Tricyclic skeleton compound and its use in the preparation of antitumor drugs

Abstract

The application discloses a tricyclic skeleton compound and application thereof in preparation of an antitumor drug, and particularly provides a compound as shown in formula (IA) or a pharmaceutically acceptable salt thereof. The tricyclic skeleton compound of the application can effectively inhibit proliferation of tumor cells.

Description

Technical Field

[0001] This invention relates to tricyclic skeleton compounds and their application in the preparation of antitumor drugs. Background Technology

[0002] Cancer is a persistent public health challenge facing the world. As the second leading cause of death globally, it is projected to become the most significant obstacle to increasing life expectancy in the 21st century. Globally, the burden of cancer is gradually increasing. Therefore, finding effective diagnostic and therapeutic targets is crucial for breakthroughs in cancer treatment.

[0003] As research progresses, our understanding of cancer is becoming increasingly profound. Since the beginning of the 21st century, 14 hallmark characteristics of cancer have been identified. Numerous related signaling and metabolic pathways have been studied in response to these characteristics, leading to the discovery of relevant targets and the development of new drugs.

[0004] The mitogen-activated protein kinase (MAPK) signaling pathway is a crucial pathway for tumorigenesis and development. The MAPK pathway transduces signals based on a three-tiered kinase phosphorylation pattern (e.g., Raf-MEK-ERK). Raf kinase inhibitors, specifically the KSR family of proteins, are important scaffold proteins in the MAPK pathway, playing a positive regulatory role. KSR2, a member of this family, acts as a scaffold protein, binding to RAF, MEK, and ERK to form a complex that participates in the regulation of the MAPK signaling pathway. Crystal structure studies of the KSR2 kinase domain have revealed that KSR2 is a key molecule in the phosphorylation of MEK by Raf (see BRENNAN DF, DAR AC, HERTZ NT, et al. ARaf-induced allosteric transition of KSR stimulates phosphorylation of MEK[J]. Nature, 2011, 472(7343):366-9). KSR2 can directly phosphorylate AMPK, which plays a regulatory role in metabolic processes such as glucose uptake and fatty acid oxidation mediated by the energy sensor AMPK, as well as insulin sensitivity (refer to COSTANZO-GARVEY DL, PFLUGER PT, DOUGHERTY MK, et al. KSR2 is anessential regulator of AMP kinase, energy expenditure, and insulin sensitivity[J]. Cell Metab, 2009, 10(5):366-78). We have confirmed the pro-cancer effect of KSR2 at the cellular, molecular, and animal levels (see 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. KSR2-14-3-3 zeta complex serves as a biomarker and potential therapeutic target in sorafenib-resistant hepatocellular carcinoma[J]. Biomark Res, 2022, 10(1):25); and elucidated 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 have developed a small molecule inhibitor of the KSR2-AMPK pathway for the treatment of tumors associated with the KSR2 protein. Summary of the Invention

[0005] The technical problem this invention aims to solve is the limited range of existing targeted cancer therapies, and it provides a tricyclic skeleton compound and its application in the preparation of antitumor drugs. This tricyclic skeleton compound can effectively inhibit the proliferation of tumor cells.

[0006] This invention provides a compound of formula (IA) or a pharmaceutically acceptable salt thereof.

[0007]

[0008] Wherein, ring C is a benzene ring or "a 5-6 membered heteroaromatic ring with 1, 2 or 3 heteroatoms selected from N, O or S, and the number of heteroatoms is 1, 2 or 3";

[0009] Each R1 is independently halogenated, cyano-based, or C-based. 1-6 Alkyl, C 3-10 cycloalkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl groups, C substituted with one or more halogens 1-6 alkoxy, "a 5-10 membered heteroaryl group selected from 1, 2, or 3 of N, O, and S, with 1, 2, or 3 heteroatoms", or alkoxy with one or more R 1-1 The substituted heteroatoms are selected from 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3 of 5-10 heteroaryl groups;

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

[0011] m and k are 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 Each can be independently hydrogen, deuterium, or C. 1-6 Alkyl, or R a R b Their shared carbon atoms connect to form 3-10 saturated carbon rings;

[0015] n is 0 or 1;

[0016] each Each can be used to independently represent 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, or C. 1-6 Alkyl, C 3-10 Cycloalkyl, "a 3-10 membered heterocycloalkyl group with one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms", C 6-10 aryl, with one or more R 2-1 Replacement C 1-6 Alkyl or with one or more R 2-2 The substituted heteroatoms are selected from 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3 of 5-10 heteroaryl groups;

[0020] Each R 2-1 and R 2-2 Each is independently a halogen, hydroxyl, or C. 1-6 Alkyl, -N(R) 2a R 2b C 3-10 cycloalkyl, C 1-6 Alkoxy, "a 3-10 membered heterocyclic alkyl group selected from 1, 2, or 3 of N, O, and S, with 1, 2, or 3 heteroatoms", C 6-10 Aryl or "5-10 membered heteroaryl with one, two or three heteroatoms selected from N, O or S, and the number of heteroatoms being one, two or three";

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

[0022] E is -N(R3)- or n1 is 1, 2 or 3; # indicates 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, by one or more R L Replacement C 1-6 Alkylene, "-(C 1-6 (alkylene)-L A -* or -LA -;

[0025] Each R L Deuterium and C are independently distinguished. 1-6 Alkoxy, C 3-10 Cycloalkyl, hydroxyl, halogen, or oxo (=O), or when two R groups are present. L When two R atoms are substituted on the same carbon atom, L The carbon atoms they share are linked to form 3-10 saturated carbon rings or "3-10 saturated heterocycles with 1, 2 or 3 heteroatoms selected from N, O, and S".

[0026] L A -C(O)NH-, -O-, -N(R) LA )-, vinylene, ethynylene, 3-10 saturated carbon ring or "a 3-10 saturated heterocycle with 1, 2 or 3 heteroatoms selected from N, O or S";

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

[0028] Ring B is a 3-10 ternary saturated or unsaturated carbon ring, bounded by one or more R... B-1 The substituted 3-10 saturated or unsaturated carbon ring, "a 3-10 saturated or unsaturated heterocycle with 1, 2, or 3 heteroatoms selected from N, O, and S", or a heterocycle substituted with one or more R B-2 The substituted heteroatoms are selected from 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3, which are 3-10 saturated or unsaturated heterocycles.

[0029] Each R B-1 and R B-2 Each can be independently represented by a hydroxyl group, halogen, oxo group (=O), or C. 1-6 Alkyl, C 1-6 alkoxy or C substituted with one or more hydroxyl groups 1-6 alkyl;

[0030] When U does not exist, ring B is

[0031] U is non-existent, -N(R')(R”), C 3-6 Alkyl, with one or more R U-1 Replacement C 1-6 Alkyl, C 3-10cycloalkyl, with one or more R U-2 Replacement C 3-10 Cycloalkyl, "a 3-10 membered heterocycloalkyl group with one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms", or formed by one or more R U-3 The substituted "heteroatom is selected from 1, 2 or 3 of N, O, and S, and the number of heteroatoms is 1, 2 or 3, which are 3-10 membered heterocyclic alkyl groups"; C 6-10 aryl, with one or more R U-4 Replacement C 6-10 aryl, "a 5-10 membered heteroaryl group with one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms", and bonded by one or more R U-5 The substituted "5-10 heteroaryl group selected from 1, 2, or 3 of N, O, and S, with 1, 2, or 3 heteroatoms" or -XR U-6 ;

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

[0033] Each R' and R” is independently hydrogen and C, respectively. 1-6 Alkyl, -C(O)-C 3-10 Cycloalkyl or C substituted with one or more R'' 1-6 Alkyl; R”' is independently C 6-10 Aryl;

[0034] Each R U-1 Independently represented as -N(R')(R”), halogen, C 3-10 cycloalkyl, C 6-10 aryl, "a 5-10 membered heteroaryl group selected from 1, 2, or 3 heteroatoms from N, O, and S, with 1, 2, or 3 heteroatoms", or aryl with one or more R U-1-1 The substituted heteroatoms are selected from 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3 of 5-10 heteroaryl groups;

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

[0036] Each R U-2 R U-3 R U-4 and R U-5 Each is independently a halogen, cyano, hydroxyl, or -SO2-C group. 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)OC 1-6 Alkyl group, -C(O)NH-C 1-6 Alkyl, C 1-6Alkyl, with one or more R U-3-1 Replacement C 1-6 Alkyl, C 1-6 Alkyl group, by one or more R U-3-2 Replacement C 1-6 Alkoxy, C 3-10 Cycloalkyl, "a 3-10 membered heterocyclic alkyl group whose heteroatoms are selected from 1, 2 or 3 of N, O or S and whose heteroatoms number 1, 2 or 3" or -O- "a 3-10 membered heterocyclic alkyl group whose heteroatoms are selected from 1, 2 or 3 of N, O or S and whose heteroatoms number 1, 2 or 3";

[0037] Each R U-3-1 and R U-3-2 Halogen and C are independently distinguished. 3-10 cycloalkyl, C 6-10 Aryl, C 1-6 The alkoxy group, hydroxyl group, cyano group or heteroatom is selected from 1, 2 or 3 of N, O, S, and the heteroatom is a 3-10 membered heterocyclic alkyl group with 1, 2 or 3 heteroatoms;

[0038] Each R U-6 C independently 6-10 Aryl or "5-10 membered heteroaryl with one, two or three heteroatoms selected from N, O or S, and the number of heteroatoms being one, two or three";

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

[0040]

[0041] This invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0042]

[0043] Wherein, ring C is a benzene ring or "a 5-6 membered heteroaromatic ring with 1, 2 or 3 heteroatoms selected from N, O or S, and the number of heteroatoms is 1, 2 or 3";

[0044] Each R1 is independently halogenated, cyano-based, or C-based. 1-6 Alkyl, C 3-10 cycloalkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl groups or C atoms substituted with one or more halogens 1-6 Alkoxy;

[0045] m and k are independently 0, 1 or 2;

[0046] X1 is -CH2-, -O-, -S-, -NH- or -S(=O)2-;

[0047] X2 is -C(R) a R b - or -O-;

[0048] R a and R b Each can be independently hydrogen, deuterium, or C. 1-6 Alkyl, or R a R b Their shared carbon atoms connect to form 3-10 saturated carbon rings;

[0049] n is 0 or 1;

[0050] each Each can be used to independently represent a single bond or a double bond;

[0051] X3 and X4 are independently C or N;

[0052] Ring A is a pyrazole ring;

[0053] Each R2 is independently a halogen or a C 1-6 Alkyl, C 3-10 Cycloalkyl, "a 3-10 membered heterocycloalkyl group with one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms", C 6-10 aryl, with one or more R 2-1 Replacement C 1-6 Alkyl or with one or more R 2-2 The substituted heteroatoms are selected from 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3 of 5-10 heteroaryl groups;

[0054] Each R 2-1 and R 2-2 Each is independently a halogen, hydroxyl, or C. 1-6 Alkyl, -N(R) 2a R 2b C 3-10 cycloalkyl, C 1-6 Alkoxy, "a 3-10 membered heterocyclic alkyl group selected from 1, 2, or 3 of N, O, and S, with 1, 2, or 3 heteroatoms", C 6-10 Aryl or "5-10 membered heteroaryl with one, two or three heteroatoms selected from N, O or S, and the number of heteroatoms being one, two or three";

[0055] R 2a and R 2b H or C, independently respectively 1-6 alkyl;

[0056] R3 is hydrogen, C 1-6 Alkyl or C 3-10cycloalkyl;

[0057] L is C 1-6 Alkylene, by one or more R L Replacement C 1-6 Alkylene, "-(C 1-6 (alkylene)-L A -* or -L A -(* indicates the end connected to ring B);

[0058] Each R L Deuterium and C are independently distinguished. 1-6 Alkoxy, C 3-10 Cycloalkyl, hydroxyl, halogen, or oxo (=O), or when two R groups are present. L When two R atoms are substituted on the same carbon atom, L The carbon atoms they share are linked to form 3-10 saturated carbon rings or "3-10 saturated heterocycles with 1, 2 or 3 heteroatoms selected from N, O, and S".

[0059] L A -C(O)NH-, -O-, -N(R) LA )-, vinylene, ethynylene, 3-10 saturated carbon ring or "a 3-10 saturated heterocycle with 1, 2 or 3 heteroatoms selected from N, O or S";

[0060] R LA For H, C 1-6 Alkyl, C 3-10 Cycloalkyl or "a 3-10 membered heterocycloalkyl group whose heteroatoms are selected from 1, 2 or 3 of N, O or S, and whose heteroatoms number 1, 2 or 3";

[0061] Ring B is a 3-10 ternary saturated or unsaturated carbon ring, bounded by one or more R... B-1 The substituted 3-10 saturated or unsaturated carbon ring, "a 3-10 saturated or unsaturated heterocycle with 1, 2, or 3 heteroatoms selected from N, O, and S", or a heterocycle substituted with one or more R B-2 The substituted heteroatoms are selected from 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3, which are 3-10 saturated or unsaturated heterocycles.

[0062] Each R B-1 and R B-2 Each can be independently represented by a hydroxyl group, halogen, oxo group (=O), or C. 1-6 Alkyl, C 1-6 alkoxy or C substituted with one or more hydroxyl groups 1-6 alkyl;

[0063] U is C 3-6 Alkyl, with one or more R U-1 Replacement C 1-6 Alkyl, C 3-10 cycloalkyl, with one or more R U-2 Replacement C 3-10 Cycloalkyl, "a 3-10 membered heterocycloalkyl group with one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms", or formed by one or more R U-3 The substituted "heteroatom is selected from 1, 2 or 3 of N, O, and S, and the number of heteroatoms is 1, 2 or 3, which are 3-10 membered heterocyclic alkyl groups"; C 6-10 aryl, with one or more R U-4 Replacement C 6-10 aryl, "a 5-10 membered heteroaryl group with one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms", and bonded by one or more R U-5 The substituted "5-10 heteroaryl group selected from 1, 2, or 3 of N, O, and S, with 1, 2, or 3 heteroatoms" or -XR U-6 ;

[0064] X is -C(O)-, -SO2-, or -O-;

[0065] Each R U-1 Halogen and C are independently distinguished. 3-10 cycloalkyl, C 6-10 aryl, "a 5-10 membered heteroaryl group selected from 1, 2, or 3 heteroatoms from N, O, and S, with 1, 2, or 3 heteroatoms", or aryl with one or more R U-1-1 The substituted heteroatoms are selected from 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3 of 5-10 heteroaryl groups;

[0066] Each R U-1-1 C independently 1-6 alkyl;

[0067] Each R U-2 R U-3 R U-4 and R U-5 Each is independently a halogen, cyano, hydroxyl, or -SO2-C group. 1-6 Alkyl, -C(O)OC 1-6 Alkyl group, -C(O)NH-C 1-6 Alkyl, C 1-6 Alkyl, with one or more R U-3-1 Replacement C 1-6 Alkyl, C 1-6 Alkyl group, by one or more R U-3-2 Replacement C 1-6Alkoxy, C 3-10 Cycloalkyl, "a 3-10 membered heterocyclic alkyl group whose heteroatoms are selected from 1, 2 or 3 of N, O or S and whose heteroatoms number 1, 2 or 3" or -O- "a 3-10 membered heterocyclic alkyl group whose heteroatoms are selected from 1, 2 or 3 of N, O or S and whose heteroatoms number 1, 2 or 3";

[0068] Each R U-3-1 and R U-3-2 Halogen and C are independently distinguished. 3-10 cycloalkyl or cyano;

[0069] Each R U-6 C independently 6-10 Aryl or "5-10 membered heteroaryl with one, two or three heteroatoms selected from N, O or S, and the number of heteroatoms being one, two or three";

[0070] Furthermore, the compound represented by formula (I) is not any of the following compounds:

[0071]

[0072]

[0073] In some embodiments, the compound represented by formula (IA) is a compound represented by formula (IIA):

[0074]

[0075] Each R1 is independently halogenated, cyano-based, or C-based. 1-6 Alkyl, C 3-10 cycloalkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl groups, C substituted with one or more halogens 1-6 alkoxy, "a 5-10 membered heteroaryl group selected from 1, 2, or 3 of N, O, and S, with 1, 2, or 3 heteroatoms", or alkoxy with one or more R 1-1 The substituted heteroatoms are selected from 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3 of 5-10 heteroaryl groups;

[0076] Each R 1-1 C independently 1-6 alkyl;

[0077] m and k are independently 0, 1 or 2;

[0078] X1 is -CH2-, -O-, -S- or -S(=O)2-;

[0079] Each R2 is independently H and C.1-6 Alkyl, with one or more R 2-1 Replacement C 1-6 Alkyl or "a 3-10 membered heterocyclic alkyl group selected from 1, 2 or 3 of N, O or S, with 1, 2 or 3 heteroatoms";

[0080] Each R 2-1 Each independently is a hydroxyl group or a C group. 3-10 cycloalkyl;

[0081] each Each can be used to independently represent a single bond or a double bond;

[0082] E is -N(R3)- or n1 is 1, 2 or 3; # indicates the end connected to -C(O)- in formula (IA);

[0083] R3 is hydrogen or C. 1-6 alkyl;

[0084] L is C 1-6 Alkylene, by one or more R L Replacement C 1-6 Alkylene or "-(C 1-6 (alkylene)-L A -*”;

[0085] Each R L Each is independently a hydroxyl or halogen, or when both R are... L When two R atoms are substituted on the same carbon atom, L Their shared carbon atoms connect to form 3-10 saturated carbon rings;

[0086] L A -NH-, -N(C 1-6 Alkyl group or 3-10 saturated carbon rings;

[0087] Ring B is "a 3- to 10-membered saturated or unsaturated heterocycle with 1, 2, or 3 heteroatoms selected from N, O, and S" or composed of one or more R atoms. B-2 The substituted heteroatoms are selected from 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3, which are 3-10 saturated or unsaturated heterocycles.

[0088] Each R B-2 Each is independently a hydroxyl group, halogen, or C. 1-6 Alkyl, C 1-6 alkoxy or C substituted with one or more hydroxyl groups 1-6 alkyl;

[0089] When U does not exist, ring B is

[0090] U is non-existent, -N(R')(R”), C 3-6 Alkyl, with one or more R U-1 Replacement C 1-6 Alkyl, C 3-10 cycloalkyl, with one or more R U-2 Replacement C 3-10 Cycloalkyl, "a 3-10 membered heterocycloalkyl group with one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms", or formed by one or more R U-3 The substituted "heteroatom is selected from 1, 2 or 3 of N, O, and S, and the number of heteroatoms is 1, 2 or 3, which are 3-10 membered heterocyclic alkyl groups"; C 6-10 aryl, with one or more R U-4 Replacement C 6-10 aryl, "a 5-10 membered heteroaryl group selected from 1, 2, or 3 heteroatoms from N, O, and S, with 1, 2, or 3 heteroatoms", or aryl with one or more R U-5 The substituted heteroatoms are selected from 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3 of 5-10 heteroaryl groups;

[0091] Each R' and R” is independently hydrogen and C, respectively. 1-6 Alkyl, -C(O)-C 3-10 Cycloalkyl or C substituted with one or more R'' 1-6 Alkyl; R”' is independently C 6-10 Aryl;

[0092] Each R U-1 Independently represented as -N(R')(R”), C 3-10 cycloalkyl or C 6-10 Aryl;

[0093] Each R U-2 R U-3 R U-4 and R U-5 Each is independently a halogen, -SO2-C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-10 Cycloalkyl, "a 3-10 membered heterocycloalkyl group with 1, 2, or 3 heteroatoms selected from N, O, and S", cyano, hydroxyl, C 1-6 Alkyl, with one or more R U-3-1 Replacement C 1-6 Alkyl, C 1-6 Alkyl groups or those with one or more R groups U-3-2 Replacement C 1-6 Alkoxy;

[0094] Each R U-3-1 and R U-3-2 Halogen and C are independently distinguished. 3-10 cycloalkyl, C 6-10 Aryl, C 1-6 The alkoxy, hydroxyl, cyano, or heteroatom is selected from 1, 2, or 3 of N, O, and S, and the heteroatom is a 3- to 10-membered heterocyclic alkyl group with 1, 2, or 3 heteroatoms.

[0095] In some embodiments, the compound represented by formula (I) is a compound represented by formula (II):

[0096]

[0097] Each R1 is an independent halogen;

[0098] m and k are independently 0, 1 or 2;

[0099] X1 is -CH2-, -O-, -S- or -S(=O)2-;

[0100] Each R2 is independently C 1-6 Alkyl or with one or more R 2-1 Replacement C 1-6 alkyl;

[0101] Each R 2-1 C independently 3-10 cycloalkyl;

[0102] each Each can be used to independently represent a single bond or a double bond;

[0103] R3 is hydrogen or C. 1-6 alkyl;

[0104] L is C 1-6 Alkylene, by one or more R L Replacement C 1-6 Alkylene or "-(C 1-6 (alkylene)-L A -*”;

[0105] Each R L Each is independently a hydroxyl or halogen, or when both R are... L When two R atoms are substituted on the same carbon atom, L Their shared carbon atoms connect to form 3-10 saturated carbon rings;

[0106] L A -NH- or -N(C) 1-6 alkyl)-;

[0107] Ring B is "a 3- to 10-membered saturated or unsaturated heterocycle with 1, 2, or 3 heteroatoms selected from N, O, and S" or composed of one or more R atoms. B-2 The substituted heteroatoms are selected from 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3, which are 3-10 saturated or unsaturated heterocycles.

[0108] Each R B-2 Each is independently a hydroxyl group, halogen, or C. 1-6 alkoxy or C substituted with one or more hydroxyl groups 1-6 alkyl;

[0109] U is C 3-6 Alkyl, with one or more R U-1 Replacement C 1-6 Alkyl, C 3-10 cycloalkyl, with one or more R U-2 Replacement C 3-10 Cycloalkyl, "a 3-10 membered heterocycloalkyl group with one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms", or formed by one or more R U-3 The substituted "heteroatom is selected from 1, 2 or 3 of N, O, and S, and the number of heteroatoms is 1, 2 or 3, which are 3-10 membered heterocyclic alkyl groups"; C 6-10 aryl, with one or more R U-4 Replacement C 6-10 aryl, "a 5-10 membered heteroaryl group selected from 1, 2, or 3 heteroatoms from N, O, and S, with 1, 2, or 3 heteroatoms", or aryl with one or more R U-5 The substituted heteroatoms are selected from 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3 of 5-10 heteroaryl groups;

[0110] Each R U-1 C independently 3-10 cycloalkyl or C 6-10 Aryl;

[0111] Each R U-2 R U-3 R U-4 and R U-5 Halogen and C are independently distinguished. 3-10 Cycloalkyl, "a 3-10 membered heterocycloalkyl group with 1, 2, or 3 heteroatoms selected from N, O, and S", cyano, hydroxyl, C 1-6 Alkyl, with one or more R U-3-1 Replacement C 1-6 Alkyl, C 1-6 Alkyl groups or those with one or more R groups U-3-2 Replacement C 1-6Alkoxy;

[0112] Each R U-3-1 and R U-3-2 Each independently is either halogen or C 3-10 Cycloalkyl.

[0113] In some embodiments, the compound represented by formula (IA) is a compound represented by formula (IIIA) or formula (IIIB):

[0114]

[0115] Each R1 is independently halogenated, cyano-based, or C-based. 1-6 Alkyl, C 3-10 cycloalkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl groups, C substituted with one or more halogens 1-6 alkoxy, "a 5-10 membered heteroaryl group selected from 1, 2, or 3 of N, O, and S, with 1, 2, or 3 heteroatoms", or alkoxy with one or more R 1-1 The substituted heteroatoms are selected from 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3 of 5-10 heteroaryl groups;

[0116] Each R 1-1 C independently 1-6 alkyl;

[0117] m is 0, 1, or 2;

[0118] X1 is -CH2-, -O-, -S- or -S(=O)2-;

[0119] Each R2 is independently H and C. 1-6 Alkyl, with one or more R 2-1 Replacement C 1-6 Alkyl or "a 3-10 membered heterocyclic alkyl group selected from 1, 2 or 3 of N, O or S, with 1, 2 or 3 heteroatoms";

[0120] Each R 2-1 Each independently is a hydroxyl group or a C group. 3-10 cycloalkyl;

[0121] E is -N(R3)- or n1 is 1, 2 or 3; # indicates the end connected to -C(O)- in formula (IA);

[0122] R3 is hydrogen or C. 1-6 alkyl;

[0123] L is C 1-6 Alkylene, by one or more RL Replacement C 1-6 Alkylene or "-(C 1-6 (alkylene)-L A -*;

[0124] Each R L Each is independently a hydroxyl or halogen, or when both R are... L When two R atoms are substituted on the same carbon atom, L Their shared carbon atoms connect to form 3-10 saturated carbon rings;

[0125] L A It consists of 3-10 saturated carbon rings;

[0126] Ring B is "a 3- to 10-membered saturated or unsaturated heterocycle with 1, 2, or 3 heteroatoms selected from N, O, and S" or composed of one or more R atoms. B-2 The substituted heteroatoms are selected from 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3, which are 3-10 saturated or unsaturated heterocycles.

[0127] Each R B-2 Each independently is either halogen or C 1-6 alkyl;

[0128] When U does not exist, ring B is

[0129] U represents non-existence, -N(R')(R”), or is defined by one or more R's. U-1 Replacement C 1-6 Alkyl, C 3-10 cycloalkyl, with one or more R U-2 Replacement C 3-10 Cycloalkyl, "a 3-10 membered heterocycloalkyl group with one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms", or formed by one or more R U-3 The substituted "heteroatom is selected from 1, 2 or 3 of N, O, and S, and the number of heteroatoms is 1, 2 or 3, which are 3-10 membered heterocyclic alkyl groups"; C 6-10 aryl, with one or more R U-4 Replacement C 6-10 Aryl or "5-10 membered heteroaryl with one, two or three heteroatoms selected from N, O or S, and the number of heteroatoms being one, two or three";

[0130] Each R' and R” is independently hydrogen and C, respectively. 1-6 Alkyl, -C(O)-C 3-10 Cycloalkyl or C substituted with one or more R'' 1-6 Alkyl; R”' is independently C 6-10 Aryl;

[0131] Each R U-1 C independently 3-10 cycloalkyl or C 6-10 Aryl;

[0132] Each R U-2 R U-3 and R U-4 Each is independently a halogen, hydroxyl group, or -SO2-C. 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, "a 3-10 membered heterocycloalkyl group with one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms", C 1-6 Alkyl groups or those with one or more R groups U-3-1 Replacement C 1-6 alkyl;

[0133] Each R U-3-1 Halogen and C are independently distinguished. 3-10 cycloalkyl, C 6-10 Aryl, C 1-6 The alkoxy, hydroxyl, cyano, or heteroatom is selected from 1, 2, or 3 of N, O, and S, and the heteroatom is a 3- to 10-membered heterocyclic alkyl group with 1, 2, or 3 heteroatoms.

[0134] In some embodiments, the compound represented by formula (I) is a compound represented by formula (III):

[0135]

[0136] Each R1 is an independent halogen;

[0137] m is 0 or 1;

[0138] X1 is -CH2-, -O-, -S- or -S(=O)2-;

[0139] Each R2 is independently C 1-6 Alkyl or with one or more R 2-1 Replacement C 1-6 alkyl;

[0140] Each R 2-1 C independently 3-10 cycloalkyl;

[0141] R3 is hydrogen or C. 1-6 alkyl;

[0142] L is C 1-6 alkylene or by one or more R L Replacement C1-6 Alkylene;

[0143] Each R L Each can be independently a hydroxyl group or a halogen;

[0144] Ring B is "a 3- to 10-membered saturated or unsaturated heterocycle with 1, 2, or 3 heteroatoms selected from N, O, and S" or composed of one or more R atoms. B-2 The substituted heteroatoms are selected from 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3, which are 3-10 saturated or unsaturated heterocycles.

[0145] Each R B-2 Each is a halogen, independent of the others;

[0146] U is a result of one or more R U-1 Replacement C 1-6 Alkyl, C 3-10 cycloalkyl, with one or more R U-2 Replacement C 3-10 Cycloalkyl, "a 3-10 membered heterocycloalkyl group with one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms", C 6-10 aryl, with one or more R U-4 Replacement C 6-10 Aryl or "5-10 membered heteroaryl with one, two or three heteroatoms selected from N, O or S, and the number of heteroatoms being one, two or three";

[0147] Each R U-1 C independently 3-10 cycloalkyl or C 6-10 Aryl;

[0148] Each R U-2 and R U-4 Halogen and C are independently distinguished. 1-6 Alkyl groups or those with one or more R groups U-3-1 Replacement C 1-6 alkyl;

[0149] Each R U-3-1 Each is a halogen, and they are independent of each other.

[0150] In some embodiments, each R1 is independently a halogen, a cyano group, or a C group. 1-6 Alkyl, C 3-10 cycloalkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, C substituted with one or more halogens 1-6 alkoxy, "a 5-10 membered heteroaryl group selected from 1, 2, or 3 of N, O, and S, with 1, 2, or 3 heteroatoms", or alkoxy with one or more R 1-1The substituted heteroatoms are selected from 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3 of 5-10 heteroaryl groups;

[0151] Each R 1-1 C independently 1-6 alkyl.

[0152] In some implementations, each R1 is a halogen independently.

[0153] In some implementations, m and k are independently 0 or 1.

[0154] In some implementations, each R2 is independently H and C. 1-6 Alkyl, with one or more R 2-1 Replacement C 1-6 Alkyl or "a 3-10 membered heterocyclic alkyl group selected from 1, 2 or 3 of N, O or S, with 1, 2 or 3 heteroatoms";

[0155] Each R 2-1 Each independently is a hydroxyl group or a C group. 3-10 Cycloalkyl.

[0156] In some implementations, each R2 is independently C 1-6 Alkyl or with one or more R 2-1 Replacement C 1-6 alkyl;

[0157] Each R 2-1 C independently 3-10 Cycloalkyl.

[0158] In some implementations, E is -N(R3)-.

[0159] In some embodiments, R3 is hydrogen or C 1-6 alkyl.

[0160] In some implementations, R3 is hydrogen.

[0161] In some implementations, L is C 1-6 Alkylene, by one or more R L Replacement C 1-6 Alkylene or "-(C 1-6 (alkylene)-L A -*”;

[0162] Each R L Each is independently a hydroxyl or halogen, or when both R are... L When two R atoms are substituted on the same carbon atom, L Their shared carbon atoms connect to form 3-10 saturated carbon rings;

[0163] L A -NH-, -N(C 1-6 Alkyl group or 3-10 saturated carbon ring; preferably 3-10 saturated carbon ring.

[0164] In some implementations, L is C 1-6 Alkylene, by one or more R L Replacement C 1-6 Alkylene or "-(C 1-6 (alkylene)-L A -*”;

[0165] Each R L Each is independently a hydroxyl or halogen, or when both R are... L When two R atoms are substituted on the same carbon atom, L Their shared carbon atoms connect to form 3-10 saturated carbon rings;

[0166] L A -NH- or -N(C) 1-6 alkyl)-.

[0167] In some implementations, L is C 1-6 Alkylene, by one or more R L Replacement C 1-6 Alkylene or "-(C 1-6 (alkylene)-L A -*”;

[0168] Each R L Each is independently a hydroxyl or halogen, or when both R are... L When two R atoms are substituted on the same carbon atom, L Their shared carbon atoms connect to form 3-10 saturated carbon rings;

[0169] L A It is -NH-.

[0170] In some implementations, L is C 1-6 alkylene or by one or more R L Replacement C 1-6 Alkylene;

[0171] Each R L Each can be a hydroxyl group or a halogen, independently.

[0172] In some implementations, L is C 1-6 alkylene or by one or more R L Replacement C 1-6 Alkylene;

[0173] Each R L Each is an independent hydroxyl group.

[0174] In some embodiments, ring B is "a 3- to 10-membered saturated or unsaturated heterocycle with one, two, or three heteroatoms selected from N, O, and S, and the number of heteroatoms is one, two, or three" or is surrounded by one or more R... B-2 The substituted heteroatoms are selected from 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3, which are 3-10 saturated or unsaturated heterocycles.

[0175] Each R B-2 Each is independently a hydroxyl group, halogen, or C. 1-6 Alkyl, C 1-6 alkoxy or C substituted with one or more hydroxyl groups 1-6 Alkyl; preferably halogen or C 1-6 alkyl.

[0176] In some embodiments, ring B is "a 3- to 10-membered saturated or unsaturated heterocycle with one, two, or three heteroatoms selected from N, O, and S, and the number of heteroatoms is one, two, or three" or is surrounded by one or more R... B-2 The substituted heteroatoms are selected from 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3, which are 3-10 saturated or unsaturated heterocycles.

[0177] Each R B-2 Each is independently a hydroxyl group, halogen, or C. 1-6 alkoxy or C substituted with one or more hydroxyl groups 1-6 Alkyl group; preferably halogen.

[0178] In some embodiments, ring B is "a 3-10 saturated or unsaturated heterocycle selected from 1, 2 or 3 of N, O, and S heteroatoms, with 1, 2 or 3 heteroatoms".

[0179] In some implementations, U represents non-existence, -N(R')(R”), and C. 3-6 Alkyl, with one or more R U-1 Replacement C 1-6 Alkyl, C 3-10 cycloalkyl, with one or more R U-2 Replacement C 3-10 Cycloalkyl, "a 3-10 membered heterocycloalkyl group with one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms", or formed by one or more R U-3 The substituted "heteroatom is selected from 1, 2 or 3 of N, O, and S, and the number of heteroatoms is 1, 2 or 3, which are 3-10 membered heterocyclic alkyl groups"; C 6-10 aryl, with one or more R U-4 Replacement C 6-10aryl, "a 5-10 membered heteroaryl group selected from 1, 2, or 3 heteroatoms from N, O, and S, with 1, 2, or 3 heteroatoms", or aryl with one or more R U-5 The substituted heteroatoms are selected from 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3 of 5-10 heteroaryl groups;

[0180] Each R' and R” is independently hydrogen and C, respectively. 1-6 Alkyl, -C(O)-C 3-10 Cycloalkyl or C substituted with one or more R'' 1-6 Alkyl; R”' is independently C 6-10 Aryl;

[0181] Each R U-1 Independently represented as -N(R')(R”), C 3-10 cycloalkyl or C 6-10 Aryl;

[0182] Each R U-2 R U-3 R U-4 and R U-5 Each is independently a halogen, -SO2-C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-10 Cycloalkyl, "a 3-10 membered heterocycloalkyl group with 1, 2, or 3 heteroatoms selected from N, O, and S", cyano, hydroxyl, C 1-6 Alkyl, with one or more R U-3-1 Replacement C 1-6 Alkyl, C 1-6 Alkyl groups or those with one or more R groups U-3-2 Replacement C 1-6 Alkoxy;

[0183] Each R U-3-1 and R U-3-2 Halogen and C are independently distinguished. 3-10 cycloalkyl, C 6-10 Aryl, C 1-6 The alkoxy, hydroxyl, cyano, or heteroatom is selected from 1, 2, or 3 of N, O, and S, and the heteroatom is a 3- to 10-membered heterocyclic alkyl group with 1, 2, or 3 heteroatoms.

[0184] In some implementations, U represents non-existence, -N(R')(R”), or is affected by one or more R's. U-1 Replacement C 1-6 Alkyl, C 3-10 cycloalkyl, with one or more R U-2 Replacement C 3-10Cycloalkyl, "a 3-10 membered heterocycloalkyl group with one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms", or formed by one or more R U-3 The substituted "heteroatom is selected from 1, 2 or 3 of N, O, and S, and the number of heteroatoms is 1, 2 or 3, which are 3-10 membered heterocyclic alkyl groups"; C 6-10 aryl, with one or more R U-4 Replacement C 6-10 Aryl or "5-10 membered heteroaryl with one, two or three heteroatoms selected from N, O or S, and the number of heteroatoms being one, two or three";

[0185] Each R' and R” is independently hydrogen and C, respectively. 1-6 Alkyl, -C(O)-C 3-10 Cycloalkyl or C substituted with one or more R'' 1-6 Alkyl; R”' is independently C 6-10 Aryl;

[0186] Each R U-1 C independently 3-10 cycloalkyl or C 6-10 Aryl;

[0187] Each R U-2 R U-3 and R U-4 Each is independently a halogen, hydroxyl group, or -SO2-C. 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, "a 3-10 membered heterocycloalkyl group with one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms", C 1-6 Alkyl groups or those with one or more R groups U-3-1 Replacement C 1-6 alkyl;

[0188] Each R U-3-1 Halogen and C are independently distinguished. 3-10 cycloalkyl, C 6-10 Aryl, C 1-6 The alkoxy, hydroxyl, cyano, or heteroatom is selected from 1, 2, or 3 of N, O, and S, and the heteroatom is a 3- to 10-membered heterocyclic alkyl group with 1, 2, or 3 heteroatoms.

[0189] In some implementations, U is C 3-6 Alkyl, with one or more R U-1 Replacement C 1-6 Alkyl, C 3-10 cycloalkyl, with one or more R U-2 Replacement C 3-10Cycloalkyl, "a 3-10 membered heterocycloalkyl group with one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms", or formed by one or more R U-3 The substituted "heteroatom is selected from 1, 2 or 3 of N, O, and S, and the number of heteroatoms is 1, 2 or 3, which are 3-10 membered heterocyclic alkyl groups"; C 6-10 aryl, with one or more R U-4 Replacement C 6-10 aryl, "a 5-10 membered heteroaryl group selected from 1, 2, or 3 heteroatoms from N, O, and S, with 1, 2, or 3 heteroatoms", or aryl with one or more R U-5 The substituted heteroatoms are selected from 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3 of 5-10 heteroaryl groups;

[0190] Each R U-1 C independently 3-10 cycloalkyl or C 6-10 Aryl;

[0191] Each R U-2 R U-3 R U-4 and R U-5 Halogen and C are independently distinguished. 3-10 Cycloalkyl, "a 3-10 membered heterocycloalkyl group with 1, 2, or 3 heteroatoms selected from N, O, and S", cyano, hydroxyl, C 1-6 Alkyl, with one or more R U-3-1 Replacement C 1-6 Alkyl, C 1-6 Alkyl groups or those with one or more R groups U-3-2 Replacement C 1-6 Alkoxy;

[0192] Each R U-3-1 and R U-3-2 Each independently is either halogen or C 3-10 Cycloalkyl.

[0193] In some implementations, U is the result of one or more R U-1 Replacement C 1-6 Alkyl, C 3-10 cycloalkyl, with one or more R U-2 Replacement C 3-10 Cycloalkyl, "a 3-10 membered heterocycloalkyl group with one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms", C 6-10 aryl, with one or more R U-4 Replacement C 6-10Aryl or "5-10 membered heteroaryl with one, two or three heteroatoms selected from N, O or S, and the number of heteroatoms being one, two or three";

[0194] Each R U-1 C independently 3-10 cycloalkyl or C 6-10 Aryl;

[0195] Each R U-2 and R U-4 Halogen and C are independently distinguished. 1-6 Alkyl groups or those with one or more R groups U-3-1 Replacement C 1-6 alkyl;

[0196] Each R U-3-1 Each is a halogen, and they are independent of each other.

[0197] In some embodiments, in ring C, the "5-6 membered heteroaromatic ring with one, two or three heteroatoms selected from N, O, and S, and the number of heteroatoms is one, two or three" is "a 5-6 membered heteroaromatic ring with N as the heteroatom and the number of heteroatoms is one or two", such as a pyridine ring or a pyrimidine ring.

[0198] In some embodiments, each “C1-C6 alkyl” is independently a C1-C4 alkyl, and may be methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, preferably methyl or ethyl.

[0199] In some embodiments, each “C1-C6 alkoxy” is independently a C1-C4 alkoxy, and may also be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, or sec-butoxy, preferably methoxy.

[0200] In some embodiments, each "halogen" is independently fluorine, chlorine, bromine, or iodine, preferably fluorine or chlorine.

[0201] In some implementations, each "halogen" is independently fluorine, chlorine, or bromine, preferably fluorine.

[0202] In some implementations, when R a R b When carbon atoms are linked together to form a 3-10 saturated carbon ring, the "3-10 saturated carbon ring" refers to a 3-membered saturated carbon ring, for example... ( (This refers to the bonds that connect to the rest of the molecule).

[0203] In some implementations, each "C3-C" 10 "Cycloalkyl" is independently a C3-C6 monocyclic cycloalkyl or a C5-C6 monocyclic cycloalkyl. 10Polycyclic (e.g., spirocyclic, fused, or bridged) cycloalkyl groups, wherein the C3-C6 monocyclic cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the C5-C6 monocyclic cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 10 Polycyclic alkyl groups are preferably C5-C 10 Spirocycloalkyl, further preferred

[0204] In some embodiments, each "3-10 membered heterocyclic alkyl group selected from 1, 2, or 3 of N, O, and S, with 1, 2, or 3 heteroatoms" is independently a 4-6 membered monocyclic heterocyclic alkyl group or a 5-10 membered polycyclic (e.g., spirocyclic, fused, or bridged) heterocyclic alkyl group. The 4-6 membered monocyclic heterocyclic alkyl group is preferably a 4-6 membered monocyclic heterocyclic alkyl group selected from 1 or 2 of N and O, with 1 or 2 heteroatoms. More preferably, it is a 4-6 membered monocyclic heterocyclic alkyl group selected from N and O. The 5-10 membered polycyclic heterocyclic alkyl group can be a 5-10 membered spirocyclic heterocyclic alkyl group, preferably a 6-membered spiro-3 membered heterocyclic alkyl group, more preferably a 5-10 membered spiro-3 membered heterocyclic alkyl group. Alternatively, the 5-10 membered polycyclic heterocyclic alkyl group may be a 5-10 membered bridged heterocyclic alkyl group, preferably.

[0205] In some embodiments, each "3-10 membered heterocyclic alkyl group selected from 1, 2, or 3 of N, O, and S, with 1, 2, or 3 heteroatoms" is independently a 4-6 membered monocyclic heterocyclic alkyl group or a 5-10 membered polycyclic (e.g., spirocyclic, fused, or bridged) heterocyclic alkyl group, wherein the 4-6 membered monocyclic heterocyclic alkyl group is preferably a 6 membered heterocyclic alkyl group with 1 or 2 of N or O heteroatoms, more preferably a 6 membered heterocyclic alkyl group. The 5-10 membered polycyclic heterocyclic alkyl group may be a 5-10 membered spirocyclic heterocyclic alkyl group, preferably a 6-membered spiro-3 membered heterocyclic alkyl group, more preferably a spiro-3 membered heterocyclic alkyl group.

[0206] In some implementations, each "C6-C" 10 The aryl group is independently phenyl or naphthyl, preferably phenyl.

[0207] In some embodiments, each "5-10 membered heteroaryl group selected from 1, 2, or 3 heteroatoms of N, O, and S, with 1, 2, or 3 heteroatoms" can independently be a 5-6 membered monocyclic heteroaryl group. The 5-6 membered monocyclic heteroaryl group is preferably a 5-6 membered monocyclic heteroaryl group with N as the heteroatom type and 1, 2, or 3 heteroatoms, for example...

[0208] In some embodiments, each "5-10 membered heteroaryl group selected from 1, 2, or 3 heteroatoms of N, O, and S, with 1, 2, or 3 heteroatoms" can independently be a 5-6 membered monocyclic heteroaryl group. Preferably, the 5-6 membered monocyclic heteroaryl group is a 5-6 membered monocyclic heteroaryl group with N as the heteroatom type and 1 or 2 heteroatoms. More preferably, it is a 5-6 membered monocyclic heteroaryl group with N as the heteroatom type.

[0209] In some implementations, each "C" 1-6 "alkylene" is independently a C1-C4 alkylene, preferably methylene.

[0210] In some implementations, each "C" 1-6 "alkylene" is independently a C1-C4 alkylene, preferably

[0211] In some implementations, when two R L When two R atoms are substituted on the same carbon atom, L The "3-10 saturated carbon rings" formed by the bonding of their shared carbon atoms are 3-membered saturated carbon rings, for example... ( (This refers to the bonds that connect to the rest of the molecule).

[0212] In some implementations, when L A When the carbon ring is 3-10 dimensional saturated, the "3-10 dimensional saturated carbon ring" refers to a 4-6 dimensional saturated carbon ring, for example...

[0213] In some embodiments, each "a 3-10 member saturated or unsaturated heterocycle with one, two, or three heteroatoms selected from N, O, and S" is independently defined as "a 4-8 member saturated or unsaturated heterocycle with one or two heteroatoms selected from N and O," for example...

[0214] In some embodiments, each "3-10 member saturated or unsaturated heterocycle with one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms" is independently defined as "a 5-6 member saturated or unsaturated heterocycle with N as the heteroatom and having one or two heteroatoms," for example... ( (This refers to the bonds that connect to the rest of the molecule).

[0215] In some embodiments, ring C is a benzene ring.

[0216] In some embodiments, each R1 is independently fluorine, chlorine, bromine, cyano, trifluoromethyl, cyclopropyl, trifluoromethoxy, methyl, m can be 0, 1, or 2.

[0217] In some implementations, each R1 is independently either fluorine or chlorine; m is 0 or 1.

[0218] In some implementations, X1 is -CH2-, -O-, -S- or -S(=O)2-; X2 is -CH2-; n is 0; X3 and X4 are C.

[0219] In some embodiments, R2 is H, methyl, ethyl, k is 0 or 1.

[0220] In some embodiments, R2 is methyl, ethyl, or... k is 1.

[0221] In some implementations, structural fragments for

[0222]

[0223]

[0224] In some embodiments, R3 is hydrogen or methyl.

[0225] In some embodiments, L is methylene,

[0226] In some implementations, ring B is

[0227]

[0228] In some implementations, U is

[0229] In some implementations, E is -NH-, -N(CH3)-, or The present invention also provides compounds or pharmaceutically acceptable salts thereof as shown below:

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236] The present invention also provides a pharmaceutical composition comprising substance A and a pharmaceutically acceptable excipient, wherein substance A is a compound of formula (XA) or a pharmaceutically acceptable salt thereof;

[0237]

[0238] Among them, rings A, B, C, X1, X2, X3, X4, R1, R2, E, m, n, k, L, B and U are defined as above.

[0239] The present invention also provides a pharmaceutical composition comprising (therapeuticly effective amount) substance A and pharmaceutically acceptable excipients, wherein substance A is a compound of formula (X) or a pharmaceutically acceptable salt thereof;

[0240]

[0241] Among them, rings A, B, C, X1, X2, X3, X4, R1, R2, R3, m, n, k, L, B and U are defined as above.

[0242] In some embodiments, the pharmaceutical composition is used to treat and / or prevent KSR2-AMPK-related diseases or disorders, such as cancer, for example, liver cancer.

[0243] This invention also provides the use of substance A or the above-described pharmaceutical composition in the preparation of a KSR2-AMPK inhibitor, wherein substance A is a compound represented by formula (XA) or a pharmaceutically acceptable salt thereof. In the described application, the KSR2-AMPK inhibitor can be used in mammalian organisms; it can also be used in vitro, primarily for experimental purposes, such as providing a standard or control sample for comparison, or preparing a kit according to conventional methods in the art to provide rapid detection of the effect of inhibiting KSR2-AMPK.

[0244] The present invention also provides the use of substance A or the above-described pharmaceutical composition in the preparation of a medicament for treating and / or preventing diseases or disorders related to KSR2-AMPK; wherein substance A is a compound represented by formula (XA) or a pharmaceutically acceptable salt thereof; wherein substance A is in a therapeutically effective amount; and wherein the disease or disorder related to KSR2-AMPK is preferably cancer, such as liver cancer.

[0245] The present invention also provides the use of substance A or the above-described pharmaceutical composition in the preparation of a medicament for the treatment and / or prevention of cancer (e.g., liver cancer); wherein substance A is a compound represented by formula (XA) or a pharmaceutically acceptable salt thereof; and wherein substance A is a therapeutically effective amount.

[0246] The present invention also provides the use of substance A or the above-described pharmaceutical composition in the inhibition of KSR2-AMPK, wherein substance A is a compound represented by formula (XA) or a pharmaceutically acceptable salt thereof.

[0247] This invention also provides the use of substance A or the above-described pharmaceutical composition in the preparation of a KSR2-AMPK inhibitor, wherein substance A is a compound represented by formula (X) or a pharmaceutically acceptable salt thereof. In the described application, the KSR2-AMPK inhibitor can be used in mammalian organisms; it can also be used in vitro, primarily for experimental purposes, such as providing a standard or control sample for comparison, or preparing a kit according to conventional methods in the art to provide rapid detection of the effect of inhibiting KSR2-AMPK.

[0248] The present invention also provides the use of substance A or the above-described pharmaceutical composition in the preparation of a medicament for treating and / or preventing diseases or disorders related to KSR2-AMPK; wherein substance A is a compound represented by formula (X) above or a pharmaceutically acceptable salt thereof; wherein substance A is in a therapeutically effective amount; and wherein the disease or disorder related to KSR2-AMPK is preferably cancer, such as liver cancer.

[0249] The present invention also provides the use of substance A or the above-described pharmaceutical composition in the preparation of a medicament for the treatment and / or prevention of cancer (e.g., liver cancer); wherein substance A is a compound represented by formula (X) or a pharmaceutically acceptable salt thereof; and wherein substance A is a therapeutically effective amount.

[0250] The present invention also provides the use of substance A or the above-described pharmaceutical composition in the inhibition of KSR2-AMPK, wherein substance A is the above-described compound as shown in formula (X) or a pharmaceutically acceptable salt thereof.

[0251] Except as otherwise specified, when used in this application, the following terms shall have the meanings as follows.

[0252] The term "multiple" refers to 2, 3, 4, or 5.

[0253] Those skilled in the art will understand that, according to conventions used in the art, the structural formulas of the groups described in this invention are... This refers to the fact that the corresponding group R is linked to other fragments or groups in the compound through this site.

[0254] The term "pharmaceutically acceptable salt" refers to a salt prepared from the compounds of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds 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 compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids and organic acids. For details, see Bergee 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).

[0255] The term "pharmaceutical composition" refers to a formulation comprising the compounds of the present invention and a medium generally accepted in the art for delivering the bioactive compound to mammals (e.g., humans). This medium includes pharmaceutically acceptable carriers. The purpose of a pharmaceutical composition is to facilitate administration to the organism, thereby promoting the absorption of the active ingredient and the exertion of its bioactivity.

[0256] The term "pharmaceuticalally acceptable excipients" refers to excipients and additives used in the manufacture and dispensing of pharmaceutical products; these are all substances contained in a pharmaceutical preparation other than the active ingredient. See the Pharmacopoeia of the People's Republic of China (2015 Edition), Volume IV, or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009 Sixth Edition). Excipients primarily serve to provide a safe, stable, and functional pharmaceutical composition, and may also provide methods for dissolving the active ingredient at a desired rate after administration to a subject, or for promoting effective absorption of the active ingredient after administration of the composition to a subject. The pharmaceutical excipients may be inert fillers or provide a function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredient. The pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesion agents, flow aids, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0257] The term “treatment” refers to a therapeutic approach or a remission measure. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations of the condition; (3) improving 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 disease or one or more biological manifestations of the condition. “Treatment” can also mean prolonging survival compared to expected survival without treatment.

[0258] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0259] The term "therapeutic effective amount" refers to an amount of compound sufficient to effectively treat the disease or condition described herein when administered to a patient. The "therapeutic effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but may be adjusted as needed by those skilled in the art.

[0260] The term "substitution" or "substituent" refers to the replacement of a hydrogen atom in a group with a specified group. Substitution can occur at any position unless the substitution site is specified, but it is only permitted if a stable or chemically viable chemical is formed. Examples are given below: The structure indicates that the hydrogen atom on ring A is replaced by p R4 atoms.

[0261] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by one or more Rs, the group can optionally be substituted by at least one R, and R has independent options in each case. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0262] The term "alkyl" refers to a saturated, straight-chain or branched monovalent hydrocarbon group. C 1-6 Alkyl refers to an alkyl group having 1-6 carbon atoms, preferably an alkyl group having 1-4 carbon atoms. 1-4 Alkyl groups, specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0263] The term "alkylene" refers to 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 that of the term "alkyl".

[0264] The term "alkoxy" refers to -OC 1-6 Alkyl, wherein "C" 1-6 "Alkyl" is as defined above. Preferably, it is an alkoxy group having 1-4 carbon atoms, such as methoxy or ethoxy.

[0265] The term "cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bridged rings, fused rings, or spirocyclic systems) carbocyclic substituent that can be linked to the rest of the molecule via a single bond through any suitable carbon atom. Examples include 3- to 10-membered cycloalkyl groups having 3 to 10 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. wait.

[0266] The term "carbon ring" refers to a ring with a specified number of carbon atoms (e.g., C3 to C4). 10 ) cyclic, saturated or unsaturated cyclic groups, which are monocyclic or polycyclic (e.g., bicyclic, tricyclic or more ring-bridged rings, fused rings or spirocyclic systems), preferably 3-membered saturated carbon rings; which satisfy any of the following conditions: (1) are connected to the rest of the molecule by two or more single bonds, for example ( (1) indicates a bond that is connected to the rest of the molecule, or (2) shares two atoms and one bond with the rest of the molecule.

[0267] The term "heterocycle" refers to a cyclic group having a specified number of ring atoms (e.g., 3-10), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatom (one or more of N, O, and S), and being saturated or unsaturated, being monocyclic or polycyclic (e.g., bicyclic, tricyclic, or more ring-bridged, fused-ring, or spirocyclic systems); preferably a 5-6 member saturated monocyclic heterocycle; which satisfies any of the following conditions: (1) being connected to the rest of the molecule by two or more single bonds, for example ( (1) indicates a bond that is connected to the rest of the molecule, or (2) shares two atoms and one bond with the rest of the molecule.

[0268] The term "heterocyclic alkyl" refers to a saturated monovalent group having a specified number of ring atoms (e.g., 3-10), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified heteroatom type (one or more of N, O, and S), and being monocyclic or polycyclic (e.g., bicyclic, tricyclic, or more ring-bridged, fused-ring, or spirocyclic systems), connected to the remainder of the molecule by a carbon atom or heteroatom. Examples of heterocyclic alkyl groups include, but are not limited to, morpholino, piperidinyl, piperazine, tetrahydropyranyl, or azaspiro[2.5]octyl, for example...

[0269] The term "aryl" refers to an aryl group having a specified number of carbon atoms (e.g., C36, C46, ​​C56, C66). 6-10 An aryl group is a cyclic, unsaturated monovalent hydrocarbon group, which may be monocyclic or polycyclic (e.g., two or three). When polycyclic, the monocyclic rings share two atoms and one bond, and at least one ring is aromatic. The aryl group is attached to the rest of the molecule through an aromatic or non-aromatic ring. Aryl groups include, but are not limited to, phenyl or naphthyl groups.

[0270] The term "heteroaryl" refers to a cyclic, unsaturated monovalent group having a specified number of ring atoms (e.g., 5-10), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), which can be monocyclic or polycyclic; when polycyclic, each pair of monocyclic rings shares two atoms and one bond, and at least one ring is aromatic. Heteroaryl groups are attached to the remainder of the molecule via carbon atoms or heteroatoms; they are attached to the remainder of the molecule via rings with or without heteroatoms; they are attached to the remainder of the molecule via aromatic or non-aromatic rings. Heteroaryl groups include, but are not limited to, pyridinyl or pyrimidinyl groups, for example... wait.

[0271] The term "heteroaromatic ring" refers to a cyclic, unsaturated group having a specified number of ring atoms (e.g., 5-10), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified heteroatom type (one or more of N, O, and S), which may be monocyclic or polycyclic; when polycyclic, each pair of monocyclic rings shares two atoms and one bond, and at least one ring is aromatic; preferably a 5-6 cyclic heteroaromatic ring; which satisfies any of the following conditions: (1) it is connected to the rest of the molecule by two or more bonds; (2) it shares two atoms and one bond with the rest of the molecule.

[0272] The term "halogen" refers to fluorine, chlorine, bromine, or iodine, especially F or Cl.

[0273] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0274] The reagents and raw materials used in this invention are all commercially available.

[0275] The positive and progressive effect of this invention is that the compound of this invention can effectively inhibit the proliferation of cancer cells. Detailed Implementation

[0276] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0277] Example 1

[0278]

[0279] Step 1: In a 500 mL three-necked flask, 120 mL of ethanol and 83 g (243.58 mmol) of 20% sodium ethoxide ethanol solution were added sequentially. Under nitrogen protection, diethyl oxalate (26.7 g, 182.69 mmol) and compound 1-1 (20 g, 121.79 mmol) were added at 0 °C, and the mixture was 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 extracted separately. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain product compound 1-2 (29 g, yield: 90%), which was used directly in the next step.

[0280] ESI(m / z) = 263.1 [M-1]

[0281] Step 2: Compounds 1-2 (7 g, 26.49 mmol) were dissolved in dioxane (70 mL), and methylhydrazine sulfate (7.64 g, 52.98 mmol) was added with stirring. After the addition was complete, the reaction was carried out at 105 °C for 16 h, and the reaction was monitored by LCMS. The reaction solution was added to water (200 mL), extracted with ethyl acetate (2 x 500 mL), the organic phase was washed once with brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain compounds 1-3 (2.65 g, 36% yield).

[0282] ESI(m / z) = 275.2 [M+H] + RT = 3.657 min.

[0283] 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).

[0284] Step 3: Compounds 1-3 (2.65 g, 9.66 mmol) were dissolved in ethanol (30 mL) and water (10 mL), and sodium hydroxide (1.16 g, 29 mmol) was added with stirring. The reaction mixture was stirred at 20 °C for 16 h. The reaction was monitored by LCMS until completion. The reaction solution was concentrated to remove ethanol, and the pH was adjusted to 4 with 4N hydrochloric acid. The mixture was then stirred with water for 30 minutes, filtered, and the filter cake was dried to obtain compounds 1-4 (2.25 g, 95% yield).

[0285] ESI(m / z) = 247.1 [M+H] + RT = 3.005 min.

[0286] 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).

[0287] Step 4: Compounds 1-4 (150 mg, 0.61 mmol), 4-(3-aminopropyl)-piperazine-1-carboxylic acid tert-butyl ester (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 hour. The reaction was monitored by LCMS until completion. The reaction solution was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain a white solid compound 1-5 (245 mg, 85%).

[0288] ESI(m / z) = 472.4 [M+H] + RT = 2.803 min.

[0289] 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).

[0290] Step 5: Add compound 1-5 (245 mg, 0.52 mmol), HCl / Dioxane (2 mL, 4 mmol / mL), and methanol (2 mL) to the reaction flask, and react at 20 °C for 1 h. Monitor the reaction end by LCMS. Add saturated sodium bicarbonate aqueous solution dropwise to the reaction mixture, extract with ethyl acetate, dry with anhydrous sodium sulfate, and evaporate to dryness to obtain compound 1-6 (60 mg, 31%).

[0291] ESI(m / z) = 372.3 [M+H] + RT = 2.281 min.

[0292] Step 6: Compounds 1-6 (60 mg, 0.16 mmol), 4,4-difluorocyclohexanone (40 mg, 0.30 mmol), and sodium borohydride acetate (70 mg, 0.33 mmol) were dissolved in dichloromethane (5 mL) and sodium borohydride acetate. The reaction mixture was stirred at 20 °C for 16 h. The reaction was monitored by LCMS until completion. The reaction solution was quenched with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and subjected to column chromatography followed by lyophilization with water to obtain compound 1 (38.9 mg, 49%).

[0293] ESI(m / z) = 490.4 [M+H] + RT = 6.364 min.

[0294] 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).

[0295] Example 2

[0296]

[0297] Step 1: In a 500 mL three-necked flask, 120 mL of ethanol and 83 g (243.58 mmol) of 20% sodium ethoxide ethanol solution were added sequentially. Under nitrogen protection, diethyl oxalate (26.7 g, 182.69 mmol) and compound 1-1 (20 g, 121.79 mmol) were added at 0 °C, and the mixture was 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 extracted separately. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain product compound 1-2 (29 g, yield: 90%), which was used directly in the next step.

[0298] ESI(m / z) = 263.1 [M-1]

[0299] Step 2: Compounds 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 the mixture was stirred at 80 °C for 6 hours. The reaction mixture was brought to room temperature, concentrated under reduced pressure to remove ethanol, and water and ethyl acetate were added. The mixture was extracted separately, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed twice with an aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Column chromatography was performed to obtain product compounds 1-3 (11 g, yield: 75.7%).

[0300] ESI(m / z) = 275.1 [M+H]+

[0301] 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).

[0302] Step 3: Compounds 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. The mixture was stirred at room temperature for 4 hours. The reaction solution 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, filtered to obtain a filter cake, and dried to obtain product compound 1-4 (4.1 g, yield: 91%).

[0303] ESI(m / z) = 247.1 [M+H]+

[0304] Step 4: Compounds 1-4 (1 g, 4.06 mmol), 4-(3-aminopropyl)-piperazine-1-carboxylic acid tert-butyl ester (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 sequentially to a 100 mL single-necked flask and stirred at room temperature for 16 hours. Water and ethyl acetate were added to the reaction mixture, and the mixture was extracted separately. The aqueous phase was extracted twice with ethyl acetate, and 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 and subjected to column chromatography to obtain product compound 1-5 (1.4 g, yield: 73.11%).

[0305] ESI(m / z)=472.3[M+H]+

[0306] Step 5: Compound 1-5 (1.4 g, 2.97 mmol) and a 1,4-dioxane solution of hydrogen chloride (4 mol / L, 15 mL) were added sequentially to a 100 mL single-necked flask, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to obtain product compound 2-1 (1.2 g, yield: 99%). This was used directly in the next step.

[0307] ESI(m / z) = 372.3[M+H]+

[0308] Step 6: Compound 2-1 (55 mg, 0.13 mmol), dichloromethane (1 mL), and triethylamine (17 mg, 0.17 mmol) were added sequentially to a 25 mL single-necked flask. The mixture was stirred at room temperature for 2 minutes. Tetrahydropyranone (26 mg, 0.26 mmol) and acetic acid (20 mg, 0.33 mmol) were then added. The mixture was stirred at room temperature for 5 minutes. Sodium triacetoxyborohydride (55 mg, 0.26 mmol) was then added, and the mixture was stirred at 35 °C for 6 hours. Water and ethyl acetate were added to the reaction mixture, and the mixture was extracted separately. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed twice with brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The product compound 2 (16.2 mg, yield: 26.37%) was prepared by reverse phase reaction.

[0309] ESI(m / z) = 456.4 [M+H]+

[0310] 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).

[0311] Example 3

[0312]

[0313] Compound 2-1 (100 mg, 0.25 mmol), dichloromethane (2 mL), and triethylamine (33 mg, 0.33 mmol) were added sequentially to a 25 mL single-necked flask. The mixture was stirred at room temperature for 2 minutes. Cyclopentanone (42 mg, 0.50 mmol) and acetic acid (38 mg, 0.63 mmol) were then added, and the mixture was stirred at room temperature for 5 minutes. Sodium triacetoxyborohydride (110 mg, 0.50 mmol) was then added, and the mixture was stirred at 35 °C for 6 hours. Water and ethyl acetate were added to the reaction mixture, and the mixture was extracted separately. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with brine, 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 reaction.

[0314] ESI(m / z)=440.4[M+H]+

[0315] 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).

[0316] Example 4

[0317]

[0318] Compound 2-1 (100 mg, 0.25 mmol), dichloromethane (2 mL), and triethylamine (33 mg, 0.33 mmol) were added sequentially to a 25 mL single-necked flask. The mixture was stirred at room temperature for 2 minutes. Spiro[3.3]heptane-2-one (55 mg, 0.50 mmol) and acetic acid (38 mg, 0.63 mmol) were then added. The mixture was stirred at room temperature for 5 minutes. Sodium triacetoxyborohydride (110 mg, 0.50 mmol) was then added, and the mixture was stirred at 35 °C for 6 hours. Water and ethyl acetate were added to the reaction mixture, and the mixture was extracted separately. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed twice with brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The product compound 4 (54.6 mg, yield: 43.53%) was prepared by reverse phase reaction.

[0319] ESI(m / z) = 466.4 [M+H]+

[0320] 1H 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).

[0321] Example 5

[0322]

[0323] 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 the mixture was stirred at 60 °C for 4 hours. The reaction solution was allowed to return to room temperature, filtered, and the filtrate was reversed to prepare product compound 5 (24.1 mg, yield: 23.1%).

[0324] ESI(m / z) = 426.3[M+H]+

[0325] 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).

[0326] Example 6

[0327]

[0328] Compound 2-1 (100 mg, 0.25 mmol), dichloromethane (2 mL), and triethylamine (33 mg, 0.33 mmol) were added sequentially to a 25 mL single-necked flask. The mixture was stirred at room temperature for 2 minutes, followed by the addition of cyclobutanone (35 mg, 0.50 mmol) and acetic acid (38 mg, 0.63 mmol). The mixture was stirred at room temperature for 5 minutes, and then sodium triacetoxyborohydride (110 mg, 0.50 mmol) was added. The mixture was stirred at 35 °C for 6 hours. Water and ethyl acetate were added to the reaction mixture, and the mixture was extracted separately. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with brine, 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 reaction.

[0329] ESI(m / z) = 426.4 [M+H]+

[0330] 1 H 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).

[0331] Example 7

[0332]

[0333] Step 1: Compounds 1-3 (200 mg, 0.73 mmol), dichloromethane (3 mL), and m-chloroperoxybenzoic acid (370 mg, 1.82 mmol) were added sequentially to a 50 mL single-necked flask and stirred at room temperature for 4 hours. An aqueous solution of sodium sulfite and ethyl acetate were added to the reaction mixture, and the mixture was extracted separately. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with an aqueous solution of sodium bicarbonate and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain product compound 7-1 (185 mg, yield: 83%).

[0334] ESI(m / z) = 307.1 [M+H]+

[0335] 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. The mixture was stirred at room temperature for 4 hours. The reaction solution 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, filtered to obtain a filter cake, and dried to obtain product compound 7-2 (150 mg, yield: 89%).

[0336] ESI(m / z) = 279.0 [M+H]+

[0337] 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'-tetramethylurea hexafluorophosphate (210 mg, 0.54 mmol) were added sequentially to a 50 mL single-necked flask, and the mixture was stirred at room temperature for 16 hours. The reaction solution was filtered, and purified by reverse-phase preparation and TLC to obtain product compound 7 (42.1 mg, yield: 24.12%).

[0338] ESI(m / z) = 486.3[M+H]+

[0339] 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).

[0340] Example 8

[0341]

[0342] 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 the mixture was stirred at 80 °C for 6 hours. The reaction mixture was allowed to return to room temperature, and the ethanol was removed by concentration under reduced pressure. Water and ethyl acetate were added, and the mixture was extracted separately. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with an aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Column chromatography was performed to obtain product compound 8-1 (1.2 g, yield: 8.26%).

[0343] ESI(m / z) = 275.1 [M+H]+

[0344] 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. The mixture was stirred at room temperature for 4 hours. The reaction solution 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, filtered to obtain a filter cake, and dried to obtain the product compound 8-2 (160 mg, yield: 89%).

[0345] ESI(m / z) = 247.1 [M+H]+

[0346] 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'-tetramethylurea hexafluorophosphate (230 mg, 0.61 mmol) were added sequentially to a 50 mL single-necked flask. The mixture was stirred at room temperature for 16 hours. The reaction solution was filtered, and the product compound 8 (43.1 mg, yield: 21.24%) was prepared by reverse phase reaction.

[0347] ESI(m / z) = 454.3[M+H]+

[0348] 1H 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).

[0349] Example 9

[0350]

[0351] Step 1: 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) were dissolved in acetonitrile (8 mL) and reacted at 80 °C for 6 hours. LC-MS showed completion, followed by direct concentration and dry column chromatography to give compound 9-2 (0.8 g, yield: 50.79%). m / z [M+H] + =220

[0352] Step 2: Compound 9-2 (0.8 g, 2.50 mmol) was dissolved in dichloromethane (8 mL), followed by the addition of trifluoroacetic acid (2 mL) reaction solution. The mixture was stirred at 25 °C for 1 hour. LC-MS showed the reaction was complete. The reaction solution was concentrated and subjected to column chromatography to obtain compound 9-3 (0.4 g, yield: 72.82%). m / z [M+H] + =220.3

[0353] Step 3: Compounds 1-4 (0.1 g, 0.41 mmol), 9-3 (0.1 g, 0.45 mmol), and HATU (0.23 g, 0.61 mmol) were dissolved in DMF (1 mL) solution, and then DIPEA (0.16 g, 1.23 mmol) was added. The reaction mixture was stirred at 25 °C for 3 hours. LCMS showed that the reaction was complete. The reaction mixture was directly purified by reverse-phase column chromatography (5 kilohydrate formic acid and acetonitrile) to give compound 9 (23.2 mg, yield: 12.5%). m / z [M+H] + =448.4.

[0354] 1H 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).

[0355] Example 10

[0356]

[0357] 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) solution and reacted at 25 °C for 3 hours. LC-MS showed completion, followed by direct concentration and dry column chromatography to give compound 10 (58.8 mg, yield: 34.64%). m / z [M+H] + =462.3

[0358] 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).

[0359] Example 11

[0360]

[0361] 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) solution and reacted at 100 °C for 3 hours. LCMS showed completion. Extraction, concentration, and dry column chromatography were then performed to obtain compound 11-2 (0.8 g, yield: 74.41%). m / z [M+H] + =342.2

[0362] Step 2: Compound 11-2 (0.8 g, 2.34 mmol) was dissolved in ethanol (8 mL), followed by the addition of hydrazine hydrate (0.31 g, 4.91 mmol). The reaction mixture was stirred at 80 °C for 15 hours. LC-MS showed the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated to give compound 11-3 (0.3 g, yield: 60.58%). m / z [M+H] + =222.3.

[0363] Step 3: Compounds 1-4 (0.1 g, 0.41 mmol), 11-3 (0.14 g, 0.49 mmol), and HATU (0.23 g, 0.61 mmol) were dissolved in DMF (1 mL) solution, and then DIPEA (0.16 g, 1.23 mmol) was added. The reaction mixture was stirred at 25 °C for 3 hours. LC-MS showed that the reaction was complete. The reaction mixture was directly purified by reverse-phase column chromatography (5 kilohydrate formic acid and acetonitrile) to give compound 11 (31.6 mg, yield: 17.7%). m / z [M+H] + =440.4.

[0364] 1 H NMR(400MHz,DMSO-d6)1H NMR (400MHz, DMSO-d6) δ8.07(s,1H),7.84(dd,J=7.5,1.6Hz,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).

[0365] Example 12

[0366]

[0367] Step 1: Compounds 1-4 (0.2 g, 0.81 mmol), 12-1 (0.1 g, 0.97 mmol), and HATU (0.4 g, 1.05 mmol) were dissolved in 2 mL of DMF solution, and then DIPEA (0.31 g, 2.43 mmol) was added. The reaction mixture was stirred at 25 °C for 3 hours. LCMS showed that the reaction was complete. The reaction mixture was extracted and concentrated, and dry column chromatography was used to obtain compound 12-2 (0.2 g, yield: 73.33%). m / z [M+H]+ = 336.2.

[0368] 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) solution and reacted at 80 °C for 6 hours. LC-MS showed completion. The reaction solution was concentrated and then purified directly by reverse-phase column chromatography (5 kilohydrate formic acid and acetonitrile) to give compound 12 (22 mg, yield: 19.75%). m / z [M+H] + =468.4

[0369] 1 H 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).

[0370] Example 13

[0371]

[0372] 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) solution and reacted at 100 °C for 3 hours. LCMS showed completion. Extraction, concentration, and dry column chromatography were then performed to obtain compound 13-2 (0.4 g, yield: 60.34%). m / z [M+H] + =342.2

[0373] 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. LC-MS showed the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated to give compound 13-3 (0.9 g, yield: 74.92%). m / z [M+H] + =226.3

[0374] Step 3: Compounds 1-4 (0.13 g, 0.53 mmol), 13-3 (0.19 g, 1.21 mmol), and HATU (0.26 g, 0.69 mmol) were dissolved in 2 mL of DMF solution, and then DIPEA (0.21 g, 1.59 mmol) was added. The reaction mixture was stirred at 25 °C for 3 hours. LC-MS showed that the reaction was complete. The reaction mixture was directly purified by reverse-phase column chromatography (5 ppm formic acid aqueous solution and acetonitrile) to give compound 13 (14.2 mg, yield: 5.93%). m / z [M+H] + =440.4.

[0375] 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)

[0376] Example 14

[0377]

[0378] Step 1: Compounds 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. LC-MS showed completion. The reaction mixture was concentrated, extracted, and subjected to dry column chromatography to obtain compound 14-1 (0.6 g, yield: 44%). m / z [MH] + =289.1

[0379] 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 (2 mL) solution. The reaction mixture was stirred at 60 °C for 1 hour. LC-MS showed the reaction was complete. The pH of the reaction mixture was adjusted to 5, and the mixture was filtered. The filter cake was the obtained product, compound 14-2 (0.15 g, yield: 83.03%). m / z[M+H] + =261.1.

[0380] 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) solution, and then DIPEA (0.18 g, 1.38 mmol) was added. The reaction mixture was stirred at 25 °C for 3 hours. LC-MS showed that the reaction was complete. The reaction mixture was directly purified by reverse-phase column chromatography (5 kilohydrate formic acid and acetonitrile) to give compound 14 (22.2 mg, yield: 10.30%). m / z [M+H] + =468.4

[0381] 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).

[0382] Example 15

[0383]

[0384] Step 1: Compounds 1-2 (0.8 g, 3.03 mmol) and cyclopropylmethylhydrazine hydrochloride (0.31 g, 3.64 mmol) were dissolved in ethanol (8 mL). The reaction mixture was stirred at 80 °C for 1 hour. LC-MS showed completion. The reaction mixture was concentrated, extracted, and subjected to dry column chromatography to obtain compound 15-1 (0.6 g, yield: 63.05%). m / z [MH] + =315.2

[0385] 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 solution of 4 / 1 (3 mL). The reaction mixture was stirred at 60 °C for 1 hour. LC-MS showed the reaction was complete. The pH of the reaction mixture was adjusted to 5, and the mixture was filtered. The filter cake was the obtained product, compound 15-2 (0.13 g, yield: 62.06%). m / z[M+H] + =287.1.

[0386] 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) solution, and then DIPEA (0.14 g, 1.05 mmol) was added. The reaction mixture was stirred at 25 °C for 3 hours. LC-MS showed that the reaction was complete. The reaction mixture was directly purified by reverse-phase column chromatography (5 ppm formic acid aqueous solution and acetonitrile) to give compound 15 (59.3 mg, yield: 34.39%). m / z [M+H] + =468.4

[0387] 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).

[0388] Example 16

[0389]

[0390] 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. Then, diethyl oxalate (0.99 g, 6.75 mmol) was added, and the mixture was stirred at 40 °C for 1 h. LC-MS showed completion. The reaction solution was concentrated, extracted, and subjected to dry column chromatography to obtain compound 16-2 (1 g, yield: 35.81%). m / z [MH] + =247.0

[0391] 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. LC-MS showed the reaction was complete. The reaction mixture was concentrated and subjected to column chromatography to obtain compound 16-3 (0.6 g, yield: 57.67%). m / z [M+H] + =259.3.

[0392] 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 (2 mL) solution. The reaction mixture was stirred at 60 °C for 1 hour. LC-MS showed the reaction was complete. The pH of the reaction mixture was adjusted to 5, and the mixture was filtered. The filter cake was the obtained product, compound 16-4 (0.1 g, yield: 56.09%). m / z[M+H] + =231.1.

[0393] 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) solution, and then DIPEA (0.2 g, 1.56 mmol) was added. The reaction mixture was stirred at 25 °C for 3 hours. LC-MS showed that the reaction was complete. The reaction mixture was directly purified by reverse-phase column chromatography (5 kilohydrate formic acid and acetonitrile) to give compound 16 (63 mg, yield: 27.62%). m / z [M+H] + =438.4

[0394] 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).

[0395] Example 17

[0396]

[0397] Step 1: Compound 17-1 (5 g, 34.2 mmol) and sodium ethoxide (2.44 g, 35.91 mmol) were dissolved in 100 mL of ethanol and stirred at 0 °C for 0.5 h. Then, diethyl oxalate (5 g, 34.2 mmol) was added, and the mixture was stirred at 40 °C for 1 h. LC-MS showed completion. The reaction solution was concentrated, extracted, and subjected to dry column chromatography to obtain compound 17-2 (8.5 g, yield: 86.35%). m / z [MH] + =247.2

[0398] 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. LC-MS showed the reaction was complete. The reaction mixture was concentrated and subjected to column chromatography to obtain compound 17-3 (0.55 g, yield: 37.75%). m / z [M+H] + =257.2.

[0399] Step 3: Compound 17-3 (0.25 g, 0.98 mmol) and KOH (0.33 g, 5.88 mmol) were dissolved in a MeOH / H₂O = 4 / 1 (2 mL) solution. The reaction mixture was stirred at 60 °C for 1 hour. LC-MS showed the reaction was complete. The pH of the reaction mixture was adjusted to 5, and the mixture was filtered. The filter cake was the obtained product, compound 17-4 (0.1 g, yield: 56.09%). m / z[M+H] + =229.2.

[0400] 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) solution, and then DIPEA (0.2 g, 1.56 mmol) was added. The reaction mixture was stirred at 25 °C for 3 hours. LC-MS showed that the reaction was complete. The reaction mixture was directly purified by reverse-phase column chromatography (5 ppm formic acid aqueous solution and acetonitrile) to give compound 17 (50.8 mg, yield: 28.62%, formate). m / z [M+H] + =436.4

[0401] 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).

[0402] Example 18

[0403]

[0404] Step 1: Compounds 1-4 (0.14 g, 0.57 mmol), 18-1 (0.075 g, 0.68 mmol), and HATU (0.28 g, 0.74 mmol) were dissolved in 2 mL of DMF solution, and then DIPEA (0.22 g, 1.71 mmol) was added. The reaction mixture was stirred at 25 °C for 3 hours. LC-MS showed that the reaction was complete. The reaction mixture was extracted and concentrated, and dry column chromatography was used to obtain compound 18-2 (0.18 g, yield: 92.3%). m / z [M+H] + =338.1.

[0405] 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) solution and reacted at 80 °C for 6 hours. LC-MS showed completion. The reaction solution was concentrated and then purified directly by reverse-phase column chromatography (5 kilohydrate formic acid and acetonitrile) to give compound 18 (63 mg, yield: 25.5%). m / z [M+H] + =464.3

[0406] 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, 5.0 Hz, 2H), 2.57 ( q, J = 5.8, 5.4 Hz, 2H), 2.42 ( td, J = 12.5, 10.9, 6.2 Hz, 2H).

[0407] Example 19

[0408]

[0409] Compounds 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) solution and reacted at 110 °C for 4 h. LC-MS showed completion, followed by direct concentration and purification directly by reverse-phase column chromatography (5 kilohydrate formic acid and acetonitrile) to give compound 19 (33.5 mg, yield: 27.74%). m / z [M+H] + =449.3

[0410] 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).

[0411] Example 20

[0412]

[0413] Compounds 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) solution and reacted at 110 °C for 15 h. LC-MS showed completion, followed by direct concentration and purification directly by reverse-phase column chromatography (5 kilohydrate formic acid and acetonitrile) to give compound 20 (9.9 mg, yield: 8.2%). m / z [M+H] + =449.3

[0414] 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).

[0415] Example 21

[0416]

[0417] Compounds 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) solution and reacted at 110 °C for 15 h. LC-MS showed completion, followed by direct concentration and purification by Pre-TLC to give compound 21 (29.8 mg, yield: 27.1%). m / z [M+H] + =449.3

[0418] 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).

[0419] Example 22

[0420]

[0421] Compounds 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) solution and reacted at 110 °C for 15 h. LC-MS showed completion, followed by direct concentration and purification directly by reverse-phase column chromatography (5 kilohydrate formic acid and acetonitrile) to give compound 22 (27 mg, yield: 20.77%). m / z [M+H] + =449.3

[0422] 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).

[0423] Example 23

[0424]

[0425] Step 1: Compounds 1-4 (0.15 g, 0.61 mmol), 23-1 (0.086 g, 0.73 mmol), and HATU (0.3 g, 0.79 mmol) were dissolved in 2 mL of DCM solution, and then DIPEA (0.24 g, 1.83 mmol) was added. The reaction mixture was stirred at 25 °C for 3 hours. LC-MS showed that the reaction was complete. The reaction mixture was extracted and concentrated, and dry column chromatography was used to obtain compound 23-2 (0.18 g, yield: 87.09%). m / z [M+H] + =340.1.

[0426] 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. LC-MS showed completion. The reaction mixture was concentrated and purified by column chromatography to give compound 23-3 (0.25 g, yield: 75.27%). m / z [M+H] + =418.2.

[0427] 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) solution and reacted at 105 °C for 5 days. LC-MS showed completion. The reaction solution was concentrated and then purified directly by reverse-phase column chromatography (5.2 mg of formic acid aqueous solution and acetonitrile) to give compound 23 (yield: 2.99%). m / z [M+H] + =484.3.

[0428] 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).

[0429] Example 24

[0430]

[0431] Compounds 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) solution and reacted at 110 °C for 5 h. LC-MS showed completion, followed by direct concentration and purification directly by reverse-phase column chromatography (5 kilohydrate formic acid and acetonitrile) to give compound 24 (32 mg, yield: 24.66%). m / z [M+H] + =482.3.

[0432] 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).

[0433] Example 25

[0434]

[0435] 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) were added sequentially to an 8 mL single-necked flask. Under nitrogen protection, 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (12 mg, 0.025 mmol) and tris(dibenzylacetone)palladium (11 mg, 0.013 mmol) were added. The mixture was stirred at 105 °C for 16 hours under nitrogen protection. The reaction solution was allowed to return to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The product compound 25 (42.8 mg, yield: 36.22%) was prepared by reverse phase reaction. ESI (m / z) = 482.3 [M+H] + .

[0436] 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).

[0437] Example 26

[0438]

[0439] Compound 2-1 (100 mg, 0.25 mmol), p-bromotrifluorotoluene (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. Under nitrogen protection, 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (12 mg, 0.025 mmol) and tris(dibenzylacetone)palladium (11 mg, 0.013 mmol) were added. The mixture was stirred at 105 °C for 16 hours under nitrogen protection. The reaction mixture was allowed to return to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The product compound 26 (36.2 mg, yield: 28.6%) was prepared by reverse phase reaction. ESI (m / z) = 516.3 [M+H] + .

[0440] 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).

[0441] Example 27

[0442]

[0443] Referring to the synthesis method of Example 26, using Compound 27 was synthesized by replacing p-bromotrifluorotoluene.

[0444] 1 H 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).

[0445] Example 28

[0446]

[0447] Referring to the synthesis method of Example 26, using Compound 28 was synthesized by replacing p-bromotrifluorotoluene.

[0448] 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).

[0449] Example 29

[0450]

[0451] Referring to the synthesis method of Example 26, using Compound 29 was synthesized by replacing p-bromotrifluorotoluene.

[0452] 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).

[0453] Example 30

[0454]

[0455] Referring to the synthesis method of Example 13, using By replacing 11-4, compound 30 was synthesized.

[0456] 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).

[0457] Example 31

[0458]

[0459] Referring to the synthesis method of Example 13, using By replacing 11-4, compound 31 was synthesized.

[0460] 1H 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).

[0461] Example 32

[0462]

[0463] Referring to the synthesis method of Example 13, using By replacing 11-4, compound 32 was synthesized.

[0464] 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).

[0465] Example 33

[0466]

[0467] Referring to the synthesis method of Example 23, using replace Compound 33 was synthesized.

[0468] 1H 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).

[0469] Example 34

[0470]

[0471] Referring to the synthesis method of Example 23, using replace Compound 34 was synthesized.

[0472] 1 H 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).

[0473] Example 35

[0474]

[0475] Referring to the synthesis method of Example 23, using replace Compound 35 was synthesized.

[0476] 1H 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).

[0477] Example 36

[0478]

[0479] Referring to the synthesis method of Example 13, using By replacing 11-4, compound 36 was synthesized.

[0480] 1 H 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).

[0481] Example 37

[0482]

[0483] Referring to the synthesis method of Example 23, using replace Compound 37 was synthesized.

[0484] 1H 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).

[0485] Example 38

[0486]

[0487] Step 1: Compounds 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) were dissolved in DMF (3 mL). 1-Amino-3,3-diethoxypropane (90 mg, 0.61 mmol, 1.0 eq) was added to the reaction solution. The reaction solution was stirred overnight at room temperature. After the reaction was complete, the reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (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 give crude product 100-1 (300 mg).

[0488] 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 solution. Stir the reaction solution at room temperature for 1 hour. After the reaction is complete, dilute the reaction solution with water (30 mL), then extract with ethyl acetate (3 × 10 mL). Combine the organic phases, wash with saturated brine (20 mL), dry to anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude 100-2 (57 mg crude). LCMS: m / z = 302.1 [M+H] +

[0489] Step 3: Dissolve 100-2 (53 mg crude, 0.18 mmol, 1.5 eq) and 100-3 (40 mg, 0.12 mmol, 1.0 eq) in MeOH (1 mL), and add NaBH3CN (14 mg, 0.22 mmol, 2.0 eq) to the reaction solution. Stir the reaction solution overnight at room temperature. After the reaction is complete, quench the reaction solution with water (20 mL), then extract with ethyl acetate (3 × 10 mL). Combine the organic phases, wash with saturated brine (20 mL), dry to anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is purified by preparative thin-layer chromatography to obtain the free product. The free product is soluble in methanol, and formic acid is added to form a salt. The resulting solution is concentrated under reduced pressure to obtain a colorless oily compound 100 (17 mg, 37%). 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).

[0490] Following the synthetic method of compound 100, the following compounds were synthesized by replacing 100-3 with the corresponding amine.

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497] Example 39

[0498]

[0499] 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 reaction was carried out at 60 °C for 8 hours. LC-MS showed completion. The mixture was then filtered, the filtrate was concentrated, and dry-column chromatography (PE / EA = 50%) was performed to give 39-1 (0.61 g, yield: 50.15%). m / z [M+H] + =376.4

[0500] Step 2: Dissolve 39-1 (0.61 g, 1.62 mmol) and hydrazine hydrate (wt 80%, 0.2 g, 3.24 mmol) in ethanol (10 mL) and heat to 80 °C overnight. LC-MS showed completion. The mixture was then filtered, and the filtrate was concentrated to form a solid. This solid was then slurried with petroleum ether, filtered again, and the filtrate was further concentrated to obtain 39-2 (0.35 g, yield: 87.8%).

[0501] Step 3: Compounds 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 2 mL DMF solution, followed by DIPEA (0.17 g, 1.29 mmol). The reaction was carried out at room temperature for 3 h. LC-MS showed completion, and direct reversed-phase column chromatography yielded product 39 (0.065 g, yield: 31.89%). 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).

[0502] Example 40

[0503]

[0504] 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

[0505] Example 41

[0506]

[0507] Step 1: Add 49-1 (450 mg, 1.50 mmol) and 49-2 (280 mg, 1.80 mmol) and N,N-dimethylformamide (4 mL) sequentially to a 50 mL single-necked flask, followed by potassium carbonate (510 mg, 3.75 mmol). Stir at 60°C for 16 hours. Add water and ethyl acetate to the reaction mixture, and extract separately. Extract twice with ethyl acetate. Combine the organic phases, dry the organic phase to anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and perform column chromatography to obtain 49-3 (420 mg, yield: 85.7%). LCMS m / z [M+H] + =324.3

[0508] Step 2: Add 49-3 (320 mg, 0.99 mmol), methanol (1 mL), and 1,4-dioxane solution (4 M, 4 mL) of HCl sequentially to a 50 mL single-necked flask, and stir at room temperature for 16 hours. Concentrate the reaction solution to dryness under reduced pressure to obtain 49-4 (200 mg, yield: 61%), which can be used directly in the next step.

[0509] Step 3: In a 50 mL single-necked flask, add 1-4 (100 mg, 0.41 mmol), 49-4 (160 mg, 0.49 mmol), and N,N-dimethylformamide (2 mL), followed by N,N-diisopropylethylamine (320 mg, 2.46 mmol) and (7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (180 mg, 0.47 mmol). Stir at room temperature for 4 hours. Filter the reaction solution, and directly purify the filtrate by reverse-phase column chromatography to obtain 49 (50.4 mg, yield: 27.5%). 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

[0510] Example 42

[0511]

[0512] Following the synthesis method of Example 30, 16-4 was used instead of 1-4 to synthesize compound 50. 1 HNMR (400MHz, DMSO-d6) δ8.56(t,J=5.6Hz,1H),7.73(dd,J=7.8,1.5Hz,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

[0513] Example 43

[0514] Referring to the synthesis method of Example 13, the following compounds were synthesized by replacing 11-4 with the corresponding amine fragments.

[0515]

[0516] Example 44

[0517]

[0518] Step 1: Add 38-2 (700mg, 2.32mmol) and... to a 100mL single-necked flask. (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). The mixture was 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 sodium hydroxide aqueous solution. The mixture was extracted separately, twice with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Column chromatography was used to purify the solution to give 41-1 (700 mg, yield: 54.3%). LCMS m / z [M+H] + =555.4

[0519] Step 2: Add 41-1 (200 mg, 0.36 mmol), methanol (1 mL), and 1,4-dioxane solution (4 M, 4 mL) of HCl sequentially to a 25 mL single-necked flask, and stir at room temperature for 4 hours. Concentrate the reaction solution to dryness under reduced pressure, and purify by reverse-phase column chromatography to obtain 41 (125.7 mg, yield: 76.6%) as its 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

[0520] Referring to the synthetic method of compound 41, using replace Compound 55 was synthesized. 1 HNMR(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

[0521] Example 45

[0522]

[0523] 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

[0524] Example 46

[0525]

[0526] Step 1: Put Dissolve 679.6 mg (4.0 mmol, 1.0 eq) and 80-1 (800 mg, 4.0 mmol, 1.0 eq) in DCE (10 mL), and add 2 drops of acetic acid. Stir the reaction mixture at room temperature for 0.5 h, then cool to 0 °C. Subsequently, add NaBH(OAc)3 (1.69 g, 8.0 mmol, 2.0 eq) in portions to the reaction mixture. Stir the reaction mixture at 0 °C for 5 min, then move it to room temperature and stir overnight at room temperature. After the reaction is complete, dilute the reaction mixture with water (50 mL), adjust the pH to alkaline with saturated NaHCO3 solution, and extract with ethyl acetate (3 × 40 mL). Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the crude product by silica gel column chromatography (eluent: dichloromethane: methanol = 10:1) to obtain a yellow oily compound 80-2 (640 mg, 45%). LCMS m / z = 353.3 [M+H] +

[0527] Step 2: Compound 80-2 (640 mg, 1.81 mmol, 1.0 eq) was dissolved in DCM (7 mL), and HCl solution (4-min dioxane, 7 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 3 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give a white solid compound 80-3 (630 mg, 100%). LCMS m / z = 253.3 [M+H] +

[0528] Step 3: Referring to the synthesis method of compound 13, replace 13-3 with 61-3 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

[0529] Example 47

[0530] Referring to the synthetic method of compound 80, the corresponding amine fragment was used instead. The following compounds were synthesized by replacing 1-4 with the corresponding acid fragments.

[0531]

[0532]

[0533]

[0534] Example 48

[0535]

[0536] Step 1: Under nitrogen protection, compound 68-1 (923 mg, 5.05 mmol, 1.0 eq) was dissolved in THF (9 mL), and the mixture was cooled to -78 °C. NaHMDS (2 M in THF, 5.1 mL, 10.11 mmol, 2.0 eq) was added dropwise to the reaction solution, and the mixture was 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 solution. The reaction solution was stirred at -78 °C for 10 min, then cooled to room temperature and stirred at room temperature for 1.5 h. After the reaction was complete, the reaction solution was quenched with saturated NH4Cl solution and extracted with ethyl acetate (3 × 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 give a white solid compound 68-2 (1.9 g, 100%). LCMS m / z = 283.1 [M+H] + .

[0537] Step 2: Compound 68-2 (1.8 g, 6.37 mmol) was dissolved in EtOH (45 mL), and methylhydrazine (293.4 mg, 6.37 mmol) was added to the reaction solution. The reaction solution was stirred at room temperature for 4 h. After the reaction was complete, the reaction solution was concentrated. The crude product was 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] + ; 1H 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] + ; 1 H 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).

[0538] 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)). Stir the reaction mixture at 60 °C for 3 h. After the reaction is complete, adjust the pH of the reaction mixture to 3–4 with 2N HCl solution, and extract with DCM (3 × 20 mL). Combine the organic phases, wash with saturated brine (40 mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a white solid compound 68-4a (200 mg, 100%). 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).

[0539] 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 mixture 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 it dropwise to the reaction mixture. Stir the reaction mixture at room temperature for 2.5 h. After the reaction is complete, dilute the reaction mixture with water (40 mL), and then extract with ethyl acetate (3 × 30 mL). Combine the organic phases, wash with saturated brine (40 mL), dry to anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by preparative chromatography to obtain a white solid compound 68 (26 mg, 28%). LCMS m / z = 487.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6)δ

[0540] 8.72–8.59(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).

[0541] Referring to the synthesis procedure of compound 68, in step 3, 68-3b was used instead of 68-3a to synthesize compound 117. 1 HNMR(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] +

[0542] Example 49

[0543] 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 68-5 with the corresponding amine fragment.

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550] Example 50

[0551]

[0552] Step 1: Put A mixture of 200 mg (0.59 mmol, 1.0 eq) and 1-methylpyrazole-4-boronic acid tinane ester (370 mg, 1.78 mmol, 3.0 eq) was placed in dioxane (4 mL) and water (1 mL). 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 mixture was purged three times with nitrogen and stirred at 90 °C under nitrogen protection for 2 hours. After the reaction was complete, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 30 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. The crude product was 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] +

[0553] 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] + . 1H 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).

[0554] Example 51

[0555] Referring to the synthetic method of compound 95, replace it with the corresponding boric acid or borate ester. Replace with the corresponding bromine fragment The following compounds were synthesized by replacing 68-5 with the corresponding amine fragment.

[0556]

[0557]

[0558]

[0559] Example 52

[0560]

[0561] Step 1: Under nitrogen protection, (300 mg, 0.89 mmol, 1.0 eq) was dissolved in DMF (10 mL). 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 complete, the reaction solution was filtered, the filtrate was diluted with water (100 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 purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether: = 1:1) to give a yellow solid 94-1 (140 mg, 55%). LCMS: m / z = 284.1 [M+H] +

[0562] Step 2: Following the synthetic method for 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).

[0563] Example 53

[0564]

[0565] Following the synthetic method of compound 30, compound 75 was synthesized by replacing 1-4 with 7-2. LCMS m / z = 501.3 [M+H] + ; 1 H 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).

[0566] Example 54

[0567]

[0568] 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 acetonitrile (2 mL) solution and reacted overnight at room temperature. LCMS showed completion. The mixture was extracted, concentrated, and purified by preparative thin-layer chromatography to give 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.

[0569] Example 55

[0570] Referring to the synthetic method of compound 94, the corresponding bromine fragment was used instead. By replacing 68-5 with the corresponding amine fragment, the following compounds were synthesized. It was prepared using the same method as intermediate 83-2.

[0571]

[0572]

[0573]

[0574] Example 56

[0575]

[0576] Step 1: Compound 1-2 (6.0 g, 22.7 mmol, 1.0 eq) was dissolved in EtOH (60 mL), and hydrazine hydrate (1.42 g, 22.7 mmol, 1.0 eq) was added to the solution. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 8:1) to give 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] +

[0577] Step 2: Referring to the synthesis method of compound 14, replace 14-1 with 83-1 and replace 7-3 with 68-5 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] +

[0578] Example 57

[0579]

[0580] Step 1: Compound 83-1 (2.0 g, 7.69 mmol) was dissolved in DMF (30 mL). Cesium carbonate (3.76 g, 11.53 mmol) and 3-iodooxetane (1.7 g, 9.23 mmol) were added to the reaction solution. The reaction solution was stirred at 110 °C for 1 h. After the reaction was complete, the reaction solution was diluted with water (200 mL) and then extracted 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 crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to give yellow solid compound 88-1a (170 mg, 2.88%) and yellow solid compound 88-1b (1.3 g, 53.43%). 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] +

[0581] 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 (NaOH (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 the reaction was complete, 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 give a yellow solid compound 88-2a (57 mg, 100%). LCMS m / z = 289.0 [M+H] +

[0582] Step 3: Compound 88-2a (57 mg, 0.198 mmol), HATU (112.93 mg, 0.297 mmol), and DIEA (76.77 mg, 0.594 mmol) were dissolved in DMF (2 mL), and 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 the reaction was complete, 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 purified by preparative 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] +

[0583] Following the synthetic method of compound 88, compound 89 was synthesized by replacing 88-1a with 88-1b. 1 H NMR(400MHz,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), 3.32–3.10(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] +

[0584] Example 58

[0585]

[0586] Following the synthetic method of compound 88, compound 90 was synthesized by replacing 3-iodooxetine with 1-chloro-2-methyl-2-propanol. 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–

[0587] 2.54(m,16H),1.90–1.72(m,6H),1.19(s,6H).LCMS:m / z=527.3[M+H] +

[0588] Example 59

[0589] Referring to the synthetic method of compound 83, using By replacing 1-2 and replacing 68-5 with a suitable amine fragment, the following compounds were synthesized.

[0590]

[0591]

[0592] Example 60

[0593]

[0594] Step 1: Place the 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). 4-MetBuXPhos (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 three times with nitrogen and stirred at 120 °C under nitrogen protection for 5 hours. After the reaction was complete, 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 purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to give a white solid compound 124-1 (100 mg, 34.6%). 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).

[0595] Step 2: Referring to the synthetic route of compound 95, 95-1 was replaced with 124-1 to synthesize compound 124. LCMSm / 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).

[0596] Effect Example

[0597] Cell IC50 detection

[0598] (1) Cell preparation: Prepare cells in good growth condition, digest and dilute them. For liver cancer cells (PLC / PRF / 5, from the Chinese Academy of Sciences; MHCC97H, from our institute), generally 1000-5000 cells / well are seeded into 96-well plates and cultured in an incubator at 37℃ and 5% CO2. After 24 hours of cell adhesion, drugs are added.

[0599] (2) Drug dilution: The drug is serially diluted, generally with 9 concentrations, and a control group with drug-free culture medium and solvent is set up;

[0600] Add the diluted drug to the cell plate on which cells were plated the day before, and incubate for 72 hours.

[0601] (3) CCK8 detection of cell viability: CCK8 was mixed with culture medium at a ratio of 1:10, added to cell plate 96, 100ul / well, and after standing for 2 hours, the value was read by microplate reader.

[0602] (4) Analyze the data: Organize the data, plot the IC50 curve, and find the IC50 isovalue;

[0603] (5) Validate IC50: Find the theoretical value of IC50 based on the IC50 curve, and verify the drug concentration by taking 1 / 2, 1, and 2 times the theoretical value respectively.

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619]

[0620]

[0621] "\" indicates that it has not been tested.

Claims

1. A compound of formula (IIIA) or a pharmaceutically acceptable salt thereof; or a compound of formula (IIIB) or a pharmaceutically acceptable salt thereof, characterized in that, or In formula (IIIA), for , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; In formula (IIIB), for , , , , , or ; E is -NH- or ; # indicates the end connected to -C(O)- in formula (IIIA) or formula (IIIB); L is , , , or ; Ring B is , , or ; U is , , , , , , , , , , , , , , , , , , , , , , -NH2, , , , or ; Furthermore, the compound represented by formula (IIIA) or the compound represented by formula (IIIB) is not any of the following compounds: , , , or .

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, E is -NH-.

3. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The compound is any one of the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

4. A pharmaceutical composition comprising substance A and a pharmaceutically acceptable excipient, wherein substance A is a compound of formula (IIIA) or a pharmaceutically acceptable salt thereof, a compound of formula (IIIB) or a pharmaceutically acceptable salt thereof, or a compound of claim 3 or a pharmaceutically acceptable salt thereof; or , in, , E, L, ring B and U are as defined in claim 1.

5. The use of substance A as described in claim 4 or the pharmaceutical composition as described in claim 4 in the preparation of a KSR2-AMPK inhibitor.

6. The application as described in claim 5, characterized in that, The KSR2-AMPK inhibitor is used in mammalian organisms.

7. The application as described in claim 5, characterized in that, The KSR2-AMPK inhibitor is used for experimental purposes in vitro.

8. The application as described in claim 7, characterized in that, The experimental purpose is to provide a standard or control sample for comparison, or to prepare a kit to provide rapid detection of the effect of inhibiting KSR2-AMPK.

9. The use of substance A as described in claim 4 or the pharmaceutical composition as described in claim 4 in the preparation of a medicament, wherein the medicament is used to treat and / or prevent diseases or disorders related to KSR2-AMPK; wherein substance A is in a therapeutically effective amount.

10. The application as described in claim 9, characterized in that, The diseases or disorders associated with KSR2-AMPK are cancer.

11. The application as described in claim 10, characterized in that, The cancer in question is liver cancer.

12. The use of substance A as described in claim 4 or the pharmaceutical composition as described in claim 4 in the preparation of a medicament, wherein the medicament is used to treat and / or prevent cancer; and wherein substance A is a therapeutically effective amount.

13. The application as described in claim 12, characterized in that, The cancer in question is liver cancer.

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