Heterocyclic compound, preparation method therefor and pharmaceutical use thereof

Abstract

The present disclosure relates to a heterocyclic compound, a preparation method therefor and the pharmaceutical use thereof. Specifically, the present disclosure relates to a heterocyclic compound as represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the heterocyclic compound and the use thereof as a therapeutic agent, particularly the use as a MASTL inhibitor and the use in the preparation of a drug for treating and / or preventing MASTL-mediated diseases.

Description

Heterocyclic compounds, their preparation methods and their applications in medicine Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a heterocyclic compound, its preparation method, and its pharmaceutical application. Specifically, this disclosure relates to a heterocyclic compound of general formula (I), its preparation method, pharmaceutical compositions containing the heterocyclic compound, and its use as a therapeutic agent, particularly as a MASTL inhibitor and in the preparation of medicaments for treating and / or preventing MASTL-mediated diseases. Background Technology

[0002] Targeting mitotic kinases is an emerging anticancer approach with promising preclinical results. Microtubule-associated serine / threonine kinase-like (MASTL), also known as Greatwall (Gwl), is classified as a member of the MAST subfamily of AGC kinases. PP2A / B55, as a cell cycle inhibitor, is an important class of phosphatases regulating cell mitosis. MASTL kinases are major regulators of mitosis and are crucial for ensuring the proper maintenance of phosphorylation of mitotic substrates. MASTL phosphorylates the direct substrates ENSA and ARPP19 at S67 and S62, respectively. pENSA and pARPP19 are natural inhibitors of PP2A / B55, inhibiting the phosphatase activity of the PP2A / B55 complex through tight binding to it. Cellular entry into mitosis is controlled by the phosphorylation of a large amount of mitotic substrate caused by CDK1 / Cyclin B activation. In order to maintain its high phosphorylation level, it is necessary to inhibit the activity of PP2A / B55 phosphatase. This inhibition process is mediated by activated MASTL (high activity of CDK1 / Cyclin B is one of the mechanisms for activating MASTL).

[0003] Furthermore, MASTL activity is crucial for coordinating mitotic exit by delaying the increase in PP2A / B55 activity until chromosome segregation is complete. During late mitosis, Cyclin B is ubiquitinated by APC / C and subsequently degraded, weakening CDK1 activity and leading to MASTL inactivation. This, in turn, increases the PP2A / B55 phosphatase activity required for mitotic exit. In summary, the MASTL-ENSA / ARPP19-PP2A / B55 pathway regulates cell cycle progression through precise control of mitotic entry and exit. In tumor cells, inhibition of MASTL activates the cell cycle inhibitor PP2A, thereby suppressing CDK1 activity, which is crucial for mitosis, leading to mitotic defects and cancer cell death.

[0004] Recent studies have demonstrated that MASTL plays a crucial role in cancer development and is associated with characteristics such as invasion and metastasis. MASTL targeting can reduce the growth of tumors in in vitro and in vivo models of multiple cancer types. Furthermore, MASTL is highly expressed in various cancer types, including breast cancer, head and neck cancer, gastric cancer, thyroid cancer, and colorectal cancer. MASTL inhibition selectively eradicates proliferating cancer cells rather than normal cells by inducing mitotic catastrophe. Therefore, mounting evidence suggests that MASTL may be an attractive and potentially druggable target for selective anticancer therapy.

[0005] Although multiple laboratories have been working to find effective MASTL inhibitors since 2016, their activity has been limited to the μM level. Truly highly active and selective MASTL inhibitors have only been discovered since 2021; however, no MASTL-targeting molecules have yet entered clinical trials. Therefore, there is still a need for novel, effective, and druggable MASTL inhibitors for the treatment of MASTL-related diseases. Summary of the Invention

[0006] The purpose of this disclosure is to provide a compound of general formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof;

[0007] in:

[0008] Ring A is selected from

[0009] Ring A1 is absent or selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 14-membered heterocyclic groups;

[0010] Cyclone A2 is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 14-membered heterocyclic groups;

[0011] Ring B is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 14-membered heterocyclic groups;

[0012] The ring C is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 14-membered heterocyclic groups;

[0013] L is selected from the bond, -NR L -(CR d R e ) p -、-O-、-S(O) q -(CR d R e ) p -;

[0014] L1 is selected from the key, -NR L -(CR d Re ) p -、-O-、-S(O) q -(CR d R e ) p -、-C(O)-、-C(O)NR n1 R n2 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 3- to 8-membered heterocyclic;

[0015] L2 is selected from the bond, -NR L -、-O-、-S(O) q -(CR d R e ) p -、-(CR 1 R 2 ) u -、-C(O)-、-C(O)NR n1 R n2 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 3- to 8-membered heterocyclic;

[0016] R L Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy group, deuterium atom, deuterated C 1-6 Alkyl and deuterated C 1-6 Alkoxy;

[0017] R d R e They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, C atoms, etc. 1-6 Alkyl, C 1-6 Alkoxy, -NR n1 R n2 Halogen, cyano, hydroxyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy group, deuterium atom, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, -C(O)NR n1 R n2 -C(O)R s , 3 to 8-membered heterocyclic groups, 3 to 8-membered cycloalkyl groups, 3 to 8-membered cycloalkenyl groups, 6 to 10-membered aryl groups and 5 to 10-membered heteroaryl groups;

[0018] Each R a1 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6Alkoxy, OR o -NR n1 R n2 Halogen, cyano, oxo, hydroxyl, -SR s -SF5, -C(O)NR n1 R n2 -C(O)R s -S(O) q R s -S(O)2NR n1 R n2 C 2-6 alkenyl, C 2-6 Alkyne, deuterium, 3- to 8-membered heterocyclic group, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl; or two R on adjacent ring atoms. a1 The atoms bonded to it together form 3- to 8-membered heterocyclic groups, 3- to 8-membered cycloalkyl groups, 3- to 8-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups; wherein, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 The alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each independently selected to be deuterated or deuterated C. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0019] Each R a2 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Alkoxy, -OR o -NR n1 R n2 Halogen, cyano group, oxo group, hydroxyl group, deuterium atom, -SR s -SF5, -C(O)NR n1 R n2 -C(O)R s -S(O)q R s -S(O)2NR n1 R n2 C 2-6 alkenyl, C 2-6 Alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl; or two R on adjacent ring atoms a2 The atoms bonded to it together form 3- to 8-membered heterocyclic groups, 3- to 8-membered cycloalkyl groups, 3- to 8-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups; wherein, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 The alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each independently selected to be deuterated or deuterated C. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, OR o Halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0020] Or one of the R a1 And one of the R a2 The atoms bonded to it together form 3- to 12-membered heterocyclic groups, 3- to 12-membered cycloalkyl groups, 3- to 12-membered cycloalkenyl groups, 6- to 12-membered aryl groups, and 5- to 12-membered heteroaryl groups; wherein each of the 3- to 12-membered heterocyclic groups, 3- to 12-membered cycloalkyl groups, 3- to 12-membered cycloalkenyl groups, 6- to 12-membered aryl groups, and 5- to 12-membered heteroaryl groups is independently selected to be bonded by a deuterium atom or a deuterated C atom. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, OR o Halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 Rn4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0021] Each R b Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Alkoxy, OR o -NR n1 R n2 Halogen, cyano, hydroxyl, deuterium atom, -SR s -SF5, -C(O)NR n1 R n2 -C(O)R s -S(O) q R s -S(O)2NR n1 R n2 C 2-6 alkenyl, C 2-6 Alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl; or two R on adjacent ring atoms b The atoms bonded to it together form 3- to 8-membered heterocyclic groups, 3- to 8-membered cycloalkyl groups, 3- to 8-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups; wherein, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 The alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each independently selected to be deuterated or deuterated C. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, OR o Halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0022] Or one of the R a2 And one of the Rb The atoms bonded to it together form 5- to 14-membered cycloalkenyl groups and 5- to 14-membered heterocyclic groups; wherein, the 5- to 14-membered cycloalkenyl groups and 5- to 14-membered heterocyclic groups are each independently selected to be deuterated or deuterated by a C atom. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, OR s , cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0023] Each R c Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Alkoxy, OR o -NR n1 R n2 Halogen, cyano, hydroxyl, deuterium atom, -SR s -SF5, -C(O)NR n1 R n2 -C(O)R s -S(O) q R s -S(O)2NR n1 R n2 C 2-6 alkenyl, C 2-6 Alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl; or two R on adjacent ring atoms therein. c The atoms bonded to it together form 3- to 8-membered heterocyclic groups, 3- to 8-membered cycloalkyl groups, 3- to 8-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups; wherein, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 The alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each independently selected from the deuterium atom, deuterated C, etc. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1-6Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, OR o Halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0024] R 1 R 2 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Alkoxy, OR o -NR n1 R n2 Halogen, cyano, hydroxyl, deuterium atom, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, -SR s -C(O)NR n1 R n2 -C(O)R s C 2-6 alkenyl, C 2-6 Alkynyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are each independently selected from halogen, oxo, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0025] Or R on the same carbon atom 1 R 2The atoms bonded to it together form 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, 5- to 14-membered spirocycloalkyl, and 5- to 14-membered spiroheterocyclic groups; wherein the 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, 5- to 14-membered spirocycloalkyl, and 5- to 14-membered spiroheterocyclic groups are each independently and optionally selected from deuterium atoms, deuterated C atoms, etc. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0026] Or R on adjacent carbon atoms 1 R 2 The atoms bonded to it together form 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, 5- to 14-membered spirocycloalkyl, and 5- to 14-membered spiroheterocyclic groups; wherein the 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, 5- to 14-membered spirocycloalkyl, and 5- to 14-membered spiroheterocyclic groups are each independently and optionally selected from deuterium atoms, deuterated C atoms, etc. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0027] Or R 1 and R c The atoms bonded to it together form a 3- to 12-membered cycloalkenyl group; wherein the 3- to 12-membered cycloalkenyl group is optionally selected from deuterium atoms, deuterated C atoms, etc. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0028] Or R 1 and R b The atoms bonded to it together form 5- to 12-membered heterocyclic groups and 5- to 12-membered heteroaryl groups; wherein the 5- to 12-membered heterocyclic groups and 5- to 14-membered heteroaryl groups are each independently and optionally selected from deuterium atoms and deuterated C atoms. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0029] R n1 R n2 R n3 and R n4 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, deuterated C atoms, etc. 1-6 Alkyl, deuterated C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0030] R s They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, C atoms, etc. 1-6 Alkyl, halogen, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6Alkoxy, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0031] R o They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, deuterated C atoms, etc. 1-6 Alkyl, deuterated C 1-6 Alkoxy, C 1-6 Alkyl, halogen, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0032] n can be 0, 1, 2, 3, or 4;

[0033] m1 can be 0, 1, 2, 3 or 4;

[0034] m2 can be 0, 1, 2, 3 or 4;

[0035] t can be 0, 1, 2, 3, or 4;

[0036] p is 0, 1, 2 or 3;

[0037] q is 0, 1, or 2; and

[0038] u can be 0, 1, 2 or 3.

[0039] The purpose of this disclosure is to provide a compound of general formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof;

[0040] in:

[0041] Ring A is selected from

[0042] Ring A1 is absent or selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 14-membered heterocyclic groups;

[0043] Cyclone A2 is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 14-membered heterocyclic groups;

[0044] Ring B is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 14-membered heterocyclic groups;

[0045] The ring C is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 14-membered heterocyclic groups;

[0046] L is selected from the bond, -NR L -(CR d Re ) p -、-O-、-S(O) q -(CR d R e ) p -;

[0047] L1 is selected from the key, -NR L -(CR d R e ) p -、-O-、-S(O) q -(CR d R e ) p -、-C(O)-、-C(O)NR n1 R n2 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 3- to 8-membered heterocyclic;

[0048] L2 is selected from the bond, -NR L -、-O-、-S(O) q -(CR d R e ) p -、-(CR 1 R 2 ) u -、-C(O)-、-C(O)NR n1 R n2 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 3- to 8-membered heterocyclic;

[0049] R L Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0050] R d R e They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, C atoms, etc. 1-6 Alkyl, C 1-6 Alkoxy, -NR n1 R n2 Halogen, cyano, hydroxyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C(O)NR n1 R n2 -C(O)R s , 3 to 8-membered heterocyclic groups, 3 to 8-membered cycloalkyl groups, 3 to 8-membered cycloalkenyl groups, 6 to 10-membered aryl groups and 5 to 10-membered heteroaryl groups;

[0051] Each R a1 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Alkoxy, OR o -NR n1 R n2 Halogen, cyano, oxo, hydroxyl, -SR s -SF5, -C(O)NR n1 R n2 -C(O)R s -S(O) q R s -S(O)2NR n1 R n2 C 2-6 alkenyl, C 2-6 Alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl; or two R on adjacent ring atoms a1 The atoms bonded to it together form 3- to 8-membered heterocyclic groups, 3- to 8-membered cycloalkyl groups, 3- to 8-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups; wherein, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 The alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each independently and optionally modified by a halogen, an oxo group, or a C-terminal group. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0052] Each R a2 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Alkoxy, -OR o -NR n1 R n2 Halogen, cyano, oxo, hydroxyl, -SR s -SF5, -C(O)NR n1 R n2-C(O)R s -S(O) q R s -S(O)2NR n1 R n2 C 2-6 alkenyl, C 2-6 Alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl; or two R on adjacent ring atoms a2 The atoms bonded to it together form 3- to 8-membered heterocyclic groups, 3- to 8-membered cycloalkyl groups, 3- to 8-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups; wherein, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 The alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each independently and optionally modified by a halogen, an oxo group, or a C-terminal group. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, OR o Halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0053] Or one of the R a1 And one of the R a2 The atoms bonded to it together form 3- to 12-membered heterocyclic groups, 3- to 12-membered cycloalkyl groups, 3- to 12-membered cycloalkenyl groups, 6- to 12-membered aryl groups, and 5- to 12-membered heteroaryl groups; wherein the 3- to 12-membered heterocyclic groups, 3- to 12-membered cycloalkyl groups, 3- to 12-membered cycloalkenyl groups, 6- to 12-membered aryl groups, and 5- to 12-membered heteroaryl groups are each independently optionally bonded by a halogen, an oxo group, or a C-terminal group. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, OR o Halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0054] Each R b Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Alkoxy, OR o -NR n1 R n2 Halogen, cyano, hydroxyl, -SR s -SF5, -C(O)NR n1 R n2 -C(O)R s -S(O) q R s -S(O)2NR n1 R n2 C 2-6 alkenyl, C 2-6 Alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl; or two R on adjacent ring atoms b The atoms bonded to it together form 3- to 8-membered heterocyclic groups, 3- to 8-membered cycloalkyl groups, 3- to 8-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups; wherein, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 The alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each independently and optionally modified by a halogen, an oxo group, or a C-terminal group. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, OR o Halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0055] Or one of the R a2 And one of the R bThe atoms bonded to it together form 5- to 14-membered cycloalkenyl groups and 5- to 14-membered heterocyclic groups; wherein the 5- to 14-membered cycloalkenyl groups and 5- to 14-membered heterocyclic groups are each independently optionally bonded by a halogen, an oxo group, or a C group. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, OR s , cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0056] Each R c Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Alkoxy, OR o -NR n1 R n2 Halogen, cyano, hydroxyl, -SR s -SF5, -C(O)NR n1 R n2 -C(O)R s -S(O) q R s -S(O)2NR n1 R n2 C 2-6 alkenyl, C 2-6 Alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl; or two R on adjacent ring atoms therein. c The atoms bonded to it together form 3- to 8-membered heterocyclic groups, 3- to 8-membered cycloalkyl groups, 3- to 8-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups; wherein, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 The alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each independently selected from halogens, oxo groups, C... 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, OR o Halogenated C 1-6 Alkoxy, cyano, -NR n3 Rn4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0057] R 1 R 2 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Alkoxy, OR o -NR n1 R n2 Halogen, cyano, hydroxyl, -SR s -C(O)NR n1 R n2 -C(O)R s C 2-6 alkenyl, C 2-6 Alkynyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are each independently selected from halogen, oxo, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0058] Or R on the same carbon atom 1 R 2 The atoms bonded to it together form 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, 5- to 14-membered spirocycloalkyl, and 5- to 14-membered spiroheterocyclic groups; wherein the 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, 5- to 14-membered spirocycloalkyl, and 5- to 14-membered spiroheterocyclic groups are each independently and optionally selected from halogens, oxo groups, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0059] Or R on adjacent carbon atoms 1 R 2 The atoms bonded to it together form 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, 5- to 14-membered spirocycloalkyl, and 5- to 14-membered spiroheterocyclic groups; wherein the 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, 5- to 14-membered spirocycloalkyl, and 5- to 14-membered spiroheterocyclic groups are each independently and optionally selected from halogens, oxo groups, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0060] Or R 1 and R c The atoms bonded to it together form a 3- to 12-membered cycloalkenyl group; wherein the 3- to 12-membered cycloalkenyl group is optionally selected from halogens, oxo groups, C... 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0061] Or R 1 and R bThe atoms bonded to it together form 5- to 12-membered heterocyclic groups and 5- to 12-membered heteroaryl groups; wherein the 5- to 12-membered heterocyclic groups and 5- to 14-membered heteroaryl groups are each independently selected from halogens, oxo groups, C... 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 The substance is substituted by one or more substituents selected from alkyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; R n1 R n2 R n3 and R n4 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, C atoms, etc. 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0062] R s They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, C atoms, etc. 1-6 Alkyl, halogen, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0063] R o They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, C atoms, etc. 1-6 Alkyl, halogen, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0064] n can be 0, 1, 2, 3, or 4;

[0065] m1 can be 0, 1, 2, 3 or 4;

[0066] m2 can be 0, 1, 2, 3 or 4;

[0067] t can be 0, 1, 2, 3, or 4;

[0068] p is 0, 1, 2 or 3;

[0069] q is 0, 1, or 2; and

[0070] u can be 0, 1, 2 or 3.

[0071] Another object of this disclosure is to provide a compound of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof;

[0072] Ring A is selected from

[0073] Ring A1 is absent or selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 14-membered heterocyclic groups;

[0074] Cyclone A2 is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 14-membered heterocyclic groups;

[0075] Ring B is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 14-membered heterocyclic groups;

[0076] The ring C is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 14-membered heterocyclic groups;

[0077] L is selected from the bond, -NR L -(CR d R e ) p -、-O-、-S(O) q -(CR d R e ) p -;

[0078] L1 is selected from the key, -NR L -(CR d R e ) p -、-O-、-S(O) q -(CR d R e ) p -、-C(O)-、-C(O)NR n1 R n2 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 3- to 8-membered heterocyclic;

[0079] L2 is selected from the bond, -NR L -、-O-、-S(O) q -(CR d R e ) p -、-(CR1 R 2 ) u -、-C(O)-、-C(O)NR n1 R n2 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 3- to 8-membered heterocyclic;

[0080] R L Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0081] R d R e They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, C atoms, etc. 1-6 Alkyl, C 1-6 Alkoxy, -NR n1 R n2 Halogen, cyano, hydroxyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C(O)NR n1 R n2 -C(O)R s , 3 to 8-membered heterocyclic groups, 3 to 8-membered cycloalkyl groups, 3 to 8-membered cycloalkenyl groups, 6 to 10-membered aryl groups and 5 to 10-membered heteroaryl groups;

[0082] Each R a1 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Alkoxy, -NR n1 R n2 Halogen, cyano, oxo, hydroxyl, -SR s -C(O)NR n1 R n2 -C(O)R s -S(O) q R s -S(O)2NR n1 R n2 C 2-6 alkenyl, C 2-6 Alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl; or two R on adjacent ring atoms a1 The atoms bonded to it together form 3- to 8-membered heterocyclic groups, 3- to 8-membered cycloalkyl groups, 3- to 8-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups; wherein, the C 1-6 Alkyl, C 1-6Alkoxy, C 2-6 alkenyl, C 2-6 The alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each independently and optionally modified by a halogen, an oxo group, or a C-terminal group. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0083] Each R a2 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Alkoxy, -NR n1 R n2 Halogen, cyano, oxo, hydroxyl, -SR s -C(O)NR n1 R n2 -C(O)R s -S(O) q R s -S(O)2NR n1 R n2 C 2-6 alkenyl, C 2-6 Alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl; or two R on adjacent ring atoms a2 The atoms bonded to it together form 3- to 8-membered heterocyclic groups, 3- to 8-membered cycloalkyl groups, 3- to 8-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups; wherein, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 The alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each independently and optionally modified by a halogen, an oxo group, or a C-terminal group. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0084] Or one of the R a1 And one of the R a2 The atoms bonded to it together form 3- to 8-membered heterocyclic groups, 3- to 8-membered cycloalkyl groups, 3- to 8-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups; wherein the 3- to 8-membered heterocyclic groups, 3- to 8-membered cycloalkyl groups, 3- to 8-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups are each independently optionally bonded by a halogen, an oxo group, or a C-terminal group. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0085] Each R b Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Alkoxy, -NR n1 R n2 Halogen, cyano, hydroxyl, -SR s -C(O)NR n1 R n2 -C(O)R s -S(O) q R s -S(O)2NR n1 R n2 C 2-6 alkenyl, C 2-6 Alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl; or two R on adjacent ring atoms b The atoms bonded to it together form 3- to 8-membered heterocyclic groups, 3- to 8-membered cycloalkyl groups, 3- to 8-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups; wherein, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6The alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each independently and optionally modified by a halogen, an oxo group, or a C-terminal group. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0086] Or one of the R a2 And one of the R b The atoms bonded to it together form 5- to 14-membered cycloalkenyl groups and 5- to 14-membered heterocyclic groups; wherein the 5- to 14-membered cycloalkenyl groups and 5- to 14-membered heterocyclic groups are each independently optionally bonded by a halogen, an oxo group, or a C group. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0087] Each R c Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Alkoxy, -NR n1 R n2 Halogen, cyano, hydroxyl, -SR s -C(O)NR n1 R n2 -C(O)R s -S(O) q R s -S(O)2NR n1 R n2 C 2-6 alkenyl, C 2-6 Alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl; or two R on adjacent ring atoms therein.c The atoms bonded to it together form 3- to 8-membered heterocyclic groups, 3- to 8-membered cycloalkyl groups, 3- to 8-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups; wherein, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 The alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each independently selected from halogens, oxo groups, C... 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0088] R 1 R 2 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Alkoxy, -NR n1 R n2 Halogen, cyano, hydroxyl, -SR s -C(O)NR n1 R n2 -C(O)R s C 2-6 alkenyl, C 2-6 Alkynyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are each independently selected from halogen, oxo, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0089] Or R on the same carbon atom 1 R 2 The atoms attached to it together form 3 to 8-membered cycloalkyl, 3 to 8-membered heterocyclic, 5 to 10-membered spirocycloalkyl, and 5 to 10-membered spiroheterocyclic groups;

[0090] Or R on adjacent carbon atoms 1 R 2 The atoms attached to it together form 3 to 8-membered cycloalkyl, 3 to 8-membered heterocyclic, 5 to 10-membered spirocycloalkyl, and 5 to 10-membered spiroheterocyclic groups;

[0091] Or R 1 and R c The atoms attached to it together form 3 to 8-membered cycloalkenyl groups;

[0092] R n1 R n2 R n3 and R n4 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, C atoms, etc. 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0093] R s They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, C atoms, etc. 1-6 Alkyl, halogen, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

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

[0095] m1 can be 0, 1, 2, 3 or 4;

[0096] m2 can be 0, 1, 2, 3 or 4;

[0097] t can be 0, 1, 2, 3, or 4;

[0098] p is 0, 1, 2 or 3;

[0099] q is 0, 1, or 2; and

[0100] u can be 0, 1, 2 or 3.

[0101] In another embodiment of this disclosure, cyclic A1 is selected from phenyl, 5- to 6-membered heteroaryl.

[0102] In another embodiment of this disclosure, cyclic A2 is selected from phenyl, 5- to 6-membered heteroaryl.

[0103] In another embodiment of this disclosure, ring A1 is selected from phenyl, 5 to 6-membered heteroaryl; and / or ring A2 is selected from phenyl, 5 to 6-membered heteroaryl.

[0104] In another embodiment of this disclosure, ring A1 is selected from 6-membered heteroaryl containing 1 to 3 N atoms or 5-membered heteroaryl; ring A2 is selected from 5-membered heteroaryl.

[0105] In another embodiment of this disclosure, ring A1 is selected from a 6-membered heteroaryl group containing 1 to 3 N atoms; ring A2 is selected from phenyl, 5 to 6-membered heteroaryl groups.

[0106] In another embodiment of this disclosure, ring A1 is selected from a 6-membered heteroaryl group containing 1 to 3 N atoms; ring A2 is selected from a 5-membered heteroaryl group.

[0107] In another embodiment of this disclosure, ring A1 is selected from 5-membered heteroaryl groups containing N, O, and S; ring A2 is selected from phenyl groups and 5- to 6-membered heteroaryl groups.

[0108] In another embodiment of this disclosure, ring A1 is selected from a 5-membered heteroaryl group, and ring A2 is selected from a phenyl group.

[0109] In another embodiment of this disclosure, ring A1 is selected from pyridyl and ring A2 is selected from 5-membered heteroaryl.

[0110] In another embodiment of this disclosure, wherein... Selected from

[0111] In another embodiment of this disclosure, wherein... Selected from

[0112] In another embodiment of this disclosure, each R a1 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Alkoxy and 3 to 6-membered cycloalkyl groups.

[0113] In another embodiment of this disclosure, each R a1 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl, halogen, amino, (C 1-6alkyl) cyano, -NH(C 1-6 alkyl).

[0114] In another embodiment of this disclosure, each R a1 They may be the same or different, and each is independently selected from hydrogen, methyl, methoxy, and cyclopropyl.

[0115] In another embodiment of this disclosure, each R a1 They may be the same or different, and each is independently selected from fluorine, -NH-CH3, -CH2CN, and -NH2.

[0116] In another embodiment of this disclosure, each R a2 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and C 1-6 Alkyl group.

[0117] In another embodiment of this disclosure, each R a2 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkyl, cyano, 3- to 6-membered cycloalkyl, -O- (3- to 6-membered cycloalkyl), C 2-6 Alkyne group, -SF5.

[0118] In another embodiment of this disclosure, each R a2 They may be the same or different, and each is independently selected from hydrogen atoms, methyl groups, and methoxy groups.

[0119] In another embodiment of this disclosure, each R a2 They may be the same or different, and each is independently selected from -O-CHF2. -CN、 -SF5, -CF3, -O-CF3.

[0120] In another embodiment of this disclosure, two R atoms on adjacent ring atoms a2 The atoms attached to it together form 3 to 6-membered heterocyclic groups.

[0121] In another embodiment of this disclosure, two R atoms on adjacent ring atoms a2 The atoms attached to it together form 3- to 6-membered heterocyclic groups and 3- to 6-membered cycloalkenyl groups.

[0122] In another embodiment of this disclosure, two R atoms on adjacent ring atoms a2 The atoms connected to it form together

[0123] In another embodiment of this disclosure, two R atoms on adjacent ring atoms a2 The atoms connected to it form together

[0124] In another embodiment of this disclosure, wherein one of the R a1 And one of the R a2 The atoms attached to it together form 3 to 6-membered heterocyclic groups.

[0125] In another embodiment of this disclosure, wherein one of the R a1 And one of the R a2 The atoms bonded to it together form an optional C 1-6 Alkyl or halogen-substituted 3 to 8-membered heterocyclic groups.

[0126] In another embodiment of this disclosure, wherein one of the R a1 And one of the R a2 The atoms connected to it form together

[0127] In another embodiment of this disclosure, wherein one of the R a1 And one of the R a2 The atoms connected to it form together

[0128] In another embodiment of this disclosure, wherein... Selected from

[0129] In another embodiment of this disclosure, wherein... Selected from

[0130] In another embodiment of this disclosure, L is selected from key.

[0131] In another embodiment of this disclosure, cyclic B is selected from 5- to 6-membered heteroaryl groups.

[0132] In another embodiment of this disclosure, ring B is selected from 5- to 6-membered heteroaryl groups and 6- to 10-membered heterocyclic groups.

[0133] In another embodiment of this disclosure, ring B is selected from... * indicates that it is connected to the L1 terminal.

[0134] In another embodiment of this disclosure, each R bThey may be the same or different, and each is independently selected from hydrogen atoms, -NR n1 R n2 , halogen, hydroxyl, -C(O)NR n1 R n2 Optional -NR n3 R n4 Replacement C 1-6 Alkyl, wherein R n1 R n2 R n3 R n4 They may be the same or different, and each is independently selected from hydrogen atoms and C atoms. 1-6 alkyl.

[0135] In another embodiment of this disclosure, each R b They may be the same or different, and each is independently selected from hydrogen atom, amino, hydroxyl, fluorine, -C(O)NH2, -CH2NH2.

[0136] In another embodiment of this disclosure, each R b They may be the same or different, and each is independently selected from -NHCH3 and -NHCH2CH3.

[0137] In another embodiment of this disclosure, two R atoms on adjacent ring atoms b The atoms bonded to it together form 5 to 6-membered heteroaryl groups.

[0138] In another embodiment of this disclosure, two R atoms on adjacent ring atoms b The atoms connected to it form together

[0139] In another embodiment of this disclosure, wherein Selected from * indicates that it is connected to the L1 terminal.

[0140] In another embodiment of this disclosure, wherein Selected from * indicates that it is connected to the L1 terminal.

[0141] In another embodiment of this disclosure, R a2 and R b The atoms attached to it together form 5- to 14-membered cyclic alkenyl groups and 5- to 14-membered heterocyclic groups.

[0142] In another embodiment of this disclosure, R a2 and R b The atoms connected to it form together

[0143] In another embodiment of this disclosure, L1 is selected from -NH- and -O-.

[0144] In another embodiment of this disclosure, L2 is selected from the bond, -(CR 1 R 2 ) u -、-NR L -, -O-, 5 to 6 membered cycloalkyl groups; wherein R 1 R 2 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 2-6 alkynyl group; R L Selected from hydrogen atoms and C 1-6 Alkyl; u is 1, 2 or 3.

[0145] In another embodiment of this disclosure, L2 is selected from the bond, -(CR 1 R 2 ) u -、-NR L -, -O-, 5 to 6 membered cycloalkyl groups; wherein R 1 R 2 The same or different, and each independently selected from hydrogen atoms, C atoms optionally substituted with 3 to 6-membered cycloalkyl groups, cyano groups, and hydroxyl groups. 1-6 Alkyl, C 2-6 Alkyne, hydroxyl, cyano, optional C 1-6 Alkyl, hydroxyl-substituted 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered heterocyclic, 5- to 8-membered bridged cycloalkyl, 5- to 8-membered spirocycloalkyl; R L Selected from hydrogen atoms and C 1-6 Alkyl; u is 1, 2 or 3.

[0146] In another embodiment of this disclosure, R on the same carbon atom 1 R 2 Together with the carbon atoms attached thereto, they form 3 to 6-membered monocyclic cycloalkyl groups and 5 to 8-membered spirocyclic cycloalkyl groups.

[0147] In another embodiment of this disclosure, R on the same carbon atom 1 R 2 Together with the carbon atoms attached thereto, they form 3 to 8-membered monocyclic cycloalkyl groups, 5 to 8-membered spirocyclic cycloalkyl groups, and 3 to 8-membered heterocyclic groups.

[0148] In another embodiment of this disclosure, R on adjacent carbon atoms 1 R 2 The atoms attached to it together form 5- to 6-membered monocyclic cycloalkyl groups and 5- to 8-membered spirocyclic cycloalkyl groups.

[0149] In another embodiment of this disclosure, R on adjacent carbon atoms1 R 2 The atoms bonded to it together form an optional C 1-6 Alkyl-substituted 3- to 6-membered monocyclic cycloalkyl groups and 5- to 8-membered spirocyclic alkyl groups.

[0150] In another embodiment of this disclosure, L2 is selected from key, -O-、 * indicates that it is connected to ring C.

[0151] In another embodiment of this disclosure, L2 is selected from... * indicates that it is connected to ring C.

[0152] In another embodiment of this disclosure, L1-L2 are selected from... -NH-; * indicates connection to ring C.

[0153] In another embodiment of this disclosure, L1-L2 are selected from... * indicates that it is connected to ring C.

[0154] In another embodiment of this disclosure, cyclic C is selected from 5- to 6-membered heteroaryl groups.

[0155] In another embodiment of this disclosure, ring C is selected from...

[0156] In another embodiment of this disclosure, ring C is selected from...

[0157] In another embodiment of this disclosure, R c Selected from hydrogen atoms, optionally substituted with -NR n3 R n4 Replacement C 1-6 Alkyl, Halogenated C 1-6 Alkyl; wherein R n3 R n4 They may be the same or different, and each is independently selected from hydrogen atoms and C atoms. 1-6 alkyl.

[0158] In another embodiment of this disclosure, R c Selected from hydrogen atoms, Trifluoromethyl

[0159] In another embodiment of this disclosure, two R atoms on adjacent ring atomsc The atoms attached to it together form 3 to 8-membered heterocyclic groups that can be optionally substituted with halogens.

[0160] In another embodiment of this disclosure, two R atoms on adjacent ring atoms c The atoms connected to it form together

[0161] In another embodiment of this disclosure, two R atoms on adjacent ring atoms c The atoms connected to it form together

[0162] In another embodiment of this disclosure, wherein... Selected from

[0163] In another embodiment of this disclosure, wherein... Selected from

[0164] In another embodiment of this disclosure, R 1 and R c The atoms attached to it together form 3 to 6-membered cycloalkenyl groups.

[0165] In another embodiment of this disclosure, R 1 and R c The atoms connected to it form together * indicates that it is connected to L1.

[0166] In another embodiment of this disclosure, m1 is 0, 1, or 2.

[0167] In another embodiment of this disclosure, m2 is 0, 1, or 2.

[0168] In another embodiment of this disclosure, n is 0, 1, or 2.

[0169] In another embodiment of this disclosure, t is 0, 1, or 2.

[0170] In another embodiment of this disclosure, u is 0, 1, or 2.

[0171] Another object of this disclosure is to provide a compound of general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3c), its stereoisomer or pharmaceutically acceptable salt thereof;

[0172] Where: X is selected from NR L -O-;

[0173] Ring A1 is selected from 6-membered heteroaryl groups containing 1 to 3 N atoms;

[0174] Y is selected from O, S, -NR a2 ;

[0175] Other groups are defined as described in any embodiment of this disclosure.

[0176] Another object of this disclosure is to provide a compound of general formula (I-1a), general formula (I-1b), general formula (I-3a), general formula (I-3b), its stereoisomer or pharmaceutically usable salt thereof;

[0177] in:

[0178] Ring A1 is selected from 5- or 6-membered heteroaryl groups containing 1 to 3 N atoms;

[0179] Y is selected from O, S, -NR a2 ;

[0180] Other groups are defined as described in any embodiment of this disclosure.

[0181] Another object of this disclosure is to provide a compound of general formula (I-1c), general formula (I-1d), its stereoisomer, or a pharmaceutically usable salt thereof;

[0182] in:

[0183] The ring C is selected from 5- to 6-membered heteroaryl groups;

[0184] Ring D is selected from 3- to 8-membered heterocyclic groups; preferably, ring D is selected from 6-membered heterocyclic groups;

[0185] Each R d Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl groups, halogens;

[0186] Each R c Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, Halogenated C 1-6 Alkyl; preferably, R c Selected from halogenated C 1-6 alkyl;

[0187] m is selected from 0, 1, or 2; and

[0188] n is selected from 0, 1, or 2.

[0189] Another object of this disclosure is to provide a compound of general formula (I-1e), general formula (I-1f), its stereoisomer, or a pharmaceutically usable salt thereof;

[0190] in:

[0191] Ring D is selected from 3- to 8-membered heterocyclic groups; preferably, ring D is selected from 6-membered heterocyclic groups;

[0192] Each R d Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl groups, halogens;

[0193] R c Selected from hydrogen atoms, C 1-6 Alkyl, Halogenated C 1-6 Alkyl; preferably, R c Selected from halogenated C 1-6 Alkyl; more preferably, R c Selected from difluoromethyl or trifluoromethyl; and

[0194] m is selected from 0, 1, or 2.

[0195] Another object of this disclosure is to provide a compound of general formula (I-3a), general formula (I-3b), its stereoisomer, or a pharmaceutically usable salt thereof;

[0196] in:

[0197] Ring A1 is selected from 5-membered heteroaryl or pyridyl; preferably, ring A1 is selected from pyridyl.

[0198] Y is selected from O, S, -NR a2 Preferably, Y is selected from S;

[0199] The ring C is selected from 5- to 6-membered heteroaryl groups;

[0200] Ring D is selected from 3- to 8-membered heterocyclic groups; preferably, ring D is selected from 6-membered heterocyclic groups;

[0201] Each R d Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl groups, halogens;

[0202] Each R a1 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl, halogen, amino, (C 1-6 alkyl) cyano, -NH(C 1-6 Alkyl); preferably, each R a1 They may be the same or different, and each is independently selected from hydrogen atom, methyl, methoxy, cyclopropyl, fluorine, -NH-CH3, -CH2CN, -NH2;

[0203] Each Rc Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, Halogenated C 1-6 Alkyl; preferably, R c Selected from halogenated C 1-6 alkyl;

[0204] R a2 Selected from hydrogen atoms, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy;

[0205] m is selected from 0, 1, or 2;

[0206] m1 is selected from 0, 1, or 2; and

[0207] n is selected from 0, 1, or 2.

[0208] Another object of this disclosure is to provide a compound of general formula (I-3d), general formula (I-3e), its stereoisomer, or a pharmaceutically usable salt thereof;

[0209] in:

[0210] Ring A1 is selected from 5-membered heteroaryl or pyridyl; preferably, ring A1 is selected from pyridyl.

[0211] Y is selected from O, S, -NR a2 Preferably, Y is selected from S;

[0212] Each R a1 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl, halogen, amino, (C 1-6 alkyl) cyano, -NH(C 1-6 Alkyl); preferably, each R a1 They may be the same or different, and each is independently selected from hydrogen atom, methyl, methoxy, cyclopropyl, fluorine, -NH-CH3, -CH2CN, -NH2;

[0213] R c Selected from hydrogen atoms, C 1-6 Alkyl, Halogenated C 1-6 Alkyl; preferably, R c Selected from halogenated C 1-6 Alkyl; more preferably, R c Selected from difluoromethyl or trifluoromethyl;

[0214] R a2 Selected from hydrogen atoms, C 1-6Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy groups; and

[0215] m1 is selected from 0, 1, or 2.

[0216] Another object of this disclosure is to provide a compound of general formula (I-1g), general formula (I-1h), its stereoisomer, or a pharmaceutically usable salt thereof;

[0217] in:

[0218] Z is selected from O, S, and -NR. a2 -CH-R a2 Preferably, Z is selected from O, S, -CH-R a2 ;

[0219] The ring C is selected from 5- to 6-membered heteroaryl groups;

[0220] Each R d Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl groups, halogens;

[0221] Each R c Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, Halogenated C 1-6 Alkyl; preferably, R c Selected from halogenated C 1-6 alkyl;

[0222] Each R a2 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy;

[0223] m is selected from 0, 1, or 2; and

[0224] n is selected from 0, 1, or 2.

[0225] Another object of this disclosure is to provide a compound of general formula (I-1i), general formula (I-1j), its stereoisomer, or a pharmaceutically usable salt thereof;

[0226] in:

[0227] Z is selected from O, S, and -NR. a2 -CH-R a2 Preferably, Z is selected from O, S, -CH-R a2 ;

[0228] Each R d Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl groups, halogens;

[0229] R c Selected from hydrogen atoms, C 1-6 Alkyl, Halogenated C 1-6 Alkyl; preferably, R c Selected from halogenated C 1-6 alkyl;

[0230] Each R a2 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy;

[0231] m is selected from 0, 1, or 2.

[0232] This disclosure also provides the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, wherein typical compounds of this disclosure include, but are not limited to, any of the structures in Table A below, their stereoisomers, or pharmaceutically acceptable salts thereof:

[0233] Table A

[0234] In another embodiment of this disclosure, any structure in Table A, its stereoisomer, or its pharmaceutically acceptable salt is further selected from the following compounds:

[0235] In another embodiment of this disclosure, the compound has a single configuration as shown below:

[0236] Under the chromatographic conditions of Daicel OJ (25×250mm, 10μm) and mobile phase gradient of CO2 / MeOH [0.05% NH3 (7M in MeOH)] = 70 / 30, the retention time was approximately 3.57 min.

[0237] Another aspect of this disclosure relates to a pharmaceutical composition comprising the compounds of the general formulas (I), (I-1), (I-2), (I-3), (I-1a), (I-1b), (I-3a), (I-3b), (I-3c), (I-1c), (I-1d), (I-1e), (I-1f), (I-1g), (I-1h), (I-1i), (I-1j), (I-3d), (I-3e) of this disclosure and those shown in Table A, their stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers.

[0238] This disclosure further relates to the use of compounds of general formula (I), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-1a), general formula (I-1b), general formula (I-3a), general formula (I-3b), general formula (I-3c), general formula (I-1c), general formula (I-1d), general formula (I-1e), general formula (I-1f), general formula (I-1g), general formula (I-1h), general formula (I-1i), general formula (I-1j), general formula (I-3d), general formula (I-3e) and those shown in Table A, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them in the preparation of a medicament for inhibiting MASTL.

[0239] This disclosure further relates to the use of compounds of general formula (I), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-1a), general formula (I-1b), general formula (I-3a), general formula (I-3b), general formula (I-3c), general formula (I-1c), general formula (I-1d), general formula (I-1e), general formula (I-1f), general formula (I-1g), general formula (I-1h), general formula (I-1i), general formula (I-1j), general formula (I-3d), general formula (I-3e) and Table A, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them in the preparation of medicaments for the treatment and / or prevention of MASTL-mediated diseases.

[0240] This disclosure further relates to the use of compounds of general formula (I), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-1a), general formula (I-1b), general formula (I-3a), general formula (I-3b), general formula (I-3c), general formula (I-1c), general formula (I-1d), general formula (I-1e), general formula (I-1f), general formula (I-1g), general formula (I-1h), general formula (I-1i), general formula (I-1j), general formula (I-3d), general formula (I-3e) and Table A, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them in the preparation of medicaments for the treatment and / or prevention of cancer.

[0241] This disclosure also relates to a method of inhibiting MASTL, comprising administering to a desired patient a therapeutically effective amount of the compounds of formula (I), formula (I-1), formula (I-2), formula (I-3), formula (I-1a), formula (I-1b), formula (I-3a), formula (I-3b), formula (I-3c), formula (I-1c), formula (I-1d), formula (I-1e), formula (I-1f), formula (I-1g), formula (I-1h), formula (I-1i), formula (I-1j), formula (I-3d), formula (I-3e), and the compounds shown in Table A, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them.

[0242] This disclosure also relates to a method of treating and / or preventing MASTL-mediated diseases, comprising administering to a desired patient a therapeutically effective amount of the compounds of formula (I), formula (I-1), formula (I-2), formula (I-3), formula (I-1a), formula (I-1b), formula (I-3a), formula (I-3b), formula (I-3c), formula (I-1c), formula (I-1d), formula (I-1e), formula (I-1f), formula (I-1g), formula (I-1h), formula (I-1i), formula (I-1j), formula (I-3d), formula (I-3e), and the compounds shown in Table A, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them.

[0243] This disclosure also relates to a method of treating and / or preventing cancer, comprising administering to a desired patient a therapeutically effective amount of the compounds of formula (I), formula (I-1), formula (I-2), formula (I-3), formula (I-1a), formula (I-1b), formula (I-3a), formula (I-3b), formula (I-3c), formula (I-1c), formula (I-1d), formula (I-1e), formula (I-1f), formula (I-1g), formula (I-1h), formula (I-1i), formula (I-1j), formula (I-3d), formula (I-3e), and the compounds shown in Table A, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them.

[0244] This disclosure further relates to a compound of general formula (I), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-1a), general formula (I-1b), general formula (I-3a), general formula (I-3b), general formula (I-3c), general formula (I-1c), general formula (I-1d), general formula (I-1e), general formula (I-1f), general formula (I-1g), general formula (I-1h), general formula (I-1i), general formula (I-1j), general formula (I-3d), general formula (I-3e), and the compound shown in Table A, its stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the thereof, which are used as pharmaceuticals.

[0245] This disclosure further relates to compounds of general formula (I), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-1a), general formula (I-1b), general formula (I-3a), general formula (I-3b), general formula (I-3c), general formula (I-1c), general formula (I-1d), general formula (I-1e), general formula (I-1f), general formula (I-1g), general formula (I-1h), general formula (I-1i), general formula (I-1j), general formula (I-3d), general formula (I-3e) and the compounds shown in Table A, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, which are used as MASTL inhibitors.

[0246] This disclosure further relates to compounds of general formulas (I), (I-1), (I-2), (I-3), (I-1a), (I-1b), (I-3a), (I-3b), (I-3c), (I-1c), (I-1d), (I-1e), (I-1f), (I-1g), (I-1h), (I-1i), (I-1j), (I-3d), (I-3e), and those shown in Table A, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, for the treatment and / or prevention of MASTL-mediated diseases.

[0247] This disclosure further relates to compounds of general formulas (I), (I-1), (I-2), (I-3), (I-1a), (I-1b), (I-3a), (I-3b), (I-3c), (I-1c), (I-1d), (I-1e), (I-1f), (I-1g), (I-1h), (I-1i), (I-1j), (I-3d), (I-3e), and those shown in Table A, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, for the treatment and / or prevention of cancer.

[0248] Preferably, the cancers described above in this disclosure are selected from breast cancer, colorectal cancer, head and neck cancer, non-small cell lung cancer, gastric cancer, pancreatic cancer, prostate cancer, and thyroid cancer; the colorectal cancer is preferably colon cancer or rectal cancer; and the head and neck cancer is preferably head and neck squamous cell carcinoma.

[0249] The active compound can be formulated into a form suitable for administration via any appropriate route, preferably in a unit dose manner or in a manner that allows the patient to self-administer a single dose.

[0250] In addition to the active compound, the pharmaceutical compositions disclosed herein may contain one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound; preferably, the composition may contain 1 to 95% by weight of the active compound.

[0251] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to: the activity of the specific compound used, the subject's age, weight, health status, behavior, diet, timing of administration, route of administration, rate of excretion, combination of drugs, and severity of disease; in addition, the optimal treatment mode, such as the treatment regimen, daily dosage of the compound, or type of pharmaceutically acceptable salt, can be validated based on conventional treatment protocols.

[0252] On the other hand, this disclosure provides compounds of the following general formula, their salts or stereoisomers thereof;

[0253] in:

[0254] G is selected from halogens; preferably, G is selected from bromine, chlorine, and iodine;

[0255] The ring C is selected from a 5-membered nitrogen-containing heteroaryl group;

[0256] Each R cWhether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, Halogenated C 1-6 Alkyl; preferably, R c Selected from halogenated C 1-6 alkyl;

[0257] n is selected from 0, 1, or 2.

[0258] On the other hand, this disclosure provides compounds of the following general formula or stereoisomers thereof;

[0259] in:

[0260] R is selected from boric acid fragments and borate ester fragments; preferably, R is selected from -B(OR) r 2.

[0261] Z is selected from O, S, and -NR. a2 -CH-R a2 Preferably, Z is selected from O, S, -CH-R a2 ;

[0262] Each R d The same or different, and each independently selected from C 1-6 Alkyl groups, halogens;

[0263] R r Selected from hydrogen atoms, C 1-4 alkyl;

[0264] Each R a2 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy groups; and

[0265] m is selected from 0, 1, or 2.

[0266] In another embodiment of this disclosure, the compound, its salt, or its stereoisomer is selected from;

[0267] Terminology Explanation

[0268] Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense.

[0269] The term "therapeutic effective dose" refers to a sufficient amount of the compound of this disclosure, its pharmaceutically acceptable salts, or its stereoisomers to provide a reasonable benefit / risk ratio for treating any medical condition and / or preventing the disorder. However, it should be understood that the total daily dose of the compound represented by the general formula of this disclosure, or its pharmaceutically acceptable salts and compositions thereof, must be determined by the attending physician within the bounds of reliable medical judgment. For any given patient, the specific therapeutic effective dose level must be determined based on a number of factors, including the disorder being treated and its severity; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health condition, sex, and diet; the timing, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors known in the medical field.

[0270] The term "isomer" as used in this disclosure includes geometric isomers and stereoisomers, such as trans-restricted isomers, cis-trans isomers, enantiomers, diastereomers, tautomers, and racemic mixtures and other mixtures thereof, all of which are within the scope of this disclosure. The term "enantiomer" refers to stereoisomers that are mirror images of each other. The term "tautomer" refers to a functional group isomer that has different hydrogen bonding sites through one or more double bond shifts; for example, a ketone and its enol form are keto-enol tautomers. The term "diastereomer" refers to stereoisomers of molecules having two or more chiral centers and being non-mirror images of each other. The term "cis-trans isomer" refers to different spatial configurations of a molecule where double bonds or single bonds of cyclic carbon atoms cannot rotate freely.

[0271] The absolute stereoconfiguration of a compound can be confirmed using conventional techniques in the art. For example, single-crystal X-ray diffraction (SFC) can be used, or the absolute configuration of the compound can be confirmed by examining the chiral structure of the starting material and the reaction mechanism of asymmetric synthesis. Alternatively, after resolution, the stereoconfiguration can be determined by comparing it with a product whose absolute configuration is known. Compounds marked as "absolute configuration unknown / undetermined" in this article are typically racemic compounds resolved into single isomers via chiral preparative SFC, followed by characterization and testing.

[0272] Those skilled in the art know that when a cyclic compound has a coplanar delocalized system and the number of π electrons is 4n+2, the ring is aromatic. The aromatic structure in a compound can be represented by either dashed lines indicating electron delocalization or by alternating single and double bonds. For example, the structure of a benzene ring can be drawn as follows: It can also be

[0273] "Optionally" or "optionally" means that the event or environment described below may but not necessarily occur, including both the occurrence and non-occurrence of the event or environment. For example, "optionally (optionally) alkyl group substituted with halogen or cyano" includes cases where the alkyl group is substituted with halogen or cyano and cases where the alkyl group is not substituted with halogen or cyano.

[0274] When the substituent structure contains... A truncated bond indicates that the bond is a linking bond to a substituent, for example... This indicates that the benzene ring is attached to a given group or a given structural formula via a carbon atom.

[0275] The presence of a dash "-" in a substituent structure indicates the connection point for the substituent. For example, -SCH3 is connected to a given group or given structural formula via a sulfur atom. The absolute configuration representing the center of a solid, i.e., the R or S configuration. It indicates cis or trans configuration. Double real or double dummy bonds both indicate cis configuration, and one real and one dummy bond indicates trans configuration.

[0276] When a substituent can be cross-bonded to a ring, it means that the substituent can bond with any atom on that ring. For example, structural units. This indicates that the substituent R can be substituted at any position on the benzene ring.

[0277] When a listed substituent does not specify which atom it is attached to a given group or given structural formula, the substituent may be attached by any of its bondable atoms.

[0278] When any variable (e.g., R) d When a compound appears more than once in its composition or structure, its definition is independent in each case. For example, This indicates that the cyclopentyl group is surrounded by 3 R groups. d Replaced, and each R d Each has its own independent options.

[0279] Unless otherwise specified, the term "halogen" refers to a fluorine, chlorine, bromine, or iodine atom.

[0280] Unless otherwise specified, the term "alkyl" refers to a branched or straight-chain saturated aliphatic alkane with a specified number of carbon atoms, minus a hydrogen-derived group. For example, "C 1-10 "Alkyl" refers to compounds including C1, C2, C3, C4, C5, C6, C7, C8, C9, C6, C7, C8, C9, C9, C1, C1, C1, C1, C2, C3, C4, C5, C6, C7, C8, C9, C1 ... 10 Alkyl, "C 1-6 Alkyl", C 1-4 Alkyl", C 1-3Alkyl; specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, sec-butyl, 2-methylbutyl, 1,1-dimethylbutyl, etc.

[0281] Unless otherwise specified, the term "halogenated alkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms. Preferred halogenated C 1-6 Alkyl, more preferably halogenated C 1-4 Alkyl groups. Examples of haloalkyl groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, etc. Alkyl groups are as defined above.

[0282] Unless otherwise specified, the term "hydroxyalkyl" refers to a group derived from an alkyl group in which one or more hydrogen atoms are replaced by hydroxyl groups, and "hydroxyalkyl" as used in this disclosure includes "hydroxyl C". 1-6 Alkyl group, hydroxyl group 1-4 Alkyl groups; specific examples include, but are not limited to, -CH2OH, -CH2CH2OH, -CH(OH)CH3, and -CH2CH2CH2OH. wait.

[0283] Unless otherwise specified, the term "alkoxy" refers to an alkyl group as defined herein, in which an alkyl group is attached to another group by an oxygen atom, i.e., "alkyl-O-". This includes "C". 1-6 Alkoxy (structure is C) 1-6 alkyl-O-), "C 1-4 "Alkoxy" is a suffix, specifically including but not limited to methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, etc.; preferably, the "alkoxy" in this disclosure is preferably C 1-4 Alkoxy, more preferably C 1-3 Alkyl group.

[0284] Unless otherwise specified, the term "haloalkoxy" refers to a group obtained by substituting one or more hydrogen atoms in an alkoxy group with a halogen. Preferably, the "haloalkoxy" described in this disclosure is "haloC". 1-6 Alkoxy, halogenated C 1-4 Alkyl groups. Specific examples described in this disclosure include: fluoromethoxy groups (including monofluoromethoxy, difluoromethoxy, and trifluoromethoxy), -OCH2CF3, -OCHFCH3, etc. Alkyl groups are as defined above.

[0285] Unless otherwise specified, the term "cycle" refers to a saturated, partially saturated, or unsaturated monocyclic or polycyclic ring, including spirocyclic, fused, or bridged rings. A group derived from a ring by removing a hydrogen atom is called a "cycloyl group," which includes monovalent, divalent (commonly referred to as a subcyclic ring), trivalent, and tetravalent rings, with the specific valence depending on the number of substituents attached to the ring. This disclosure no longer specifically distinguishes the valence of the ring in its description of "cycloyl groups." Representative "cycloyl groups" include substituted or unsubstituted cycloalkyl, heterocyclic alkyl, cycloalkenyl, heterocyclic alkenyl, cycloynyl, heterocyclic alynyl, aryl, or heteroaryl groups.

[0286] The term "hetero" refers to substituted or unsubstituted heteroatoms and their oxidized forms (also called heteroatomic groups). The heteroatoms are generally selected from N, O, S, and P, and the oxidized forms generally include NO, SO, S(O)2, and P(O). The nitrogen atom may be substituted, i.e., NR (R is H or other substituents defined in the text). The number of atoms on the ring is usually defined as the ring number. For example, "3-6 membered heterocyclic alkyl" refers to a ring consisting of 3-6 atoms arranged in a ring, each ring optionally containing 1 to 3 heteroatoms and / or heteroatomic groups, i.e., N, O, S, NO, SO, S(O)2, P(O), or NR. Each ring is optionally substituted by an R group, R being a group defined in the text.

[0287] Unless otherwise specified, the term "cycloalkyl" refers to a saturated cyclic alkyl group derived from a cycloalkane by removing a hydrogen atom, including monocyclic or polycyclic saturated hydrocarbon groups; the polycyclic saturated hydrocarbon group refers to a polycyclic group formed by two or more cyclic alkyl structures linked by spiro, bridging, fused, or other means. The carbon atom in the cycloalkyl group can be further oxidized, i.e., forming C(O). Unless otherwise specified, "membered cycloalkyl" as used herein includes both monocyclic cycloalkyl and polycyclic cycloalkyl such as spiro, fused, or bridged cycloalkyl groups. The cycloalkyl group includes "3 to 12-membered cycloalkyl", "3 to 10-membered cycloalkyl", "5 to 10-membered cycloalkyl", "5 to 12-membered cycloalkyl", "3 to 8-membered cycloalkyl", "4 to 8-membered cycloalkyl", "3 to 6-membered cycloalkyl", and "3 to 5-membered cycloalkyl". Preferably, the cycloalkyl group is a monocyclic, saturated structure; specific examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0288] Unless otherwise specified, "cycloalkenyl" means one or more of the cyclic bonds in a "cycloalkyl" group that are double bonds and that the cycloalkenyl group is not aromatic. The carbon atom in the cycloalkenyl group may be further oxidized, forming a C(O) group. The cycloalkenyl group includes "3- to 12-membered cycloalkenyl", "3- to 10-membered cycloalkenyl", "5- to 10-membered cycloalkenyl", "5- to 12-membered cycloalkenyl", "3- to 8-membered cycloalkenyl", "3- to 6-membered cycloalkenyl", "3- to 5-membered cycloalkenyl", and "5- to 6-membered cycloalkenyl". Specific examples include, but are not limited to, those mentioned above.

[0289] Unless otherwise specified, the term "heterocyclic group" refers to a saturated cyclic group derived by replacing one or more cyclic carbon atoms in a cycloalkyl group with heteroatoms and / or heteroatom groups. The heteroatoms and / or heteroatom groups are generally selected from N, O, S, NO, SO, S(O)2, P(O), and NR, wherein the carbon atoms in the heterocycle are optionally oxidized to form -C(O); preferably, the heteroatoms are independently selected from 1 to 3 N and / or O atoms. Unless otherwise specified, the term "membered heterocyclic group" as used herein includes both monocyclic and polycyclic heterocyclic groups such as spiro, fused, or bridged heterocyclic groups. The heterocyclic groups include "3 to 12-membered heterocyclic groups," "3 to 10-membered heterocyclic groups," "5 to 10-membered heterocyclic groups," "3 to 8-membered heterocyclic groups," "3 to 6-membered heterocyclic groups," "3 to 5-membered heterocyclic groups," "4 to 8-membered heterocyclic groups," "4 to 6-membered heterocyclic groups," "5 to 6-membered heterocyclic groups," and "5 to 12-membered heterocyclic groups." Specific examples include, but are not limited to, nitrogen-containing heterocyclic butyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, etc.

[0290] Unless otherwise specified, the term "heterocyclic alkenyl" refers to a "heterocyclic group" in which one or more cyclic bonds are double bonds and the heterocycle is not aromatic. Preferably, the heteroatoms are independently selected from 1-3 N and / or O atoms. The heterocyclic group includes "3- to 12-membered heterocyclic alkenyl", "3- to 10-membered heterocyclic alkenyl", "5- to 10-membered heterocyclic alkenyl", "3- to 8-membered heterocyclic alkenyl", "3- to 6-membered heterocyclic alkenyl", "3- to 5-membered heterocyclic alkenyl", "4- to 8-membered heterocyclic alkenyl", "4- to 6-membered heterocyclic alkenyl", "5- to 6-membered heterocyclic alkenyl", and "5- to 12-membered heterocyclic alkenyl". Specific examples include, but are not limited to: wait.

[0291] Unless otherwise specified, the term "aryl" refers to an unsaturated, usually aromatic, hydrocarbon group, which may be a monocyclic or a plurality of rings fused together. Preferably, it is a 5- to 12-membered aryl, more preferably a 5- to 10-membered aryl, even more preferably a 5- to 8-membered aryl, and most preferably a monocyclic 5- to 6-membered aryl; examples of aryl include, but are not limited to, phenyl and naphthyl.

[0292] The term "heteroaryl" as used in this disclosure refers to an aromatic monocyclic or polycyclic group comprising one or more heteroatoms and / or heterogroups, wherein the heteroatoms and / or heterogroups are generally selected from N, O, S, P, NO, SO, S(O)2, P(O), and NR, where R is H or any substituent that may exist, wherein the carbon atom in the heterocycle is optionally oxidized to form -C(O); preferably, the heteroatoms are independently selected from 1-3 N and / or O atoms, and the N and S atoms may optionally be oxidized and the N atom may optionally be quaternized. The term "heteroaryl" includes "monocyclic heteroaryl" and "fused heteroaryl," wherein a fused heteroaryl refers to an aromatic group comprising one or more heteroatoms formed by two or more cyclic structures sharing two adjacent atoms. The heteroaryl is preferably a 5- to 12-membered heteroaryl, more preferably a 5- to 10-membered heteroaryl, even more preferably a 5- to 6-membered heteroaryl, and most preferably a monocyclic 5- to 6-membered heteroaryl. Unless otherwise specified, the term "heteroaryl" as used herein generally refers to a "monocyclic heteroaryl," such as the "5- to 6-membered heteroaryl" described herein, which does not possess the potential to form a fused-ring heteroaryl. When it is a "fused heteroaryl," it will be specifically indicated that it is a "fused" heteroaryl structure, such as an "8- to 10-membered fused heteroaryl." The heteroaryl described in this disclosure is preferably a "nitrogen-containing heteroaryl," more preferably a "5- to 6-membered nitrogen-containing heteroaryl." The heteroatom in the "nitrogen-containing heteroaryl" contains at least one nitrogen atom, for example, containing only 1, 2, or 3 nitrogen atoms, or containing one nitrogen atom and 1 or 2 other heteroatoms (e.g., S and / or O atoms), or containing 2 nitrogen atoms and 1 or 2 other heteroatoms. Specific examples of the heteroaryl include, but are not limited to: furanyl, thiophene, pyrrole, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazole, pyrazolyl, etc.

[0293] Unless otherwise specified, the term "spirocycloalkyl" refers to a cyclic structure formed by two or more cycloalkyl groups sharing a single ring atom, wherein the carbon atom in the spirocycloalkyl group may be further oxidized to form a C(O). The cycloalkyl group includes "5-14-membered spirocycloalkyl", "5-8-membered spirocycloalkyl", "6-11-membered spirocycloalkyl", "7-11-membered spirocycloalkyl", and "7-9-membered spirocycloalkyl", and specific examples include, but are not limited to, those shown below.

[0294] Unless otherwise specified, the term "bridged cycloalkyl" refers to a saturated cyclic structure formed by two or more carbon rings sharing two non-adjacent carbon atoms. Optionally, the carbon atoms in the cyclic structure may be substituted with oxygen. "Bridged cycloalkyl" includes, for example, "5-14-membered bridged cycloalkyl," "5-11-membered bridged cycloalkyl," "6-11-membered bridged cycloalkyl," "5-10-membered bridged cycloalkyl," "7-10-membered bridged cycloalkyl," "6-9-membered bridged cycloalkyl," "7-8-membered bridged cycloalkyl," "9-10-membered bridged cycloalkyl," etc. Specific examples include, but are not limited to: ...

[0295] Unless otherwise specified, the term "bridged heterocyclic group" refers to a saturated or partially saturated cyclic structure derived from the substitution of at least one carbon atom in the "bridged cyclic group" by a heteroatom / heteroatomic group selected from N, O, S, P, NO, SO, S(O)2, P(O), and NR, where R is H or any possible substituent group, and the "bridged cycloalkyl group" is as defined above. "Bridged heterocyclic groups" include, for example, "4- to 10-membered bridged heterocyclic groups," "5- to 14-membered bridged heterocyclic groups," "5- to 11-membered bridged heterocyclic groups," "6- to 11-membered bridged heterocyclic groups," "5- to 10-membered bridged heterocyclic groups," "7- to 10-membered bridged heterocyclic groups," "6- to 9-membered bridged heterocyclic groups," "7- to 8-membered bridged heterocyclic groups," "9- to 10-membered bridged heterocyclic groups," "6- to 10-membered bridged heterocyclic alkenyl groups," "6- to 8-membered bridged heterocyclic alkenyl groups," and "7- to 8-membered nitrogen-containing bridged heterocyclic alkenyl groups," etc. Preferably, the heteroatoms are independently selected from 1 to 3 N and / or O atoms. Preferably, the bridging heterocyclic group is a "nitrogen-containing bridging heterocyclic group," meaning that at least one ring atom is N, and optionally contains one or more other heteroatoms; preferably, the "nitrogen-containing bridging heterocyclic group" contains one N atom and 0-2 atoms selected from N and / or O and / or S. Preferably, the "nitrogen-containing bridging heterocyclic group" contains one N atom and 0-1 atoms selected from O and / or S. Preferably, the bridging heterocyclic group is an "oxygen-containing bridging heterocyclic group," meaning that at least one ring atom is O, and optionally contains one or more other heteroatoms; preferably, the "oxygen-containing heterocyclic group" contains one O atom and 0-2 atoms selected from N and / or O. Specific examples include, but are not limited to: wait.

[0296] Unless otherwise specified, the term "spiroheterocyclic group" refers to a saturated or partially saturated cyclic structure derived from the substitution of at least one carbon atom in a "spirocyclic group" by a heteroatom / heteroatomic group selected from N, O, S, P, NO, SO, S(O)2, P(O), and NR, where R is H or any possible substituent group. The "spirocyclic group" is as defined above. It includes, but is not limited to, cyclic structures formed from heterocyclic spiroheterocycles and heterocyclic spirocyclic alkanes. The spiroheterocycle preferably contains 1-2 heteroatoms selected from NR and / or O, more preferably 1 NR and 0-1 NR or O heteroatoms. The spiroheterocycle is preferably a "nitrogen-containing spiroheterocyclic group," which refers to a spiroheterocyclic group where at least one ring atom is NR. The spiroheterocycle includes 5-14 membered spiroheterocyclic groups, 5-10 membered spiroheterocyclic groups, 7-11 membered spiroheterocyclic groups, 7-9 membered spiroheterocyclic groups, 7-11 membered nitrogen-containing spiroheterocyclic groups, and 7-9 membered nitrogen-containing spiroheterocyclic groups. Specific examples include, but are not limited to: wait.

[0297] When a substituent can be cross-bonded to a ring, it means that the substituent can bond with any atom on that ring. For example, structural units. Indicates substituent R b Substitution can occur at any position on ring B (including NH), and R b The number of atoms is n; when the ring contains NH, it means that NH, like other ring atoms, can be converted by R. b What it replaces, namely R b It can replace H, or it can choose not to replace H.

[0298] When any variable (e.g., R) b When a structural unit appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, structural units. This indicates that ring B is divided by n R's. b Replaced, and each R b Each has its own independent options.

[0299] When a listed substituent does not specify which atom it is attached to a given group or given structural formula, the substituent may be attached by any of its bondable atoms. For example, pyrimidine as a substituent means that any carbon or nitrogen atom on the pyrimidine ring is attached to the substituted group. Another example is ring B in this disclosure, selected from... The absence of a defined connection site in the structural unit means that any carbon atom on the tetrahydropyran ring can be attached to a given group or a given structural formula.

[0300] In particular, all combinations of substituents and / or their variants are permitted only if such combinations produce stable compounds.

[0301] "Substitution" or "substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, which are independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0302] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0303] The term "medicinal salt" refers to derivatives obtained from the compounds of this disclosure by reacting with relatively non-toxic acids or bases. These salts can be prepared during the synthesis, isolation, and purification of the compounds, or by reacting the purified free form of the compounds with suitable acids or bases. When the compounds contain relatively acidic functional groups, they react with alkali metal, alkaline earth metal hydroxides, or organic amines to yield base addition salts, including alkali metal and alkaline earth metal-based cations, as well as non-toxic ammonium, quaternary ammonium, and amine cations, and also encompassing amino acid salts. When the compounds contain relatively basic functional groups, they react with organic or inorganic acids to yield acid addition salts.

[0304] The term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in human and animal tissues to the extent of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0305] The term "pharmaceutically acceptable carrier" refers to a medium generally acceptable in the art for delivering a bioactive pharmaceutical agent to animals, particularly mammals. Depending on the route of administration and dosage form, this includes, for example, adjuvants, excipients, or excipients such as diluents, preservatives, fillers, flow modifiers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatizers, antibacterial agents, antifungal agents, lubricants, and dispersants. Pharmaceutically acceptable carriers are formulated based on a multitude of factors, within the scope of those skilled in the art. These include, but are not limited to, the type and nature of the formulated active pharmaceutical agent, the recipient to whom the composition containing the pharmaceutical agent is to be administered, the intended route of administration of the composition, and the target therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media, as well as various solid and semi-solid dosage forms. In addition to the active pharmaceutical agent, such carriers include many different components and additives, and the inclusion of such additional components in the formulation for various reasons (e.g., stabilizing active pharmaceutical agents, binders, etc.) is well known to those skilled in the art.

[0306] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0307] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are usually given for illustrative purposes only, not as limitations. Detailed Implementation

[0308] The present disclosure is described in detail below with reference to embodiments, but this does not imply any adverse limitation on the present disclosure. The present disclosure has been described in detail herein, including specific embodiments thereof. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the invention.

[0309] In the embodiments of this disclosure, if there is a discrepancy between the compound name and the compound structure, the discrepancy can be determined by comprehensively considering relevant information and reaction routes. The preparation methods for some compounds in this disclosure reference the preparation methods for similar compounds described above. Those skilled in the art should understand that when using or referring to the referenced preparation methods, the reactant ratio, reaction solvent, reaction temperature, etc., can be appropriately adjusted according to the different reactants. The compounds of this disclosure can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of this disclosure.

[0310] The preparation method of the compound disclosed herein is based on prior patent WO2022260441A1.

[0311] The synthetic route of the compounds disclosed herein is described as follows:

[0312] The compounds in Table A of this disclosure were synthesized according to the above scheme and with reference to the preparation routes in prior patents. The structures of the target compounds obtained according to the above synthetic routes were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS).

[0313] Example 1

[0314] 6-(1-Methoxy-1H-indazol-5-yl)-N 2 -(2-Methyl-1-(2-(trifluoromethyl)-1H-imidazol-4-yl)propyl)-1,3,5-triazine-2,4-diamine

[0315] Step A: 2-(trifluoromethyl)-1H-imidazole (3.07 g, 22.56 mmol) was dissolved in THF (30 mL), purged three times with nitrogen, and cooled to 0 °C. NaH (1.08 g, 27.07 mmol, 60% dispersed in mineral oil) was slowly added in batches. After reacting for 30 min, SEMCl (4.51 g, 27.07 mmol) was slowly added. The resulting mixture was reacted at 0 °C for another 2 hours. LCMS analysis showed that the starting material was largely consumed and the product was formed. The reaction solution was quenched with water (30 mL), extracted with ethyl acetate (20 mL × 3), the mixed organic phase was concentrated, and purified by silica gel column chromatography to obtain 2-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (6 g).

[0316] 1 H NMR (400MHz, DMSO-d6) δ7.72(d,J=1.2Hz,1H),7.18(d,J=1.2Hz,1H),5.53(s,2H),3.65–3.48(m,2H),0.95–0.78(m,2H),-0.00(s,9H).

[0317] Step B: 2-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (6 g, 22.53 mmol) was dissolved in THF (60 mL), purged three times with nitrogen, and cooled to -78 °C. Butyllithium (11.72 mL, 29.29 mmol, 2.5 M in hexane) was slowly added dropwise. After 30 min, DMF (10.42 mL, 135.18 mmol) was slowly added. The resulting mixture was reacted at -78 °C for another 2 hours. LCMS analysis showed that the starting material was consumed and the product was formed. The reaction was quenched by slowly adding saturated ammonium chloride (50 mL), extracted with ethyl acetate (20 mL × 2), the mixed organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 2-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-carboxaldehyde (7 g, crude), which was directly added to the next step.

[0318] 1 H NMR (400MHz, DMSO-d6) δ9.94(s,1H),8.09(s,1H),5.83(s,2H),3.68–3.46(m,2H),0.92–0.69(m,2H),-0.06(s,9H).

[0319] Step C: 2-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-carboxaldehyde (6.7 g, 22.76 mmol) was dissolved in THF (100 mL), and tetraisopropyl titanate (32.34 g, 113.80 mmol) and (R)-(+)-tert-butylsulfinamide (13.79 g, 113.80 mmol) were added. The resulting mixture was heated in an oil bath at 80 °C for 2 hours under nitrogen protection. LCMS analysis showed that the starting material was consumed and the product was formed. The reaction solution was cooled to room temperature and slowly poured into water (300 mL). The large amount of solid precipitate generated was removed by diatomaceous earth filtration. The filtrate was collected, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were concentrated and purified by silica gel column chromatography to obtain (E)-2-methyl-N-((2-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methylene)propane-2-sulfonamide (7.7 g).

[0320] 1 H NMR (400MHz, DMSO-d6) δ8.56(s,1H),7.97(s,1H),6.04–5.74(m,2H),3.53(t,J=8.1Hz,2H),1.18(s,9H),0.84(t,J=8.0Hz,2H),-0.08(s,9H).

[0321] Step D: (E)-2-methyl-N-((2-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methylene)propane-2-sulfonamide (3 g, 7.55 mmol) was dissolved in THF (30 mL). The reaction system was purged with nitrogen three times and cooled to 0 °C. Isopropyl magnesium chloride lithium chloride (17.42 mL, 22.65 mmol, 1.3 M in THF) was slowly added. The resulting mixture was reacted at 0 °C for 2 hours. LCMS analysis showed that the raw materials were consumed, the reaction solution was quenched by slowly adding saturated ammonium chloride (30 mL), extracted with ethyl acetate (20 mL × 3), the combined organic phases were directly concentrated, and purified by silica gel column chromatography to obtain 2-methyl-N-(2-methyl-1-(2-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)propyl)propane-2-sulfinamide (2.06 g).

[0322] 1 H NMR(400MHz,DMSO-d6)δ7.16(d,J=37.5Hz,1H),5.54–5.45(m,2H),4.41–4.09(m,1H),3.54(m,2H),2.35–2 .09(m,1H),1.11(d,J=12.5Hz,9H),1.05(dd,J=19.0,6.6Hz,3H),0.98–0.79(m,5H),0.00(d,J=1.3Hz,9H).

[0323] Step E: 2-Methyl-N-(2-methyl-1-(2-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)propyl)propane-2-sulfinamide (1 g, 2.26 mmol) was dissolved in DCM (10 mL), and 4M hydrochloric acid-dioxane solution (5.65 mL, 22.60 mmol) was added. The resulting mixture was reacted at room temperature for 2 hours. LCMS analysis showed that the starting material was consumed and the product was formed. The reaction solution was directly concentrated to give crude 2-methyl-1-(2-(trifluoromethyl)-1H-imidazol-4-yl)propane-1-amine (680 mg), which was directly added to the next step.

[0324] MS(ESI)M / Z:208.2[M+H] + .

[0325] Step F: Under nitrogen protection in an ice-water bath, 5-bromo-2-nitrobenzene (4 g, 17.7 mmol) was dissolved in boranetetrahydrofuran solution (53 mL). Then, boron trifluoride diethyl ether solution (3.77 g, 26.55 mmol) was slowly added dropwise to the above solution. The reaction system was then stirred at room temperature for 16 hours. After LCMS monitoring showed the disappearance of the starting material, 4M 1,4-dioxane hydrochloride was added to the reaction solution until pH = 3. The mixture was then concentrated under reduced pressure to obtain crude (5-bromo-2-nitrobenzene)methylamine (4 g).

[0326] MS(ESI)M / Z:231.0[M+H + ].

[0327] Step G: (5-Bromo-2-nitrophenyl)methylamine (4 g, 17.39 mmol) was dissolved in methanol (43.5 mL) under ice-water bath conditions. Subsequently, sodium hydroxide (1.4 g, 34.78 mmol) was added to the solution. The reaction system was then stirred at 80°C for 16 hours. After LCMS monitoring showed the disappearance of the starting material, water (40 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL × 3 times), and the combined organic phases were washed with saturated saline solution (50 mL × 2 times). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude 5-bromo-1H-indazole-1-ol (2 g).

[0328] MS(ESI)M / Z:213.0[M+H + ].

[0329] Step H: Crude 5-bromo-1H-indazole-1-ol (2 g, 9.43 mmol) was dissolved in N,N-dimethylformamide (47 mL) under ice-water bath conditions. Subsequently, potassium carbonate (2 g, 14.15 mmol) and methyl iodide (1.6 g, 11.32 mmol) were added to the solution. The reaction mixture was then stirred at 45°C for 4 hours. After LCMS monitoring showed the disappearance of the starting material, water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (40 mL × 3 times), and the combined organic phases were washed with saturated saline solution (40 mL × 2 times). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give 5-bromo-1-methoxy-1H-indazole (850 mg).

[0330] MS(ESI)M / Z:227.0[M+H + ].

[0331] Step I: At room temperature, 5-bromo-1-methoxy-1H-indazole (450 mg, 1.99 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane) (1.26 g, 4.98 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (327 mg, 0.4 mmol), and potassium acetate (585 mg, 5.97 mmol) were dissolved in acetonitrile (10 mL). The mixture was evacuated to nitrogen three times, and the reaction mixture was stirred at 90°C for 16 hours.

[0332] After LCMS monitoring showed the raw material had disappeared, water (30 mL) was added to the solution to quench the reaction. The mixture was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined and washed with saturated saline solution (30 mL × 2 times). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indazole (400 mg).

[0333] MS(ESI)M / Z:275.2[M+H + ].

[0334] Step J: At room temperature, 1-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indazole (45 mg, 0.16 mmol) and 6-chloro-N 2 -(2-methyl-1-(2-(trifluoromethyl)-1H-imidazol-4-yl)propyl)-1,3,5-triazine-2,4-diamine (34 mg, 0.1 mmol), [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (10 mg, 0.02 mmol), and potassium phosphate (64 mg, 0.3 mmol) were dissolved in tetrahydrofuran / water (1.8 / 0.2 mL). Nitrogen gas was purged three times under vacuum, and the reaction mixture was stirred at 90°C for 16 hours.

[0335] After LCMS monitoring showed the disappearance of the raw material, water (30 mL) was added to the above solution to quench it. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated saline solution (20 mL × 2 times). The solution was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by preparative high-performance liquid chromatography to give 6-(1-methoxy-1H-indazole-5-yl)-N 2 -(2-Methyl-1-(2-(trifluoromethyl)-1H-imidazol-4-yl)propyl)-1,3,5-triazine-2,4-diamine (8.23 mg).

[0336] MS(ESI)M / Z:448.2[M+H + ].

[0337] 1 H NMR (400MHz, DMSO-d6) δ12.96(s,1H),8.75(s,1H),8.43(dd,J=8.8,1.2Hz,1H),8.04(s,1H),7.64(d,J=8.8Hz,1H),7.23(s, 1H),6.96(s,1H),6.54(s,2H),5.15(brs,1H),4.18(s,3H),2.28-2.16(m,1H),0.97(d,J=6.4Hz,3H),0.89(d,J=6.8Hz,3H).

[0338] Example 1-P2

[0339] (R or S)-6-(1-Methoxy-1H-indazol-5-yl)-N 2 -(2-Methyl-1-(2-(trifluoromethyl)-1H-imidazol-4-yl)propyl)-1,3,5-triazine-2,4-diamine

[0340] Step A: Referring to patent WO2024 / 128741, compound 1a was synthesized and then chirally separated to prepare two single-configuration compounds.

[0341] Single configuration compound 1-2P1 (retention time: 3.46 min, 600 mg)

[0342] Chromatographic conditions: Column: DAICL AS-10 25*250mm 10μm; Mobile phase: n-Hexane (+0.05% DEA) / IPA (+0.05% DEA); Gradient: 90%-10%; Retention time: 4.5min; Flow rate: 90mL / min.

[0343] MS(ESI)M / Z:336.4[M+H] + .

[0344] 1 H NMR(400MHz,DMSO-d6)δ13.36(s,1H),7.89(m,1H),7.34-6.91(m,3H),5.07-4.76 (m,1H),2.14(h,J=6.8Hz,1H),0.88(dd,J=6.8,2.9Hz,3H),0.80(p,J=6.5Hz,3H).

[0345] Single configuration compound 1-2P2 (retention time: 4.93 min, 600 mg)

[0346] Chromatographic conditions: Column: DAICL AS-10 25*250mm 10μm; Mobile phase: n-Hexane (+0.05% DEA) / IPA (+0.05% DEA); Gradient: 90%-10%; Retention time: 4.5min; Flow rate: 90mL / min.

[0347] MS(ESI)M / Z:336.4[M+H] + .

[0348] 1 H NMR (400MHz, DMSO-d6) δ13.41 (s, 1H), 8.01 (d, J = 6.6Hz, 1H), 7.39-7.01 (m, 3H), 5.15-4.8 1(m,1H),2.19(h,J=6.8Hz,1H),0.92(dd,J=6.8,3.0Hz,3H),0.84(dd,J=10.0,6.7Hz,3H).

[0349] Step B: At room temperature, the single-configuration compound 1-2P2 (122.47 mg, 364.80 μmol), compound 1-11 (100 mg, 364.80 μmol), [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (23.78 mg, 36.48 μmol), and potassium phosphate (154.87 mg, 729.60 μmol) were dissolved in 1,4-dioxane (3 mL) and water (0.3 mL). The mixture was purged with nitrogen three times, and the reaction system was stirred in an oil bath at 90 °C for 16 hours. After LCMS monitoring showed that the starting material had disappeared, water (30 mL) was added to the above solution to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed with saturated saline solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give a single-configuration compound 1-P2 (2.13 mg).

[0350] MS(ESI)M / Z:448.2[M+H] + .

[0351] 1H NMR (400MHz, DMSO-d6) δ13.35(s,1H),8.75(d,J=13.1Hz,1H),8.46–8.36(m,1H),8.10(d,J=9.9Hz,1H),7.67(d,J=8.9Hz,1H),7.4 5–7.25(m,2H),6.87(s,2H),5.10(dt,J=81.3,8.3Hz,1H),4.17(s,3H),2.20(s,1H),0.94(d,J=6.7Hz,3H),0.85(t,J=7.0Hz,3H).

[0352] Example 2-P1 and Example 2-P2

[0353] (R or S)-6-(2,3-dihydro-[1,4]oxazinco[2,3,4-hi]indazole-8-yl)-N 2 -(2-methyl-1-(2-(trifluoromethyl)-1H-imidazol-4-yl)propyl)-1,3,5-triazine-2,4-diamine and (R or S)-6-(2,3-dihydro-[1,4]oxazinco[2,3,4-hi]indazole-8-yl)-N 2 -(2-Methyl-1-(2-(trifluoromethyl)-1H-imidazol-4-yl)propyl)-1,3,5-triazine-2,4-diamine

[0354] Step A: 5-Bromo-7-methoxy-1H-indazole (5 g, 22.02 mmol) was dissolved in dichloromethane (50 mL), and then tribromoborane (110 mL, 220.21 mmol) was added at 0 °C. The mixture was allowed to react at room temperature for 24 hours. The reaction was monitored by LCMS until complete. The reaction was quenched by adding methanol dropwise to the reaction solution at -78 °C until complete quenching. The solution was then concentrated under reduced pressure to obtain the product 5-bromo-1H-indazole-7-ol (6.28 g).

[0355] MS(ESI) M / Z: 212.87, 214.85 [M+H] + .

[0356] Step B: 5-Bromo-1H-indazole-7-ol (1 g, 3.40 mmol), 1,2-dibromoethane (639.11 mg, 3.40 mmol), and cesium carbonate (5.54 g, 17.01 mmol) were dissolved in N,N-dimethylformamide (15 mL), and the mixture was reacted at 100 °C for 16 hours. The reaction was monitored by LCSM until complete, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the product 8-bromo-2,3-dihydro-[1,4]oxazinco[2,3,4-hi]indazole (610 mg).

[0357] MS(ESI) M / Z: 238.85, 240.86 [M+H] +

[0358] Step C: Under nitrogen protection, 8-bromo-2,3-dihydro-[1,4]oxazindo[2,3,4-hi]inazole (600 mg, 2.51 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,3,2-dioxaborane (637.32 mg, 2.51 mmol), potassium acetate (492.62 mg, 5.02 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (183.64 mg, 0.25 mmol) were dissolved in anhydrous 1,4-dioxane (10 mL), and the mixture was reacted at 100 °C for 2 hours. The reaction was monitored by LCMS until it was complete. The reaction solution was filtered and the filtrate was concentrated to obtain the product 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-2,3-dihydro-[1,4]oxazinco[2,3,4-hi]indazole (718 mg).

[0359] MS(ESI)M / Z: 286.94 [M+H] + .

[0360] Step D: Under nitrogen protection, 6-chloro-N 2 [2-Methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine (550 mg, 1.64 mmol), 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-2,3-dihydro-[1,4]oxazinco[2,3,4-hi]indazole (515.65 mg, 1.80 mmol), [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (106.77 mg, 0.16 mmol) and potassium phosphate (1.04 g, 4.91 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL), and the mixture was reacted at 100 °C for 2 hours. The reaction was monitored by LCMS until completion. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the product 6-(2,3-dihydro-[1,4]oxazinco[2,3,4-hi]indazole-8-yl)-N 2 -(2-Methyl-1-(2-(trifluoromethyl)-1H-imidazol-4-yl)propyl)-1,3,5-triazine-2,4-diamine (255 mg).

[0361] MS(ESI)M / Z:460.20[M+H] + .

[0362] Step E: Chiral separation of compounds 2-5 yielded single-configuration compounds 2-P1 and 2-P2.

[0363] Chromatographic conditions: Daicel OJ (25×250mm, 10um), mobile phase gradient: CO2 / MeOH [0.05% NH3 (7M in MeOH)] = 70 / 30.

[0364] The single-configuration compound 2-P1 (80.29 mg, retention time: 3.57 min)

[0365] MS(ESI)M / Z:460.20[M+H] + .

[0366] 1 H NMR (400MHz, DMSO-d6) δ13.17(s,1H),8.44–8.33(m,1H),8.13(s,1H),7.70(d,J=0.8Hz,1H),7.33-6.84(m,2H),6.69-6.38(m,2H),5.28 -4.93(m,1H),4.66(dd,J=5.2,4.0Hz,2H),4.53(dd,J=5.2,4.0Hz,2H),2.27-2.13(m,1H),0.96(d,J=6.8Hz,3H),0.87(d,J=6.8Hz,3H).

[0367] The single-configuration compound 2-P2 (80.6 mg, retention time: 4.09 min).

[0368] MS(ESI)M / Z:460.20[M+H] + .

[0369] Example 3

[0370] 6-(7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-4-yl)-N 2 -(2-Methyl-1-(2-(trifluoromethyl)-1H-imidazol-4-yl)propyl)-1,3,5-triazine-2,4-diamine

[0371] Step A: 5-Bromo-7-iodo-1H-indazole (1 g, 3.10 mmol), bis(triphenylphosphine)palladium dichloride (217 mg, 309.7 μmol), and cuprous iodide (59 mg, 309.7 μmol) were dissolved in tetrahydrofuran (15 mL). Triethylamine (1.3 mL, 9.29 mmol) and tert-butyldimethyl(prop-2-yn-1-yloxy)silane (791.15 mg, 4.64 mmol) were added under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours under nitrogen atmosphere. After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 5-bromo-7-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-1H-indazole (1 g).

[0372] 1 H NMR (400MHz, Chloroform-d) δ10.43(s,1H),8.03(s,1H),7.87(s,1H),7.56(s,1H),4.63(s,2H),0.96(s,9H),0.19(s,6H).

[0373] Step B: 5-Bromo-7-(3-((tert-butyldimethylsilyl)oxy)propyl-1-yn-1-yl)-1H-indazole (1 g, 2.7 mmol) was dissolved in ethanol (50 mL), and platinum dioxide (622 mg, 2.7 mmol) was added at room temperature. The mixture was stirred for 48 hours under a hydrogen atmosphere. After LCMS monitoring showed that the starting material had disappeared, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 5-Bromo-7-(3-((tert-butyldimethylsilyl)oxy)propyl)-1H-indazole (800 mg, crude).

[0374] MS(ESI)M / Z:369.34[M+H] + .

[0375] Step C: Dissolve 800 mg (2.2 mmol) of 5-bromo-7-(3-((tert-butyldimethylsilyl)oxy)propyl)-1H-indazole in 10 mL of dichloromethane, add 3 mL (12 mmol) of hydrochloric acid-dioxane solution, and stir at room temperature for 2 hours. After LCMS monitoring showed that the starting material had disappeared, filter the reaction solution, concentrate the filtrate under reduced pressure to obtain 500 mg (crude) of 3-(5-bromo-1H-indazole-7-yl)prop-1-ol.

[0376] MS(ESI)M / Z:255.22,257.20[M+H] + .

[0377] Step D: Dissolve 3-(5-bromo-1H-indolezol-7-yl)prop-1-ol (433 mg, 1.70 mmol) in dichloromethane (15 mL), add triethylamine (343.50 mg, 3.39 mmol) and methanesulfonyl chloride (233.31 mg, 2.04 mmol) at 0 °C, stir the reaction solution at room temperature for 1 hour, and after LCMS monitoring shows that the starting material has disappeared, concentrate the reaction solution under reduced pressure to obtain propyl 3-(5-bromo-1H-indolezol-7-yl)methanesulfonate (550 mg, crude).

[0378] MS(ESI)M / Z: 333.26, 335.32 [M+H] + .

[0379] Step E: Propyl 3-(5-bromo-1H-indoleazol-7-yl)methanesulfonate (550 mg, 1.7 mmol) was dissolved in THF (20 mL), and sodium hydride (132 mg, 3.3 mmol) was added at 0 °C. The mixture was stirred at room temperature for 2 hours. After LCMS monitoring showed that the starting material had disappeared, the reaction solution was quenched with ammonium chloride aqueous solution (20 mL), extracted with ethyl acetate (20 mL × 2), and the organic phase was concentrated under reduced pressure. The residue was purified by normal phase column chromatography to obtain 4-bromo-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline (330 mg).

[0380] MS(ESI)M / Z:237.19,239.21[M+H] + .

[0381] Step F: 4-Bromo-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline was synthesized using the method described in Example 2, intermediates 2-5, to obtain 6-(7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-4-yl)-N 2 -(2-Methyl-1-(2-(trifluoromethyl)-1H-imidazol-4-yl)propyl)-1,3,5-triazine-2,4-diamine 3 (35 mg).

[0382] MS(ESI)M / Z:458.3[M+H] + .

[0383] 1H NMR(400MHz,DMSO-d6)δ13.19(s,1H),8.59(s,1H),8.25-8.00(m,2H),7.24-7.05(m,2H),6.62-6.50(m,2 H),5.22-5.06(m,1H),4.39(t,J=5.7Hz,2H),3.05(t,J=6.1Hz,2H),2.31-2.19(m,3H),0.97-0.87(m,6H).

[0384] Example 4-P2

[0385] (R or S)-N 2 -[2-Methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-6-thieno[3,2-c]pyridin-2-yl-1,3,5-triazine-2,4-diamine

[0386] Step A: Thiophene[3,2-c]pyridine (200 mg, 1.48 mmol) and triisopropyl borate (417.36 mg, 2.22 mmol) were dissolved in tetrahydrofuran (5 mL), and then diisopropylaminolithium (0.9 mL, 1.78 mmol) was added under nitrogen protection at -78 °C. The mixture was then stirred for 2 hours while maintaining the temperature. LCMS detected the disappearance of the starting material. The reaction mixture was quenched with dilute hydrochloric acid aqueous solution (2 mL) and concentrated under reduced pressure. The resulting mixture was purified by reversed-phase column chromatography to obtain thiophene[3,2-c]pyridin-2-ylboronic acid (230 mg).

[0387] MS(ESI)M / Z:180.06[M+H] + .

[0388] Step B: Thiophene[3,2-c]pyridin-2-ylboronic acid (100 mg, 558.65 μmol) and the monoconfiguration compound 1-2P2 (206.30 mg, 614.51 μmol) were dissolved in a mixture of 1,4-dioxane (3 mL) and water (0.3 mL), followed by the addition of [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (36.41 mg, 55.86 μmol) and potassium phosphate (237.16 mg, 1.12 mmol). The mixture was then heated to 90 °C and stirred for 3 hours under nitrogen protection. LC-MS detected the disappearance of the starting material. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give the title product 4-P2 (9.81 mg).

[0389] MS(ESI)M / Z:435.2[M+H] + .

[0390] 1 H NMR (400MHz, DMSO-d6) δ13.10(s,1H),9.21(s,1H),8.47(d,J=5.6Hz,1H),8.31(s,1H),8.03(d,J=5.6Hz,1H),7.2 5(s,2H),6.78(d,J=42.7Hz,2H),5.06(s,1H),2.24(q,J=6.9Hz,1H),0.97(d,J=6.7Hz,3H),0.88(d,J=6.7Hz,3H).

[0391] Example 5-P2

[0392] (R or S)-N 2 -[2-Methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-6-thieno[2,3-c]pyridin-2-yl-1,3,5-triazine-2,4-diamine

[0393] Using thieno[2,3-c]pyridine and a single-configuration compound 1-2P2 as starting materials, compound 5-P2 (21.79 mg) was synthesized according to Example 4.

[0394] MS(ESI)M / Z:435.2[M+H + ].

[0395] 1 H NMR (400MHz, DMSO-d6) δ13.09(s,1H),9.26(s,1H),8.50(d,J=5.5Hz,1H),8.23(s,1H),7.90(dd,J=5.5,1.1Hz,1H),7.29(d,J=3 4.9Hz, 2H), 6.82 (d, J = 43.6Hz, 2H), 5.10 (d, J = 31.2Hz, 1H), 2.24 (h, J = 6.8Hz, 1H), 0.97 (d, J = 6.7Hz, 3H), 0.88 (d, J = 6.7Hz, 3H).

[0396] Example 6

[0397] 6-(7-methoxy-1-methyl-1H-indazol-5-yl)-N 2 -(2-Methyl-1-(2-(trifluoromethyl)-1H-imidazol-4-yl)propyl)-1,3,5-triazine-2,4-diamine

[0398] Using 5-bromo-7-methoxy-1H-indazole as a starting material, the synthesis method is as described in Example 1, yielding (R or S)-6-(7-methoxy-1-methyl-1H-indazole-5-yl)-N 2 -(2-Methyl-1-(2-(trifluoromethyl)-1H-imidazol-4-yl)propyl)-1,3,5-triazine-2,4-diamine 6 (29.63 mg).

[0399] MS(ESI)M / Z:462.3[M+H] + .

[0400] 1 H NMR (400MHz, DMSO-d6) δ13.12(s,1H),8.34(d,J=1.2Hz,1H),8.09(s,1H),7.78(s,1H),7.14(d,J=102.8Hz ,2H),6.57(s,2H),5.12(s,1H),4.24(s,3H),4.03(s,3H),2.29–2.17(m,1H),0.93(dd,J=35.4,6.7Hz,6H).

[0401] Example 7

[0402] 6-(3,4-dihydro-2H-[1,4]oxazolo[2,3,4-hi]indazole-9-yl)-N 2 -(2-Methyl-1-(2-(trifluoromethyl)-1H-imidazol-4-yl)propyl)-1,3,5-triazine-2,4-diamine

[0403] Using 5-bromo-1H-indazole-7-ol as a starting material, and following the synthetic method described in Example 1, 6-(3,4-dihydro-2H-[1,4]oxazolo[2,3,4-hi]indazole-9-yl)-N 2 -(2-Methyl-1-(2-(trifluoromethyl)-1H-imidazol-4-yl)propyl)-1,3,5-triazine-2,4-diamine 7 (9.55 mg).

[0404] MS(ESI)M / Z:474.3[M+H] + .

[0405] 1H NMR (400MHz, DMSO-d6) δ12.93(s,1H),8.35(s,1H),8.22(s,1H),7.82(s,1H),7.33-6.86(m,2H),6.64-6. 32(m,2H),5.34-4.92(m,1H),4.55-4.35(m,4H),2.43-2.38(m,2H),2.27–2.16(m,1H),1.00-0.83(m,6H).

[0406] Biological evaluation

[0407] The present disclosure is further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present disclosure.

[0408] The control compound in the test example has the structure described in WO2024128741A1:

[0409] Test Example 1: Inhibitory effect of the disclosed compound on MASTL

[0410] The enzyme activity of some of the compounds in the examples was verified using the ADP-GLO method.

[0411] Experimental materials:

[0412] MASTL enzyme protein was purchased from Thermo Scientific (catalog number: A32896), and the ADP-GLO kit was purchased from Promega (catalog number: V9103).

[0413] MASTL enzyme activation reaction buffer: 70mM HEPES, 3mM MgCl2, 3mM MnCl2, 50μg ml-1 PEG20000, 3μM sodium orthovanadate, 1.2mM DTT.

[0414] Experimental steps:

[0415] Using an ultra-micro pipette, the test compound (concentration: 3.33 mM, dissolved in DMSO) was serially diluted 10 times at a 1:3 ratio (10000 nM, 3333 nM, 1111 nM, 370 nM, 123 nM, 41 nM, 13.7 nM, 4.6 nM, 1.5 nM, 0.5 nM) to a 384-well reaction plate, with two replicates for each concentration. Sixteen wells were also set up for positive and 16 wells for negative controls. The positive control consisted of replicates of 1 μM of the positive compound, and the negative control consisted of replicates of DMSO. The reaction plate with the added compounds was centrifuged at 2500 rpm for 1 minute.

[0416] Add the prepared enzyme solution to the reaction plate, 5 μL per well, to achieve a final enzyme concentration of 10 nM. Centrifuge at 1000 rpm for 1 minute. Incubate at 37°C for 15 minutes.

[0417] Add the prepared ATP substrate solution to the reaction plate, 5 μL per well, to achieve a final ATP concentration of 5 μM. Centrifuge at 1000 rpm for 1 minute. Seal the plate with aluminum foil and incubate at 37°C for 90 minutes.

[0418] Add 10uL of ADP-glo TM The reagent is used to stop the kinase reaction and consume unused ATP, leaving only ADP and a very low ATP background. Centrifuge at 1000 rpm for 1 minute. Seal with aluminum foil and react at room temperature for 60 minutes.

[0419] Add 20 μL of kinase assay reagent to convert ADP to ATP, then introduce luciferase and luciferin to detect ATP. Centrifuge at 1000 rpm for 1 minute. Seal with aluminum foil and react at room temperature for 60 minutes.

[0420] The Pherastar microplate reader was used to read the ADP-GLO luminescence signal values, and the readings were analyzed. The average inhibition rate of the positive control replicates was set as the relative inhibition rate of 100%; the average inhibition rate of the negative control replicates was set as the relative inhibition rate of 0%. The ADP-GLO readings were converted into relative inhibition rates, and the IC50 values ​​of the compounds were fitted using a 4-parameter model. 50 The specific results are shown in Table 1 below.

[0421] Table 1. Inhibitory activity of the compounds disclosed in this study against MASTL.

[0422] The results showed that the disclosed compound had a significant inhibitory effect on MASTL.

[0423] Test Example 2: Inhibitory effect of the disclosed compound on the growth of SW48 cells

[0424] Experimental objective: To verify the biological activity of the MASTLi compound using the CTG assay (SW48).

[0425] Experimental steps:

[0426] 1. SW48 cells were purchased from ATCC (catalog number: CCL-231) and cultured at 37°C in a 100% Air cell culture incubator. SW48 complete culture medium consisted of Leibovitz's L-15 Medium (catalog number: Gibico 11415-064), 10% FBS (catalog number: Gibico 10099-141), and 1% Pen Strep (catalog number: Gibico 15070-063).

[0427] 2. Place 75cm 2 SW48 cells in the culture flask were digested with 2 mL of trypsin for 2-3 min, and then neutralized with 2 mL of L-15 complete medium. The cells were centrifuged at 1200 rpm for 5 min. The cells were then resuspended in 4 mL of 1640 complete medium. 500 μL of the cell suspension was used for cell counting using a Vi-CELL-XR cell counter.

[0428] 3. Using a Multidrop instrument, seed 1000 SW48 cells per well (40uL L-15Growth Media) in 384-well plates and add drugs 24 hours later.

[0429] 4. Using an ultra-micro pipette, the compound (concentration: 3.33 mM, dissolved in DMSO) was sequentially diluted in 1:3 ratios at a maximum starting concentration of 10 μM for 10 gradients (10000 nM, 3333 nM, 1111 nM, 370 nM, 123 nM, 41 nM, 13.7 nM, 4.6 nM, 1.5 nM, 0.5 nM). Two replicates were set up for each concentration. Fourteen wells were also set up for positive and negative controls. The positive control consisted of replicates of the 10 μM positive compound, and the negative control consisted of replicates of DMSO.

[0430] 5. After drug administration, cells were placed in a 37°C incubator and cultured for 6 days. After 6 days, 25 μL of CTG buffer was added to each well for CTG assay and plate reading analysis was performed using an ELISA reader.

[0431] 6. Analyze the CTG readings.

[0432] The average inhibition rate of the positive control replicates was set as the relative inhibition rate of 100%.

[0433] The average value of the negative control replicates was set as the relative inhibition rate of 0%.

[0434] Convert the CTG readings to relative inhibition rates, and then calculate the inhibition rate (inhibition%) of each compound concentration on cells using the following formula.

[0435] Inhibition%=(bx) / (ba)×100%

[0436] a=CTG value(highest concentration)

[0437] b = CTG value (blank well)

[0438] x = CTG value

[0439] 7. Use GraphPad PRISM 8 to pair ICs 50 Perform the calculation.

[0440] (1) The concentrations and inhibition rates corresponding to 10000 nM, 3333 nM, 1111 nM, 370 nM, 123 nM, 41 nM, 13.7 nM, 4.6 nM, 1.5 nM, and 0.5 nM were statistically analyzed. The Log10 value was used for statistical calculation.

[0441] (2) Input the data into GraphPad PRISM 8 and select Analysis.

[0442] (3) Select Nonlinear regression (curve fit)

[0443] (4) Select Log(inhibitor) vs. response — Variable slope.

[0444] (5) Select a calculation formula and calculate it according to the following formula.

[0445] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0446] X:log of dose or concentration

[0447] Y:Response,decreasing as X increases

[0448] Top and Bottom:Plateaus in same units as Y.

[0449] (6) Fit the data to obtain IC. 50 value.

[0450] (7) Adjust the fitting conditions according to the specific data. Adjust the bottom, top, and hill slope conditions appropriately to achieve the curve that best reflects the actual situation. See Table 2 below for the specific results.

[0451] Table 2. Growth-inhibiting activity of the disclosed compounds against SW48 cells.

[0452] Test Example 3: Pharmacokinetic determination of the disclosed compound in mice

[0453] Using mice as test animals, plasma samples were collected at specific time points after intravenous bolus injection and oral injection of the compound disclosed herein. The concentration of the compound in plasma was detected by LC-MS / MS, and the PK parameters were calculated to reflect the pharmacokinetic behavior of the compound disclosed herein in mouse plasma.

[0454] Test Plan

[0455] Test drugs: Some compounds disclosed herein.

[0456] experimental animals

[0457] Mice, balb / c nude, female, supplied by Zhejiang Vitonlihua Laboratory Animal Technology Co., Ltd.

[0458] Dosage

[0459] Dosage information: The IV (intravenous bolus) and PO (oral) experimental groups each consisted of 3 mice. The IV dose for mice was 1 mg / kg, and the administration volume was 5 mL / kg.

[0460] Control compound: The dosage of PO in mice was 100 mg / kg, the volume of administration was 10 mL / kg, and the solvent was 5 vol% DMSO / 10 vol% Solutol / 85 vol% Saline;

[0461] 2-P1: The PO dosage for mice was 100 mg / kg, the administration volume was 10 mL / kg, and the administration solvent was 0.5% (w / v) MC at pH 3.5.

[0462] Experimental equipment

[0463] The centrifuge and pipettes were purchased from Eppendorf.

[0464] Sample collection

[0465] After administration to mice, 0.025 mL of blood was collected intravenously at 0.0833 (IV), 0.25, 0.5, 1, 2, 4, 8 and 24 hours, placed in EDTA-K2 tubes, and separated into plasmas by centrifugation at 2000g for 10 min at 4℃. The plasmas were then stored at -80℃.

[0466] Sample processing

[0467] Mouse plasma sample processing:

[0468] a) Add 200 μL of acetonitrile to 15 μL of plasma sample, vortex mix and centrifuge for 15 minutes.

[0469] b) After treatment, the supernatant was diluted with water and the concentration of the analyte was analyzed by LC / MS / MS.

[0470] Experimental results

[0471] Pharmacokinetic parameters were calculated using WinNonlin 6.1 for intravenous and oral administration of the drug in Balb / c Nude mice, as shown in Table 7. Among them, C... max The maximum plasma concentration is represented by CL, the clearance rate is represented by Vss, and the steady-state volume of distribution is represented by T. 1 / 2 MRT represents the terminal elimination half-life. Inf represents the average residence time, and AUC represents the area under the curve during drug administration.

[0472] Table 3. Pharmacokinetic parameters of the disclosed compounds in mice. Note: " / " indicates that the measurement was not performed.

[0473] Results: As shown in Table 3, the compounds disclosed herein exhibit good pharmacokinetic properties in mice.

[0474] Test Example 4: Tolerance and Pharmacokinetic Determination of the Disclosed Compound in Mice After 7 Days of Repeated Dosing

[0475] Mice were used as test animals to study the changes in body weight of the compound of the present invention after oral administration for seven days, twice a day. Plasma samples were collected at specific time points after a single administration on the eighth day. The concentration of the compound in the plasma was detected by LC-MS / MS, and the pharmacokinetic parameters were calculated to reflect the tolerance of the compound of the present invention after repeated oral administration in mice and the pharmacokinetic behavior of the plasma.

[0476] Test Plan

[0477] Test drugs: Some compounds disclosed herein.

[0478] experimental animals

[0479] Mice, balb / c nude, female, provided by Shanghai Lingchang Biotechnology Co., Ltd.

[0480] Dosage

[0481] Balb / c Nude mice were administered the drug orally at a dose of 100 mg / kg, with a volume of 10 μL / g, using a solvent of 5 vol% DMSO / 10 vol% Solutol / 85 vol% Saline.

[0482] Experimental equipment

[0483] The centrifuge and pipettes were purchased from Eppendorf.

[0484] Weight measurement and plasma sample collection

[0485] Mouse body weight was tested and recorded daily. On day 8, after oral administration, 0.025 mL of blood was collected intravenously at 0.5, 2, 4, 8 and 24 hours, placed in EDTA-K2 tubes, and separated into plasma by centrifugation at 2000g for 10 min at 4℃. The plasma was then stored at -80℃.

[0486] Sample processing

[0487] Mouse plasma sample processing:

[0488] a) Add 200 μL of acetonitrile to 15 μL of plasma sample, vortex mix and centrifuge for 15 minutes.

[0489] b) After treatment, the supernatant was diluted with water and the concentration of the analyte was analyzed by LC / MS / MS.

[0490] Experimental results

[0491] Pharmacokinetic parameters were calculated using WinNonlin 6.1 for oral administration of the drug in Balb / c Nude mice and are shown in Table 4. Among them, C... max T represents the maximum blood drug concentration. 1 / 2 The terminator represents the terminal elimination half-life, and AUC represents the area under the curve during drug administration.

[0492] Table 4. Pharmacokinetic parameters and body weight change rates of some compounds disclosed herein in Balb / c Nude mice after oral administration. a Mean ± standard error;

[0493] Results: As shown in Table 4, the compounds disclosed herein exhibit good pharmacokinetic properties and tolerability in mice.

[0494] Test Example 5: In vivo efficacy study

[0495] Experimental Objective

[0496] The antitumor activity of the disclosed compound, administered orally for 17 consecutive days, in a subcutaneous xenograft colorectal cancer model of SW48 cells was evaluated.

[0497] Experimental materials

[0498] BALB / c nude mice, female, SPF grade, purchased from Shanghai Lingchang Biotechnology Co., Ltd.

[0499] SW48 cells, purchased from ATCC.

[0500] Compound information

[0501] Experimental steps

[0502] a. Cell culture

[0503] SW48 tumor cells (colorectal cancer, ATCC, Cat No. CCL231) were cultured in L-15 medium + 10% FBS + 1% P / S + 1% GlutaMax at 37°C in a CO2-free incubator and passaged for 3-4 days. When the cells were in the exponential growth phase and the cell density was 80%-90%, the cells were harvested, counted, and seeded.

[0504] b. Cell inoculation

[0505] 3 × 10⁻⁶ serum-free L-15 culture medium-resuspended SW48 tumor cells 6 +Matrigel (1:1) / 100μL was injected subcutaneously into the dorsal side of the right forelimb of 80 experimental animals, of which 36 animals were used for efficacy experiments. Tumors were allowed to grow to 150-200mm. 3 At approximately 10:00 AM, animals were randomly assigned to groups and administered the drugs. A total of 6 groups were formed, with 6 animals in each group. The specific administration regimens are shown in the table below.

[0506] c. Tumor grouping, drug administration, and measurement

[0507] 1. Groups and dosing regimens are shown in Table 5.

[0508] Table 5. Grouping and Dosing Regimens of Experimental Animals Note: a.Vehicle: 5% DMSO+10% Solutol+85% Saline

[0509] 2. After the animals were grouped, the administration was started. The administration volume was 10 μL / g based on the experimental animal's body weight, and the administration was done orally (po). The animals were weighed and administered the medication twice a day for 17 consecutive days. The tumor diameter was measured twice a week.

[0510] 3. Tumor volume (TV): Tumor volume was measured twice weekly to observe changes in tumor volume and growth rate. Tumor volume V = 1 / 2 × a × b², where a and b represent the long and short diameters of the tumor, respectively. The inhibitory effect of the compound on tumor tissue growth was evaluated using the tumor growth inhibition rate (TGI) (%). TGI (%) = [1 - (average tumor volume of a given treatment group - average tumor volume of the given treatment group on the day of grouping) / (average tumor volume of the negative control group - average tumor volume of the negative control group on the day of grouping)] × 100%. Data from the same day were used for both the treatment group and the negative control group.

[0511] 4. While measuring tumor volume, weigh the mice. Record the relationship between changes in mouse weight and administration time. Simultaneously observe the mice's survival and health status, such as activity and feeding during administration. If a single animal's weight decreases by more than 15%, discontinue administration. Resume administration when the weight recovers to within 10%. If administration is stopped for more than 48 hours and the animal is in good condition, administration can be resumed even if the weight has not recovered to within 10%. Provide nutritional support during the discontinuation period.

[0512] 5. After the experiment reached its endpoint, the mice were euthanized, and the animal carcasses were frozen in a freezer and transferred to a qualified medical waste disposal unit for treatment.

[0513] Experimental results

[0514] Table 6. Tumor volume and tumor inhibition rate in the SW48 model 17 days after drug administration. a, mean ± standard error;

[0515] Experimental conclusions

[0516] The disclosed compound exhibited good tumor-suppressive activity in the SW48 subcutaneous xenograft model of colorectal cancer. At a dose of 75 / 100 mpk, the tumor-suppressive effect was dose-dependent, while the control compound showed intolerance.

Claims

1. A compound of general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof; in: Ring A is selected from Ring A1 is absent or selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 14-membered heterocyclic groups; Cyclone A2 is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 14-membered heterocyclic groups; Ring B is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 14-membered heterocyclic groups; The ring C is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 14-membered heterocyclic groups; L is selected from the bond, -NR L -(CR d R e ) p -、-O-、-S(O) q -(CR d R e ) p -; L1 is selected from the key, -NR L -(CR d R e ) p -、-O-、-S(O) q -(CR d R e ) p -、-C(O)-、-C(O)NR n1 R n2 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 3- to 8-membered heterocyclic; L2 is selected from the bond, -NR L -、-O-、-S(O) q -(CR d R e ) p -、-(CR 1 R 2 ) u -、-C(O)-、-C(O)NR n1 R n2 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 3- to 8-membered heterocyclic; R L Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy group, deuterium atom, deuterated C 1-6 Alkyl and deuterated C 1-6 Alkoxy; R d R e They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, C atoms, etc. 1-6 Alkyl, C 1-6 Alkoxy, -NR n1 R n2 Halogen, cyano, hydroxyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy group, deuterium atom, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, -C(O)NR n1 R n2 -C(O)R s , 3 to 8-membered heterocyclic groups, 3 to 8-membered cycloalkyl groups, 3 to 8-membered cycloalkenyl groups, 6 to 10-membered aryl groups and 5 to 10-membered heteroaryl groups; Each R a1 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Alkoxy, OR o -NR n1 R n2 Halogen, cyano, oxo, hydroxyl, -SR s -SF5, -C(O)NR n1 R n2 -C(O)R s -S(O) q R s -S(O)2NR n1 R n2 C 2-6 alkenyl, C 2-6 Alkyne, deuterium, 3- to 8-membered heterocyclic group, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl; or two R on adjacent ring atoms. a1 The atoms bonded to it together form 3- to 8-membered heterocyclic groups, 3- to 8-membered cycloalkyl groups, 3- to 8-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups; wherein, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 The alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each independently chosen to be deuterated or deuterated C. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; Each R a2 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Alkoxy, -OR o -NR n1 R n2 Halogen, cyano group, oxo group, hydroxyl group, deuterium atom, -SR s -SF5, -C(O)NR n1 R n2 -C(O)R s -S(O) q R s -S(O)2NR n1 R n2 C 2-6 alkenyl, C 2-6 Alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl; or two R on adjacent ring atoms a2 The atoms bonded to it together form 3- to 8-membered heterocyclic groups, 3- to 8-membered cycloalkyl groups, 3- to 8-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups; wherein, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 The alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each independently chosen to be deuterated or deuterated C. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, OR o Halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; Or one of the R a1 And one of the R a2 The atoms bonded to it together form 3- to 12-membered heterocyclic groups, 3- to 12-membered cycloalkyl groups, 3- to 12-membered cycloalkenyl groups, 6- to 12-membered aryl groups, and 5- to 12-membered heteroaryl groups; wherein each of the 3- to 12-membered heterocyclic groups, 3- to 12-membered cycloalkyl groups, 3- to 12-membered cycloalkenyl groups, 6- to 12-membered aryl groups, and 5- to 12-membered heteroaryl groups is independently selected to be bonded by a deuterium atom or a deuterated C atom. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, OR o Halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; Each R b Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Alkoxy, OR o -NR n1 R n2 Halogen, cyano, hydroxyl, deuterium atom, -SR s -SF5, -C(O)NR n1 R n2 -C(O)R s -S(O) q R s -S(O)2NR n1 R n2 C 2-6 alkenyl, C 2-6 Alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl; or two R on adjacent ring atoms b The atoms bonded to it together form 3- to 8-membered heterocyclic groups, 3- to 8-membered cycloalkyl groups, 3- to 8-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups; wherein, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 The alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each independently chosen to be deuterated or deuterated C. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, OR o Halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; Or one of the R a2 And one of the R b The atoms bonded to it together form 5- to 14-membered cycloalkenyl groups and 5- to 14-membered heterocyclic groups; wherein, the 5- to 14-membered cycloalkenyl groups and 5- to 14-membered heterocyclic groups are each independently selected to be deuterated or deuterated by a C atom. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, OR s , cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; Each R c Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Alkoxy, OR o -NR n1 R n2 Halogen, cyano, hydroxyl, deuterium atom, -SR s -SF5, -C(O)NR n1 R n2 -C(O)R s -S(O) q R s -S(O)2NR n1 R n2 C 2-6 alkenyl, C 2-6 Alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl; or two R on adjacent ring atoms therein. c The atoms bonded to it together form 3- to 8-membered heterocyclic groups, 3- to 8-membered cycloalkyl groups, 3- to 8-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups; wherein, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 The alkynyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each independently selected from the deuterium atom, deuterated C, etc. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, OR o Halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; R 1 R 2 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Alkoxy, OR o -NR n1 R n2 Halogen, cyano, hydroxyl, deuterium atom, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, -SR s -C(O)NR n1 R n2 -C(O)R s C 2-6 alkenyl, C 2-6 Alkynyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are each independently selected from halogen, oxo, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; Or R on the same carbon atom 1 R 2 The atoms bonded to it together form 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, 5- to 14-membered spirocycloalkyl, and 5- to 14-membered spiroheterocyclic groups; wherein the 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, 5- to 14-membered spirocycloalkyl, and 5- to 14-membered spiroheterocyclic groups are each independently and optionally selected from deuterium atoms, deuterated C atoms, etc. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; Or R on adjacent carbon atoms 1 R 2 The atoms bonded to it together form 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, 5- to 14-membered spirocycloalkyl, and 5- to 14-membered spiroheterocyclic groups; wherein the 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, 5- to 14-membered spirocycloalkyl, and 5- to 14-membered spiroheterocyclic groups are each independently and optionally selected from deuterium atoms, deuterated C atoms, etc. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; Or R 1 and R c The atoms bonded to it together form a 3- to 12-membered cycloalkenyl group; wherein the 3- to 12-membered cycloalkenyl group is optionally selected from deuterium atoms, deuterated C atoms, etc. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; Or R 1 and R b The atoms bonded to it together form 5- to 12-membered heterocyclic groups and 5- to 12-membered heteroaryl groups; wherein the 5- to 12-membered heterocyclic groups and 5- to 14-membered heteroaryl groups are each independently and optionally selected from deuterium atoms and deuterated C atoms. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more of the following substituents: alkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; R n1 R n2 R n3 and R n4 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, deuterated C atoms, etc. 1-6 Alkyl, deuterated C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy; R s They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, C atoms, etc. 1-6 Alkyl, halogen, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; R o They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, deuterated C atoms, etc. 1-6 Alkyl, deuterated C 1-6 Alkoxy, C 1-6 Alkyl, halogen, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; n can be 0, 1, 2, 3, or 4; m1 can be 0, 1, 2, 3 or 4; m2 can be 0, 1, 2, 3 or 4; t can be 0, 1, 2, 3, or 4; p is 0, 1, 2 or 3; q is 0, 1, or 2; and u can be 0, 1, 2 or 3.

2. The compound, its stereoisomer, or its pharmaceutically usable salt according to claim 1, wherein it is a compound, its stereoisomer, or its pharmaceutically usable salt represented by general formula (I-1c) or general formula (I-1d); in: The ring C is selected from 5- to 6-membered heteroaryl groups; Ring D is selected from 3- to 8-membered heterocyclic groups; preferably, ring D is selected from 6-membered heterocyclic groups; Each R d Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl groups, halogens; Each R c Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, Halogenated C 1-6 Alkyl; preferably, R c Selected from halogenated C 1-6 alkyl; m is selected from 0, 1, or 2; and n is selected from 0, 1, or 2.

3. The compound, its stereoisomer, or its pharmaceutically usable salt according to claim 1 or 2, wherein the compound is represented by general formula (I-1e) or general formula (I-1f), its stereoisomer, or its pharmaceutically usable salt; in: Ring D is selected from 3- to 8-membered heterocyclic groups; preferably, ring D is selected from 6-membered heterocyclic groups; Each R d Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl groups, halogens; R c Selected from hydrogen atoms, C 1-6 Alkyl, Halogenated C 1-6 Alkyl; preferably, R c Selected from halogenated C 1-6 Alkyl; more preferably, R c Selected from difluoromethyl or trifluoromethyl; and m is selected from 0, 1, or 2.

4. The compound, its stereoisomer, or its pharmaceutically usable salt according to any one of claims 1 to 3, wherein the compound is represented by general formula (I-1g), general formula (I-1h), its stereoisomer, or its pharmaceutically usable salt; in: Z is selected from O, S, and -NR. a2 -CH-R a2 Preferably, Z is selected from O, S, -CH-R a2 ; The ring C is selected from 5- to 6-membered heteroaryl groups; Each R d Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl groups, halogens; Each R c Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, Halogenated C 1-6 Alkyl; preferably, R c Selected from halogenated C 1-6 alkyl; Each R a2 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy; m is selected from 0, 1, or 2; and n is selected from 0, 1, or 2.

5. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 1 to 4, wherein the compound is represented by general formula (I-1i) or general formula (I-1j), its stereoisomer, or its pharmaceutically acceptable salt; in: Z is selected from O, S, and -NR. a2 -CH-R a2 Preferably, Z is selected from O, S, -CH-R a2 ; Each R d The same or different, and each independently selected from C 1-6 Alkyl groups, halogens; R c Selected from hydrogen atoms, C 1-6 Alkyl, Halogenated C 1-6 Alkyl; preferably, R c Selected from halogenated C 1-6 alkyl; Each R a2 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy groups; and m is selected from 0, 1, or 2.

6. The compound according to claim 1, its stereoisomers, or its pharmaceutically acceptable salts, wherein, Ring A1 is selected from phenyl, 5 to 6-membered heteroaryl; and / or ring A2 is selected from phenyl, 5 to 6-membered heteroaryl; preferably, ring A1 is selected from 5-membered heteroaryl and ring A2 is selected from phenyl.

7. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to claim 1 or 6, wherein, Ring A1 is selected from 6-membered heteroaryl containing 1 to 3 N atoms or 5-membered heteroaryl; ring A2 is selected from 5-membered heteroaryl; preferably, ring A1 is selected from pyridyl and ring A2 is selected from 5-membered heteroaryl.

8. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1, 6, or 7, wherein, Selected from 9. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 1, 6 to 8, wherein, Each R a1 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl, halogen, amino, (C 1-6 alkyl) cyano, -NH(C 1-6 Alkyl); preferably, each R a1 They may be the same or different, and each is independently selected from hydrogen atom, methyl, methoxy, cyclopropyl, fluorine, -NH-CH3, -CH2CN, -NH2.

10. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1, 6 to 9, wherein, Each R a2 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkyl, cyano, 3- to 6-membered cycloalkyl, -O- (3- to 6-membered cycloalkyl), C 2-6 Alkyne group, -SF5; preferably, each R a2 They may be the same or different, and each is independently selected from hydrogen atoms, methyl groups, methoxy groups, -O-CHF2, -CN、 -SF5, -CF3, -O-CF3.

11. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 1, 6 to 10, wherein, Two R on adjacent ring atoms a2 The atoms bonded to it together form 3- to 6-membered heterocyclic groups and 3- to 6-membered cycloalkenyl groups; preferably, the two R atoms on adjacent ring atoms a2 The atoms connected to it form together 12. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 1, 6 to 11, wherein, One of the R a1 And one of the R a2 The atoms bonded to it together form an optional C 1-6 Alkyl or halogen-substituted 3- to 8-membered heterocyclic groups; preferably, one of the R groups is... a1 And one of the R a2 The atoms connected to it form together 13. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 1, 6 to 12, wherein, Selected from 14. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 1, 6 to 13, wherein, Ring B is selected from 5- to 6-membered heteroaryl groups and 6- to 10-membered heterocyclic groups; preferably, ring B is selected from... * indicates that it is connected to the L1 terminal.

15. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to any one of claims 1, 6 to 14, wherein each R b They may be the same or different, and each is independently selected from hydrogen atoms, -NR n1 R n2 , halogen, hydroxyl, -C(O)NR n1 R n2 Optional -NR n3 R n4 Replacement C 1-6 Alkyl, wherein R n1 R n2 R n3 R n4 They may be the same or different, and each is independently selected from hydrogen atoms and C atoms. 1-6 Alkyl group, or two R atoms on adjacent ring atoms b The atoms bonded to it together form 5 to 6-membered heteroaryl groups; Preferably, each R b They may be the same or different, and each is independently selected from hydrogen atoms, amino groups, hydroxyl groups, fluorine, -C(O)NH2, -CH2NH2, -NHCH3, -NHCH2CH3, or two R atoms on adjacent ring atoms. b The atoms connected to it form together 16. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 1, 6 to 15, wherein... Selected from * indicates that it is connected to the L1 terminal.

17. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 1, 6 to 16, wherein L1 is selected from -NH- and -O-.

18. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1, 6 to 17, wherein L2 is selected from the group consisting of a bond, -(CR) bond, or a tert-resin bond. 1 R 2 ) u -、-NR L -, -O-, 5 to 6 membered cycloalkyl groups; wherein R 1 R 2 The same or different, and each independently selected from hydrogen atoms, C atoms optionally substituted with 3 to 6-membered cycloalkyl groups, cyano groups, and hydroxyl groups. 1-6 Alkyl, C 2-6 Alkyne, hydroxyl, cyano, optional C 1-6 Alkyl, hydroxyl-substituted 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered heterocyclic, 5- to 8-membered bridged cycloalkyl, 5- to 8-membered spirocycloalkyl; R L Selected from hydrogen atoms and C 1-6 Alkyl; u is 1, 2 or 3; or L2 is selected from the bond, -(CR 1 R 2 ) u -、-NR L -, -O-, 5 to 6 membered cycloalkyl; wherein R on the same carbon atom 1 R 2 The carbon atoms attached to it together form 3- to 8-membered monocyclic cycloalkyl groups, 5- to 8-membered spirocyclic alkyl groups, and 3- to 8-membered heterocyclic groups; R L Selected from hydrogen atoms and C 1-6 Alkyl; u is 1, 2 or 3; or L2 is selected from the bond, -(CR 1 R 2 ) u -、-NR L -, -O-, 5 to 6 membered cycloalkyl; wherein the R on adjacent carbon atoms 1 R 2 The atoms bonded to it together form an optional C 1-6 Alkyl-substituted 3- to 6-membered monocyclic cycloalkyl groups, 5- to 8-membered spirocyclic alkyl groups; R L Selected from hydrogen atoms and C 1-6 Alkyl; u is 1, 2 or 3.

19. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 1, 6 to 18, wherein L2 is selected from bonds, -O-、 * indicates that it is connected to ring C.

20. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1, 6 to 19, wherein L1-L2 are selected from... -NH-、 * indicates that it is connected to ring C.

21. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to any one of claims 1, 6 to 20, wherein the ring C is selected from 5- to 6-membered heteroaryl groups; preferably, the ring C is selected from...

22. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 1, 6 to 21, wherein R c Selected from hydrogen atoms, optionally substituted with -NR n3 R n4 Replacement C 1-6 Alkyl, Halogenated C 1-6 Alkyl; wherein R n3 R n4 They may be the same or different, and each is independently selected from hydrogen atoms and C atoms. 1-6 Alkyl; or two R atoms on adjacent ring atoms therein c The atoms bonded to it together form 3 to 8-membered heterocyclic groups that can be optionally substituted with halogens; Preferably, R c Selected from hydrogen atoms, Trifluoromethyl; or two R atoms on adjacent ring atoms c The atoms connected to it form together 23. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 1, 6 to 22, wherein... Selected from 24. The compound, its stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1, 6 to 23, wherein it is a compound, its stereoisomer or pharmaceutically acceptable salt thereof represented by general formula (I-3a) or general formula (I-3b); in: Ring A1 is selected from 5-membered heteroaryl or pyridyl; preferably, ring A1 is selected from pyridyl. Y is selected from O, S, -NR a2 Preferably, Y is selected from S; The ring C is selected from 5- to 6-membered heteroaryl groups; Each R a1 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl, halogen, amino, (C 1-6 alkyl) cyano, -NH(C 1-6 Alkyl); preferably, each R a1 They may be the same or different, and each is independently selected from hydrogen atom, methyl, methoxy, cyclopropyl, fluorine, -NH-CH3, -CH2CN, -NH2; Each R c Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, Halogenated C 1-6 Alkyl; preferably, R c Selected from halogenated C 1-6 alkyl; R a2 Selected from hydrogen atoms, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy; m1 is selected from 0, 1, or 2; and n is selected from 0, 1, or 2.

25. The compound, its stereoisomer or pharmaceutically acceptable salt thereof, according to any one of claims 1, 6 to 24, wherein the compound is represented by general formula (I-3d) or general formula (I-3e), its stereoisomer or pharmaceutically acceptable salt thereof; in: Ring A1 is selected from 5-membered heteroaryl or pyridyl; preferably, ring A1 is selected from pyridyl. Y is selected from O, S, -NR a2 Preferably, Y is selected from S; Each R a1 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl, halogen, amino, (C 1-6 alkyl) cyano, -NH(C 1-6 Alkyl); preferably, each R a1 They may be the same or different, and each is independently selected from hydrogen atom, methyl, methoxy, cyclopropyl, fluorine, -NH-CH3, -CH2CN, -NH2; R c Selected from hydrogen atoms, C 1-6 Alkyl, Halogenated C 1-6 Alkyl; preferably, R c Selected from halogenated C 1-6 Alkyl; more preferably, R c Selected from difluoromethyl or trifluoromethyl; R a2 Selected from hydrogen atoms, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy groups; and m1 is selected from 0, 1, or 2.

26. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 1 to 25, wherein, The compounds mentioned are selected from:

27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 26, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

28. Use of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 26, or the pharmaceutical composition according to claim 27, in the preparation of a medicament for inhibiting MASTL.

29. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 26, or the pharmaceutical composition according to claim 27, in the preparation of a medicament for treating and / or preventing MASTL-mediated diseases.

30. Use of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 26, or the pharmaceutical composition according to claim 27, in the preparation of a medicament for treating and / or preventing cancer.

31. The use according to claim 30, wherein the cancer is selected from breast cancer, colorectal cancer, head and neck cancer, non-small cell lung cancer, gastric cancer, pancreatic cancer, prostate cancer, and thyroid cancer.

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