Tricyclic skeletal compounds and their applications in the manufacture of antitumor drugs

Abstract

The present invention discloses tricyclic skeletal compounds and their application in the manufacture of antitumor drugs, specifically providing a compound represented by formula (IA) or a pharmaceutically acceptable salt thereof. The tricyclic skeletal compounds of the present invention can effectively inhibit the proliferation of tumor cells.

Description

Technology Field

[0001] The present application claims priority to Chinese patent application 2024103339139, filed on March 22, 2024, and Chinese patent application 2024118381355, filed on December 13, 2024. The present application incorporates the full text of the aforementioned Chinese patent applications.

[0002] The present invention relates to tricyclic skeletal compounds and their application in the manufacture of antitumor drugs. Background Technology

[0003] Cancer is an ongoing public health challenge currently faced by the entire world. As the world's second-leading cause of death, it is predicted to become the primary obstacle to increasing life expectancy in the 21st century. The burden of cancer is gradually increasing globally. Cancer is the leading cause of death among Chinese residents, and the burden of malignant tumor diseases in China is showing an upward trend. It is also a major disease that affects the probability of premature death from major chronic diseases and life expectancy per capita. Therefore, identifying effective diagnostic and therapeutic targets can contribute to humanity achieving a breakthrough in the field of cancer treatment.

[0004] As research advances, humanity is gaining a deeper understanding of cancer. Since the 21st century, 14 major characteristics of cancer have been identified. Numerous related signaling or metabolic pathways have been studied based on these characteristics, and based on this, related targets are being discovered and new drugs are being developed.

[0005] The mitogen-activated protein kinase (MAPK) signaling pathway is an important pathway in the development and progression of tumors. The MAPK pathway transmits signals based on a three-step kinase phosphorylation scheme (e.g., Raf-MEK-ERK). Proteins of the Ras kinase inhibitor (KSR) family are important scaffold proteins of the MAPK pathway and act as positive regulators of the signaling pathway. KSR2 is a member of this family and, as a scaffold protein, binds to RAF, MEK, and ERK to form a complex and participates in the regulation of the MAPK signaling pathway. Crystal structure studies of the KSR2 kinase domain revealed that KSR2 is a key molecule in Raf-induced MEK phosphorylation (cf. BRENNAN DF, DAR AC, HERTZ NT, et al. A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK [J]. Nature, 2011, 472(7343): 366-9). KSR2 can directly phosphorylate AMPK and regulates metabolic processes mediated by the energy sensor AMPK, such as glucose uptake and fatty acid oxidation, as well as insulin sensitivity (cf. COSTANZO-GARVEY DL, PFLUGER PT, DOUGHERTY MK, et al. KSR2 is an essential regulator of AMP kinase, energy expenditure, and insulin sensitivity [J]. Cell Metab, 2009, 10(5): 366-78). The inventors have demonstrated the tumor-promoting activity of KSR2 at the cellular, molecular, and animal levels (Reference: FERNANDEZ MR, HENRY MD, LEWIS R E. Kinase suppressor of Ras 2 (KSR2) regulates tumor cell transformation via AMPK [J].Mol Cell Biol, 2012, 32(18): 3718-31, GAO C, WANG SW, LU JC, et al. KSR2-14-3-3zeta complex serves as a biomarker and potential therapeutic target in sorafenib-resistant hepatocellular carcinoma [J]. Biomark Res, 2022, 10(1): 25), identified the key mechanism by which the KSR2-14-3-3zeta complex activates AMPK to participate in oxidative phosphorylation and acquires stem cell characteristics, thereby achieving targeted drug resistance. Currently, there are no cases of KSR2 inhibitors entering clinical trials. Based on this, the inventors developed a small molecule inhibitor of the KSR2-AMPK pathway for use in the treatment of KSR2 protein-related tumors. The problem to be solved

[0006] The technical problem to be solved by the present invention is the issue of the monolithiasis of conventional cancer targeted therapy drugs. To solve this, the invention provides a tricyclic backbone compound and its application in the manufacture of antitumor drugs. The tricyclic backbone compound can effectively inhibit the proliferation of tumor cells. means of solving the problem

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

[0008]

[0009] Ring C is a benzene ring or a "5-6-membered heteroaryl ring in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and

[0010] Each R1 is independently a halogen, cyano group, C 1-6 Alkyl group, C 3-10 Cycloalkyl group, C 1-6 Alkoxy group, C substituted with one or more halogens 1-6C substituted with an alkyl group or one or more halogens 1-6 Alkoxy group, "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or one or more R 1-1 It is a "5-10-membered heteroaryl group substituted with , in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and

[0011] Each R 1-1 C each independently 1-6 It is an alkyl group, and

[0012] m and k are independently 0, 1, or 2, respectively, and

[0013] X1 is -CH2-, -O-, -S-, -NH- or -S(=O)2-, and

[0014] X2 is -C(R a R b )- or -O- and,

[0015] R a and R b Each independently hydrogen, deuterium, or C 1-6 It is an alkyl group, or R a , R b and the carbon atoms they share are connected to form a 3-10 saturated carbon ring,

[0016] n is 0 or 1, and

[0017] each " Each represents a single bond or a double bond independently,

[0018] X3 and X4 are each independently C or N, and

[0019] Ring A is a pyrazol ring, and

[0020] Each R2 is independently H, halogen, and C 1-6 Alkyl group, C 3-10Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", C 6-10 Aryl group, one or more R 2-1 C substituted with 1-6 alkyl group or one or more R 2-2 It is a "5-10-membered heteroaryl group substituted with , in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and

[0021] Each R 2-1 and R 2-2 Each independently consists of a halogen, a hydroxyl group, and C 1-6 Alkyl group, -N(R 2a R 2b ), C 3-10 Cycloalkyl group, C 1-6 Alkoxy group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", C 6-10 An aryl group or "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and

[0022] R 2a and R 2b Each independently H or C 1-6 It is an alkyl group, and

[0023] E is -N(R3)- or and, n1 is 1, 2 or 3, and # represents one end connected to -C(O)- in expression (IA), and

[0024] R3 is hydrogen, C 1-6 alkyl group or C 3-10 It is a cycloalkyl group, and

[0025] L is C 1-6 Alkylene group, one or more R L C substituted with 1-6 Alkylene group, "-(C1-6 Alkylene group)-L A -*" or -L A - and,

[0026] Each R L Each independently deuterium, C 1-6 Alkoxy group, C 3-10 It is a cycloalkyl group, a hydroxyl group, a halogen or an oxo group (=O), or two Rs L If substituted into this same carbon atom, 2 R L and the carbon atoms they share are connected to form a 3-10-membered saturated carbon ring or a "3-10-membered saturated heteroring in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and

[0027] L A -C(O)NH-, -O-, -N(R LA )-, ethenylene group, ethinylene group, 3-10 saturated carbon ring or "a 3-10 saturated heterocycle in which one, two, or three heterovalence atoms are selected from N, O, and S, and the number of heterovalence atoms is one, two, or three", and

[0028] R LA is H, C 1-6 Alkyl group, C 3-10 A cycloalkyl group or a "3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", and

[0029] Ring B is a 3-10-membered saturated or unsaturated carbon ring, with one or more R B-1 A 3-10-membered saturated or unsaturated carbon ring substituted with, "a 3-10-membered saturated or unsaturated heterocycle in which one, two, or three heterovalence atoms are selected from N, O, and S, and the number of heterovalence atoms is one, two, or three" or one or more of R B-2It is a "3-10 saturated or unsaturated heterocycle in which the heteroatoms are 1, 2, or 3 selected from N, O, and S and the number of heteroatoms is 1, 2, or 3" substituted with, and

[0030] Each R B-1 and R B-2 Each independently consists of a hydroxyl group, a halogen, an oxo group (=O), and C 1-6 Alkyl group, C 1-6 C substituted with an alkoxy group or one or more hydroxyl groups 1-6 It is an alkyl group, and

[0031] If U does not exist, ring B is And,

[0032] U does not exist, or -N(R')(R"), C 3-6 Alkyl group, one or more R U-1 C substituted with 1-6 Alkyl group, C 3-10 Cycloalkyl group, one or more R U-2 C substituted with 3-10 Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", one or more R U-3 "a 3-10-membered heterocycloalkyl group substituted with, wherein one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", C 6-10 Aryl group, one or more R U-4 C substituted with 6-10 Aryl group, "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", one or more Rs U-5 "a 5-10-membered heteroaryl group substituted with , in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or -XR U-6 And,

[0033] X is -C(O)-, -SO2- or -O-, and

[0034] Each R' and R" is independently hydrogen, C 1-6 Alkyl group, -C(O)-C 3-10 C substituted with a cycloalkyl group or one or more R"' 1-6 It is an alkyl group, and R"' is independently C 6-10 Arilgi,

[0035] Each R U-1 -N(R')(R"), halogen, C, respectively, independently 3-10 Cycloalkyl group, C 6-10 An aryl group, "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or one or more R U-1-1 It is a "5-10-membered heteroaryl group substituted with , in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and

[0036] Each R U-1-1 C each independently 1-6 It is an alkyl group, and

[0037] Each R U-2 , R U-3 , R U-4 and R U-5 Each independently consists of a halogen, cyano group, hydroxyl group, and -SO2-C 1-6 Alkyl group, -C(O)-C 1-6 Alkyl group, -C(O)OC 1-6 Alkyl group, -C(O)NH-C 1-6 Alkyl group, C 1-6 Alkyl group, one or more R U-3-1 C substituted with 1-6 Alkyl group, C 1-6 Alkoxy group, one or more R U-3-2 C substituted with 1-6 Alkoxy group, C 3-10A cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or -O-"a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", and

[0038] Each R U-3-1 and R U-3-2 Each independently halogen, C 3-10 Cycloalkyl group, C 6-10 Arylgi, C 1-6 an alkoxy group, a hydroxyl group, a cyano group, or a "3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", and

[0039] Each R U-6 C each independently 6-10 An aryl group or "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and

[0040] The compound represented by formula (I) is not any of the following compounds.

[0041]

[0042] and

[0043]

[0044] The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and

[0045]

[0046] Ring C is a benzene ring or a "5-6-membered heteroaryl ring in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and

[0047] Each R1 is independently a halogen, cyano group, C 1-6 Alkyl group, C 3-10 Cycloalkyl group, C 1-6 Alkoxy group, C substituted with one or more halogens 1-6 C substituted with an alkyl group or one or more halogens 1-6 It is an alkoxy period, and

[0048] m and k are independently 0, 1, or 2, respectively, and

[0049] X1 is -CH2-, -O-, -S-, -NH- or -S(=O)2-, and

[0050] X2 is -C(R a R b )- or -O- and,

[0051] R a and R b Each independently hydrogen, deuterium, or C 1-6 It is an alkyl group, or R a , R b and the carbon atoms they share are connected to form a 3-10 saturated carbon ring,

[0052] n is 0 or 1, and

[0053] each " Each represents a single bond or a double bond independently,

[0054] X3 and X4 are each independently C or N, and

[0055] Ring A is a pyrazol ring, and

[0056] Each R2 is independently a halogen, C 1-6 Alkyl group, C 3-10 Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", C 6-10 Aryl group, one or more R 2-1 C substituted with 1-6 alkyl group or one or more R 2-2It is a "5-10-membered heteroaryl group substituted with , in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and

[0057] Each R 2-1 and R 2-2 Each independently consists of a halogen, a hydroxyl group, and C 1-6 Alkyl group, -N(R 2a R 2b ), C 3-10 Cycloalkyl group, C 1-6 Alkoxy group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", C 6-10 An aryl group or "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and

[0058] R 2a and R 2b Each independently H or C 1-6 It is an alkyl group, and

[0059] R3 is hydrogen, C 1-6 alkyl group or C 3-10 It is a cycloalkyl group, and

[0060] L is C 1-6 Alkylene group, one or more R L C substituted with 1-6 Alkylene group, "-(C 1-6 Alkylene group)-L A -*" or -L A - and (* indicates one end connected to ring B),

[0061] Each R L Each independently deuterium, C 1-6 Alkoxy group, C 3-10 It is a cycloalkyl group, a hydroxyl group, a halogen or an oxo group (=O), or two Rs L If substituted into this same carbon atom, 2 R Land the carbon atoms they share are connected to form a 3-10-membered saturated carbon ring or a "3-10-membered saturated heteroring in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and

[0062] L A -C(O)NH-, -O-, -N(R LA )-, ethenylene group, ethinylene group, 3-10 saturated carbon ring or "a 3-10 saturated heterocycle in which one, two, or three heterovalence atoms are selected from N, O, and S, and the number of heterovalence atoms is one, two, or three", and

[0063] R LA is H, C 1-6 Alkyl group, C 3-10 A cycloalkyl group or a "3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", and

[0064] Ring B is a 3-10-membered saturated or unsaturated carbon ring, with one or more R B-1 A 3-10-membered saturated or unsaturated carbon ring substituted with, "a 3-10-membered saturated or unsaturated heterocycle in which one, two, or three heterovalence atoms are selected from N, O, and S, and the number of heterovalence atoms is one, two, or three" or one or more of R B-2 It is a "3-10 saturated or unsaturated heterocycle in which the heteroatoms are 1, 2, or 3 selected from N, O, and S and the number of heteroatoms is 1, 2, or 3" substituted with, and

[0065] Each R B-1 and R B-2 Each independently consists of a hydroxyl group, a halogen, an oxo group (=O), and C 1-6 Alkyl group, C 1-6 C substituted with an alkoxy group or one or more hydroxyl groups 1-6 It is an alkyl group, and

[0066] U is C 3-6Alkyl group, one or more R U-1 C substituted with 1-6 Alkyl group, C 3-10 Cycloalkyl group, one or more R U-2 C substituted with 3-10 Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", one or more R U-3 "a 3-10-membered heterocycloalkyl group substituted with, wherein one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", C 6-10 Aryl group, one or more R U-4 C substituted with 6-10 Aryl group, "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", one or more Rs U-5 "a 5-10-membered heteroaryl group substituted with , in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or -XR U-6 And,

[0067] X is -C(O)-, -SO2- or -O-, and

[0068] Each R U-1 Each independently halogen, C 3-10 Cycloalkyl group, C 6-10 An aryl group, "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or one or more R U-1-1 It is a "5-10-membered heteroaryl group substituted with , in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and

[0069] Each R U-1-1 C each independently 1-6 It is an alkyl group, and

[0070] Each R U-2 , R U-3 , R U-4 and R U-5 Each independently consists of a halogen, cyano group, hydroxyl group, and -SO2-C 1-6 Alkyl group, -C(O)OC 1-6 Alkyl group, -C(O)NH-C 1-6 Alkyl group, C 1-6 Alkyl group, one or more R U-3-1 C substituted with 1-6 Alkyl group, C 1-6 Alkoxy group, one or more R U-3-2 C substituted with 1-6 Alkoxy group, C 3-10 A cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or -O-"a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", and

[0071] Each R U-3-1 and R U-3-2 Each independently halogen, C 3-10 It is a cycloalkyl group or a cyano group, and

[0072] Each R U-6 C each independently 6-10 An aryl group or "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and

[0073] The compound represented by formula (I) is not any of the following compounds.

[0074]

[0075] and

[0076]

[0077] In some embodiments, the compound represented by the above formula (IA) is a compound represented by the following formula (IIA).

[0078]

[0079] Each R1 is independently a halogen, cyano group, C 1-6 Alkyl group, C 3-10 Cycloalkyl group, C 1-6 Alkoxy group, C substituted with one or more halogens 1-6 C substituted with an alkyl group or one or more halogens 1-6 Alkoxy group, "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or one or more R 1-1 It is a "5-10-membered heteroaryl group substituted with , in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and

[0080] Each R 1-1 C each independently 1-6 It is an alkyl group, and

[0081] m and k are independently 0, 1, or 2, respectively, and

[0082] X1 is -CH2-, -O-, -S- or -S(=O)2-, and

[0083] Each R2 is independently H and C 1-6 Alkyl group, one or more R 2-1 C substituted with 1-6 An alkyl group or "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and

[0084] Each R 2-1 Each independently consists of a hydroxyl group or C 3-10 It is a cycloalkyl group, and

[0085] each " Each represents a single bond or a double bond independently,

[0086] E is -N(R3)- or and, n1 is 1, 2 or 3, and # represents one end connected to -C(O)- in expression (IA), and

[0087] R3 is hydrogen or C 1-6 It is an alkyl group, and

[0088] L is C 1-6 Alkylene group, one or more R L C substituted with 1-6 alkylene group or "-(C 1-6 Alkylene group)-L A -*" and,

[0089] Each R L Each is independently a hydroxyl group or a halogen, or two Rs L If substituted into this same carbon atom, 2 R L and the carbon atoms they share are connected to form a 3-10 saturated carbon ring,

[0090] L A is -NH-, -N(C 1-6 It is an alkyl group)- or a 3-10 member saturated carbon ring, and

[0091] Ring B is a "3-10 saturated or unsaturated heterocycle in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or one or more R B-2 It is a "3-10 saturated or unsaturated heterocycle in which the heteroatoms are 1, 2, or 3 selected from N, O, and S and the number of heteroatoms is 1, 2, or 3" substituted with, and

[0092] Each R B-2 Each independently consists of a hydroxyl group, a halogen, and C 1-6 Alkyl group, C 1-6 C substituted with an alkoxy group or one or more hydroxyl groups 1-6 It is an alkyl group, and

[0093] If U does not exist, ring B is And,

[0094] U does not exist, or -N(R')(R"), C 3-6 Alkyl group, one or more R U-1 C substituted with 1-6 Alkyl group, C 3-10 Cycloalkyl group, one or more R U-2 C substituted with 3-10 Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", one or more R U-3 "a 3-10-membered heterocycloalkyl group substituted with, wherein one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", C 6-10 Aryl group, one or more R U-4 C substituted with 6-10 An aryl group, "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or one or more R U-5 It is a "5-10-membered heteroaryl group substituted with , in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and

[0095] Each R' and R" is independently hydrogen, C 1-6 Alkyl group, -C(O)-C 3-10 C substituted with a cycloalkyl group or one or more R"' 1-6 It is an alkyl group, and R"' is independently C 6-10 Arilgi,

[0096] Each R U-1 are independently -N(R')(R"), C 3-10 Cycloalkyl group or C 6-10 Arilgi,

[0097] Each R U-2 , RU-3 , R U-4 and R U-5 Each independently halogen, -SO2-C 1-6 Alkyl group, -C(O)-C 1-6 Alkyl group, C 3-10 Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", cyano group, hydroxyl group, C 1-6 Alkyl group, one or more R U-3-1 C substituted with 1-6 Alkyl group, C 1-6 Alkoxy group or one or more R U-3-2 C substituted with 1-6 It is an alkoxy period, and

[0098] Each R U-3-1 and R U-3-2 Each independently halogen, C 3-10 Cycloalkyl group, C 6-10 Arylgi, C 1-6 It is an alkoxy group, a hydroxyl group, a cyano group, or a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three.

[0099] In some embodiments, the compound represented by the above formula (I) is a compound represented by the following formula (II).

[0100]

[0101] Each R1 is independently a halogen, and

[0102] m and k are independently 0, 1, or 2, respectively, and

[0103] X1 is -CH2-, -O-, -S- or -S(=O)2-, and

[0104] Each R2 is independently C 1-6 alkyl group or one or more R 2-1 C substituted with 1-6 It is an alkyl group, and

[0105] Each R 2-1 C each independently 3-10 It is a cycloalkyl group, and

[0106] each " Each represents a single bond or a double bond independently,

[0107] R3 is hydrogen or C 1-6 It is an alkyl group, and

[0108] L is C 1-6 Alkylene group, one or more R L C substituted with 1-6 alkylene group or "-(C 1-6 Alkylene group)-L A -*" and,

[0109] Each R L Each is independently a hydroxyl group or a halogen, or two Rs L If substituted into this same carbon atom, 2 R L and the carbon atoms they share are connected to form a 3-10 saturated carbon ring,

[0110] L A is -NH- or -N(C 1-6 alkyl group)- and,

[0111] Ring B is a "3-10 saturated or unsaturated heterocycle in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or one or more R B-2 It is a "3-10 saturated or unsaturated heterocycle in which the heteroatoms are 1, 2, or 3 selected from N, O, and S and the number of heteroatoms is 1, 2, or 3" substituted with, and

[0112] Each R B-2 Each independently consists of a hydroxyl group, a halogen, and C 1-6 C substituted with an alkoxy group or one or more hydroxyl groups 1-6 It is an alkyl group, and

[0113] U is C 3-6 Alkyl group, one or more RU-1 C substituted with 1-6 Alkyl group, C 3-10 Cycloalkyl group, one or more R U-2 C substituted with 3-10 Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", one or more R U-3 "a 3-10-membered heterocycloalkyl group substituted with, wherein one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", C 6-10 Aryl group, one or more R U-4 C substituted with 6-10 An aryl group, "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or one or more R U-5 It is a "5-10-membered heteroaryl group substituted with , in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and

[0114] Each R U-1 C each independently 3-10 Cycloalkyl group or C 6-10 Arilgi,

[0115] Each R U-2 , R U-3 , R U-4 and R U-5 Each independently halogen, C 3-10 Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", cyano group, hydroxyl group, C 1-6 Alkyl group, one or more R U-3-1 C substituted with 1-6 Alkyl group, C 1-6 Alkoxy group or one or more R U-3-2 C substituted with 1-6 It is an alkoxy period, and

[0116] Each R U-3-1 and R U-3-2 Each independently is a halogen or C 3-10 It is a cycloalkyl group.

[0117] In some embodiments, the compound represented by the above formula (IA) is a compound represented by the following formula (IIIA) or formula (IIIB).

[0118] or

[0119] Each R1 is independently a halogen, cyano group, C 1-6 Alkyl group, C 3-10 Cycloalkyl group, C 1-6 Alkoxy group, C substituted with one or more halogens 1-6 C substituted with an alkyl group or one or more halogens 1-6 Alkoxy group, "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or one or more R 1-1 It is a "5-10-membered heteroaryl group substituted with , in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and

[0120] Each R 1-1 C each independently 1-6 It is an alkyl group, and

[0121] m is 0, 1, or 2, and

[0122] X1 is -CH2-, -O-, -S- or -S(=O)2-, and

[0123] Each R2 is independently H and C 1-6 Alkyl group, one or more R 2-1 C substituted with 1-6 An alkyl group or "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and

[0124] Each R 2-1 Each independently consists of a hydroxyl group or C 3-10 It is a cycloalkyl group, and

[0125] E is -N(R3)- or and, n1 is 1, 2 or 3, and # represents one end connected to -C(O)- in expression (IA), and

[0126] R3 is hydrogen or C 1-6 It is an alkyl group, and

[0127] L is C 1-6 Alkylene group, one or more R L C substituted with 1-6 alkylene group or "-(C 1-6 Alkylene group)-L A -*" and,

[0128] Each R L Each is independently a hydroxyl group or a halogen, or two Rs L If substituted into this same carbon atom, 2 R L and the carbon atoms they share are connected to form a 3-10 saturated carbon ring,

[0129] L A is a 3-10 member saturated carbon ring, and

[0130] Ring B is a "3-10 saturated or unsaturated heterocycle in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or one or more R B-2 It is a "3-10 saturated or unsaturated heterocycle in which the heteroatoms are 1, 2, or 3 selected from N, O, and S and the number of heteroatoms is 1, 2, or 3" substituted with, and

[0131] Each R B-2 Each independently is a halogen or C 1-6 It is an alkyl group, and

[0132] If U does not exist, ring B is And,

[0133] U does not exist, or -N(R')(R"), one or more R U-1 C substituted with 1-6 Alkyl group, C 3-10 Cycloalkyl group, one or more R U-2 C substituted with 3-10 Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", one or more R U-3 "a 3-10-membered heterocycloalkyl group substituted with, wherein one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", C 6-10 Aryl group, one or more R U-4 C substituted with 6-10 An aryl group or "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and

[0134] Each R' and R" is independently hydrogen, C 1-6 Alkyl group, -C(O)-C 3-10 C substituted with a cycloalkyl group or one or more R"' 1-6 It is an alkyl group, and R"' is independently C 6-10 Arilgi,

[0135] Each R U-1 C each independently 3-10 Cycloalkyl group or C 6-10 Arilgi,

[0136] Each R U-2 , R U-3 and R U-4 Each independently consists of a halogen, a hydroxyl group, and -SO2-C 1-6 Alkyl group, -C(O)-C 1-6 Alkyl group, C 1-6 Alkyl group, C 3-10Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", C 1-6 Alkoxy group or one or more R U-3-1 C substituted with 1-6 It is an alkyl group, and

[0137] Each R U-3-1 Each independently halogen, C 3-10 Cycloalkyl group, C 6-10 Arylgi, C 1-6 It is an alkoxy group, a hydroxyl group, a cyano group, or a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three.

[0138] In some embodiments, the compound represented by the above formula (I) is a compound represented by the following formula (III).

[0139]

[0140] Each R1 is independently a halogen, and

[0141] m is 0 or 1, and

[0142] X1 is -CH2-, -O-, -S- or -S(=O)2-, and

[0143] Each R2 is independently C 1-6 alkyl group or one or more R 2-1 C substituted with 1-6 It is an alkyl group, and

[0144] Each R 2-1 C each independently 3-10 It is a cycloalkyl group, and

[0145] R3 is hydrogen or C 1-6 It is an alkyl group, and

[0146] L is C 1-6 alkylene group or one or more R L C substituted with 1-6 It is an alkylene group, and

[0147] Each R L Each is independently a hydroxyl group or a halogen, and

[0148] Ring B is a "3-10 saturated or unsaturated heterocycle in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or one or more R B-2 It is a "3-10 saturated or unsaturated heterocycle in which the heteroatoms are 1, 2, or 3 selected from N, O, and S and the number of heteroatoms is 1, 2, or 3" substituted with, and

[0149] Each R B-2 Each is independently a halogen, and

[0150] U is one or more R U-1 C substituted with 1-6 Alkyl group, C 3-10 Cycloalkyl group, one or more R U-2 C substituted with 3-10 Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", C 6-10 Aryl group, one or more R U-4 C substituted with 6-10 An aryl group or "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and

[0151] Each R U-1 C each independently 3-10 Cycloalkyl group or C 6-10 Arilgi,

[0152] Each R U-2 and R U-4 Each independently halogen, C 1-6 Alkoxy group or one or more R U-3-1 C substituted with 1-6 It is an alkyl group, and

[0153] Each R U-3-1Each is independently a halogen.

[0154] In some embodiments, each R1 is independently a halogen, a cyano group, C 1-6 Alkyl group, C 3-10 C substituted with a cycloalkyl group and one or more halogens 1-6 C substituted with an alkyl group or one or more halogens 1-6 Alkoxy group, "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or one or more R 1-1 It is a "5-10-membered heteroaryl group substituted with , in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and

[0155] Each R 1-1 C each independently 1-6 It is an alkyl group.

[0156] In some embodiments, each R1 is independently a halogen.

[0157] In some embodiments, m and k are each independently 0 or 1.

[0158] In some embodiments, each R2 is independently H, C 1-6 Alkyl group, one or more R 2-1 C substituted with 1-6 An alkyl group or "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and

[0159] Each R 2-1 Each independently consists of a hydroxyl group or C 3-10 It is a cycloalkyl group.

[0160] In some embodiments, each R2 is independently C 1-6 alkyl group or one or more R 2-1 C substituted with 1-6 It is an alkyl group, and

[0161] Each R 2-1 C each independently 3-10 It is a cycloalkyl group.

[0162] In some embodiments, E is -N(R3)-.

[0163] In some embodiments, R3 is hydrogen or C 1-6 It is an alkyl group.

[0164] In some embodiments, R3 is hydrogen.

[0165] In some embodiments, L is C 1-6 Alkylene group, one or more R L C substituted with 1-6 alkylene group or "-(C 1-6 Alkylene group)-L A -*" and,

[0166] Each R L Each is independently a hydroxyl group or a halogen, or two Rs L If substituted into this same carbon atom, 2 R L and the carbon atoms they share are connected to form a 3-10 saturated carbon ring,

[0167] L A is -NH-, -N(C 1-6 It is an alkyl group - or a 3-10-membered saturated carbon ring, preferably a 3-10-membered saturated carbon ring.

[0168] In some embodiments, L is C 1-6 Alkylene group, one or more R L C substituted with 1-6 alkylene group or "-(C 1-6 Alkylene group)-L A -*" and,

[0169] Each R L Each is independently a hydroxyl group or a halogen, or two Rs L If substituted into this same carbon atom, 2 R L and the carbon atoms they share are connected to form a 3-10 saturated carbon ring,

[0170] L A is -NH- or -N(C 1-6 alkyl group)- is.

[0171] In some embodiments, L is C 1-6 Alkylene group, one or more R L C substituted with 1-6 alkylene group or "-(C 1-6 Alkylene group)-L A -*" and,

[0172] Each R L Each is independently a hydroxyl group or a halogen, or two Rs L If substituted into this same carbon atom, 2 R L and the carbon atoms they share are connected to form a 3-10 saturated carbon ring,

[0173] L A is -NH-.

[0174] In some embodiments, L is C 1-6 alkylene group or one or more R L C substituted with 1-6 It is an alkylene group, and

[0175] Each R L Each is independently a hydroxyl group or a halogen.

[0176] In some embodiments, L is C 1-6 alkylene group or one or more R L C substituted with 1-6 It is an alkylene group, and

[0177] Each R L Each is an independent hydroxyl group.

[0178] In some embodiments, ring B is a "3-10 saturated or unsaturated heterocycle in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or one or more R B-2It is a "3-10 saturated or unsaturated heterocycle in which the heteroatoms are 1, 2, or 3 selected from N, O, and S and the number of heteroatoms is 1, 2, or 3" substituted with, and

[0179] Each R B-2 Each independently consists of a hydroxyl group, a halogen, and C 1-6 Alkyl group, C 1-6 C substituted with an alkoxy group or one or more hydroxyl groups 1-6 It is an alkyl group, preferably a halogen or C 1-6 It is an alkyl group.

[0180] In some embodiments, ring B is a "3-10 saturated or unsaturated heterocycle in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or one or more R B-2 It is a "3-10 saturated or unsaturated heterocycle in which the heteroatoms are 1, 2, or 3 selected from N, O, and S and the number of heteroatoms is 1, 2, or 3" substituted with, and

[0181] Each R B-2 Each independently consists of a hydroxyl group, a halogen, and C 1-6 C substituted with an alkoxy group or one or more hydroxyl groups 1-6 It is an alkyl group, preferably a halogen.

[0182] In some embodiments, ring B is a "3-10 saturated or unsaturated heterocycle in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three".

[0183] In some embodiments, U is not present, or -N(R')(R"), C 3-6 Alkyl group, one or more R U-1 C substituted with 1-6 Alkyl group, C 3-10 Cycloalkyl group, one or more R U-2 C substituted with 3-10Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", one or more R U-3 "a 3-10-membered heterocycloalkyl group substituted with, wherein one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", C 6-10 Aryl group, one or more R U-4 C substituted with 6-10 An aryl group, "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or one or more R U-5 It is a "5-10-membered heteroaryl group substituted with , in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and

[0184] Each R' and R" is independently hydrogen, C 1-6 Alkyl group, -C(O)-C 3-10 C substituted with a cycloalkyl group or one or more R"' 1-6 It is an alkyl group, and R"' is independently C 6-10 Arilgi,

[0185] Each R U-1 are independently -N(R')(R"), C 3-10 Cycloalkyl group or C 6-10 Arilgi,

[0186] Each R U-2 , R U-3 , R U-4 and R U-5 Each independently halogen, -SO2-C 1-6 Alkyl group, -C(O)-C 1-6 Alkyl group, C 3-10 Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", cyano group, hydroxyl group, C1-6 Alkyl group, one or more R U-3-1 C substituted with 1-6 Alkyl group, C 1-6 Alkoxy group or one or more R U-3-2 C substituted with 1-6 It is an alkoxy period, and

[0187] Each R U-3-1 and R U-3-2 Each independently halogen, C 3-10 Cycloalkyl group, C 6-10 Arylgi, C 1-6 It is an alkoxy group, a hydroxyl group, a cyano group, or a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three.

[0188] In some embodiments, U is non-existent, -N(R')(R"), or one or more R U-1 C substituted with 1-6 Alkyl group, C 3-10 Cycloalkyl group, one or more R U-2 C substituted with 3-10 Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", one or more R U-3 "a 3-10-membered heterocycloalkyl group substituted with, wherein one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", C 6-10 Aryl group, one or more R U-4 C substituted with 6-10 An aryl group or "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and

[0189] Each R' and R" is independently hydrogen, C 1-6 Alkyl group, -C(O)-C 3-10 C substituted with a cycloalkyl group or one or more R"'1-6 It is an alkyl group, and R"' is independently C 6-10 Arilgi,

[0190] Each R U-1 C each independently 3-10 Cycloalkyl group or C 6-10 Arilgi,

[0191] Each R U-2 , R U-3 and R U-4 Each independently consists of a halogen, a hydroxyl group, and -SO2-C 1-6 Alkyl group, -C(O)-C 1-6 Alkyl group, C 1-6 Alkyl group, C 3-10 Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", C 1-6 Alkoxy group or one or more R U-3-1 C substituted with 1-6 It is an alkyl group, and

[0192] Each R U-3-1 Each independently halogen, C 3-10 Cycloalkyl group, C 6-10 Arylgi, C 1-6 It is an alkoxy group, a hydroxyl group, a cyano group, or a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three.

[0193] In some embodiments, U is C 3-6 Alkyl group, one or more R U-1 C substituted with 1-6 Alkyl group, C 3-10 Cycloalkyl group, one or more R U-2 C substituted with 3-10 Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", one or more R U-3"a 3-10-membered heterocycloalkyl group substituted with, wherein one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", C 6-10 Aryl group, one or more R U-4 C substituted with 6-10 An aryl group, "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or one or more R U-5 It is a "5-10-membered heteroaryl group substituted with , in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and

[0194] Each R U-1 C each independently 3-10 Cycloalkyl group or C 6-10 Arilgi,

[0195] Each R U-2 , R U-3 , R U-4 and R U-5 Each independently halogen, C 3-10 Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", cyano group, hydroxyl group, C 1-6 Alkyl group, one or more R U-3-1 C substituted with 1-6 Alkyl group, C 1-6 Alkoxy group or one or more R U-3-2 C substituted with 1-6 It is an alkoxy period, and

[0196] Each R U-3-1 and R U-3-2 Each independently is a halogen or C 3-10 It is a cycloalkyl group.

[0197] In some embodiments, U is one or more R U-1 C substituted with 1-6 Alkyl group, C 3-10Cycloalkyl group, one or more R U-2 C substituted with 3-10 Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", C 6-10 Aryl group, one or more R U-4 C substituted with 6-10 An aryl group or "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and

[0198] Each R U-1 C each independently 3-10 Cycloalkyl group or C 6-10 Arilgi,

[0199] Each R U-2 and R U-4 Each independently halogen, C 1-6 Alkoxy group or one or more R U-3-1 C substituted with 1-6 It is an alkyl group, and

[0200] Each R U-3-1 Each is independently a halogen.

[0201] In some embodiments, in ring C, the “5-6-membered heteroaryl ring having one, two, or three heteroatoms selected from N, O, and S and one, two, or three heteroatoms” is “a 5-6-membered heteroaryl ring having one or two heteroatoms and one heteroatom”, for example, a pyridine ring or a pyrimidine ring.

[0202] In some embodiments, each "C1-C6 alkyl group" is independently a C1-C4 alkyl group and may also be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, an isobutyl group, or a sec-butyl group, preferably a methyl group or an ethyl group.

[0203] In some embodiments, each "C1-C6 alkoxy group" is independently a C1-C4 alkoxy group and may also be a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a tert-butoxy group, an isobutoxy group, or a sec-butoxy group, preferably a methoxy group.

[0204] In some embodiments, each "halogen" is independently fluorine, chlorine, bromine, or iodine, preferably fluorine or chlorine.

[0205] In some embodiments, each "halogen" is independently fluorine, chlorine, or bromine, preferably fluorine.

[0206] In some embodiments, R a , R b And when the carbon atoms they share are connected to form a 3-10-membered saturated carbon ring, the "3-10-membered saturated carbon ring" is a ternary saturated carbon ring, for example am(" " indicates a bond connecting to the rest of the molecule).

[0207] In some embodiments, each "C3-C 10 The "cycloalkyl group" is independently a C3-C6 monocyclic cycloalkyl group or a C5-C 10 It is a polycyclic (e.g., spiro ring, condensation ring, or bridge ring) cycloalkyl group, and the C3-C6 monocyclic cycloalkyl group may be a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, and the C5-C 10 The polycyclic cycloalkyl group is preferably C5-C 10 It is a spirocyclic cycloalkyl group, and more preferably am.

[0208] In some embodiments, each "3-10-membered heterocycloalkyl group having one, two, or three heteroatoms selected from N, O, and S and one, two, or three heteroatoms" is independently a 4-6-membered monocyclic heterocycloalkyl group or a 5-10-membered polycyclic (e.g., spiro ring, condensation ring, or bridge ring) heterocycloalkyl group, wherein the 4-6-membered monocyclic heterocycloalkyl group is preferably a 4-6-membered monocyclic heterocycloalkyl group having one or two heteroatoms selected from N and O and one or two heteroatoms, and more preferably or And, the above 5-10-membered polycyclic heterocycloalkyl group may be a 5-10-membered spiro-ring heterocycloalkyl group, preferably a 6-membered spiro-ternary heterocycloalkyl group, and more preferably And, or the above 5-10-membered polycyclic heterocycloalkyl group may be a 5-10-membered bridge-ring heterocycloalkyl group, preferably am.

[0209] In some embodiments, each "3-10-membered heterocycloalkyl group having one, two, or three heteroatoms selected from N, O, and S and one, two, or three heteroatoms" is independently a 4-6-membered monocyclic heterocycloalkyl group or a 5-10-membered polycyclic (e.g., spiro ring, condensation ring, or bridge ring) heterocycloalkyl group, wherein the 4-6-membered monocyclic heterocycloalkyl group is preferably a 6-membered heterocycloalkyl group having one or two heteroatoms selected from N and O and one or two heteroatoms, and more preferably or And, the above 5-10-membered polycyclic heterocycloalkyl group may be a 5-10-membered spiro-ring heterocycloalkyl group, preferably a 6-membered spiro-ternary heterocycloalkyl group, and more preferably am.

[0210] In some embodiments, each "C6-C 10 The aryl group is independently a phenyl group or a naphthyl group, preferably a phenyl group.

[0211] In some embodiments, each "5-10-membered heteroaryl group having one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms" may independently be a 5-6-membered monocyclic heteroaryl group, and the 5-6-membered monocyclic heteroaryl group is preferably a 5-6-membered monocyclic heteroaryl group having one, two, or three heteroatoms and having N as the type of heteroatom, for example or am.

[0212] In some embodiments, each "5-10-membered heteroaryl group having one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms" may independently be a 5-6-membered monocyclic heteroaryl group, wherein the 5-6-membered monocyclic heteroaryl group is preferably a 5-6-membered monocyclic heteroaryl group having one or two heteroatoms and, more preferably, the type of heteroatom is N. or am.

[0213] In some embodiments, each "C 1-6 The "alkylene group" is independently a C1-C4 alkylene group, preferably a methylene group, or am.

[0214] In some embodiments, each "C 1-6 The "alkylene group" is independently a C1-C4 alkylene group, preferably or am.

[0215] In some embodiments, 2 R L If substituted into this same carbon atom, 2 R Land the "3-10-membered saturated carbon ring" formed by the connection of carbon atoms shared by them is a ternary saturated carbon ring, for example am(" " indicates a bond connecting to the rest of the molecule).

[0216] In some embodiments, L A If is a 3-10 member saturated carbon ring, the above "3-10 member saturated carbon ring" is a 4-6 member saturated carbon ring, for example am.

[0217] In some embodiments, each "3-10-membered saturated or unsaturated heterocycle in which one, two, or three heterovalence atoms are selected from N, O, and S and the number of heterovalence atoms is one, two, or three" is independently a "4-8-membered saturated or unsaturated heterocycle in which one or two heterovalence atoms are selected from N and O and the number of heterovalence atoms is one or two", for example or am.

[0218] In some embodiments, each "3-10-membered saturated or unsaturated heterocycle in which one, two, or three heteroatoms are selected from N, O, and S and the number of heteroatoms is one, two, or three" is independently a "5-6-membered saturated or unsaturated heterocycle in which the heteroatom is N and the number of heteroatoms is one or two", for example or am(" " indicates a bond connecting to the rest of the molecule).

[0219] In some embodiments, ring C is a benzene ring.

[0220] In some embodiments, each R1 is independently fluorine, chlorine, bromine, cyano group, trifluoromethyl group, cyclopropyl group, trifluoromethoxy group, methyl group, , or and m is 0, 1, or 2.

[0221] In some embodiments, each R1 is independently fluorine or chlorine, and m is 0 or 1.

[0222] In some embodiments, X1 is -CH2-, -O-, -S- or -S(=O)2-, X2 is -CH2-, n is 0, and X3 and X4 are C.

[0223] In some embodiments, R2 is H, a methyl group, an ethyl group, or and k is 0 or 1.

[0224] In some embodiments, R2 is a methyl group, an ethyl group, or and k is 1.

[0225] In some embodiments, structural fragments silver

[0226]

[0227]

[0228]

[0229] or am.

[0230] In some embodiments, R3 is hydrogen or a methyl group.

[0231] In some embodiments, L is a methylene group,

[0232]

[0233] am.

[0234] In some embodiments, ring B is

[0235]

[0236] am.

[0237] In some embodiments, U is

[0238]

[0239]

[0240]

[0241]

[0242]

[0243] or am.

[0244] In some embodiments, E is -NH-, -N(CH3)- or am.

[0245] The present invention further provides the following compounds or pharmaceutically acceptable salts thereof.

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263] The present invention further provides a pharmaceutical composition, said pharmaceutical composition comprising a substance A and a pharmaceutically acceptable excipient, said substance A is a compound represented by formula (XA) or a pharmaceutically acceptable salt thereof.

[0264]

[0265] Rings A, B, C, X1, X2, X3, X4, R1, R2, E, m, n, k, L, B, and U are defined as described above.

[0266] The present invention further provides a pharmaceutical composition, said pharmaceutical composition comprising a substance A (therapeutic effective amount) and a pharmaceutically acceptable excipient, said substance A is a compound represented by formula (X) or a pharmaceutically acceptable salt thereof, and

[0267]

[0268] Here, ring A, ring B, ring C, X1, X2, X3, X4, R1, R2, R3, m, n, k, L, B, and U are defined as previously described.

[0269] In some embodiments, the pharmaceutical composition is used for the treatment and / or prevention of KSR2-AMPK-related diseases or disorders, e.g., cancer, e.g., liver cancer.

[0270] The present invention further provides an application of substance A or the aforementioned pharmaceutical composition in the manufacture of a KSR2-AMPK inhibitor, wherein substance A is a compound represented by the aforementioned formula (XA) or a pharmaceutically acceptable salt thereof. In the said application, the KSR2-AMPK inhibitor may be used in vivo in mammals; may also be used in vitro, primarily for experimental purposes, for example, to provide comparison as a standard sample or control sample, or to provide rapid detection of the KSR2-AMPK inhibitory effect by being prepared as a kit according to conventional methods in the art.

[0271] The present invention further provides for the application of substance A or the aforementioned pharmaceutical composition in the manufacture of a drug, said drug being used for the treatment and / or prevention of a KSR2-AMPK-related disease or disorder; said substance A being a compound represented by the aforementioned formula (XA) or a pharmaceutically acceptable salt thereof, said substance A being in a therapeutically effective amount, and said KSR2-AMPK-related disease or disorder being preferably cancer, e.g., liver cancer.

[0272] The present invention further provides the application of substance A or the aforementioned pharmaceutical composition in the manufacture of a drug, said drug being used for the treatment and / or prevention of cancer (e.g., liver cancer), said substance A being a compound represented by the aforementioned formula (XA) or a pharmaceutically acceptable salt thereof, said substance A being in a therapeutically effective amount.

[0273] The present invention further provides the application of substance A or the aforementioned pharmaceutical composition in the inhibition of KSR2-AMPK, wherein substance A is a compound represented by the aforementioned formula (XA) or a pharmaceutically acceptable salt thereof.

[0274] The present invention further provides an application of substance A or the aforementioned pharmaceutical composition in the manufacture of a KSR2-AMPK inhibitor, wherein substance A is a compound represented by the aforementioned formula (X) or a pharmaceutically acceptable salt thereof. In the said application, the KSR2-AMPK inhibitor may be used in vivo in mammals; may also be used in vitro, primarily for experimental purposes, for example, to provide comparison as a standard sample or control sample, or to provide rapid detection of the KSR2-AMPK inhibitory effect by being prepared as a kit according to conventional methods in the art.

[0275] The present invention further provides for the application of substance A or the aforementioned pharmaceutical composition in the manufacture of a drug, said drug being used for the treatment and / or prevention of a KSR2-AMPK-related disease or disorder; said substance A being a compound represented by the aforementioned formula (X) or a pharmaceutically acceptable salt thereof, said substance A being in a therapeutically effective amount, and said KSR2-AMPK-related disease or disorder being preferably cancer, e.g., liver cancer.

[0276] The present invention further provides for the application of substance A or the aforementioned pharmaceutical composition in the manufacture of a drug, said drug being used for the treatment and / or prevention of cancer (e.g., liver cancer); said substance A is a compound represented by the aforementioned formula (X) or a pharmaceutically acceptable salt thereof, said substance A is a therapeutically effective amount.

[0277] The present invention further provides the application of substance A or the aforementioned pharmaceutical composition in the inhibition of KSR2-AMPK, wherein substance A is a compound represented by the aforementioned formula (X) or a pharmaceutically acceptable salt thereof.

[0278] In addition, unless otherwise specified in this application, the following terms have the following meanings.

[0279] The term "plural" means two, three, four, or five.

[0280] Those skilled in the art, in accordance with convention used in the art, [candidates] use "in the structural formula having a group in the present invention" It can be understood that this indicates that the corresponding group R is connected to another fragment or group within the compound through that position.

[0281] The term "pharmaceuticalally acceptable salt" refers to a salt obtained by preparing a compound of the present invention with a relatively low-toxicity and pharmaceutically acceptable acid or base. If the compound of the present invention contains a relatively acidic functional group, a base-added salt may be obtained by contacting a sufficient amount of a pharmaceutically acceptable base with the neutral form of the compound in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base-added 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. If the compound of the present invention contains a relatively basic functional group, an acid-added salt may be obtained by contacting a sufficient amount of a pharmaceutically acceptable acid with the neutral form of the compound in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acid includes inorganic acids and organic acids. Specifically, you may refer to Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0282] The term "pharmaceutical composition" means a formulation comprising a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). The medium comprises a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate administration to a living organism and to enable the absorption of the active ingredient to exert biological activity.

[0283] The term "pharmaceutical excipients" refers to excipients and additives used in the manufacture and dispensing of pharmaceuticals, meaning all substances included in a pharmaceutical formulation excluding the active ingredient. Reference may be made to Volume 4 of the Pharmacopoeia of the People's Republic of China (2015 edition) or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009 Sixth Edition). Excipients are primarily used to provide safe, stable, and functional pharmaceutical compositions and may also provide a method to facilitate the dissolution of the active ingredient at a predetermined rate after administration to a subject, or to promote the effective absorption of the active ingredient after administration to a subject. The above-mentioned pharmaceutical excipients may be inert fillers or may provide specific functions, such as stabilizing the overall pH of the composition or preventing the degradation of the active ingredient of the composition. The above medicinal excipient may include one or more of binders, suspenders, emulsifiers, diluents, fillers, agglomerators, adhesives, disintegrants, lubricants, anti-adhesives, fluidizers, wetting agents, gelling agents, absorption retardants, solubility inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, coloring agents, synergists, and sweeteners.

[0284] The term “treatment” means therapeutic therapy or palliative measures. With respect to a specific pathology, treatment means (1) alleviation of one or more biological manifestations of the disease or pathology; (2) intervention of one or more points (a) in the biological cascade that cause or lead to the pathology or one or more biological manifestations (b) of the pathology; (3) improvement of one or more symptoms, effects, or side effects related to the pathology or one or more symptoms, effects, or side effects related to the pathology or its treatment; or (4) delaying the progression of the pathology or one or more biological manifestations of the pathology. “Treatment” may also mean extending survival time compared to the expected survival time without treatment.

[0285] The term "prevention" means lowering the risk of acquiring or developing a disease or disability.

[0286] The term "therapeutic effective dose" refers to an amount of compound sufficient to effectively treat the disease or condition described herein when administered to a patient. The "therapeutic effective dose" varies depending on the compound, the condition and its severity, and the age of the patient to be treated, but may be adjusted by a person skilled in the art as necessary.

[0287] The terms "substitution" or "substituent" mean that a hydrogen atom within a group is replaced by a specified group. If the substitution position is not specified, it may be substituted at any position, but only if it forms a stable or chemically feasible compound. For example indicates that a hydrogen atom on ring A is substituted with p R4 atoms.

[0288] If a variable (e.g., R) appears one or more times in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted with one or more Rs, the group may be substituted with any one or more Rs, and R in each case has independent options. Furthermore, combinations of substituents and / or variables are permitted only if the combination produces a stable compound.

[0289] The term "alkyl group" refers to a saturated straight-chain or branched-chain monovalent hydrocarbon group. C 1-6 An alkyl group refers to an alkyl group having 1 to 6 carbon atoms, and preferably a C group having 1 to 4 carbon atoms. 1-4 It is an alkyl group, specifically a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group or tert-butyl group.

[0290] The term "alkylene group" is a divalent group connected to the rest of the molecule through two single bonds, and the rest of the definition is the same as the term "alkyl group."

[0291] The term "alkoxy" is -OC 1-6 It refers to an alkyl group, and the above "C 1-6 The "alkyl group" is defined as described above. Preferably, it is an alkoxy group having 1 to 4 carbon atoms, for example, a methoxy group or an ethoxy group.

[0292] The term "cycloalkyl group" refers to a saturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or higher-order bridging, condensed (fusion) or spirocyclic) carbon-ring substituent that can be connected to the rest of the molecule by a single bond through any suitable carbon atom. For example, a 3-10-membered cycloalkyl group with 3 to 10 carbon atoms. Examples of cycloalkyl groups include the cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, There are, but are not limited to, the following.

[0293] The term "carbon ring" refers to a specified number of carbon atoms (e.g., C3–C4). 10 It refers to a cyclic saturated or unsaturated cyclic group having ), which is monocyclic or polycyclic (e.g., bicyclic, tricyclic or more bridging rings, condensed rings (fusion rings), or spiro-cyclic systems), and preferably is a ternary saturated carbon ring. It satisfies any one of the following conditions: (1) where it is connected to the rest of the molecule through two or more single bonds, e.g. (" " indicates a bond that connects to the rest of the molecule), or (2) a case where it shares two atoms and one bond with the rest of the molecule.

[0294] The term "heterocycle" means a saturated or unsaturated cyclic group having a specified number of ring atoms (e.g., 3-10), 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), and is monocyclic or polycyclic (e.g., bicyclic, tricyclic or more bridging rings, condensed rings (fusion rings), or spiro-cyclic systems), preferably a 5-6 saturated monocyclic heterocycle. It satisfies any one of the following conditions: (1) connected to the rest of the molecule through two or more single bonds, e.g. or (" " indicates a bond that connects to the rest of the molecule), or (2) a case where it shares two atoms and one bond with the rest of the molecule.

[0295] The term "heterocycloalkyl group" means a saturated monovalent group of monocyclic or polycyclic (e.g., bicyclic, tricyclic or more bridging, condensed (fusion) or spirocyclic) having a specified number of ring atoms (e.g., 3-10), 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), and is connected to the rest of the molecule through carbon atoms or heteroatoms. Examples of heterocycloalkyl groups include, but are not limited to, morpholinyl groups, piperidinyl groups, piperazinyl groups, tetrahydropyranyl groups, or azaspiro[2.5]octyl groups, e.g., or am.

[0296] The term "aryl group" refers to a specified number of carbon atoms (e.g., C 6-10 It refers to a cyclic unsaturated monovalent hydrocarbon group having ), which is monocyclic or polycyclic (e.g., 2 or 3), and in the case of polycyclic, shares two atoms and one bond between the monocyclic rings, and at least one ring is aromatic. The aryl group is connected to the rest of the molecule through an aromatic ring or a non-aromatic ring. The aryl group includes, but is not limited to, a phenyl group or a naphthyl group.

[0297] The term "heteroaryl group" means 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); being monocyclic or polycyclic, and in the case of polycyclic, sharing two atoms and one bond between two monocyclic rings, and at least one ring being aromatic. The heteroaryl group is connected to the rest of the molecule through carbon atoms or heteroatoms; is connected to the rest of the molecule through a ring having heteroatoms or a ring not having heteroatoms; and is connected to the rest of the molecule through an aromatic ring or a non-aromatic ring. The heteroaryl group includes, but is not limited to, pyridinyl groups or pyrimidinyl groups, for example or It is the back.

[0298] The term “heteroaryl ring” means 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 type of heteroatom (one or more of N, O, and S), being monocyclic or polycyclic, and in the case of polycyclic, sharing two atoms and one bond between two monocyclic rings, having at least one ring being aromatic, and preferably being a 5-6 monocyclic heteroaryl ring. It satisfies any one of the following conditions: (1) being connected to the rest of the molecule through two or more bonds, or (2) sharing two atoms and one bond with the rest of the molecule.

[0299] The term "halogen" refers to fluorine, chlorine, bromine, or iodine, specifically referring to F or Cl.

[0300] Within the scope consistent with ordinary knowledge of the art, each of the aforementioned preferred conditions may be arbitrarily combined, thereby obtaining each preferred embodiment of the present invention.

[0301] All reagents and raw materials used in this invention can be purchased and used from the market. Effects of the invention

[0302] The positive effects of the present invention are as follows.

[0303] The compound of the present invention can effectively inhibit the proliferation of cancer cells. Specific details for implementing the invention

[0304] The present invention will be explained in more detail through the following examples, but the present invention is not limited to the scope of the following examples. Experimental methods for which specific conditions are not specified in the following examples shall follow conventional methods and conditions or be selected according to the product manual.

[0305] Example 1

[0306]

[0307] Step 1: Ethanol (120 mL) and a 20% mass fraction sodium ethoxide-ethanol solution (83 g, 243.58 mmol) were sequentially added to a 500 mL three-necked flask, and diethyl oxalate (26.7 g, 182.69 mmol) and at 0°C under nitrogen protection were added. Compound 1-1 After adding (20 g, 121.79 mmol), 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 ethanol was removed by concentrating under reduced pressure. Separative extraction was performed by adding water and ethyl acetate; the aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with saline solution, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the product. Compound 1-2 (29 g, yield: 90%) was obtained and used directly in the next step.

[0308] ESI(m / z) = 263.1 [M-1]

[0309] Step 2: Compound 1-2(7 g, 26.49 mmol) was dissolved in 1,4-dioxane (70 mL), and methylhydrazine sulfate (7.64 g, 52.98 mmol) was added while stirring. After the addition was complete, the reaction was carried out at 105°C for 16 hours, and the reaction was monitored using LCMS. The reaction solution was added to water (200 mL) and extracted with ethyl acetate (2 × 500 mL). The organic phase was washed once with saline solution (200 mL), dried with anhydrous sodium sulfate, and filtered. After concentration under reduced pressure, the product was separated by column chromatography. Compound 1-3 (2.65 g, yield 36%) was obtained.

[0310] ESI(m / z) = 275.2 [M+H] + , RT = 3.657 min.

[0311] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 7.88 - 7.84 (m, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 7.33 (pd, J = 7.4, 1.6 Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H), 4.16 (s, 3H), 4.15 (s, 2H), 1.31 (t, J = 7.1 Hz, 3H).

[0312] Step 3: Compound 1-3 (2.65 g, 9.66 mmol) was dissolved in ethanol (30 mL) and water (10 mL), and sodium hydroxide (1.16 g, 29 mmol) was added while stirring. The reaction mixture was stirred at 20°C for 16 hours. The termination of the reaction was confirmed by LCMS. The reaction solution was concentrated to remove ethanol, the pH was adjusted to 4 with 4N hydrochloric acid, and the mixture was slurried with water for 30 minutes. After filtration, the filter cake was dried. Compound 1-4 (2.25 g, yield 95%) was obtained.

[0313] ESI(m / z) =247.1[M+H]+ , RT = 3.005 min.

[0314] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 7.85 (dd, J = 7.4, 1.7 Hz, 1H), 7.51 (dd, J = 7.4, 1.7 Hz, 1H), 7.37 - 7.28 (m, 2H), 4.14 (s, 5H).

[0315] Step 4: Compound 1-4 4-(3-aminopropyl)-piperazine-1-carboxylic acid tert-butyl ester (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). After adding TCFH (200 mg, 0.71 mmol) at 0°C, the reaction mixture was stirred at 20°C for 1 hour. Reaction termination was confirmed by LCMS. The reaction was quenched by adding water to the reaction mixture, and extracted with ethyl acetate. The organic phase was washed with saturated saline, dried with anhydrous sodium sulfate, and separated by column chromatography to obtain a white solid. Compound 1-5 (245 mg, yield 85%) was obtained.

[0316] ESI(m / z) =472.4[M+H] + , RT = 2.803 min.

[0317] 1 1H NMR (400 MHz, Chloroform- d ) δ 8.20 (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 = 6.2 Hz, 2H), 2.45 (t, J = 5.0 Hz, 4H), 1.78 (p, J= 6.2 Hz, 2H), 1.47 (s, 9H).

[0318] Step 5: In the reaction flask Compound 1-5 (245 mg, 0.52 mmol), HCl / dioxane (2 mL, 4 mmol / mL), and methanol (2 mL) were added, and the reaction was carried out at 20°C for 1 hour. Reaction completion was confirmed by LCMS. The reaction mixture was added dropwise to an aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate. After drying with anhydrous sodium sulfate, spin-dried Compound 1-6 (60 mg, yield 31%) was obtained.

[0319] ESI(m / z) = 372.3 [M+H] + , RT = 2.281 min.

[0320] Step 6: Compound 1-6 Compound 1 (38.9 mg, yield 49%) was obtained by dissolving sodium borohydrogen acetate (60 mg, 0.16 mmol) and 4,4-difluorocyclohexanone (40 mg, 0.30 mmol) in dichloromethane (5 mL), adding sodium borohydrogen acetate (70 mg, 0.33 mmol), and stirring the reaction mixture at 20°C for 16 hours. The termination of the reaction was confirmed by LCMS. The reaction was quenched by adding an aqueous solution of saturated sodium bicarbonate to the reaction mixture and extracted with ethyl acetate. The organic phase was washed with saturated saline, dried with anhydrous sodium sulfate, and filtered. Compound 1 (38.9 mg, yield 49%) was obtained by freeze-drying after adding water following column chromatography.

[0321] ESI(m / z) =490.4[M+H] + , RT = 6.364 min.

[0322] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.34 (t, J = 5.7 Hz, 1H), 7.84 (dd, J = 7.6, 1.6 Hz, 1H), 7.50 (dd, J= 7.4, 1.6 Hz, 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 = 10.9 Hz, 2H), 1.91 (s, 1H), 1.88 - 1.38 (m, 8H).

[0323] Example 2

[0324]

[0325] Step 1: Ethanol (120 mL) and a 20% mass fraction sodium ethoxide-ethanol solution (83 g, 243.58 mmol) were sequentially added to a 500 mL three-necked flask, and at 0°C under nitrogen protection Diethyl oxalate (26.7 g, 182.69 mmol) and Compound 1-1 After adding (20 g, 121.79 mmol), 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 ethanol was removed by concentrating under reduced pressure. Separative extraction was performed by adding water and ethyl acetate; the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed twice with saline solution, and the organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the product. Compound 1-2 (29 g, yield: 90%) was obtained and used directly in the next step.

[0326] ESI(m / z) = 263.1 [M-1]

[0327] Step 2: In a 500 mL single-neck flask Compound 1-2methylhydrazine sulfate (14 g, 52.97 mmol), ethanol (200 mL), and methylhydrazine sulfate (11.45 g, 79.45 mmol) were added sequentially and stirred at 80°C for 6 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the ethanol. Separative extraction was performed by adding water and ethyl acetate; the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed twice with an aqueous sodium bicarbonate solution, and the organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography to obtain the product. Compound 1-3 (11 g, yield: 75.7%) was obtained.

[0328] ESI(m / z) =275.1 [M+H]+

[0329] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 7.88 - 7.84 (m, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 7.33 (pd, J = 7.4, 1.6 Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H), 4.16 (s, 3H), 4.15 (s, 2H), 1.31 (t, J = 7.1 Hz, 3H).

[0330] Step 3: In a 250 mL single-neck flask Compound 1-3 (5 g, 18.23 mmol), tetrahydrofuran (25 mL), methanol (25 mL), water (50 mL), and sodium hydroxide (0.88 g, 21.88 mmol) were added sequentially. The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to remove the organic solvent, diluted with water, adjusted to pH 2–3 with dilute hydrochloric acid, stirred for 30 minutes, and then filtered to obtain a filter cake. The filter cake was dried to obtain product compound 1-4 (4.1 g, yield: 91%).

[0331] ESI(m / z) = 247.1 [M+H]+

[0332] Step 4: In a 100 mL single-neck flask Compound 1-4 (1 g, 4.06 mmol), 4-(3-aminopropyl)-piperazine-1-carboxylic acid tert-butyl ester N,N-dimethylformamide (15 mL), N-methylimidazole (0.83 g, 10.15 mmol), and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (1.37 g, 4.87 mmol) were added sequentially, and the mixture was stirred at room temperature for 16 hours. Water and ethyl acetate were added to the reaction mixture for fractional extraction; the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed twice with saline solution, and the organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography to obtain the product. Compound 1-5 (1.4 g, yield: 73.11%) was obtained.

[0333] ESI(m / z) = 472.3 [M+H]+

[0334] Step 5: In a 100 mL single-neck flask 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, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain the product. Compound 2-1 (1.2 g, yield: 99%) was obtained. It was used directly in the next step.

[0335] ESI(m / z) = 372.3 [M+H]+

[0336] Step 6: In a 25 mL single-neck flask Compound 2-1 (55 mg, 0.13 mmol), dichloromethane (1 mL), and triethylamine (17 mg, 0.17 mmol) were added sequentially, and after stirring at room temperature for 2 minutes, TetrahydropyranonSodium triacetoxyhydroboride (26 mg, 0.26 mmol) and acetic acid (20 mg, 0.33 mmol) were added, and the mixture was stirred at room temperature for 5 minutes. Subsequently, sodium triacetoxyboride (55 mg, 0.26 mmol) was added, and the mixture was stirred at 35°C for 6 hours. Water and ethyl acetate were added to the reaction mixture for fractional extraction; the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed twice with saline solution, and the organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by reverse phase fractionation to obtain the product. Compound 2 (16.2 mg, yield: 26.37%) was obtained.

[0337] ESI(m / z) =456.4 [M+H]+

[0338] 1 H NMR (400 MHz, ) δ 8.35 (t, J = 5.7 Hz, 1H), 8.23 ​​(s, 1H), 7.84 (dd, J = 7.5, 1.7 Hz, 1H), 7.50 (dd, J = 7.4, 1.7 Hz, 1H), 7.37 - 7.27 (m, 2H), 4.19 (s, 2H), 4.14 (s, 3H), 3.90 - 3.82 (m, 2H), 3.33 - 3.20 (m, 4H), 2.51 (s, 3H), 2.49 (s, 2H), 2.32 (q, J = 6.8 Hz, 6H), 1.68 (tt, J = 13.5, 9.5 Hz, 4H), 1.36 (qd, J = 12.2, 4.5 Hz, 2H).

[0339] Example 3

[0340]

[0341] In a 25 mL single-neck flask Compound 2-1 (100 mg, 0.25 mmol), dichloromethane (2 mL), and triethylamine (33 mg, 0.33 mmol) were added sequentially, and after stirring at room temperature for 2 minutes, CyclopentanoneSodium triacetoxyhydroboride (42 mg, 0.50 mmol) and acetic acid (38 mg, 0.63 mmol) were added, and the mixture was stirred at room temperature for 5 minutes. Subsequently, sodium triacetoxyboride (110 mg, 0.50 mmol) was added, and the mixture was stirred at 35°C for 6 hours. Water and ethyl acetate were added to the reaction mixture for fractional extraction; the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed twice with saline solution, and the organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by reverse phase fractionation to obtain the product. Compound 3 (38.8 mg, yield: 32.6%) was obtained.

[0342] ESI(m / z) = 440.4 [M+H]+

[0343] 1 H NMR (400 MHz, ) δ 8.37 (t, J = 5.7 Hz, 1H), 8.20 (s, 1H), 7.87 - 7.80 (m, 1H), 7.50 (dd, J = 7.3, 1.7 Hz, 1H), 7.37 - 7.26 (m, 2H), 4.18 (s, 2H), 4.14 (s, 3H), 3.95 (s, 3H), 3.28 (q, J = 6.5 Hz, 2H), 2.64 - 2.52 (m, 3H), 2.47 - 2.27 (m, 5H), 1.78 (dq, J = 11.3, 6.5 Hz, 2H), 1.71 - 1.42 (m, 6H), 1.33 (ddd, J = 16.7, 13.5, 8.4 Hz, 2H).

[0344] Example 4

[0345]

[0346] In a 25 mL single-neck flask Compound 2-1 (100 mg, 0.25 mmol), dichloromethane (2 mL), and triethylamine (33 mg, 0.33 mmol) were added sequentially, and after stirring at room temperature for 2 minutes, Spiro[3.3]heptan-2-oneSodium triacetoxyhydrogen (55 mg, 0.50 mmol) and acetic acid (38 mg, 0.63 mmol) were added, and the mixture was stirred at room temperature for 5 minutes. Subsequently, sodium triacetoxyborohydride (110 mg, 0.50 mmol) was added, and the mixture was stirred at 35°C for 6 hours. Water and ethyl acetate were added to the reaction mixture for fractional extraction; the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed twice with saline solution, and the organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by reverse-phase fractionation to obtain the product. Compound 4 (54.6 mg, yield: 43.53%) was obtained.

[0347] ESI(m / z) = 466.4 [M+H]+

[0348] 1 H NMR (400 MHz, ) δ 8.36 (t, J = 5.7 Hz, 1H), 8.20 (s, 1H), 7.84 (dd, J = 7.6, 1.6 Hz, 1H), 7.50 (dd, J = 7.4, 1.7 Hz, 1H), 7.32 (dtd, J = 16.7, 7.4, 1.6 Hz, 2H), 4.25 (s, 5H), 4.18 (s, 2H), 4.14 (s, 3H), 3.27 (q, J = 6.4 Hz, 2H), 2.76 (p, J = 7.8 Hz, 1H), 2.38 (p, J = 12.9, 11.8 Hz, 9H), 2.02 - 1.88 (m, 2H), 1.86 - 1.71 (m, 2H), 1.72 - 1.52 (m, 4H).

[0349] Example 5

[0350]

[0351] In a 50 mL single-neck flask 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, and the mixture was stirred at 60°C for 4 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was purified by reverse-phase aliquoting to obtain the product. Compound 5 (24.1 mg, yield: 23.1%) was obtained.

[0352] ESI(m / z) = 426.3 [M+H]+

[0353] 1 H NMR (400 MHz, ) δ 8.38 (t, J = 5.7 Hz, 1H), 8.20 (s, 1H), 7.83 (dd, J = 7.6, 1.7 Hz, 1H), 7.50 (dd, J = 7.3, 1.8 Hz, 1H), 7.37 - 7.26 (m, 2H), 4.18 (s, 2H), 4.13 (s, 3H), 3.28 (q, J = 6.5 Hz, 2H), 2.53 (d, J = 12.5 Hz, 4H), 2.50 - 2.30 (m, 6H), 2.24 (d, J = 6.6 Hz, 2H), 1.66 (p, J = 6.8 Hz, 2H), 0.83 (dddd, J = 12.6, 9.6, 4.6, 3.2 Hz, 1H), 0.50 - 0.43 (m, 2H), 0.12 - 0.05 (m, 2H).

[0354] Example 6

[0355]

[0356] In a 25 mL single-neck flask Compound 2-1 (100 mg, 0.25 mmol), dichloromethane (2 mL), and triethylamine (33 mg, 0.33 mmol) were added sequentially, and after stirring at room temperature for 2 minutes, CyclobutanoneSodium triacetoxyhydroboride (35 mg, 0.50 mmol) and acetic acid (38 mg, 0.63 mmol) were added, and the mixture was stirred at room temperature for 5 minutes. Subsequently, sodium triacetoxyboride (110 mg, 0.50 mmol) was added, and the mixture was stirred at 35°C for 6 hours. Water and ethyl acetate were added to the reaction mixture for fractional extraction; the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed twice with saline solution, and the organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by reverse-phase fractionation to obtain the product. Compound 6 (45.7 mg, yield: 39.53%) was obtained.

[0357] ESI(m / z) = 426.4 [M+H]+

[0358] 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (t, J = 5.7 Hz, 1H), 8.17 (s, 1H), 7.84 (dd, J = 7.6, 1.6 Hz, 1H), 7.50 (dd, J = 7.4, 1.7 Hz, 1H), 7.37 - 7.27 (m, 2H), 4.18 (s, 2H), 4.14 (s, 3H), 3.27 (q, J = 6.5 Hz, 2H), 2.59 - 2.52 (m, 1H), 2.39 - 2.22 (m, 6H), 2.07 (ddd, J = 9.4, 7.0, 3.0 Hz, 2H), 1.96 (t, J = 7.1 Hz, 2H), 1.80 (dddd, J = 21.9, 8.9, 6.3, 2.2 Hz, 4H), 1.73 - 1.60 (m, 4H).

[0359] Example 7

[0360]

[0361] Step 1: In a 50 mL single-neck flask Compound 1-3Sodium bisulfite (200 mg, 0.73 mmol), dichloromethane (3 mL), and m-chloroperoxybenzoic acid (370 mg, 1.82 mmol) were added sequentially, and the mixture was stirred at room temperature for 4 hours. Dihydrous sodium bisulfite solution and ethyl acetate were added to the reaction mixture for fractional extraction; the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed twice with an aqueous sodium bicarbonate solution, and the organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the product. Compound 7-1 (185 mg, yield: 83%) was obtained.

[0362] ESI(m / z) = 307.1 [M+H]+

[0363] Step 2: In a 50 mL single-neck flask 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. 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, adjusted to pH 2–3 with dilute hydrochloric acid, stirred for 30 minutes, and then filtered to obtain a filter cake. The filter cake was dried to produce the product. Compound 7-2 (150 mg, yield: 89%) was obtained.

[0364] ESI(m / z) = 279.0 [M+H]+

[0365] Step 3: In a 50 mL single-neck flask Compound 7-2 (100 mg, 0.36 mmol), Compound 7-3 N,N-dimethylformamide (120 mg, 0.54 mmol), N,N-diisopropylethylamine (140 mg, 1.08 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (210 mg, 0.54 mmol) were added sequentially, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, and the product was purified by reverse-phase aliquoting and TLC aliquoting. Compound 7(42.1 mg, yield: 24.12%) was obtained.

[0366] ESI(m / z) = 486.3 [M+H]+

[0367] 1 H NMR (400 MHz, ) δ 8.51 (t, J = 5.9 Hz, 1H), 8.08 - 7.99 (m, 2H), 7.89 (td, J = 7.7, 1.4 Hz, 1H), 7.73 (td, J = 7.7, 1.1 Hz, 1H), 4.92 (s, 2H), 4.27 (s, 3H), 3.28 (t, J = 6.4 Hz, 6H), 2.84 - 2.54 (m, 3H), 2.36 (d, J = 24.3 Hz, 3H), 1.69 (ddd, J = 51.8, 41.2, 20.9 Hz, 7H), 1.35 - 0.96 (m, 6H).

[0368] Example 8

[0369]

[0370] Step 1: In a 500 mL single-neck flask Compound 1-2 (14 g, 52.97 mmol), ethanol (200 mL) and Methylhydrazine sulfate (11.45 g, 79.45 mmol) was added sequentially, and the mixture was stirred at 80°C for 6 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove ethanol. Separative extraction was performed by adding water and ethyl acetate; the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed twice with an aqueous sodium bicarbonate solution, and the organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography to obtain the product. Compound 8-1 (1.2 g, yield: 8.26%) was obtained.

[0371] ESI(m / z) = 275.1 [M+H]+

[0372] Step 2: In a 100 mL single-neck flask 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. 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 using dilute hydrochloric acid. After stirring for 30 minutes, the mixture was filtered to obtain a filter cake. The filter cake was dried to produce the product. Compound 8-2 (160 mg, yield: 89%) was obtained.

[0373] ESI(m / z) = 247.1 [M+H]+

[0374] Step 3: In a 50 mL single-neck flask Compound 8-2 (100 mg, 0.41 mmol), Compound 7-3 N,N-dimethylformamide (140 mg, 0.61 mmol), N,N-diisopropylethylamine (160 mg, 1.23 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (230 mg, 0.61 mmol) were added sequentially, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and purified by reverse-phase preparative extraction to obtain the product. Compound 8 (43.1 mg, yield: 21.24%) was obtained.

[0375] ESI(m / z) = 454.3 [M+H]+

[0376] 1H NMR (400 MHz, DMSO-d6) δ 8.40 (t, J = 5.6 Hz, 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 = 6.6 Hz, 2H), 2.58 (s, 4H), 2.49 - 2.21 (m, 7H), 1.84 - 1.62 (m, 6H), 1.55 (d, J = 12.3 Hz, 1H), 1.27 - 0.97 (m, 5H).

[0377] Example 9

[0378]

[0379] 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. After confirming the termination of the reaction by LCMS, the solution was concentrated directly and, by dry sampling column chromatography Compound 9-2 (0.8 g, yield: 50.79%) was obtained. m / z [M+H] + = 220

[0380] Step 2: Compound 9-2 (0.8 g, 2.50 mmol) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (2 mL) was added, and the reaction mixture was stirred at 25°C for 1 hour. Reaction completion was confirmed by LCMS, and after concentrating the reaction mixture, by sampling column chromatography Compound 9-3 (0.4 g, yield: 72.82%) was obtained. m / z [M+H] + = 220.3

[0381] Step 3: Compound 1-4(0.1 g, 0.41 mmol), compound 9-3 (0.1 g, 0.45 mmol), and HATU (0.23 g, 0.61 mmol) were dissolved in DMF (1 mL), and after adding DIPEA (0.16 g, 1.23 mmol), the reaction mixture was stirred at 25°C for 3 hours. Reaction termination was confirmed by LCMS, and the reaction mixture was directly purified using a reverse-phase C18 column (0.5% aqueous formic acid solution and acetonitrile) Compound 9 (23.2 mg, yield: 12.5%) was obtained. m / z [M+H] + = 448.4

[0382] 1 H NMR (400 MHz, DMSO-d6) 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d,J = 5.5 Hz, 1H), 8.15 (s, 0H), 7.79 (dd, J = 7.6, 1.5 Hz, 1H), 7.50 (dd, J = 7.4, 1.6 Hz, 1H), 7.31 (pd, J = 7.4, 1.5 Hz, 2H), 7.23 - 7.17 (m, 2H), 6.94 (d, J = 8.0 Hz, 2H), 6.77 (t, J = 7.2 Hz, 1H), 4.19 (s, 2H), 4.01 (s, 3H), 3.33 (d,J = 6.0 Hz, 2H), 3.21 - 3.18 (m, 4H), 2.58 - 2.53 (m, 4H), 2.45 (t, J = 6.6 Hz, 2H), 1.72 (p, J = 6.5 Hz, 2H).

[0383] Example 10

[0384]

[0385] Compound 2-1(0.15 g, 0.37 mmol), benzyl bromide (0.063 g, 0.37 mmol), and triethylamine (TEA) (0.19 g, 1.85 mmol) were dissolved in dichloromethane (DCM) (2 mL) and reacted at 25°C for 3 hours. After confirming the termination of the reaction by LCMS, the solution was concentrated directly and analyzed by dry sampling column chromatography Compound 10 (58.8 mg, yield: 34.64%) was obtained. m / z [M+H] + = 462.3

[0386] 1 H NMR (400 MHz, DMSO-d6) 1H NMR (400 MHz, DMSO-d6) δ 8.39 (t, J = 5.6 Hz, 1H), 7.84 (dd, J = 7.6, 1.7 Hz, 1H), 7.50 (dd, J = 7.5, 1.7 Hz, 1H), 7.35 - 7.28 (m, 6H), 7.24 (ddd, J = 8.6, 5.3, 2.2 Hz, 1H), 4.18 (s, 2H), 4.16 (s, 3H), 3.47 (s, 2H), 3.28 (q, J = 6.4 Hz, 2H), 2.51 (s, 1H), 2.43 (s, 5H), 2.38 (t, J = 6.8 Hz, 4H), 1.66 (p, J = 6.6 Hz, 2H).

[0387] Example 11

[0388]

[0389] Step 1: Compound 11-1 (0.8 g, 3.15 mmol), Compound 11-4 (0.53 g, 3.15 mmol) and K2CO3 (0.87 g, 6.3 mmol) were dissolved in DMF (8 mL) and reacted at 100°C for 3 hours. After confirming the termination of the reaction by LCMS, extraction, concentration, and dry sampling were performed by column chromatography. Compound 11-2(0.8 g, yield: 74.41%) was obtained. m / z [M+H] + = 342.2

[0390] Step 2: Compound 11-2 (0.8 g, 2.34 mmol) was dissolved in ethanol (8 mL), and after adding hydrazine hydrate (0.31 g, 4.91 mmol), the reaction mixture was stirred at 80°C for 15 hours. Reaction termination was confirmed by LCMS, the reaction mixture was subjected to suction filtration, and the filtrate was concentrated. Compound 11-3 (0.3 g, yield: 60.58%) was obtained. m / z [M+H] + = 222.3

[0391] Step 3: Compound 1-4 (0.1 g, 0.41 mmol), compound 11-3 (0.14 g, 0.49 mmol), and HATU (0.23 g, 0.61 mmol) were dissolved in DMF (1 mL), and after adding DIPEA (0.16 g, 1.23 mmol), the reaction mixture was stirred at 25°C for 3 hours. Reaction termination was confirmed by LCMS, and the reaction mixture was directly purified using a reverse-phase C18 column (0.5% aqueous formic acid solution and acetonitrile) Compound 11 (31.6 mg, yield: 17.7%) was obtained. m / z [M+H] + = 440.4

[0392] 1 H NMR (400 MHz, DMSO-d6) 1H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.84 (dd, J = 7.5, 1.6 Hz, 1H), 7.51 (dd, J = 7.4, 1.6 Hz, 1H), 7.32 (dtd, J = 16.9, 7.4, 1.6 Hz, 2H), 4.18 (s, 2H), 4.13 (s, 3H), 3.23 (dd, J= 10.5, 2.7 Hz, 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 = 11.4 Hz, 1H), 1.22 (q, J = 10.3, 8.2 Hz, 5H), 1.14 - 1.01 (m, 1H).

[0393] Example 12

[0394]

[0395] Step 1: Compound 1-4 (0.2 g, 0.81 mmol), compound 12-1 (0.1 g, 0.97 mmol), and HATU (0.4 g, 1.05 mmol) were dissolved in DMF (2 mL), and after adding DIPEA (0.31 g, 2.43 mmol), the reaction mixture was stirred at 25°C for 3 hours. Reaction termination was confirmed by LCMS, and the reaction mixture was extracted, concentrated, and by dry column chromatography Compound 12-2 (0.2 g, yield: 73.33%) was obtained. m / z [M+H]+ = 336.2

[0396] Step 2: Compound 12-2 (0.1 g, 0.24 mmol), Compound 11-4 (0.04 g, 0.24 mmol), K2CO3 (0.083 g, 0.6 mmol), and potassium iodide (0.02 g, 0.12 mmol) were dissolved in acetonitrile (2 mL) and reacted at 80°C for 6 hours. Reaction completion was confirmed by LCMS, and after concentrating the reaction solution, it was directly purified using a reverse-phase C18 column (0.5% aqueous formic acid solution and acetonitrile). Compound 12 (22 mg, yield: 19.75%) was obtained. m / z [M+H] + = 468.4

[0397] 1H NMR (400 MHz, DMSO-d6) 1H NMR (400 MHz, DMSO-d6) δ 7.62 - 7.57 (m, 1H), 7.49 (dd, J = 7.2, 1.9 Hz, 1H), 7.26 - 7.18 (m, 2H), 4.12 (d, J = 3.7 Hz, 3H), 4.09 (d, J = 4.6 Hz, 2H), 3.81 (t, J = 7.4 Hz, 1H), 3.55 (t, J = 7.4 Hz, 1H), 3.36 (s, 1H), 3.07 (s, 2H), 2.67 (d) ,J = 35.8 Hz, 7H), 2.44 (dt, J = 43.9, 7.2 Hz, 4H), 2.07 - 1.76 (m, 7H), 1.64 (s, 1H), 1.37 - 1.27 (m, 2H), 1.11 (d, J = 12.1 Hz, 2H).

[0398] Example 13

[0399]

[0400] Step 1: Compound 13-1 (0.5 g, 1.86 mmol), Compound 11-4 (0.31 g, 1.86 mmol) and K2CO3 (0.51 g, 3.72 mmol) were dissolved in DMF (5 mL) and reacted at 100°C for 3 hours. After confirming the termination of the reaction by LCMS, extraction, concentration, and dry sampling were performed by column chromatography. Compound 13-2 (0.4 g, yield: 60.34%) was obtained. m / z [M+H] + = 342.2

[0401] Step 2: Compound 13-2(0.4 g, 1.13 mmol) was dissolved in ethanol (5 mL), and after adding hydrazine hydrate (0.15 g, 2.37 mmol), the reaction mixture was stirred at 80°C for 15 hours. Reaction termination was confirmed by LCMS, the reaction mixture was subjected to suction filtration, and the filtrate was concentrated. Compound 13-3 (0.9 g, yield: 74.92%) was obtained. m / z [M+H] + = 226.3

[0402] Step 3: Compound 1-4 (0.13 g, 0.53 mmol), Compound 13-3 (0.19 g, 1.21 mmol) and HATU (0.26 g, 0.69 mmol) were dissolved in DMF (2 mL), and after adding DIPEA (0.21 g, 1.59 mmol), the reaction mixture was stirred at 25°C for 3 hours. Reaction completion was confirmed by LCMS, and the reaction mixture was directly purified using a reverse-phase C18 column (0.5% aqueous formic acid solution and acetonitrile) Compound 13 (14.2 mg, yield: 5.93%) was obtained. m / z [M+H] + = 440.4

[0403] 1 H NMR (400 MHz, DMSO-d6) 1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.84 (dd, J = 7.6, 1.6 Hz, 1H), 7.51 (dd, J = 7.4, 1.6 Hz, 1H), 7.33 (dtd, J = 16.9, 7.4, 1.6 Hz, 2H), 4.19 (s, 2H), 4.14 (s, 3H), 3.27 (q, J = 6.5 Hz, 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)

[0404] Example 14

[0405]

[0406] Step 1: Compound 1-2 (1 g, 3.78 mmol) and ethylhydrazine hydrochloride (0.23 g, 3.78 mmol) were dissolved in ethanol (10 mL), and the reaction mixture was stirred at 80°C for 1 hour. Reaction termination was confirmed by LCMS, and the reaction mixture was concentrated, extracted, and by dry sampling column chromatography. Compound 14-1 (0.6 g, yield: 44%) was obtained. m / z [MH] + = 289.1

[0407] Step 2: Compound 14-1 (0.2 g, 0.69 mmol) and NaOH (0.055 g, 1.38 mmol) were dissolved in THF / H2O = 4 / 1 (2 mL), and the reaction mixture was stirred at 60°C for 1 hour. Reaction termination was confirmed by LCMS, and after adjusting the pH of the reaction mixture to 5, suction filtration was performed. The filter cake was the product. Compound 14-2 (0.15 g, yield: 83.03%). m / z [M+H] + = 261.1

[0408] Step 3: Compound 14-2 Compound 7-3 (0.12 g, 0.46 mmol), Compound 7-3 (0.12 g, 0.55 mmol), and HATU (0.26 g, 0.69 mmol) were dissolved in DMF (1 mL), and after adding DIPEA (0.18 g, 1.38 mmol), the reaction mixture was stirred at 25°C for 3 hours. Reaction termination was confirmed by LCMS, and the reaction mixture was directly purified using a reverse-phase C18 column (0.5% aqueous formic acid and acetonitrile) Compound 14 (22.2 mg, yield: 10.30%) was obtained. m / z [M+H] + = 468.4

[0409] 1 H NMR (400 MHz, DMSO-d6) 1H NMR (400 MHz, DMSO-d6) δ 8.28 (t, J= 5.8 Hz, 1H), 7.72 (dd, J = 7.8, 1.5 Hz, 1H), 7.51 (dd, J = 7.6, 1.5 Hz, 1H), 7.35 (td, J = 7.6, 1.6 Hz, 1H), 7.30 (td, J = 7.5, 1.5 Hz, 1H), 4.46 (q, J = 7.2 Hz, 2H), 4.17 (s, 2H), 3.28 (q, J = 6.6 Hz, 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, 4.9 Hz, 4H), 1.56 (d, J = 12.4 Hz, 1H), 1.44 (t, J = 7.2 Hz, 3H), 1.25 - 1.16 (m, 4H), 1.15 - 1.00 (m, 1H).

[0410] Example 15

[0411]

[0412] Step 1: Compound 1-2 (0.8 g, 3.03 mmol) and cyclopropylmethylhydrazine hydrochloride (0.31 g, 3.64 mmol) were dissolved in ethanol (8 mL), and the reaction mixture was stirred at 80°C for 1 hour. Reaction termination was confirmed by LCMS, and the reaction mixture was concentrated, extracted, and analyzed by dry sampling column chromatography. Compound 15-1 (0.6 g, yield: 63.05%) was obtained. m / z [MH] + = 315.2

[0413] Step 2: Compound 15-1 (0.23 g, 0.73 mmol) and NaOH (0.058 g, 1.46 mmol) were dissolved in THF / H2O = 4 / 1 (3 mL), and the reaction mixture was stirred at 60°C for 1 hour. Reaction termination was confirmed by LCMS, and after adjusting the pH of the reaction mixture to 5, suction filtration was performed. The filter cake was the product. Compound 15-2 (0.13 g, yield: 62.06%). m / z [M+H] + = 287.1

[0414] Step 3: Compound 15-2 (0.1 g, 0.35 mmol), Compound 7-3 (0.13 g, 0.42 mmol) and HATU (0.17 g, 0.45 mmol) were dissolved in DMF (1 mL), and after adding DIPEA (0.14 g, 1.05 mmol), the reaction mixture was stirred at 25°C for 3 hours. Reaction completion was confirmed by LCMS, and the reaction mixture was directly purified using a reverse-phase C18 column (0.5% aqueous formic acid solution and acetonitrile) Compound 15 (59.3 mg, yield: 34.39%) was obtained. m / z [M+H] + = 468.4

[0415] 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 5.6 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.51 (dd, J = 7.7, 1.5 Hz, 1H), 7.32 (dtd, J = 23.5, 7.5, 1.4 Hz, 2H), 4.35 (d, J = 6.6 Hz, 2H), 4.17 (s, 2H), 3.28 (q, J = 6.5 Hz, 2H), 2.56 (s, 4H), 2.44 (d, J = 21.5 Hz, 3H), 2.35 (t, J = 6.6 Hz, 3H), 2.29 - 2.18 (m, 1H), 1.77 (d, J= 7.3 Hz, 2H), 1.68 (dt, J = 13.3, 7.7 Hz, 4H), 1.55 (d, J = 11.6 Hz, 1H), 1.33 - 1.24 (m, 1H), 1.16 (d, J = 10.2 Hz, 4H), 1.05 (d, J = 11.6 Hz, 1H), 0.54 - 0.47 (m, 2H), 0.35 (q, J = 6.0, 5.3 Hz, 2H).

[0416] Example 16

[0417]

[0418] 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 after stirring at 0°C for 0.5 hours, Diethyl oxalate (0.99 g, 6.75 mmol) was added and stirred at 40°C for 1 hour. Reaction termination was confirmed by LCMS, and the reaction solution was concentrated, extracted, and dry-sampled by column chromatography. Compound 16-2 (1 g, yield: 35.81%) was obtained. m / z [MH] + = 247.0

[0419] 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), and the reaction mixture was stirred at 80°C for 1 hour. Reaction completion was confirmed by LCMS, and after concentrating the reaction mixture, by sampling column chromatography Compound 16-3 (0.6 g, yield: 57.67%) was obtained. m / z [M+H] + = 259.3

[0420] Step 3: Compound 16-3(0.2 g, 0.77 mmol) and NaOH (0.062 g, 1.54 mmol) were dissolved in THF / H2O = 4 / 1 (2 mL), and the reaction mixture was stirred at 60°C for 1 hour. Reaction termination was confirmed by LCMS, and after adjusting the pH of the reaction mixture to 5, suction filtration was performed. The filter cake was the product. Compound 16-4 (0.1 g, yield: 56.09%). m / z [M+H] + = 231.1

[0421] Step 4: Compound 16-4 (0.12 g, 0.52 mmol), Compound 7-3 (0.14 g, 0.62 mmol) and HATU (0.3 g, 0.78 mmol) were dissolved in DMF (1 mL), and after adding DIPEA (0.2 g, 1.56 mmol), the reaction mixture was stirred at 25°C for 3 hours. Reaction completion was confirmed by LCMS, and the reaction mixture was directly purified using a reverse-phase C18 column (0.5% aqueous formic acid solution and acetonitrile) Compound 16 (63 mg, yield: 27.62%) was obtained. m / z [M+H]+ = 438.4

[0422] 1 H NMR (400 MHz, DMSO-d6) δ 8.36 - 8.30 (m, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.28 (t, J = 7.7 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 7.01 (d, J = 6.5 Hz, 1H), 5.39 (d, J = 1.8 Hz, 2H), 4.15 (d, J = 2.4 Hz, 3H), 3.26 (q, J = 5.7 Hz, 2H), 2.60 (s, 4H), 2.43 (s, 3H), 2.34 (q, J= 14.8, 10.8 Hz, 4H), 1.79 (s, 2H), 1.71 (s, 2H), 1.68 - 1.61 (m, 2H), 1.55 (d, J = 11.9 Hz, 1H), 1.18 (t, J = 8.9 Hz, 4H), 1.11 - 1.00 (m, 1H).

[0423] Example 17

[0424]

[0425] Step 1: Compound 17-1 (5 g, 34.2 mmol) and sodium ethoxide (2.44 g, 35.91 mmol) were dissolved in ethanol (100 mL), and after stirring at 0°C for 0.5 hours, Diethyl oxalate (5 g, 34.2 mmol) was added and stirred at 40°C for 1 hour. Reaction termination was confirmed by LCMS, and the reaction solution was concentrated, extracted, and analyzed by dry sampling column chromatography. Compound 17-2 (8.5 g, yield: 86.35%) was obtained. m / z [MH] + = 247.2

[0426] 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), and the reaction mixture was stirred at 25°C for 16 hours. Reaction completion was confirmed by LCMS, and after concentrating the reaction mixture, by sampling column chromatography Compound 17-3 (0.55 g, yield: 37.75%) was obtained. m / z [M+H] + = 257.2

[0427] Step 3: Compound 17-3 (0.25 g, 0.98 mmol) and KOH (0.33 g, 5.88 mmol) were dissolved in MeOH / H2O = 4 / 1 (2 mL), and the reaction mixture was stirred at 60°C for 1 hour. Reaction termination was confirmed by LCMS, and after adjusting the pH of the reaction mixture to 5, suction filtration was performed. The filter cake was the product. Compound 17-4 (0.1 g, yield: 56.09%). m / z [M+H] + = 229.2

[0428] Step 4: Compound 17-4 (0.12 g, 0.52 mmol), Compound 7-3 (0.14 g, 0.62 mmol), and HATU (0.3 g, 0.78 mmol) were dissolved in DMF (1 mL), and after adding DIPEA (0.2 g, 1.56 mmol), the reaction mixture was stirred at 25°C for 3 hours. Reaction termination was confirmed by LCMS, and the reaction mixture was directly purified using a reverse-phase C18 column (0.5% aqueous formic acid solution and acetonitrile) Compound 17 (50.8 mg, yield: 28.62%, formate) was obtained. m / z [M+H] + = 436.4

[0429] 1 H NMR (400 MHz, DMSO-d6) 8.25 (s, 1H), 8.16 (t, J = 5.5 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.39 - 7.32 (m, 2H), 7.28 (t, J = 7.3 Hz, 1H), 4.15 (s, 3H), 3.26 (q, J = 6.2 Hz, 2H), 2.89 (d, J = 6.9 Hz, 2H), 2.84 (d, J = 6.7 Hz, 2H), 2.65 (s, 4H), 2.48 (s, 2H), 2.38 (t, J = 6.7 Hz, 4H), 1.85 - 1.50 (m, 8H), 1.19 (p, J = 11.7 Hz, 4H), 1.11 - 0.99 (m, 1H).

[0430] Example 18

[0431]

[0432] Step 1: Compound 1-4(0.14 g, 0.57 mmol), Compound 18-1 (0.075 g, 0.68 mmol) and HATU (0.28 g, 0.74 mmol) were dissolved in DMF (2 mL), and after adding DIPEA (0.22 g, 1.71 mmol), the reaction mixture was stirred at 25°C for 3 hours. Reaction termination was confirmed by LCMS, and the reaction mixture was extracted, concentrated, and by dry column chromatography Compound 18-2 (0.18 g, yield: 92.3%) was obtained. m / z [M+H] + = 338.1

[0433] Step 2: Compound 18-2 (0.18 g, 0.53 mmol), N-phenylpiperazine (0.086 g, 0.53 mmol), K2CO3 (0.18 g, 1.33 mmol), and potassium iodide (0.044 g, 0.27 mmol) were dissolved in acetonitrile (2 mL) and reacted at 80°C for 6 hours. Reaction completion was confirmed by LCMS, and after concentrating the reaction solution, it was directly purified using a reverse-phase C18 column (0.5% aqueous formic acid solution and acetonitrile). Compound 18 (63 mg, yield: 25.5%) was obtained. m / z [M+H] + = 464.3

[0434] 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (t, J = 5.6 Hz, 1H), 7.80 (dd, J = 7.4, 1.8 Hz, 1H), 7.50 (dd, J = 7.1, 1.8 Hz, 1H), 7.31 (pd, J = 7.4, 1.6 Hz, 2H), 7.20 (t, J = 7.7 Hz, 2H), 6.93 (d, J = 8.2 Hz, 2H), 6.76 (t, J = 7.2 Hz, 1H), 4.94 (s, 1H), 4.19 (s, 2H), 4.02 (s, 3H), 3.84 (t, J= 6.1 Hz, 1H), 3.34 - 3.29 (m, 2H), 3.18 (t, J = 5.0 Hz, 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)

[0435] Example 19

[0436]

[0437] Compound 1-6 (0.1 g, 0.27 mmol), 2-bromopyridine (0.043 g, 0.27 mmol), palladium acetate (6 mg, 0.027 mmol), BINAP (34 mg, 0.054 mmol), and sodium tert-butoxide (78 mg, 0.81 mmol) were dissolved in 1,4-dioxane (2 mL) and reacted at 110°C for 4 hours. After confirming the termination of the reaction by LCMS, the solution was concentrated directly and purified directly using a reverse-phase C18 column (0.5% aqueous formic acid and acetonitrile). Compound 19 (33.5 mg, yield: 27.74%) was obtained. m / z [M+H] + = 449.3

[0438] 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (t, J = 5.6 Hz, 1H), 8.11 (dd, J = 5.0, 1.9 Hz, 1H), 7.80 (dd, J = 7.3, 1.9 Hz, 1H), 7.55 - 7.47 (m, 2H), 7.31 (pd, J = 7.4, 1.7 Hz, 2H), 6.82 (d, J = 8.6 Hz, 1H), 6.63 (dd, J = 7.1, 4.9 Hz, 1H), 4.19 (s, 2H), 4.03 (s, 3H), 3.53 (t,J = 5.0 Hz, 5H), 3.32 - 3.30 (m, 3H), 2.48 (s, 2H), 2.43 (t, J = 6.6 Hz, 2H), 1.72 (p, J = 6.7 Hz, 2H).

[0439] Example 20

[0440]

[0441] Compound 1-6 3-bromopyridine (0.1 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 1,4-dioxane (2 mL) and reacted at 110°C for 15 hours. After confirming the termination of the reaction by LCMS, the solution was concentrated directly and purified directly using a reverse-phase C18 column (0.5% aqueous formic acid and acetonitrile). Compound 20 (9.9 mg, yield: 8.2%) was obtained. m / z [M+H] + = 449.3

[0442] 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (t, J = 5.6 Hz, 1H), 8.31 (d, J = 2.9 Hz, 1H), 8.01 - 7.97 (m, 1H), 7.82 - 7.77 (m, 1H), 7.50 (dd, J = 7.4, 1.7 Hz, 1H), 7.34 - 7.28 (m, 3H), 7.20 (dd, J = 8.5, 4.5 Hz, 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 = 6.3 Hz, 2H).

[0443] Example 21

[0444]

[0445] Compound 1-6 (0.1 g, 0.27 mmol), 4-bromopyridine (0.043 g, 0.27 mmol), palladium acetate (6 mg, 0.027 mmol), BINAP (34 mg, 0.054 mmol), and sodium tert-butoxide (78 mg, 0.81 mmol) were dissolved in 1,4-dioxane (2 mL) and reacted at 110°C for 15 hours. After confirming the termination of the reaction by LCMS, the solution was concentrated directly and purified by Pre-TLC. Compound 21 (29.8 mg, yield: 27.1%) was obtained. m / z [M+H] + = 449.3

[0446] 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (t, J = 5.6 Hz, 1H), 8.16 (d, J = 5.9 Hz, 2H), 7.80 (dd, J = 7.4, 1.8 Hz, 1H), 7.50 (dd, J = 7.3, 1.9 Hz, 1H), 7.35 - 7.27 (m, 2H), 6.88 (d, J = 6.0 Hz, 2H), 4.19 (s, 2H), 4.03 (s, 3H), 3.43 (d, J = 4.7 Hz, 3H), 3.34 - 3.29 (m, 4H), 2.52 (s, 3H), 2.43 (t, J = 6.7 Hz, 2H), 1.70 (q, J = 6.7 Hz, 2H).

[0447] Example 22

[0448]

[0449] Compound 1-6(0.1 g, 0.27 mmol), 2-bromochlorobenzene (0.043 g, 0.27 mmol), palladium acetate (6 mg, 0.027 mmol), BINAP (34 mg, 0.054 mmol), and sodium tert-butoxide (78 mg, 0.81 mmol) were dissolved in 1,4-dioxane (2 mL) and reacted at 110°C for 15 hours. After confirming the termination of the reaction by LCMS, the solution was concentrated directly and purified directly using a reverse-phase C18 column (0.5% aqueous formic acid and acetonitrile). Compound 22 (27 mg, yield: 20.77%) was obtained. m / z [M+H] + = 449.3

[0450] 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (t, J = 5.6 Hz, 1H), 7.83 (dd, J = 7.6, 1.7 Hz, 1H), 7.50 (dd, J = 7.4, 1.7 Hz, 1H), 7.40 (dd, J = 7.9, 1.5 Hz, 1H), 7.31 (dddd, J = 16.0, 8.9, 7.4, 1.6 Hz, 3H), 7.17 (dd, J = 8.1, 1.6 Hz, 1H), 7.03 (td, J = 7.6, 1.5 Hz, 1H), 4.19 (s, 2H), 4.11 (s, 3H), 3.33 (s, 3H), 3.05 (d, J = 4.8 Hz, 4H), 2.59 (s, 3H), 2.47 (d, J = 6.6 Hz, 2H), 1.72 (t, J = 6.6 Hz, 2H).

[0451] Example 23

[0452]

[0453] Step 1: Compound 1-4(0.15 g, 0.61 mmol), compound 23-1 (0.086 g, 0.73 mmol), and HATU (0.3 g, 0.79 mmol) were dissolved in DCM (2 mL), and after adding DIPEA (0.24 g, 1.83 mmol), the reaction mixture was stirred at 25°C for 3 hours. Reaction termination was confirmed by LCMS, and the reaction mixture was extracted, concentrated, and by dry column chromatography Compound 23-2 (0.18 g, yield: 87.09%) was obtained. m / z [M+H] + = 340.1

[0454] Step 2: Compound 23-2 (0.27 g, 0.8 mmol), methanesulfonyl chloride (MsCl) (0.11 g, 0.96 mmol), and TEA (0.16 g, 1.6 mmol) were reacted. Reaction completion was confirmed by LCMS, the reaction solution was concentrated, and purified by column chromatography. Compound 23-3 (0.25 g, yield: 75.27%) was obtained. m / z [M+H] + = 418.2

[0455] 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 1,4-dioxane (3 mL) and reacted at 105°C for 5 days. Reaction termination was confirmed by LCMS, and after concentrating the reaction solution, it was directly purified using a reverse-phase C18 column (0.5% aqueous formic acid solution and acetonitrile). Compound 23 (5.2 mg, yield: 2.99%) was obtained. m / z [M+H] + = 484.3

[0456] 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (t, J = 6.2 Hz, 1H), 7.84 - 7.78 (m, 1H), 7.51 (dd, J= 7.5, 1.7 Hz, 1H), 7.32 (pd, J = 7.4, 1.7 Hz, 2H), 7.24 - 7.17 (m, 2H), 6.94 (d, J = 7.9 Hz, 2H), 6.80 - 6.75 (m, 1H), 4.19 (s, 2H), 4.05 (s, 3H), 3.86 (td, J = 14.4, 6.3 Hz, 2H), 3.22 - 3.16 (m, 4H), 2.92 (t, J = 14.0 Hz, 2H), 2.73 (t, J = 4.9 Hz, 4H).

[0457] Example 24

[0458]

[0459] Compound 1-6 (0.1 g, 0.27 mmol), m-chlorobromobenzene (0.062 g, 0.32 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), RuPhos (25 mg, 0.054 mmol), and potassium tert-butoxide (91 mg, 0.81 mmol) were dissolved in 1,4-dioxane (2 mL) and reacted at 110°C for 5 hours. After confirming the termination of the reaction by LCMS, the solution was concentrated directly and purified directly using a reverse-phase C18 column (0.5% aqueous formic acid and acetonitrile). Compound 24 (32 mg, yield: 24.66%) was obtained. m / z [M+H] + = 482.3

[0460] 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (t, J = 5.6 Hz, 1H), 7.80 (dd, J = 7.4, 1.8 Hz, 1H), 7.50 (dd, J = 7.3, 1.8 Hz, 1H), 7.31 (pd, J = 7.4, 1.6 Hz, 2H), 7.20 (t, J= 8.1 Hz, 1H), 6.95 (t, J = 2.2 Hz, 1H), 6.90 (dd, J = 8.4, 2.4 Hz, 1H), 6.78 (dd, J = 7.8, 1.8 Hz, 1H), 4.19 (s, 2H), 4.03 (s, 3H), 3.23 (d,J = 5.4 Hz, 8H), 2.55 (s, 3H), 2.46 (s, 1H), 1.72 (p, J = 6.8 Hz, 2H).

[0461] Example 25

[0462]

[0463] In an 8 mL single-neck flask 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. Under nitrogen protection, 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (12 mg, 0.025 mmol) and tris(dibenzylideneacetone)palladium (11 mg, 0.013 mmol) were added, followed by stirring at 105°C for 16 hours under nitrogen protection. The reaction mixture was cooled to room temperature, filtered, concentrated under reduced pressure, and purified by reverse-phase preparative extraction to obtain the product. Compound 25 (42.8 mg, yield: 36.22%) was obtained. ESI(m / z) = 482.3 [M+H] +

[0464] 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (t, J = 5.6 Hz, 1H), 7.84 - 7.76 (m, 1H), 7.53 - 7.47 (m, 1H), 7.31 (pd, J= 7.4, 1.7 Hz, 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 = 5.0 Hz, 6H), 2.53 (t, J = 5.0 Hz, 4H), 2.44 (t, J = 6.6 Hz, 2H), 1.71 (p, J = 6.6 Hz, 2H).

[0465] Example 26

[0466]

[0467] In an 8 mL single-neck flask Compound 2-1 (100 mg, 0.25 mmol), p-bromotrifluoromethylbenzene Potassium tert-butoxide (68 mg, 0.3 mmol), 1,4-dioxane (2 mL), and potassium tert-butoxide (93 mg, 0.82 mmol) were added sequentially. Under nitrogen protection, 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (12 mg, 0.025 mmol) and tris(dibenzylideneacetone)palladium (11 mg, 0.013 mmol) were added, followed by stirring at 105°C for 16 hours under nitrogen protection. The reaction mixture was cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure. The product was then purified by reverse-phase preparative extraction. Compound 26 (36.2 mg, yield: 28.6%) was obtained. ESI(m / z) = 516.3 [M+H] +

[0468] 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (t, J = 5.6 Hz, 1H), 7.80 (dd, J = 7.3, 1.9 Hz, 1H), 7.54 - 7.44 (m, 3H), 7.31 (pd, J = 7.4, 1.7 Hz, 2H), 7.07 (d, J= 8.6 Hz, 2H), 4.19 (s, 2H), 4.03 (s, 3H), 3.31 (s, 6H), 2.53 (t, J = 5.1 Hz, 4H), 2.43 (t, J = 6.6 Hz, 2H), 1.72 (p, J = 6.7 Hz, 2H).

[0469] Example 27

[0470]

[0471] Referring to the synthesis method of Example 26, instead of p-bromotrifluoromethylbenzene Compound 27 was synthesized using [the method].

[0472] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.54 (t, J = 5.6 Hz, 1H), 8.18 (s, 0.42H), 7.83 (dd, J = 7.3, 1.9 Hz, 1H), 7.53 (dd, J = 7.2, 1.9 Hz, 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 = 6.0 Hz, 2H), 3.11 (t, J = 4.9 Hz, 4H), 2.59 (d, J = 4.8 Hz, 4H), 2.48 (t, J = 6.6 Hz, 2H), 1.79 - 1.67 (m, 2H).

[0473] Example 28

[0474]

[0475] Referring to the synthesis method of Example 26, instead of p-bromotrifluoromethylbenzene Compound 28 was synthesized using [the source].

[0476] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.56 (t, J = 5.7 Hz, 1H), 8.39 (d, J = 4.7 Hz, 2H), 7.85 (d, J = 7.5 Hz, 1H), 7.53 (dd, J = 7.0, 1.8 Hz, 1H), 7.40 - 7.26 (m, 2H), 6.66 (t, J = 4.7 Hz, 1H), 4.22 (s, 2H), 4.10 (s, 3H), 3.80 (s, 4H), 3.34 (d, J = 8.2 Hz, 2H), 2.48 (s, 4H), 1.75 (s, 2H), 1.26 (s, 2H).

[0477] Example 29

[0478]

[0479] Referring to the synthesis method of Example 26, instead of p-bromotrifluoromethylbenzene

[0480] Compound 29 was synthesized using [the method].

[0481] 1H NMR (400 MHz, DMSO- d 6) δ 8.52 (t, J = 5.6 Hz, 1H), 7.81 (dd, J = 7.4, 1.9 Hz, 1H), 7.60 - 7.56 (m, 2H), 7.50 (dd, J = 7.2, 1.9 Hz, 1H), 7.31 (pd, J = 7.4, 1.7 Hz, 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, 5.8 Hz, 2H).

[0482] Example 30

[0483]

[0484] Referring to the synthesis method of Example 13, instead of 11-4 Compound 30 was synthesized using [the method].

[0485] 1 H NMR (400 MHz, DMSO- d 6) δ 8.47 (t, J = 6.1 Hz, 1H), 7.88 (dd, J = 7.6, 1.6 Hz, 1H), 7.54 (dd, J = 7.5, 1.6 Hz, 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).

[0486] Example 31

[0487]

[0488] Referring to the synthesis method of Example 13, instead of 11-4 Compound 31 was synthesized using [the method].

[0489] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.45 (t, J = 5.9 Hz, 1H), 7.84 (dd, J = 7.6, 1.6 Hz, 1H), 7.51 (dd, J= 7.4, 1.7 Hz, 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).

[0490] Example 32

[0491]

[0492] Referring to the synthesis method of Example 13, instead of 11-4 Compound 32 was synthesized using [the source].

[0493] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.46 (t, J = 5.9 Hz, 1H), 7.84 (dd, J = 7.6, 1.6 Hz, 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 = 6.4 Hz, 4H), 3.08 (s, 4H), 2.17 (d, J = 14.2 Hz, 2H), 1.92 (s, 2H), 1.83 - 1.75 (m, 2H).

[0494] Example 33

[0495]

[0496] Referring to the synthesis method of Example 23, instead Compound 33 was synthesized using [the source].

[0497] 1 H NMR (400 MHz, ) δ 8.42 (t, J = 6.1 Hz, 1H), 8.20 (s, 1H), 7.86 (dd, J= 7.5, 1.6 Hz, 1H), 7.51 (dd, J = 7.4, 1.7 Hz, 1H), 7.33 (dtd, J = 16.8, 7.4, 1.6 Hz, 2H), 4.19 (s, 2H), 4.17 (s, 3H), 3.81 (td, J = 14.2, 6.1 Hz, 4H), 2.98 (d, J = 11.3 Hz, 2H), 2.82 (t, J = 13.9 Hz, 2H), 2.34 (s, 6H), 2.21 - 2.04 (m, 6H), 1.74 (d, J = 11.7 Hz, 2H), 1.59 - 1.42 (m, 2H).

[0498] Example 34

[0499]

[0500] Referring to the synthesis method of Example 23, instead Compound 34 was synthesized using [the method].

[0501] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.36 (t, J = 6.3 Hz, 1H), 8.24 (s, 1H), 7.86 (dd, J = 7.5, 1.7 Hz, 1H), 7.51 (dd, J = 7.4, 1.7 Hz, 1H), 7.39 - 7.27 (m, 2H), 4.17 (s, 3H), 3.80 (d, J = 6.3 Hz, 2H), 2.99 (d, J = 11.2 Hz, 2H), 2.81 (t, J = 14.0 Hz, 2H), 2.56 (t, J = 5.2 Hz, 4H), 2.37 - 2.26 (m, 1H), 2.22 - 2.11 (m, 2H), 1.74 (d, J= 12.4 Hz, 2H), 1.53 (tt, J = 11.2, 4.6 Hz, 6H), 1.39 (t, J = 5.9 Hz, 2H).

[0502] Example 35

[0503]

[0504] Referring to the synthesis method of Example 23, instead Compound 35 was synthesized using [the method].

[0505] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.46 (t, J = 6.1 Hz, 1H), 8.18 (s, 0H), 7.86 (dd, J = 7.5, 1.6 Hz, 1H), 7.51 (dd, J = 7.4, 1.7 Hz, 1H), 7.38 - 7.27 (m, 2H), 4.19 (s, 5H), 3.81 (td, J = 14.1, 6.0 Hz, 2H), 3.55 (t, J = 4.6 Hz, 4H), 2.99 (d, J = 11.4 Hz, 2H), 2.83 (t, J = 13.9 Hz, 2H), 2.43 (t, J = 4.6 Hz, 4H), 2.23 - 2.12 (m, 2H), 2.04 (tt, J = 11.1, 3.8 Hz, 1H), 1.77 (d, J = 11.8 Hz, 2H), 1.50 (qd, J = 12.1, 3.7 Hz, 2H).

[0506] Example 36

[0507]

[0508] Referring to the synthesis method of Example 13, instead of 11-4 Compound 36 was synthesized using [the source].

[0509] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.27 (s, 1H), 7.84 (dd, J = 7.7, 1.5 Hz, 1H), 7.51 (dd, J = 7.5, 1.6 Hz, 1H), 7.33 (dtd, J = 16.6, 7.4, 1.5 Hz, 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).

[0510] Example 37

[0511]

[0512] Referring to the synthesis method of Example 23, instead Compound 37 was synthesized using [the method].

[0513] 1 ¹H NMR (400 MHz, ) δ 8.36 (t, J = 6.2 Hz, 1H), 7.86 (dd, J = 7.5, 1.7 Hz, 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, 6.2 Hz, 2H), 2.98 (d, J = 10.8 Hz, 2H), 2.81 (t, J = 14.0 Hz, 2H), 2.57 (t, J = 5.6 Hz, 4H), 2.35 - 2.09 (m, 3H), 1.90 (ddt, J= 20.0, 13.7, 5.6 Hz, 4H), 1.69 (d, J = 12.1 Hz, 2H), 1.52 (qd, J = 11.9, 3.7 Hz, 2H).

[0514] Example 38

[0515]

[0516] Step 1: Compound 1-4 (150 mg, 0.61 mmol, 1.0 eq), HATU (325 mg, 0.85 mmol, 1.4 eq), and DIEA (315 mg, 2.44 mmol, 4.0 eq) were dissolved in DMF (3 mL), and 1-amino-3,3-diethoxypropane (90 mg, 0.61 mmol, 1.0 eq) was added to the reaction mixture. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, washed with saturated saline (40 mL), dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure Early-maturing product 100-1 (300 mg, crude) was obtained.

[0517] Step 2: 100-1 (100 mg, crude, 0.27 mmol, 1.0 eq) was dissolved in acetone / water (v / v = 10 / 1, 2 mL / 0.2 mL), and TsOH (56 mg, 0.29 mmol, 1.1 eq) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, washed with saturated saline (20 mL), dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure Early-maturing products 100-2 (57 mg, crude) was obtained. LCMS: m / z = 302.1 [M+H]+

[0518] Step 3: 100-2(53 mg, crude, 0.18 mmol, 1.5 eq) and 100-3 (40 mg, 0.12 mmol, 1.0 eq) was dissolved in MeOH (1 mL), and NaBH3CN (14 mg, 0.22 mmol, 2.0 eq) was added to the reaction mixture. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x 10 mL). The organic phases were combined, washed with saturated saline (20 mL), dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The obtained crude product was separated and purified by preparative thin-layer chromatography to obtain a free product. The free product was dissolved in methanol, and formic acid was added to form a salt; the resulting solution was then concentrated under reduced pressure to obtain a colorless oily phase. Compound 100 (17 mg, yield 37%) was obtained.

[0519] LCMS: m / z = 412.2 [M + H] + ; 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.27 (t, J = 5.8 Hz, 1H), 8.19 (s, 1H), 7.83 (dd, J = 7.6, 1.7 Hz, 1H), 7.50 (dd, J = 7.4, 1.7 Hz, 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).

[0520] Referring to the synthesis method of compound 100, 100-3 Instead, the following compounds were synthesized using corresponding amines.

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528] Example 39

[0529]

[0530] 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 a 10 mL acetonitrile solution, N-phenylpiperazine (0.53 g, 3.24 mmol) was added, and the mixture was reacted at 60°C for 8 hours. After confirming the termination of the reaction by LCMS, the solution was filtered by suction, the filtrate was concentrated, and purified by dry sampling column chromatography (PE / EA = 50%). 39-1 (0.61 g, yield: 50.15%) was obtained. m / z [M+H] + = 376.4

[0531] Step 2: 39-1 (0.61 g, 1.62 mmol) and hydrazine hydrate (wt 80%, 0.2 g, 3.24 mmol) were dissolved in ethanol (10 mL) and reacted overnight at 80°C. After confirming the termination of the reaction using LCMS, the mixture was subjected to suction filtration. The filtrate was concentrated, the precipitated solid was slurried with petroleum ether, and then suction filtered again. The filtrate was re-concentrated 39-2 (0.35 g, yield: 87.8%) was obtained.

[0532] Step 3: Compound 1-4(0.106 g, 0.43 mmol), 39-2 (0.21 g, 0.52 mmol), and HATU (0.25 g, 0.62 mmol) were added to DMF (2 mL), followed by the addition of DIPEA (0.17 g, 1.29 mmol), and the reaction was carried out at room temperature for 3 hours. Reaction completion was confirmed by LCMS, and the product was directly purified by reverse-phase column chromatography. Product 39 (0.065 g, yield: 31.89%) was obtained. m / z [M+H] + = 474.4. 1 H NMR (400 MHz, DMSO-d6) δ 8.74 (t,J = 5.5 Hz, 1H), 7.75 (dd,J = 6.7, 2.4 Hz, 1H), 7.49 (dd,J = 6.5, 2.4 Hz, 1H), 7.29 (dt,J = 6.3, 2.6 Hz, 2H), 7.21 (t,J = 7.8 Hz, 2H), 6.96 (d,J = 8.2 Hz, 2H), 6.78 (t,J = 7.2 Hz, 1H), 4.18 (s, 2H), 3.88 (s, 3H), 3.33 (d,J = 5.4 Hz, 3H), 3.31 - 3.27 (m, 4H), 2.64 (t,J = 4.8 Hz, 3H), 2.43 (s, 2H), 0.52 (d,J = 4.7 Hz, 2H), 0.38 (d,J = 4.8 Hz, 2H).

[0533] Example 40

[0534]

[0535] Referring to the synthesis method of Example 39, a compound using 1,1-dibromo-2-methylpropane instead of 1,1-bis-bromomethylcyclopropane 40 Synthesized. 1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 4.1 Hz, 1H), 7.78 - 7.72 (m, 1H), 7.48 (dd, J = 7.2, 1.9 Hz, 1H), 7.28 (tt, J = 7.4, 5.6 Hz, 2H), 7.23 - 7.16 (m, 2H), 6.94 (d, J = 8.1 Hz, 2H), 6.76 (t, J = 7.2 Hz, 1H), 4.17 (s, 2H), 3.91 (s, 3H), 3.41 (dd, J = 13.5, 7.3 Hz, 2H), 3.22 (s, 4H), 3.02 (dd, J = 12.7, 8.6 Hz, 1H), 2.64 (s, 2H), 2.39 (t, J = 10.9 Hz, 2H), 2.28 - 2.20 (m, 1H), 2.04 (s, 1H), 0.86 (d, J = 6.6 Hz, 3H). m / z [M+H] + = 462.4

[0536] Example 41

[0537]

[0538] Step 1: 49-1 (450 mg, 1.50 mmol), 49-2 (280 mg, 1.80 mmol), and N,N-dimethylformamide (4 mL) were added sequentially to a 50 mL single-neck flask, followed by the addition of potassium carbonate (510 mg, 3.75 mmol) and stirring at 60°C for 16 hours. Separative extraction was performed by adding water and ethyl acetate to the reaction mixture, followed by two extractions with ethyl acetate. The organic phases were combined, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography to obtain 49-3 (420 mg, yield: 85.7%). LCMS m / z [M+H] + = 324.3

[0539] Step 2: 49-3 (320 mg, 0.99 mmol), methanol (1 mL), and 1,4-dioxane solution of HCl (4 M, 4 mL) were added sequentially to a 50 mL single-neck flask and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain 49-4 (200 mg, yield: 61%) in a dry state, which was used directly in the next step.

[0540] Step 3: 1-4 (100 mg, 0.41 mmol), 49-4 (160 mg, 0.49 mmol), and N,N-dimethylformamide (2 mL) were added sequentially to a 50 mL single-neck flask, followed by the addition of N,N-diisopropylethylamine (320 mg, 2.46 mmol) and (7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (180 mg, 0.47 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered, and the filtrate was directly purified using a reverse-phase column to obtain 49 (50.4 mg, yield: 27.5%). 1 H NMR (400 MHz, DMSO-d6) δ 7.83 (dd, J = 7.6, 1.7 Hz, 1H), 7.50 (dd, J = 7.4, 1.7 Hz, 1H), 7.37 - 7.26 (m, 2H), 4.56 (t, J = 9.0 Hz, 1H), 4.16 (s, 2H), 4.15 - 4.04 (m, 5H), 3.63 (dd, J = 9.9, 5.5 Hz, 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 = 5.9 Hz, 1H). m / z [M+H] + = 452.3

[0541] Example 42

[0542]

[0543] Referring to the synthesis method of Example 30, 1-4 instead 16-4 Using Compound 50 Synthesized. 1 HNMR (400 MHz, DMSO-d6) δ 8.56 (t,J = 5.6 Hz, 1H), 7.73 (dd,J = 7.8, 1.5 Hz, 1H), 7.28 (td,J = 7.8, 1.6 Hz, 1H), 7.08 (td,J = 7.6, 1.2 Hz, 1H), 7.01 (dd,J = 8.2, 1.2 Hz, 1H), 5.39 (s, 2H), 4.17 (s, 3H), 3.28 (q, J = 6.3 Hz, 4H), 3.01 (d,J = 11.2 Hz, 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 = 11.3 Hz, 2H), 1.68 (p,J = 6.6 Hz, 2H), 1.54 (tt,J = 12.1, 6.1 Hz, 2H). LCMS m / z [M+H] + = 453.3

[0544] Example 43

[0545] Referring to the synthesis method of Example 13, 11-4 Instead, the following compounds were synthesized using the corresponding amine fragment.

[0546]

[0547] Example 44

[0548]

[0549] Step 1: 38-2 (700 mg, 2.32 mmol), in a 100 mL single-neck flask, Sodium triacetoxyborohydride (720 mg, 2.67 mmol) and dichloromethane (15 mL) were added sequentially, followed by the addition of sodium triacetoxyborohydride (1.08 g, 5.10 mmol) and acetic acid (6 mg, 0.1 mmol), and the mixture was stirred at room temperature for 2 hours. Water and dichloromethane were added to the reaction mixture, and the pH was adjusted to 8–9 with a dilute aqueous sodium hydroxide solution before performing fractional extraction. The mixture was extracted twice with dichloromethane, the organic phases were combined, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to a dry state and purified by column chromatography to obtain 41-1 (700 mg, yield: 54.3%). LCMS m / z [M+H] + = 555.4

[0550] Step 2: 41-1 (200 mg, 0.36 mmol), methanol (1 mL), and 1,4-dioxane solution of HCl (4 M, 4 mL) were sequentially added to a 25 mL single-neck flask and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to a dry state and purified using a reverse-phase column to obtain 41 (125.7 mg, yield: 76.6%) as a hydrochloride. 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (t, J = 5.8 Hz, 1H), 8.18 (s, 1H), 7.84 (dd, J = 7.6, 1.6 Hz, 1H), 7.50 (dd, J = 7.5, 1.6 Hz, 1H), 7.32 (dtd, J = 17.6, 7.4, 1.6 Hz, 2H), 4.19 (s, 2H), 4.15 (s, 3H), 3.29 (q, J = 6.3 Hz, 2H), 3.16 (d, J = 11.7 Hz, 2H), 3.02 (t, J = 4.9 Hz, 4H), 2.73 - 2.59 (m, 6H), 2.41 - 2.26 (m, 3H), 1.79 (dt, J = 13.9, 8.9 Hz, 4H), 1.65 (q, J = 11.2 Hz, 2H). LCMS m / z [M+H] + = 455.4

[0551] Referring to the synthesis method of compound 41, instead Compound 55 was synthesized using [the method]. 1 HNMR (400 MHz, DMSO-d6) δ 8.47 (s, 2H), 8.39 (t,J = 6.0 Hz, 1H), 7.84 (dd,J = 7.6, 1.6 Hz, 1H), 7.50 (dd,J = 7.5, 1.6 Hz, 1H), 7.32 (dtd,J = 16.9, 7.4, 1.6 Hz, 2H), 4.19 (d,J = 2.1 Hz, 2H), 4.14 (s, 3H), 3.51 (d,J = 12.3 Hz, 2H), 3.30 (q,J = 6.5 Hz, 3H), 3.00 (q,J = 11.6, 11.1 Hz, 4H), 2.12 (d,J = 13.1 Hz, 2H), 1.97 (dd,J = 14.8, 9.0 Hz, 4H).LCMS m / z [M+H] + = 386.2

[0552] Example 45

[0553]

[0554] 1HNMR (400 MHz, DMSO-d6) δ 8.38 (t,J = 5.7 Hz, 1H), 8.20 (HCOOH, 0.53H), 7.95 (d,J = 7.4 Hz, 1H), 7.83 (dd,J = 7.7, 1.6 Hz, 1H), 7.50 (dd,J = 7.4, 1.7 Hz, 1H), 7.37 - 7.26 (m, 2H), 4.19 (s, 2H), 4.14 (s, 3H), 3.28 (q,J = 6.5 Hz, 3H), 2.85 (d,J = 11.5 Hz, 2H), 2.38 (t,J = 6.8 Hz, 2H), 2.06 - 1.96 (m, 2H), 1.80 - 1.71 (m, 2H), 1.66 (q,J = 6.8 Hz, 2H), 1.56 - 1.43 (m, 3H), 0.66 - 0.58 (m, 4H).LCMS m / z [M+H] + = 454.2

[0555] Example 46

[0556]

[0557] Step 1: (679.6 mg, 4.0 mmol, 1.0 eq) and 80-1 800 mg (4.0 mmol, 1.0 eq) was dissolved in 10 mL of DCE, 2 drops of acetic acid were added, the reaction mixture was stirred at room temperature for 0.5 hours, and then cooled to 0°C. Subsequently, NaBH(OAc)3 (1.69 g, 8.0 mmol, 2.0 eq) was added to the reaction mixture in portions. The reaction mixture was stirred at 0°C for 5 minutes, then transferred to room temperature and stirred overnight. After the reaction was complete, the reaction mixture was diluted with water (50 mL), the pH was adjusted to alkaline with a saturated NaHCO3 solution, and then extracted with ethyl acetate (3 x 40 mL). The organic phases were combined, washed with saturated saline, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 10:1) to obtain the yellow oil phase. Compound 80-2(640 mg, yield 45%) was obtained. LCMS m / z = 353.3 [M+H] +

[0558] Step 2: Compound 80-2 (640 mg, 1.81 mmol, 1.0 eq) was dissolved in DCM (7 mL), and HCl solution (4 M in dioxane, 7 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a white solid Compound 80-3 (630 mg, yield 100%) was obtained. LCMS m / z = 253.3 [M+H] +

[0559] Step 3: Referring to the synthesis method of Compound 13, use 61-3 instead of 13-3 Compound 80 Synthesized. 1 HNMR (400 MHz, DMSO-d6) δ 8.32 (q,J = 5.6 Hz, 1H), 8.14 (HCOOH, H0.45), 7.87 - 7.81 (m, 1H), 7.51 (dd,J = 7.5, 1.7 Hz, 1H), 7.38 - 7.27 (m, 2H), 4.18 (d,J = 1.7 Hz, 2H), 4.14 (s, 3H), 3.91-3.85 (m, 2H), 3.78-3.72 (m, 1H), 3.65-3.61 (m, 3H), 3.34 - 3.25 (m, 4H), 3.17 (dd,J = 9.9, 5.9 Hz, 2H), 2.83-2.74 (m, 4H), 2.46 - 2.32 (m, 2H), 2.21 (dt,J = 28.0, 7.7 Hz, 2H), 2.02 (t,J = 7.2 Hz, 2H), 1.80 - 1.70 (m, 1H), 1.10 (q,J = 7.5 Hz, 3H).LCMS m / z [M+H] + = 481.3

[0560] Example 47

[0561] Referring to the synthesis method of compound 80, Instead, the corresponding amine fragment was used, and the corresponding acid fragment was used instead of 1-4 to synthesize the following compounds.

[0562]

[0563]

[0564]

[0565] Example 48

[0566]

[0567] Step 1: Under nitrogen protection Compound 68-1 (923 mg, 5.05 mmol, 1.0 eq) was dissolved in THF (9 mL) and cooled to -78°C. Then, NaHMDS (2 M in THF, 5.1 mL, 10.11 mmol, 2.0 eq) was added dropwise to the reaction mixture, and the mixture was stirred at -78°C for 0.5 hours. Diethyl oxalate (1.48 g, 10.11 mmol, 2.0 eq) was dissolved in THF (4.5 mL) and added dropwise to the reaction mixture. The reaction mixture was stirred at -78°C for 10 minutes, then transferred to room temperature and stirred for 1.5 hours. After the reaction was complete, the reaction mixture was quenched with a saturated NH4Cl solution and extracted with ethyl acetate (3 x 40 mL). The organic phases were combined, washed with saturated saline (50 mL), dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a white solid Compound 68-2 (1.9 g, yield 100%) was obtained. LCMS m / z = 283.1 [M+H] +

[0568] 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 mixture. The reaction mixture was stirred at room temperature for 4 hours. 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 = 10:1) to obtain a white solid Compound 68-3a(350 mg, yield 19%) and 68-3b (405 mg, yield 21.7%) were obtained. 68-3a :LCMS m / z = 293.1 [M+H] + ; 1 ¹H NMR (400 MHz, DMSO- d 6) δ 7.43 (d, J = 8.3 Hz, 1H), 7.04 (d, J = 2.1 Hz, 1H), 7.01 (dd, J = 8.3, 2.1 Hz, 1H), 5.49 (s, 2H), 4.42 (q, J = 7.1 Hz, 2H), 4.20 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H). 68-3b :LCMS m / z = 293.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.1 Hz, 1H), 6.94 (dd, J = 8.1, 2.0 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 5.41 (s, 2H), 4.34 (q, J = 7.1 Hz, 2H), 4.18 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H).

[0569] Step 3: Compound 68-3a (200 mg, 0.68 mmol, 1.0 eq) was dissolved in THF (1.5 mL), and NaOH solution (NaOH (54.7 mg, 1.37 mmol, 2.0 eq) dissolved in H2O (0.5 mL)) was slowly added. The reaction mixture was stirred at 60°C for 3 hours. 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 organic phases were combined, washed with saturated saline (40 mL), dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a white solid Compound 68-4a (200 mg, yield 100%) was obtained. LCMS m / z = 265.0 [M+H] + ; 1 ¹H NMR (400 MHz, DMSO- d 6) δ 7.73 (d, J = 8.2 Hz, 1H), 7.16 - 7.09 (m, 2H), 5.42 (s, 2H), 4.16 (s, 3H).

[0570] Step 4: Compound 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) were dissolved in DMF (2 mL), and the reaction mixture was stirred at room temperature for 0.5 hours. Compound 68-5 (170.4 mg, 0.76 mmol, 2.0 eq) was dissolved in DMF (1 mL) and added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 2.5 hours. After the reaction was complete, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, washed with saturated saline (40 mL), dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was separated and purified using a preparative chromatography column to obtain a white solid. Compound 68 (26 mg, yield 28%) was obtained. LCMS m / z = 487.3 [M+H] + ; 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.72 - 8.59 (m, 1H), 7.74 (d, J= 8.3 Hz, 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).

[0571] Referring to the synthesis operation of Compound 68, in Step 3 68-3a instead 68-3b Compound 117 was synthesized using [the source]. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.32 (t, J = 5.6 Hz, 1H), 8.18 (s, HCOOH, 1.27H), 7.60 (d, J = 8.7 Hz, 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 = 11.4 Hz, 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 = 11.5 Hz, 2H), 1.80 - 1.68 (m, 4H), 1.49 - 1.39 (m, 2H). LCMS m / z = 487.3 [M+H] +

[0572] Example 49

[0573] Referring to the synthesis methods of compounds 68 and 117, 68-1 Instead, use the corresponding ketone fragment, 68-5 Instead, the following compounds were synthesized using the corresponding amine fragment.

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580] Example 50

[0581]

[0582] Step 1: (200 mg, 0.59 mmol, 1.0 eq) and 1-methylpyrazole-4-boronic acid pinacol ester (370 mg, 1.78 mmol, 3.0 eq) was mixed with 1,4-dioxane (4 mL) and water (1 mL), and Pd(dppf)2Cl2 (45 mg, 0.059 mmol, 0.1 eq) and potassium carbonate (244.6 mg, 1.78 mmol, 3.0 eq) were added. The reaction mixture was purged with nitrogen three times and stirred for 2 hours under nitrogen protection at 90°C. After the reaction was complete, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, washed with saturated saline (50 mL), dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography to obtain a yellow solid Compound 95-1 (190 mg, yield 94.6%) was obtained. LCMS m / z = 339.1 [M+H] +

[0583] Step 2: Referring to the synthesis method of Compound 68, Compound 95 was synthesized using 95-1 instead of 68-3a. LCMS m / z = 533.3 [M+H] + . 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.45 (t, J= 5.8 Hz, 1H), 8.20 (s, 1H), 8.15 (s, HCOOH, 3.5H), 7.92 (s, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.28 (dd, J = 8.0, 1.8 Hz, 1H), 7.24 (d, J = 1.8 Hz, 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).

[0584] Example 51

[0585] Referring to the synthesis method of compound 95, Instead, use the corresponding boronic acid or boronic acid ester, The following compounds were synthesized using a corresponding bromo fragment instead, and a corresponding amine fragment instead of 68-5.

[0586]

[0587]

[0588] Example 52

[0589]

[0590] Step 1: Under nitrogen protection Zn(CN)2 (300 mg, 0.89 mmol, 1.0 eq) was dissolved in DMF (10 mL), and Zn(CN)2 (209 mg, 1.78 mmol, 2.0 eq) and Pd(PPh3)4 (205.6 mg, 0.178 mmol, 0.2 eq) were added to the reaction mixture. The reaction mixture was purged with nitrogen three times and stirred for 2 hours at 130°C under nitrogen protection. After the reaction was complete, the reaction mixture was filtered, the filtrate was diluted with water (100 mL), and extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, washed with saturated saline, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (eluent: ethyl acetate:petroleum ether = 1:1) to obtain a yellow solid 94-1 (140 mg, yield 55%) was obtained. LCMS: m / z = 284.1 [M+H] +

[0591] Step 2: Referring to the synthesis method of Compound 68, Compound 94 was synthesized using 94-1 instead of 68-3a. LCMS: m / z = 478.3 [M+H] + . 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.69 (t, J = 5.4 Hz, 1H), 8.20 (s, 2H), 7.90 (d, J = 8.1 Hz, 1H), 7.57 - 7.46 (m, 2H), 5.50 (s, 2H), 4.21 (s, 3H), 3.28 (q, J = 6.2 Hz, 2H), 2.96 (d, J = 11.2 Hz, 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).---

[0592] Example 53

[0593]

[0594] Referring to the synthesis method of Compound 30, Compound 75 was synthesized using 7-2 instead of 1-4. LCMS m / z = 501.3 [M+H] + ; 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.75 - 8.63 (s, 1H), 8.04 (t, J = 7.8 Hz, 2H), 7.90 (t, J = 7.8 Hz, 1H), 7.73 (t, J = 7.7 Hz, 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).

[0595] Example 54

[0596]

[0597] 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), and the mixture was reacted overnight at room temperature. Reaction completion was confirmed by LCMS, and after extraction and concentration, the product was purified by preparative thin-layer chromatography. Compound 79 (0.03 g, yield: 23.98%) was obtained. 1HNMR (400 MHz, DMSO-d6) δ 8.55 (t,J = 5.6 Hz, 1H), 7.84 (dd,J = 7.6, 1.6 Hz, 1H), 7.50 (dd,J = 7.5, 1.6 Hz, 1H), 7.32 (dtd,J = 17.0, 7.5, 1.5 Hz, 2H), 4.18 (s, 2H), 4.15 (s, 3H), 3.26 (m, 6H), 2.97 (m, 2H), 2.64 (t,J = 6.7 Hz, 2H), 2.52 (m, 3H), 2.39 (m, 4H), 2.14 (dd,J = 13.3, 5.6 Hz, 1H), 2.05 - 1.87 (m, 2H), 1.79 (d,J = 11.3 Hz, 2H), 1.72 - 1.63 (m, 2H), 1.59 - 1.44 (m, 2H), 1.27 (d,J = 16.0 Hz, 1H)..LCMS m / z [M+H] + = 508.3.

[0598] Example 55

[0599] Referring to the synthesis method of compound 94, The following compounds were synthesized using the corresponding bromo fragment instead, and the corresponding amine fragment instead of 68-5. Fragment and It was prepared by referring to the synthesis method of intermediate 83-2.

[0600]

[0601]

[0602] Example 56

[0603]

[0604] 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. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was concentrated. The crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 8:1) to obtain a yellow solid Compound 83-1 (4.45 g, yield 75.39%) was obtained. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 14.06 (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] +

[0605] Step 2: Referring to the synthesis method of compound 14, compound 83 was synthesized using 83-1 instead of 14-1 and 68-5 instead of 7-3. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.41 - 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] +

[0606] Example 57

[0607]

[0608] Step 1: Compound 83-1 Cesium carbonate (2.0 g, 7.69 mmol) was dissolved in DMF (30 mL), and cesium carbonate (3.76 g, 11.53 mmol) and 3-iodooxetane (1.7 g, 9.23 mmol) were added to the reaction mixture. The reaction mixture was stirred at 110°C for 1 hour. After the reaction was complete, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 x 80 mL). The organic phases were combined, washed with saturated saline, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain a yellow solid Compound 88-1a( 170 mg (yield 2.88%) and yellow solid Compound 88-1b (1.3 g, yield 53.43%) was obtained. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 7.55 - 7.52 (m, 1H), 7.50 - 7.47 (m, 1H), 7.36 - 7.32 (m, 2H), 6.01 - 5.92 (m, 1H), 5.03 - 4.97 (m, 4H), 4.35 (q, J = 7.1 Hz, 2H), 4.14 (s, 2H), 1.33 (d, J = 7.1 Hz, 3H). LCMS m / z = 317.1 [M+H] +

[0609] Step 2: Compound 88-1a(63 mg, 0.199 mmol, 1.0 eq) was dissolved in 1 mL of MeOH and 1 mL of THF, and a NaOH solution (25.32 mg, 0.633 mmol, 2.0 eq of NaOH dissolved in 1 mL of H2O) was slowly added. The reaction mixture was stirred at 60°C for 2 hours. 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 x 20 mL). The organic phases were combined, washed with saturated saline, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a yellow solid Compound 88-2a (57 mg, yield 100%) was obtained. LCMS m / z = 289.0 [M+H] +

[0610] 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 hours. Compound 68-5 (118.82 mg, 0.494 mmol) was added to the reaction mixture. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (3 x 20 mL). It was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude product was separated and purified using a preparative chromatography column. Compound 88 (20.6 mg, yield 20.4%) was obtained. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.46 (t, J= 6.1 Hz, 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] +

[0611] Compound 89 was synthesized by referring to the synthesis method of compound 88 and using 88-1b instead of 88-1a. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.51 - 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] +

[0612] Example 58

[0613]

[0614] Compound 90 was synthesized by referring to the synthesis method of compound 88 and using 1-chloro-2-methyl-2-propanol instead of 3-iodooxetane. 1 ¹H NMR (400 MHz, DMSO- d6 ) δ 8.33 (t, J = 6.2 Hz, 1H), 8.23 ​​(dd, J = 7.6, 1.6 Hz, 1H), 7.51 (dd, J = 7.4, 1.6 Hz, 1H), 7.35 - 7.26 (m, 2H), 4.92 (s, 1H), 4.30 (s, 2H), 4.16 (s, 2H), 3.33 - 3.28 (m, 2H), 3.17 - 2.54 (m, 16H), 1.90 - 1.72 (m, 6H), 1.19 (s, 6H). LCMS: m / z = 527.3 [M + H] +

[0615] Example 59

[0616] Referring to the synthesis method of compound 83, instead of 1-2 The following compounds were synthesized using [the appropriate amine fragment] instead of 68-5.

[0617]

[0618] Example 60

[0619]

[0620] Step 1: Compound (300 mg, 0.89 mmol, 1.0 eq), 1,2,3-triazole (74 mg, 1.07 mmol, 1.2 eq), and K3PO4 (380 mg, 1.78 mmol, 2.0 eq) were mixed in toluene (5 mL), and 4MetBuXPhos (85 mg, 0.18 mmol, 0.2 eq) and Pd2(dba)3 (80 mg, 0.09 mmol, 0.1 eq) were added. The reaction mixture was purged with nitrogen three times and stirred for 5 hours under nitrogen protection at 120°C. After the reaction was complete, water (50 mL) was added to the reaction mixture and quenched, and extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, washed with saturated saline, dried with anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure, and the crude product is separated and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain a white solid Compound 124-1 (100 mg, yield 34.6%) was obtained. LCMS m / z = 326.1 [M+H] + ; 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.13 (s, 2H), 7.77 (d, J = 8.3 Hz, 1H), 7.68 (dd, J = 8.4, 2.1 Hz, 1H), 7.55 - 7.50 (m, 1H), 5.51 (s, 2H), 4.31 (q, J = 7.1 Hz, 2H), 4.14 (s, 3H), 1.33 (t, J = 7.0 Hz, 3H).

[0621] Step 2: Referring to the synthesis route of Compound 95, Compound 124 was synthesized using 124-1 instead of 95-1. LCMS m / z = 520.4 [M+H] + ; 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.34 (t, J= 5.6 Hz, 1H), 8.13 (s, 2H), 7.78 (d, J = 8.3 Hz, 1H), 7.69 (dd, J = 8.3, 2.1 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 5.46 (s, 2H), 4.00 (s, 3H), 3.30 - 3.36 (m, 2H), 3.00 (d, J = 11.2 Hz, 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).

[0622] Effect Examples

[0623] Cell IC50 measurement

[0624] (1) Cell preparation: Liver cancer cells in good growth condition (PLC / PRF / 5, provided by the Chinese Academy of Sciences; MHCC97H, provided by this institute) were digested and diluted and inoculated into 96-well cell culture plates, with 1,000 to 3,000 cells added to each well and cultured in a cell culture incubator at 37°C and 5% CO2. After 24 hours, when the cells attached, a drug was administered.

[0625] (2) Drug administration: The drug was diluted stepwise to set 9 concentrations, and a control group consisting of a medium without the drug and a medium containing only the drug solvent was set separately. The diluted drug was added to cell culture plates inoculated with cells the previous day and cultured in an incubator for 72 hours.

[0626] (3) Measurement of cell activity using CCK8: CCK8 and medium were mixed in a 1:10 ratio and 100 μL was added to each well of a cell culture plate. After standing for 2 to 4 hours, the OD value was measured using a microplate reader.

[0627] (4) Data analysis: Data was organized based on the OD value, and the IC50 curve was created to obtain the IC50 value.

[0628] (5) IC50 verification: The theoretical IC50 value was derived from the IC50 curve, and the drug concentration was verified by taking half, one, and two times the theoretical value, respectively.

[0629]

[0630]

[0631]

[0632]

[0633]

[0634]

[0635]

[0636]

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653]

[0654] "\" indicates unmeasured

[0655] Although specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely examples and that various changes or modifications can be made to the embodiments without departing from the principles and essence of the present invention. Accordingly, the scope of protection of the present invention is limited by the appended claims.

Claims

Claim 1 In a compound represented by formula (IA) or a pharmaceutically acceptable salt thereof, Ring C is a benzene ring or a "5-6-membered heteroaryl ring in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and each R1 is independently a halogen, a cyano group, C 1-6 Alkyl group, C 3-10 Cycloalkyl group, C 1-6 Alkoxy group, C substituted with one or more halogens 1-6 C substituted with an alkyl group or one or more halogens 1-6 Alkoxy group, "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or one or more R 1-1 "a 5-10-membered heteroaryl group substituted with , wherein the heteroatom is 1, 2, or 3 selected from N, O, and S, and the number of heteroatoms is 1, 2, or 3," and each R 1-1 C each independently 1-6 It is an alkyl group, where m and k are each independently 0, 1 or 2, X1 is -CH2-, -O-, -S-, -NH- or -S(=O)2-, and X2 is -C(R a R b )- or -O- and,R a and R b Each independently hydrogen, deuterium, or C 1-6 It is an alkyl group, or R a , R b and the carbon atoms they share are connected to form a 3-10 saturated carbon ring, where n is 0 or 1, and each " Each represents a single or double bond independently, X3 and X4 are each independently C or N, ring A is a pyrazole ring, and each R2 is each independently H, halogen, or C 1-6 Alkyl group, C 3-10 Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", C 6-10 Aryl group, one or more R 2-1 C substituted with 1-6 alkyl group or one or more R 2-2 "a 5-10-membered heteroaryl group substituted with , wherein the heteroatom is 1, 2, or 3 selected from N, O, and S, and the number of heteroatoms is 1, 2, or 3," and each R 2-1 and R 2-2 Each independently consists of a halogen, a hydroxyl group, and C 1-6 Alkyl group, -N(R 2a R 2b ), C 3-10 Cycloalkyl group, C 1-6 Alkoxy group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", C 6-10 An aryl group or "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and R 2a and R 2b Each independently H or C 1-6 It is an alkyl group, and E is -N(R3)- or and, n1 is 1, 2, or 3, # indicates one end connected to -C(O)- in equation (IA), and R3 is hydrogen, C 1-6 alkyl group or C 3-10 It is a cycloalkyl group, and L is C 1-6 Alkylene group, one or more R L C substituted with 1-6 Alkylene group, "-(C 1-6 Alkylene group)-LA-*" or -L A - and, each R L Each independently deuterium, C 1-6 Alkoxy group, C 3-10 It is a cycloalkyl group, a hydroxyl group, a halogen or an oxo group (=O), or two Rs L If substituted into this same carbon atom, 2 R L and the carbon atoms they share are connected to form a 3-10-membered saturated carbon ring or a "3-10-membered saturated heterocycle in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and L A -C(O)NH-, -O-, -N(R LA )-, ethenylene group, ethinylene group, 3-10 saturated carbon ring or "a 3-10 saturated heterocycle in which one, two, or three heterovalence atoms are selected from N, O, and S, and the number of heterovalence atoms is one, two, or three", and R LA is H, C 1-6 Alkyl group, C 3-10 A cycloalkyl group or "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and ring B is a 3-10-membered saturated or unsaturated carbon ring, one or more R B-1 A 3-10-membered saturated or unsaturated carbon ring substituted with, "a 3-10-membered saturated or unsaturated heterocycle in which one, two, or three heterovalence atoms are selected from N, O, and S, and the number of heterovalence atoms is one, two, or three" or one or more of R B-2 A "3-10 saturated or unsaturated heterocycle in which one, two, or three heteroatoms are selected from N, O, and S and the number of heteroatoms is one, two, or three" substituted with , and each R B-1 and R B-2 Each independently consists of a hydroxyl group, a halogen, an oxo group (=O), and C 1-6 Alkyl group, C 1-6 C substituted with an alkoxy group or one or more hydroxyl groups 1-6 If it is an alkyl group and U is absent, ring B is and, U does not exist, or -N(R')(R"), C 3-6 Alkyl group, one or more R U-1 C substituted with 1-6 Alkyl group, C 3-10 Cycloalkyl group, one or more R U-2 C substituted with 3-10 Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", one or more R U-3 "a 3-10-membered heterocycloalkyl group substituted with , wherein the heteroatom is 1, 2, or 3 selected from N, O, and S, and the number of heteroatoms is 1, 2, or 3", C 6-10 Aryl group, one or more R U-4 C substituted with 6-10 Aryl group, "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", one or more R U-5 "a 5-10-membered heteroaryl group substituted with , in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or -XR U-6 and X is -C(O)-, -SO2- or -O-, and each R' and R" is independently hydrogen, C 1-6 Alkyl group, -C(O)-C 3-10 C substituted with a cycloalkyl group or one or more R"' 1-6 It is an alkyl group, and R"' is independently C 6-10 Arylgi and each R U-1 -N(R')(R"), halogen, C, respectively, independently 3-10 Cycloalkyl group, C 6-10 An aryl group, "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or one or more R U-1-1 "a 5-10-membered heteroaryl group substituted with , wherein the heteroatom is 1, 2, or 3 selected from N, O, and S, and the number of heteroatoms is 1, 2, or 3," and each R U-1-1 C each independently 1-6 It is an alkyl group, and each R U-2 , R U-3 , R U-4 and R U-5 Each independently consists of a halogen, cyano group, hydroxyl group, and -SO2-C 1-6 Alkyl group, -C(O)-C 1-6 Alkyl group, -C(O)OC 1-6 Alkyl group, -C(O)NH-C 1-6 Alkyl group, C 1-6 Alkyl group, one or more R U-3-1 C substituted with 1-6 Alkyl group, C 1-6 Alkoxy group, one or more R U-3-2 C substituted with 1-6 Alkoxy group, C 3-10 A cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or -O-"a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", and each R U-3-1 and R U-3-2 Each independently halogen, C 3-10 Cycloalkyl group, C 6-10 Arylgi, C 1-6 an alkoxy group, a hydroxyl group, a cyano group, or a "3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and each R U-6 C each independently 6-10 A compound represented by formula (I) is an aryl group or "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and is represented by formula (I). and A compound or a pharmaceutically acceptable salt thereof characterized by not being any of the compounds. Claim 2 In claim 1, the compound represented by the above formula (IA) is a compound represented by the following formula (IIA), and Each R1 is independently a halogen, cyano group, C 1-6 Alkyl group, C 3-10 Cycloalkyl group, C 1-6 Alkoxy group, C substituted with one or more halogens 1-6 C substituted with an alkyl group or one or more halogens 1-6 Alkoxy group, "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or one or more R 1-1 "a 5-10-membered heteroaryl group substituted with , wherein the heteroatom is 1, 2, or 3 selected from N, O, and S, and the number of heteroatoms is 1, 2, or 3," and each R 1-1 C each independently 1-6 It is an alkyl group, m and k are each independently 0, 1 or 2, X1 is -CH2-, -O-, -S- or -S(=O)2-, and each R2 is each independently H, C 1-6 Alkyl group, one or more R 2-1 C substituted with 1-6 An alkyl group or "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and each R 2-1 Each independently consists of a hydroxyl group or C 3-10 It is a cycloalkyl group, and each " Each represents a single bond or a double bond independently, and E is -N(R3)- or and, n1 is 1, 2, or 3, # represents one end connected to -C(O)- in formula (IA), and R3 is hydrogen or C 1-6 It is an alkyl group, and L is C 1-6 Alkylene group, one or more R L C substituted with 1-6 alkylene group or "-(C 1-6 Alkylene group)-L A -*" and, each R L Each is independently a hydroxyl group or a halogen, or two Rs L If substituted into this same carbon atom, 2 R L and the carbon atoms they share are connected to form a 3-10 saturated carbon ring, L A is -NH-, -N(C 1-6 alkyl group)- or a 3-10-membered saturated carbon ring, and ring B is "a 3-10-membered saturated or unsaturated heterocycle in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or one or more R B-2 A "3-10 saturated or unsaturated heterocycle in which one, two, or three heteroatoms are selected from N, O, and S and the number of heteroatoms is one, two, or three" substituted with , and each R B-2 Each independently consists of a hydroxyl group, a halogen, and C 1-6 Alkyl group, C 1-6 C substituted with an alkoxy group or one or more hydroxyl groups 1-6 If it is an alkyl group and U is absent, ring B is and, U does not exist, or -N(R')(R"), C 3-6 Alkyl group, one or more R U-1 C substituted with 1-6 Alkyl group, C 3-10 Cycloalkyl group, one or more R U-2 C substituted with 3-10 Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", one or more R U-3 "a 3-10-membered heterocycloalkyl group substituted with, wherein one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", C 6-10 Aryl group, one or more R U-4 C substituted with 6-10 An aryl group, "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or one or more R U-5 A "5-10-membered heteroaryl group substituted with , wherein the heteroatoms are 1, 2, or 3 selected from N, O, and S, and the number of heteroatoms is 1, 2, or 3," and each R' and R' is independently hydrogen, C 1-6 Alkyl group, -C(O)-C 3-10 C substituted with a cycloalkyl group or one or more R"' 1-6 It is an alkyl group, and R"' is independently C 6-10 Arylgi and each R U-1 are independently -N(R')(R"), C 3-10 Cycloalkyl group or C 6-10 Arylgi and each R U-2 , R U-3 , R U-4 and R U-5 Each independently halogen, -SO2-C 1-6 Alkyl group, -C(O)-C 1-6 Alkyl group, C 3-10 Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", cyano group, hydroxyl group, C 1-6 Alkyl group, one or more R U-3-1 C substituted with 1-6 Alkyl group, C 1-6 Alkoxy group or one or more R U-3-2 C substituted with 1-6 It is an alkoxy group, and each R U-3-1 and R U-3-2 Each independently halogen, C 3-10 Cycloalkyl group, C 6-10 Arylgi, C 1-6 A compound or a pharmaceutically acceptable salt thereof, characterized by being an alkoxy group, a hydroxyl group, a cyano group, or a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S. Claim 3 In claim 1, the compound represented by the formula (IA) is a compound represented by the following formula (IIIA) or formula (IIIB), and or Each R1 is independently a halogen, cyano group, C 1-6 Alkyl group, C 3-10 Cycloalkyl group, C 1-6 Alkoxy group, C substituted with one or more halogens 1-6 C substituted with an alkyl group or one or more halogens 1-6 Alkoxy group, "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or one or more R 1-1 "a 5-10-membered heteroaryl group substituted with , wherein the heteroatom is 1, 2, or 3 selected from N, O, and S, and the number of heteroatoms is 1, 2, or 3," and each R 1-1 C each independently 1-6 It is an alkyl group, m is 0, 1, or 2, X1 is -CH2-, -O-, -S-, or -S(=O)2-, and each R2 is independently H, C 1-6 Alkyl group, one or more R 2-1 C substituted with 1-6 An alkyl group or "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and each R 2-1 Each independently consists of a hydroxyl group or C 3-10 It is a cycloalkyl group, and E is -N(R3)- or and, n1 is 1, 2, or 3, # represents one end connected to -C(O)- in formula (IA), and R3 is hydrogen or C 1-6 It is an alkyl group, and L is C 1-6 Alkylene group, one or more R L C substituted with 1-6 alkylene group or "-(C 1-6 Alkylene group)-L A -*" and, each R L Each is independently a hydroxyl group or a halogen, or two Rs L If substituted into this same carbon atom, 2 R L and the carbon atoms they share are connected to form a 3-10 saturated carbon ring, L A is a 3-10-membered saturated carbon ring, and ring B is a "3-10-membered saturated or unsaturated heterocycle in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or one or more R B-2 A "3-10 saturated or unsaturated heterocycle in which one, two, or three heteroatoms are selected from N, O, and S and the number of heteroatoms is one, two, or three" substituted with , and each R B-2 Each independently is a halogen or C 1-6 If it is an alkyl group and U is absent, ring B is and, U does not exist, or -N(R')(R"), one or more R U-1 C substituted with 1-6 Alkyl group, C 3-10 Cycloalkyl group, one or more R U-2 C substituted with 3-10 Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", one or more R U-3 "a 3-10-membered heterocycloalkyl group substituted with , wherein the heteroatom is 1, 2, or 3 selected from N, O, and S, and the number of heteroatoms is 1, 2, or 3", C 6-10 Aryl group, one or more R U-4 C substituted with 6-10 An aryl group or "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and each R' and R' is independently hydrogen, C 1-6 Alkyl group, -C(O)-C 3-10 C substituted with a cycloalkyl group or one or more R"' 1-6 It is an alkyl group, and R"' is independently C 6-10 Arylgi and each R U-1 C each independently 3-10 Cycloalkyl group or C 6-10 Arylgi and each R U-2 , R U-3 and R U-4 Each independently consists of a halogen, a hydroxyl group, and -SO2-C 1-6 Alkyl group, -C(O)-C 1-6 Alkyl group, C 1-6 Alkyl group, C 3-10 Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", C 1-6 Alkoxy group or one or more R U-3-1 C substituted with 1-6 It is an alkyl group, and each R U-3-1 Each independently halogen, C 3-10 Cycloalkyl group, C 6-10 Arylgi, C 1-6 A compound or a pharmaceutically acceptable salt thereof, characterized by being an alkoxy group, a hydroxyl group, a cyano group, or a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S. Claim 4 In paragraph 1, (1) each R1 is independently a halogen, a cyano group, C 1-6 Alkyl group, C 3-10 C substituted with a cycloalkyl group and one or more halogens 1-6 C substituted with an alkyl group or one or more halogens 1-6 Alkoxy group, "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or one or more R 1-1 "a 5-10-membered heteroaryl group substituted with , wherein the heteroatom is 1, 2, or 3 selected from N, O, and S, and the number of heteroatoms is 1, 2, or 3," and each R 1-1 C each independently 1-6 It is an alkyl group, (2) and each R2 is independently H, C 1-6 Alkyl group, one or more R 2-1 C substituted with 1-6 An alkyl group or "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and each R 2-1 Each independently consists of a hydroxyl group or C 3-10 It is a cycloalkyl group, (3) E is -N(R3)-, (4) L is C 1-6 Alkylene group, one or more R L C substituted with 1-6 alkylene group or "-(C 1-6 Alkylene group)-L A -*" and angle R L Each is independently a hydroxyl group or a halogen, or two Rs L If substituted into this same carbon atom, 2 R L and the carbon atoms they share are connected to form a 3-10 saturated carbon ring, L A is -NH-, -N(C 1-6 (5) ring B is an alkyl group)- or a 3-10-membered saturated carbon ring, preferably a 3-10-membered saturated carbon ring, and ring B is a “3-10-membered saturated or unsaturated heterocycle in which one, two, or three heteroatoms are selected from N, O, and S” or one or more R B-2 A "3-10 saturated or unsaturated heterocycle in which one, two, or three heteroatoms are selected from N, O, and S and the number of heteroatoms is one, two, or three" substituted with , and each R B-2 Each independently consists of a hydroxyl group, a halogen, and C 1-6 Alkyl group, C 1-6 C substituted with an alkoxy group or one or more hydroxyl groups 1-6 It is an alkyl group, preferably a halogen or C 1-6 It is an alkyl group, (6) U is not present, or -N(R')(R"), C 3-6 Alkyl group, one or more R U-1 C substituted with 1-6 Alkyl group, C 3-10 Cycloalkyl group, one or more R U-2 C substituted with 3-10 Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", one or more R U-3 "a 3-10-membered heterocycloalkyl group substituted with , wherein the heteroatom is 1, 2, or 3 selected from N, O, and S, and the number of heteroatoms is 1, 2, or 3", C 6-10 Aryl group, one or more R U-4 C substituted with 6-10 An aryl group, "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or one or more R U-5 A "5-10-membered heteroaryl group substituted with , wherein the heteroatoms are 1, 2, or 3 selected from N, O, and S, and the number of heteroatoms is 1, 2, or 3," and each R' and R' is independently hydrogen, C 1-6 Alkyl group, -C(O)-C 3-10 C substituted with a cycloalkyl group or one or more R"' 1-6 It is an alkyl group, and R"' is independently C 6-10 Arylgi and each R U-1 are independently -N(R')(R"), C 3-10 Cycloalkyl group or C 6-10 Arylgi and each R U-2 , R U-3 , R U-4 and R U-5 Each independently halogen, -SO2-C 1-6 Alkyl group, -C(O)-C 1-6 Alkyl group, C 3-10 Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", cyano group, hydroxyl group, C 1-6 Alkyl group, one or more R U-3-1 C substituted with 1-6 Alkyl group, C 1-6 Alkoxy group or one or more R U-3-2 C substituted with 1-6 It is an alkoxy group, and each R U-3-1 and R U-3-2 Each independently halogen, C 3-10 Cycloalkyl group, C 6-10 Arylgi, C 1-6 It is an alkoxy group, a hydroxyl group, a cyano group, or a "3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and preferably, U is absent, or -N(R')(R"), one or more of R U-1 C substituted with 1-6 Alkyl group, C 3-10 Cycloalkyl group, one or more R U-2 C substituted with 3-10 Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", one or more R U-3 "a 3-10-membered heterocycloalkyl group substituted with , wherein the heteroatom is 1, 2, or 3 selected from N, O, and S, and the number of heteroatoms is 1, 2, or 3", C 6-10 Aryl group, one or more R U-4 C substituted with 6-10 An aryl group or "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and each R' and R' is independently hydrogen, C 1-6 Alkyl group, -C(O)-C 3-10 C substituted with a cycloalkyl group or one or more R"' 1-6 It is an alkyl group, and R"' is independently C 6-10 Arylgi and each R U-1 C each independently 3-10 Cycloalkyl group or C 6-10 Arylgi and each R U-2 , R U-3 and R U-4 Each independently consists of a halogen, a hydroxyl group, and -SO2-C 1-6 Alkyl group, -C(O)-C 1-6 Alkyl group, C 1-6 Alkyl group, C 3-10 Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", C 1-6 Alkoxy group or one or more R U-3-1 C substituted with 1-6 It is an alkyl group, and each R U-3-1 Each independently halogen, C 3-10 Cycloalkyl group, C 6-10 Arylgi, C 1-6 A compound or a pharmaceutically acceptable salt thereof, characterized by satisfying one or more of the conditions of being an alkoxy group, a hydroxyl group, a cyano group, or a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S. Claim 5 In paragraph 1, (1) each R1 is independently a halogen, (2) m and k are independently 0 or 1, and (3) each R2 is independently C 1-6 alkyl group or one or more R 2-1 C substituted with 1-6 It is an alkyl group, and each R 2-1 C each independently 3-10 It is a cycloalkyl group, (4) and R3 is hydrogen or C 1-6 It is an alkyl group, (5) and L is C 1-6 Alkylene group, one or more R L C substituted with 1-6 alkylene group or "-(C 1-6 Alkylene group)-L A -" and, each R L Each is independently a hydroxyl group or a halogen, or two Rs L If substituted into this same carbon atom, 2 R L These are connected to form a 3-10 member saturated carbon ring, and L A is -NH- or -N(C 1-6 (6) ring B is an alkyl group -, preferably -NH-, and ring B is a 3-10 saturated or unsaturated heterocycle in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three, or one or more R B-2 A "3-10 saturated or unsaturated heterocycle in which one, two, or three heteroatoms are selected from N, O, and S and the number of heteroatoms is one, two, or three" substituted with , and each R B-2 Each independently consists of a hydroxyl group, a halogen, and C 1-6 C substituted with an alkoxy group or one or more hydroxyl groups 1-6 It is an alkyl group, preferably a halogen, (7) and U is C 3-6 Alkyl group, one or more R U-1 C substituted with 1-6 Alkyl group, C 3-10 Cycloalkyl group, one or more R U-2 C substituted with 3-10 Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", one or more R U-3 "a 3-10-membered heterocycloalkyl group substituted with , wherein the heteroatom is 1, 2, or 3 selected from N, O, and S, and the number of heteroatoms is 1, 2, or 3", C 6-10 Aryl group, one or more R U-4 C substituted with 6-10 An aryl group, "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three" or one or more R U-5 "a 5-10-membered heteroaryl group substituted with , wherein the heteroatom is 1, 2, or 3 selected from N, O, and S, and the number of heteroatoms is 1, 2, or 3," and each R U-1 C each independently 3-10 Cycloalkyl group or C 6-10 Arylgi and each R U-2 , R U-3 , R U-4 and R U-5 Each independently halogen, C 3-10 Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", cyano group, hydroxyl group, C 1-6 Alkyl group, one or more R U-3-1 C substituted with 1-6 Alkyl group, C 1-6 Alkoxy group or one or more R U-3-2 C substituted with 1-6 It is an alkoxy group, and each R U-3-1 and R U-3-2 Each independently is a halogen or C 3-10 A compound or a pharmaceutically acceptable salt thereof characterized by satisfying one or more of the conditions of being a cycloalkyl group. Claim 6 In paragraph 1, (1) R3 is hydrogen, and (2) L is C 1-6 alkylene group or one or more R L C substituted with 1-6 It is an alkylene group, and each R L Each is independently a hydroxyl group or a halogen, preferably a hydroxyl group, (3) ring B is a “3-10 saturated or unsaturated heterocycle in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three”, (4) U is one or more R U-1 C substituted with 1-6 Alkyl group, C 3-10 Cycloalkyl group, one or more R U-2 C substituted with 3-10 Cycloalkyl group, "a 3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three", C 6-10 Aryl group, one or more R U-4 C substituted with 6-10 An aryl group or "a 5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S, and the number of heteroatoms is one, two, or three," and each R U-1 C each independently 3-10 Cycloalkyl group or C 6-10 Arylgi and each R U-2 and R U-4 Each independently halogen, C 1-6 Alkoxy group or one or more R U-3-1 C substituted with 1-6 It is an alkyl group, and each R U-3-1 A compound or a pharmaceutically acceptable salt thereof, characterized by satisfying one or more of the conditions that each is independently a halogen. Claim 7 In any one of claims 1 to 6, (1) in ring C, the “5-6-membered heteroaryl ring in which the heteroatom is one, two, or three selected from N, O, and S and the number of heteroatoms is one, two, or three” is a “5-6-membered heteroaryl ring in which the heteroatom is N and the number of heteroatoms is one or two”, and (2) each “C 1-6 The "alkyl group" is independently a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, tert-butyl group, isobutyl group or sec-butyl group, (3) each "C 1-6 “Alkoxy group” is independently a methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, tert-butoxy group, isobutoxy group, or sec-butoxy group,(4) each “halogen” is independently fluorine, chlorine, bromine, or iodine,(5) R a , R b And when the carbon atoms they share are connected to form a 3-10 saturated carbon ring, the "3-10 saturated carbon ring" is a 3-membered saturated carbon ring, (6) and each "C3-C 10 The "cycloalkyl group" is independently a C3-C6 monocyclic cycloalkyl group or a C5-C 10 A polycyclic (e.g., spiro ring, condensation ring, or bridge ring) cycloalkyl group, (7) and each "3-10-membered heterocycloalkyl group in which one, two, or three heteroatoms are selected from N, O, and S and the number of heteroatoms is one, two, or three" is independently a 4-6-membered monocyclic heterocycloalkyl group or a 5-10-membered polycyclic (e.g., spiro ring, condensation ring, or bridge ring) heterocycloalkyl group, (8) and each "C6-C 10 "Aryl group" is independently a phenyl group or a naphthyl group (9), and each "5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S and the number of heteroatoms is one, two, or three" is independently a 5-6-membered monocyclic heteroaryl group, preferably in which the type of heteroatom is N and the number of heteroatoms is one, two, or three, and (10), each "C 1-6 The "alkylene group" is independently a C1-C4 alkylene group, (11) and two R L If substituted into this same carbon atom, 2 R L and the "3-10-membered saturated carbon ring" formed by connecting the carbon atoms they share is a 3-membered saturated carbon ring, (12) L A If is a 3-10 member saturated carbon ring, the above "3-10 member saturated carbon ring" is a 4-6 member saturated carbon ring, for example A compound or a pharmaceutically acceptable salt thereof, characterized in that (12) each “3-10 saturated or unsaturated heterocycle having one, two, or three heteroatoms selected from N, O, and S and one, two, or three heteroatoms” independently satisfies one or more of the conditions of “4-8 saturated or unsaturated heterocycle having one or two heteroatoms selected from N and O and one or two heteroatoms”, preferably “5-6 saturated or unsaturated heterocycle having one or two heteroatoms and one heteroatom”: Claim 8 In claim 7, (1) in ring C, the “5-6-membered heteroaryl ring having one, two, or three heteroatoms selected from N, O, and S and one, two, or three heteroatoms” is a pyridine ring or a pyrimidine ring, (2) each “C1-C6 alkyl group” is independently a methyl group or an ethyl group, (3) each “C1-C6 alkoxy group” is independently a methoxy group, (4) each “halogen” is independently fluorine, chlorine, or bromine, preferably fluorine or chlorine, more preferably fluorine, (5) R a , R b And when the carbon atoms they share are connected to form a 3-10 member saturated carbon ring, the "3-10 member saturated carbon ring" is and, (6) the "C3-C6 monocyclic cycloalkyl group" is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, and (7) the "C5-C 10 The polycyclic cycloalkyl group is C5-C 10 It is a spiro cycloalkyl group, preferably (8) The "4-6-membered monocyclic heterocycloalkyl group" is "a 4-6-membered monocyclic heterocycloalkyl group in which one or two heteroatoms are selected from N and O, and the number of heteroatoms is one or two", and preferably or and, or "a 6-membered heterocycloalkyl group in which one or two heteroatoms are selected from N and O, and the number of heteroatoms is one or two," preferably or (9) The "5-10-membered polycyclic heterocycloalkyl group" is a 5-10-membered spiro-ring heterocycloalkyl group or a bridge-ring heterocycloalkyl group, preferably or a 6-membered spiro ternary heterocycloalkyl group, more preferably And, (10) each "C6-C 10 "Aryl group" is independently a phenyl group (11), and each "5-10-membered heteroaryl group in which one, two, or three heteroatoms are selected from N, O, and S and the number of heteroatoms is one, two, or three" is independently a 5-6-membered monocyclic heteroaryl group, and the 5-6-membered monocyclic heteroaryl group is a 5-6-membered monocyclic heteroaryl group in which the type of heteroatom is N and the number of heteroatoms is one or two, preferably or And, or the above 5-6 member monocyclic heteroaryl group is a 5-6 member monocyclic heteroaryl group having N type of heteroatom and 3 heteroatoms, preferably And, (12) each "C 1-6 The "alkylene group" independently is a methylene group, or And, (13) 2 R L If substituted into this same carbon atom, 2 R L and the "3-10 saturated carbon ring" formed by the connection of carbon atoms they share is And, (14) each “3-10 saturated or unsaturated heterocycle in which one, two, or three heteroatoms are selected from N, O, and S and the number of heteroatoms is one, two, or three” is independently or A compound or a pharmaceutically acceptable salt thereof characterized by satisfying one or more of the following conditions: Claim 9 In paragraph 1, (1) ring C is a benzene ring, and (2) each R1 is independently fluorine, chlorine, bromine, cyano group, trifluoromethyl group, cyclopropyl group, trifluoromethoxy group, methyl group, , or and, m is 0, 1 or 2, (3) X1 is -CH2-, -O-, -S- or -S(=O)2-, X2 is -CH2-, n is 0, X3 and X4 are C, (4) R2 is H, methyl group, ethyl group, or and k is 0 or 1, (5) structural fragment silver or (6) R3 is hydrogen or a methyl group, and (7) L is a methylene group, And, (8) ring B is And, (9) U is or and, (10) E is -NH-, -N(CH3)- or A compound or a pharmaceutically acceptable salt thereof characterized by satisfying one or more of the conditions. Claim 10 In paragraph 1, the above compound is, A compound or a pharmaceutically acceptable salt thereof characterized as being any one of the compounds. Claim 11 A pharmaceutical composition comprises a substance A and a pharmaceutically acceptable excipient, wherein the substance A is a compound represented by the formula (XA) or a pharmaceutically acceptable salt thereof. Ring A, ring B, ring C, X1, X2, X3, X4, R1, R2, E, m, n, k, L, B and U are as defined in claim 1, and preferably, the pharmaceutical composition is characterized by being used for the treatment and / or prevention of KSR2-AMPK-related diseases or disorders, e.g., cancer, e.g., liver cancer. Claim 12 The application of substance A according to claim 11 or the pharmaceutical composition according to claim 11 in the manufacture of a KSR2-AMPK inhibitor, wherein the KSR2-AMPK inhibitor in the application may be used in vivo in mammals or in vitro, and is primarily used for experimental purposes, for example, to provide comparison as a standard sample or control sample, or is manufactured into a kit according to conventional methods in the art to provide rapid detection of the KSR2-AMPK inhibitory effect. Claim 13 In the application of substance A according to claim 11 or a pharmaceutical composition according to claim 11 in the manufacture of a drug, said drug is used for the treatment and / or prevention of a KSR2-AMPK-related disease or disorder; said substance A is in a therapeutically effective amount, and said KSR2-AMPK-related disease or disorder is preferably cancer, e.g. liver cancer. Claim 14 In the application of substance A according to claim 11 or a pharmaceutical composition according to claim 11 in the manufacture of a drug, said drug is used for the treatment and / or prevention of cancer, e.g., liver cancer; said substance A is characterized in that it is a therapeutically effective amount.

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