 heteroatoms selected from N, O and S", C 6-10 Aryl, one or more R U-4 Substituted C 6-10 Aryl or "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S"; Each R' and R" are independently hydrogen, C 1-6 Alkyl, -C(O)-C 3-10 Cycloalkyl or C substituted by one or more R" 1-6 Alkyl; R"' is independently C 6-10 aryl; Each R U-1 C 3-10 Cycloalkyl or C 6-10 aryl; Each R U-2 、R U-3 and R U-4 are independently halogen, hydroxyl, -SO2-C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S", C 1-6 Alkoxy or one or more R U-3-1 Substituted C 1-6 alkyl; Each R U-3-1 are independently halogen, C 3-10 Cycloalkyl, C 6-10 Aryl, C 1-6 Alkoxy, hydroxy, cyano or heteroatoms selected from 1, 2 or 3 of N, O and S, and a 3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein It meets one or more of the following conditions: (1) Each R1 is independently halogen, cyano, C 1-6 Alkyl, C 3-10 Cycloalkyl, C substituted by one or more halogen 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkoxy, "heteroatoms selected from 1, 2 or 3 of N, O, S, 5-10 membered heteroaryl with 1, 2 or 3 heteroatoms" or one or more R 1-1 Substituted "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S"; Each R 1-1 C 1-6 alkyl; (2) Each R2 is independently H, C 1-6 Alkyl, one or more R 2-1 Substituted C 1-6 Alkyl or "3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S"; Each R 2-1 are independently hydroxyl or C 3-10 Cycloalkyl; (3) E is -N(R3)-; (4) L is C 1-6 Alkylene, one or more R L Substituted C 1-6 Alkylene or "-(C 1-6 Alkylene)-L A -*”; Each R L are independently hydroxy or halogen, or when two R L When substituted on the same carbon atom, two R L and their common carbon atoms are connected to form a 3-10 membered saturated carbocyclic ring; L A -NH-, -N(C 1-6 alkyl)- or 3-10 membered saturated carbocyclic ring; preferably 3-10 membered saturated carbocyclic ring; (5) Ring B is a "3-10 membered saturated or unsaturated heterocyclic ring with 1, 2 or 3 heteroatoms selected from N, O and S" or is replaced by one or more R B-2 Substituted "3-10 membered saturated or unsaturated heterocyclic ring having 1, 2 or 3 heteroatoms selected from N, O and S"; Each R B-2 are independently hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C substituted by one or more hydroxyl groups 1-6 Alkyl; preferably halogen or C 1-6 alkyl; (6) U is absent, -N(R')(R"), C 3-6 Alkyl, one or more R U-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, one or more R U-2 Substituted C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl with 1, 2 or 3 heteroatoms selected from N, O and S", "heteroatoms selected from 1, 2 or 3 heteroatoms selected from N, O and S", "heteroatoms selected from 1, 2 or 3 heteroatoms" U-3 Substituted "3-10 membered heterocycloalkyl group with 1, 2 or 3 heteroatoms selected from N, O and S", C 6-10 Aryl, one or more R U-4 Substituted C 6-10 Aryl, "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S" or "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms ... U-5 Substituted "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S"; Each R' and R" are independently hydrogen, C 1-6 Alkyl, -C(O)-C 3-10 Cycloalkyl or C substituted by one or more R" 1-6 Alkyl; R"' is independently C 6-10 aryl; Each R U-1 are independently -N(R')(R"), C 3-10 Cycloalkyl or C 6-10 aryl; Each R U-2 、R U-3 、R U-4 and R U-5 are independently halogen, -SO2-C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S", cyano, hydroxyl, C 1-6 Alkyl, one or more R U-3-1 Substituted C 1-6 Alkyl, C 1-6 Alkoxy or one or more R U-3-2 Substituted C 1-6 alkoxy; Each R U-3-1 and R U-3-2 are independently halogen, C 3-10 Cycloalkyl, C 6-10 Aryl, C 1-6 Alkoxy, hydroxy, cyano or heteroatoms selected from 1, 2 or 3 of N, O and S, and a 3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms; Preferably, U is absent, -N(R')(R"), replaced by one or more R U-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, one or more R U-2 Substituted C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl with 1, 2 or 3 heteroatoms selected from N, O and S", "heteroatoms selected from 1, 2 or 3 heteroatoms selected from N, O and S", "heteroatoms selected from 1, 2 or 3 heteroatoms" U-3 Substituted "3-10 membered heterocycloalkyl group with 1, 2 or 3 heteroatoms selected from N, O and S", C 6-10 Aryl, one or more R U-4 Substituted C 6-10 Aryl or "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S"; Each R' and R" are independently hydrogen, C 1-6 Alkyl, -C(O)-C 3-10 Cycloalkyl or C substituted by one or more R" 1-6 Alkyl; R"' is independently C 6-10 aryl; Each R U-1 C 3-10 Cycloalkyl or C 6-10 aryl; Each R U-2 、R U-3 and R U-4 are independently halogen, hydroxyl, -SO2-C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S", C 1-6 Alkoxy or one or more R U-3-1 Substituted C 1-6 alkyl; Each R U-3-1 are independently halogen, C 3-10 Cycloalkyl, C 6-10 Aryl, C 1-6 Alkoxy, hydroxy, cyano or heteroatoms selected from 1, 2 or 3 of N, O and S, and a 3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein It meets one or more of the following conditions: (1) Each R1 is independently halogen; (2) m and k are independently 0 or 1; (3) Each R2 is independently C 1-6 Alkyl or one or more R 2-1 Substituted C 1-6 alkyl; Each R 2-1 C 3-10 Cycloalkyl; (4) R3 is hydrogen or C 1-6 alkyl; (5) L is C 1-6 Alkylene, one or more R L Substituted C 1-6 Alkylene or "-(C 1-6 Alkylene)-L A -”; Each R L are independently hydroxy or halogen, or when two R L When substituted on the same carbon atom, two R L Connected to form a 3-10 membered saturated carbon ring; L A -NH- or -N(C 1-6 Alkyl)-, preferably -NH-; (6) Ring B is a "3-10 membered saturated or unsaturated heterocyclic ring with 1, 2 or 3 heteroatoms selected from N, O and S" or is replaced by one or more R B-2 Substituted "3-10 membered saturated or unsaturated heterocyclic ring having 1, 2 or 3 heteroatoms selected from N, O and S"; Each R B-2 are independently hydroxyl, halogen, C 1-6 Alkoxy or C substituted by one or more hydroxyl groups 1-6 Alkyl, preferably halogen; and (7)U is C 3-6 Alkyl, one or more R U-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, one or more R U-2 Substituted C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl with 1, 2 or 3 heteroatoms selected from N, O and S", "heteroatoms selected from 1, 2 or 3 heteroatoms selected from N, O and S", "heteroatoms selected from 1, 2 or 3 heteroatoms" U-3 Substituted "3-10 membered heterocycloalkyl group with 1, 2 or 3 heteroatoms selected from N, O and S", C 6-10 Aryl, one or more R U-4 Substituted C 6-10 Aryl, "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S" or "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms ... U-5 Substituted "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S"; Each R U-1 C 3-10 Cycloalkyl or C 6-10 aryl; Each R U-2 、R U-3 、R U-4 and R U-5 are independently halogen, C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S", cyano, hydroxyl, C 1-6 Alkyl, one or more R U-3-1 Substituted C 1-6 Alkyl, C 1-6 Alkoxy or one or more R U-3-2 Substituted C 1-6 alkoxy; Each R U-3-1 and R U-3-2 are independently halogen or C 3-10 Cycloalkyl.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein It meets one or more of the following conditions: (1) R3 is hydrogen; (2) L is C 1-6 Alkylene or one or more R L Substituted C 1-6 alkylene; Each R L are independently hydroxy or halogen, preferably hydroxy; (3) Ring B is a "3-10 membered saturated or unsaturated heterocyclic ring having 1, 2 or 3 heteroatoms selected from N, O and S"; and (4) U is represented by one or more R U-1 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, one or more R U-2 Substituted C 3-10 Cycloalkyl, "3-10 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S", C 6-10 Aryl, one or more R U-4 Substituted C 6-10 Aryl or "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S"; Each R U-1 C 3-10 Cycloalkyl or C 6-10 aryl; Each R U-2 and R U-4 are independently halogen, C 1-6 Alkoxy or one or more R U-3-1 Substituted C 1-6 alkyl; Each R U-3-1 are each independently halogen.

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, characterized in that: It meets one or more of the following conditions: (1) In ring C, the "5- to 6-membered heteroaromatic ring having 1, 2 or 3 heteroatoms selected from N, O and S" is "a 5- to 6-membered heteroaromatic ring having 1 or 2 heteroatoms and N as the heteroatom"; (2) Each "C 1-6 "Alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl; (3) Each "C 1-6 "Alkoxy" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy or sec-butoxy; (4) Each "halogen" is independently fluorine, chlorine, bromine or iodine; (5) When R a 、R b and their common carbon atoms are connected to form a 3-10 membered saturated carbocyclic ring, the "3-10 membered saturated carbocyclic ring" is a 3-membered saturated carbocyclic ring; (6) Each "C3-C 10 "Cycloalkyl" is independently a C3-C6 monocyclic cycloalkyl or a C5-C 10 polycyclic (e.g., spirocyclic, fused, or bridged) cycloalkyl groups; (7) Each "3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" is independently a 4-6 membered monocyclic heterocycloalkyl group or a 5-10 membered polycyclic (e.g., spirocyclic, fused or bridged) heterocycloalkyl group; (8) Each "C6-C 10 "Aryl" is independently phenyl or naphthyl; (9) Each "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S" is independently a 5-6 membered monocyclic heteroaryl group; preferably, the heteroatom type is N, and the number of heteroatoms is 1, 2 or 3; (10) Each "C 1-6 "Alkylene" is independently C1-C4 alkylene; (11) When two R L When substituted on the same carbon atom, two R L and their shared carbon atoms to form a "3-10 membered saturated carbocyclic ring" is a 3-membered saturated carbocyclic ring; (12) When L A When is a 3-10 membered saturated carbocyclic ring, the “3-10 membered saturated carbocyclic ring” is a 4-6 membered saturated carbocyclic ring, for example and (12) Each "3-10 membered saturated or unsaturated heterocyclic ring having 1, 2 or 3 heteroatoms selected from N, O and S" is independently "a 4-8 membered saturated or unsaturated heterocyclic ring having 1 or 2 heteroatoms selected from N and O", preferably "a 5-6 membered saturated or unsaturated heterocyclic ring having 1 or 2 heteroatoms selected from N".

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein It meets one or more of the following conditions: (1) In ring C, the "5- to 6-membered heteroaromatic ring having 1, 2, or 3 heteroatoms selected from N, O, and S" is a pyridine ring or a pyrimidine ring; (2) Each "C1-C6 alkyl" is independently methyl or ethyl; (3) each "C1-C6 alkoxy" is independently a methoxy group; (4) each "halogen" is independently fluorine, chlorine or bromine, preferably fluorine or chlorine, more preferably fluorine; (5) When R a 、R b and their common carbon atoms are connected to form a 3-10 membered saturated carbocyclic ring, the "3-10 membered saturated carbocyclic ring" is (6) The "C3-C6 monocyclic cycloalkyl" is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (7) The "C5-C 10 Polycyclic cycloalkyl" is C5-C 10 Spirocyclic cycloalkyl, preferably (8) The "4-6 membered monocyclic heterocycloalkyl" is "a 4-6 membered monocyclic heterocycloalkyl group having one or two heteroatoms selected from N and O, and having one or two heteroatoms", preferably Alternatively, "a 6-membered heterocycloalkyl group containing one or two heteroatoms selected from N and O, and having one or two heteroatoms", preferably (9) The "5-10 membered polycyclic heterocycloalkyl" is a 5-10 membered spirocyclic heterocycloalkyl or a bridged heterocycloalkyl, preferably or 6-membered spiro 3-membered heterocycloalkyl, more preferably (10) Each "C6-C 10 "Aryl" is independently phenyl; (11) Each "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S" is independently a 5-6 membered monocyclic heteroaryl group, wherein the 5-6 membered monocyclic heteroaryl group is a 5-6 membered monocyclic heteroaryl group having N as the heteroatom and 1 or 2 heteroatoms, preferably Or the 5-6 membered monocyclic heteroaryl group is a 5-6 membered monocyclic heteroaryl group having N as the heteroatom and 3 heteroatoms, preferably (12) Each "C 1-6 "Alkylene" is independently methylene, (13) When two R L When substituted on the same carbon atom, two R L and their common carbon atoms connected to form a "3-10 membered saturated carbon ring" is and (14) Each "heteroatom selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 3-membered saturated or unsaturated heterocyclic ring" is independently 9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein It meets one or more of the following conditions: (1) Ring C is a benzene ring; (2) Each R1 is independently fluorine, chlorine, bromine, cyano, trifluoromethyl, cyclopropyl, trifluoromethoxy, methyl, m is 0, 1, or 2; (3) X1 is -CH2-, -O-, -S- or -S(=O)2-; X2 is -CH2-; n is 0; X3 and X4 are C; (4) R2 is H, methyl, ethyl, k is 0 or 1; (5) Structural fragments for (6) R3 is hydrogen or methyl; (7) L is a methylene group, (8) Ring B is and (9) U is (10) E is -NH-, -N(CH3)- or 10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The compound is any of the following compounds:

11. A pharmaceutical composition comprising substance A and a pharmaceutically acceptable excipient, wherein substance A is a compound represented by formula (XA) or a pharmaceutically acceptable salt thereof; in, Ring A, Ring B, Ring C, X1, X2, X3, X4, R1, R2, E, m, n, k, L, B and U are as defined in claim 1; Preferably, the pharmaceutical composition is used to treat and / or prevent KSR2-AMPK related diseases or disorders, such as cancer, for example liver cancer.

12. Use of the substance A according to claim 11 or the pharmaceutical composition according to claim 11 in the preparation of a KSR2-AMPK inhibitor; in such use, the KSR2-AMPK inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: as a standard or control sample for comparison, or prepared into a kit according to conventional methods in the art to provide rapid detection of the effect of inhibiting KSR2-AMPK.

13. Use of the substance A according to claim 11 or the pharmaceutical composition according to claim 11 in the preparation of a medicament for treating and / or preventing a disease or disorder associated with KSR2-AMPK; the substance A is in a therapeutically effective amount; the disease or disorder associated with KSR2-AMPK is preferably cancer, such as liver cancer.

14. Use of the substance A according to claim 11 or the pharmaceutical composition according to claim 11 in the preparation of a medicament for treating and / or preventing cancer, such as liver cancer; the substance A is in a therapeutically effective amount.

Images