Polycyclic compound, preparation method therefor and pharmaceutical use thereof

Abstract

A polycyclic compound, a preparation method therefor and the pharmaceutical use thereof. Specifically provided are a polycyclic compound as represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and the use thereof as a therapeutic agent, particularly the use as a RAS inhibitor and the use in the preparation of a drug for treating and / or preventing RAS-mediated or -dependent diseases or conditions, wherein each group in general formula (I) is as defined in the description.

Description

A polycyclic compound, its preparation method and its pharmaceutical application Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a polycyclic compound of general formula (I), a method for its preparation, a pharmaceutical composition containing the polycyclic compound, and its use as a therapeutic agent, particularly as a RAS inhibitor, and in the preparation of medicaments for the treatment and / or prevention of diseases or conditions mediated or dependent on RAS mutant proteins. Background Technology

[0002] RAS (Rapid Adenosine Reproductive Genes) are among the most common oncogenes in tumors, accounting for approximately 30% of tumors, and include KRAS, HRAS, and NRAS. The most frequently mutated sites in RAS are codons 12, 13, and 61, with codon 12 mutations being the most common. Under normal conditions, RAS proteins switch between a GDP-binding inactive state and a GTP-binding activated state. Mutations in RAS disrupt the activity of GTPase-activating proteins (GAPs)-dependent or endogenous GTP hydrolases, thus keeping the RAS protein in a persistently GTP-binding activated state. This continuously activates downstream signaling pathways such as MAPK and PI3K, promoting tumor development and progression.

[0003] Because the RAS protein lacks traditional small molecule binding sites and has a pM affinity for GTP, making it extremely difficult to inhibit with compounds, RAS has long been considered an untreatable drug target. Although KRAS G12C inhibitors are already on the market, drugs that directly target the GTP-bound activated state of RAS have not yet been approved. Therefore, there is still a need to develop such inhibitors for the treatment of RAS-mutant tumors. Summary of the Invention

[0004] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof.

[0005] in:

[0006] R D The alkynyl group is optionally selected from halogens, alkoxy groups optionally substituted with one or more R*, haloalkoxy groups, cyano groups, and -NR groups. 9a R 9bThe hydroxyl group, a cycloalkyl group optionally substituted with one or more R*, a heterocyclic group optionally substituted with one or more R*, an aryl group optionally substituted with one or more R*, a heteroaryl group optionally substituted with one or more R*, a cycloalkylalkyl group optionally substituted with one or more R*, a heterocyclic alkyl group optionally substituted with one or more R*, an arylalkyl group optionally substituted with one or more R*, and a heteroarylalkyl group optionally substituted with one or more R* are substituted with one or more substituents.

[0007] Y is selected from hydrogen atom, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7a R 7b -NR 7a OR 7b -ONR 7a R 7b -NR 7c NR 7a R 7b hydroxyl group, -C(O)R 8 -C(O)OR 8 -C(O)NR 7a R 7b -S(O) w R 8 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 9a R 9b The substance is substituted by one or more substituents selected from hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0008] Z and R R The same or different, and each independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted by one or more R*;

[0009] G 1 G 2 Whether the CR is the same as or different from G, and each is independent of the other. 6 N=O, NR N Or N;

[0010] Ring A is a heterocyclic group;

[0011] The ring carbons may be the same or different, and each is independently selected from cycloalkyl, heterocyclic, aryl or heteroaryl groups;

[0012] R A RB R C R N and R 6 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7a R 7b -NR 7a OR 7b -ONR 7a R 7b -NR 7c NR 7a R 7b hydroxyl group, -C(O)R 8 -C(O)OR 8 -C(O)NR 7a R 7b -S(O) w R 8 , Oxide group, =S, =NOR 61 =CR 62 R 63 =NR 64 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 9a R 9b The substance is substituted by one or more substituents selected from hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; or

[0013] Two Rs A Together with the attached atoms, it forms a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. AA replace;

[0014] R 2 Selected from O, NH and N-alkyl;

[0015] L 2 The alkylene group is optionally alkylene oxide (R0) or alkylene oxide (R0) by one or more R0. L2 replace;

[0016] R L2 Same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, oxo, =S, =NOR 61 =CR 62 R 63 =NR64 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted with one or more R* groups; or

[0017] Two Rs L2 Together with the attached atoms, it forms a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. LL2 replace;

[0018] L 1 Selected from cycloalkyl, heterocyclic and -CH(cycloQ)-, wherein each of the cycloQ, cycloalkyl and heterocyclic groups is independently optionally converted by one or more R L1 replace;

[0019] Ring Q is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0020] L is R 10 or

[0021] R 11 and R 12 The same or different, and each independently selected from hydrogen atoms, halogens, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally separated by one or more R E replace;

[0022] L 3 For key or -N(R) L3 )C(O)-;

[0023] L 4 For bonds or -(alkylene) y -N(R L4 )C(=O)-;

[0024] R 10 Selected from alkyl, cycloalkyl, heterocyclic and NR 101 R 102 The alkyl, cycloalkyl, and heterocyclic groups are each independently and optionally influenced by one or more R groups. F replace;

[0025] Each R F They may be the same or different, and each is independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7a R 7b hydroxyl group, oxo group, =S, =NOR 61 =CR62 R 63 =NR 64 cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R F1 -C(O)OR F1 -C(O)NR F2 R F3 -S(O) w R F1 and -S(O) w OR F1 The alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally converted by one or more R groups. FF replace;

[0026] R 7a R 7b R 7c R 9a R 9b R L3 R L4 R 101 R 102 R F2 and R F3 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, heteroalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocyclic groups, wherein each of the alkyl, heteroalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocyclic groups is independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl and haloalkoxy;

[0027] Or R 7a and R 7b Together with the attached nitrogen atom, it forms a heterocyclic group, or R 9a and R 9b Together with the attached nitrogen atom, it forms a heterocyclic group, or R 101 and R 102 Together with the attached nitrogen atom, it forms a heterocyclic group, or R F2 and R F3 Together with the attached nitrogen atom, a heterocyclic group is formed, wherein the heterocyclic group is optionally selected from halogens, oxo groups, =S, =NR. 64 It is substituted by one or more substituents selected from alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0028] R 8 R F1 R 61 R 62 R 63 and R 64The same or different, and each independently selected from hydrogen atoms, halogens, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl, and heterocyclic groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups are each independently optionally selected by one or more R atoms. # Replace; or

[0029] R 62 R 63 Together with the attached atoms, they form cycloalkyl or heterocyclic groups, each of which is optionally independently bound by one or more R groups. FF replace;

[0030] Each R*, R AA R LL2 R L1 R E R FF and R # The same or different, and each independently selected from oxo, =S, =N-alkyl, =NH, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkylthio, amino, -NHalkyl, -N(alkyl)2, -alkylene-amino, -alkylene-NHalkyl, -alkylene-N(alkyl)2, amide, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclic oxy, aryloxy, and heteroaryloxy, wherein the =N-alkyl, alkyl, alkenyl, alkoxy, alkoxyalkyl, alkoxyalkyl, alkylthio, -NHalkyl, -N(alkyl)2, -alkylene-amino, -alkylene-NHalkyl, -alkylene The alkyl-N(alkyl)2, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclicalkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclicoxy, aryloxy and heteroaryloxy are each independently and optionally substituted by one or more substituents selected from oxo, =S, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkylthio, amino, -NHalkyl, -N(alkyl)2, -alkylene-amino, -alkylene-NHalkyl, -alkylene-N(alkyl)2, amide, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclicalkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclicoxy, aryloxy and heteroaryloxy;

[0031] w is 0, 1, or 2;

[0032] n is 0, 1, 2, 3, 4, 5, or 6;

[0033] p is 0, 1, 2, 3, 4, 5 or 6;

[0034] q is 0, 1, 2, or 3; and

[0035] y can be 0, 1, 2, 3, 4, 5 or 6.

[0036] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof.

[0037] in:

[0038] R D The alkynyl group is optionally selected from halogens, alkoxy groups optionally substituted with one or more R*, haloalkoxy groups, cyano groups, and -NR groups. 9a R 9b The hydroxyl group, a cycloalkyl group optionally substituted with one or more R*, a heterocyclic group optionally substituted with one or more R*, an aryl group optionally substituted with one or more R*, a heteroaryl group optionally substituted with one or more R*, a cycloalkylalkyl group optionally substituted with one or more R*, a heterocyclic alkyl group optionally substituted with one or more R*, an arylalkyl group optionally substituted with one or more R*, and a heteroarylalkyl group optionally substituted with one or more R* are substituted with one or more substituents.

[0039] Y is selected from hydrogen atom, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7a R 7b -NR 7a OR 7b -ONR 7a R 7b -NR 7c NR 7a R 7b hydroxyl group, -C(O)R 8 -C(O)OR 8 -C(O)NR 7a R 7b -S(O) w R 8 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 9a R 9b The substance is substituted by one or more substituents selected from hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0040] Z and R RThey may be the same or different, and each is independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted by one or more R*;

[0041] G 1 G 2 Whether the CR is the same as or different from G, and each is independent of the other. 6 N = O or N;

[0042] Ring A is a heterocyclic group;

[0043] The ring carbons may be the same or different, and each is independently selected from cycloalkyl, heterocyclic, aryl or heteroaryl groups;

[0044] R A R B R C and R 6 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7a R 7b -NR 7a OR 7b -ONR 7a R 7b -NR 7c NR 7a R 7b hydroxyl group, -C(O)R 8 -C(O)OR 8 -C(O)NR 7a R 7b -S(O) w R 8 , Oxide group, =S, =NOR 61 =CR 62 R 63 =NR 64 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 9a R 9b The substance is substituted by one or more substituents selected from hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; or

[0045] Two Rs A Together with the attached atoms, it forms a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. AA Replace; R2 Selected from O, NH and N-alkyl;

[0046] L 2 The alkylene group is optionally alkylene oxide (R0) or alkylene oxide (R0) by one or more R0. L2 replace;

[0047] R L2 Same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, oxo, =S, =NOR 61 =CR 62 R 63 =NR 64 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted with one or more R* groups; or

[0048] Two Rs L2 Together with the attached atoms, it forms a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. LL2 replace;

[0049] L 1 It is a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally surrounded by one or more R L1 replace;

[0050] L is R 10 or

[0051] R 11 and R 12 The same or different, and each independently selected from hydrogen atoms, halogens, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally separated by one or more R E replace;

[0052] L 3 For key or -N(R) L3 )C(O)-;

[0053] L 4 For bonds or -(alkylene) y -N(R L4 )C(=O)-;

[0054] R 10 Selected from alkyl, cycloalkyl, heterocyclic and NR 101 R 102The alkyl, cycloalkyl, and heterocyclic groups are each independently and optionally influenced by one or more R groups. F replace;

[0055] Each R F They may be the same or different, and each is independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7a R 7b hydroxyl group, oxo group, =S, =NOR 61 =CR 62 R 63 =NR 64 cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R F1 -C(O)OR F1 -C(O)NR F2 R F3 -S(O) w R F1 and -S(O) w OR F1 The alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally converted by one or more R groups. FF replace;

[0056] R 7a R 7b R 7c R 9a R 9b R L3 R L4 R 101 R 102 R F2 and R F3 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, heteroalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocyclic groups, wherein each of the alkyl, heteroalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocyclic groups is independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl and haloalkoxy;

[0057] Or R 7a and R 7b Together with the attached nitrogen atom, it forms a heterocyclic group, or R 9a and R 9b Together with the attached nitrogen atom, it forms a heterocyclic group, or R 101 and R 102 Together with the attached nitrogen atom, it forms a heterocyclic group, or R F2 and R F3 Together with the attached nitrogen atom, a heterocyclic group is formed, wherein the heterocyclic group is optionally selected from halogens, oxo groups, =S, =NR.64 It is substituted by one or more substituents selected from alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0058] R 8 R F1 R 61 R 62 R 63 and R 64 The same or different, and each independently selected from hydrogen atoms, halogens, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl, and heterocyclic groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups are each independently optionally selected by one or more R atoms. # Replace; or

[0059] R 62 R 63 Together with the attached atoms, they form cycloalkyl or heterocyclic groups, each of which is optionally independently bound by one or more R groups. FF replace;

[0060] Each R*, R AA R LL2 R L1 R E R FF and R #The same or different, and each independently selected from oxo, =S, =N-alkyl, =NH, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkylthio, amino, -NHalkyl, -N(alkyl)2, -alkylene-amino, -alkylene-NHalkyl, -alkylene-N(alkyl)2, amide, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclic oxy, aryloxy, and heteroaryloxy, wherein the =N-alkyl, alkyl, alkenyl, alkoxy, alkoxyalkyl, alkoxyalkyl, alkylthio, -NHalkyl, -N(alkyl)2, -alkylene-amino, -alkylene-NHalkyl, -alkylene The alkyl-N(alkyl)2, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclicalkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclicoxy, aryloxy and heteroaryloxy are each independently and optionally substituted by one or more substituents selected from oxo, =S, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkylthio, amino, -NHalkyl, -N(alkyl)2, -alkylene-amino, -alkylene-NHalkyl, -alkylene-N(alkyl)2, amide, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclicalkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclicoxy, aryloxy and heteroaryloxy;

[0061] w is 0, 1, or 2;

[0062] n is 0, 1, 2, 3, 4, 5, or 6;

[0063] p is 0, 1, 2, 3, 4, 5 or 6;

[0064] q is 0, 1, 2, or 3; and

[0065] y can be 0, 1, 2, 3, 4, 5 or 6.

[0066] In some embodiments disclosed herein, R 2 It is O.

[0067] In some embodiments disclosed herein, R R It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R R It is a hydrogen atom.

[0068] In some embodiments of this disclosure, ring A is a 5- to 8-membered heterocyclic group; in some embodiments, ring A is a 6-membered heterocyclic group.

[0069] In some embodiments disclosed herein, L 1It is a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclic group; in some embodiments, L 1 It is a 3- to 6-membered cycloalkyl group; in some embodiments, L 1 It is cyclopropyl; in some embodiments, L 1 for In some implementations, L 1 Selected from 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic, -CH(cyclic Q)-, wherein the cyclic Q, 3- to 8-membered cycloalkyl, or 3- to 8-membered heterocyclic is optionally surrounded by one or more R L1 Substitution, where ring Q is a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group, wherein R L1 As defined in general formula I; in some implementations, L 1 It is a 3- to 8-membered cycloalkyl group or -CH (3- to 8-membered heterocyclic group)-, wherein the 3- to 8-membered cycloalkyl group or 3- to 8-membered heterocyclic group is optionally converted by one or more halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups or cyano groups are substituted; in some embodiments, L 1 The 3- to 8-membered heterocyclic group is optionally surrounded by one or more halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups or cyano groups are substituted; in some embodiments, L 1 For optional use with one or more halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and cyano groups substituted In some implementations, L 1 for

[0070] In some embodiments of this disclosure, ring Q is a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group; in some embodiments, ring Q is a 3- to 8-membered heterocyclic group; in some embodiments, ring Q is a 5- to 8-membered heterocyclic group; in some embodiments, ring Q is...

[0071] In some embodiments disclosed herein, R L1 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano; in some embodiments, R L1 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups.

[0072] In some embodiments of this disclosure, q1 is 0, 1, or 2; in some embodiments, q1 is 0; and in some embodiments, q1 is 1.

[0073] In some embodiments disclosed herein, R D -C≡CR 2D R 2D The alkyl group is selected from cycloalkyl, heterocycloalkyl, arylalkyl, and heteroarylalkyl groups, each of which is optionally independently substituted by one or more R*, where R* is as defined in general formula (I); in some embodiments, R... D The group is selected from -C≡C-CH2-3 to 12-membered cycloalkyl, -C≡C-CH2-3 to 12-membered heterocyclic, -C≡C-CH2-6 to 10-membered aryl, and -C≡C-CH2-6 to 10-membered heteroaryl, wherein each of the 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclic, 6 to 10-membered aryl, and 6 to 10-membered heteroaryl groups is independently optionally substituted by one or more R*, where R* is as defined in general formula (I); in some embodiments, R D The heterocyclic group is -C≡C-CH2-3 to 12-membered, wherein the 3 to 12-membered heterocyclic group is optionally selected from oxo groups, halogens, C 1-6 Alkyl, C 1-6 The substituted group is one or more of a haloalkyl, cyano, or 3- to 6-membered cycloalkyl group; in some embodiments, R D The heterocyclic group is -C≡C-CH2-3 to 12-membered, wherein the 3 to 12-membered heterocyclic group is optionally selected from halogens, C 1-6 Alkyl, C 1-6 The substituted group is one or more of a haloalkyl, cyano, or 3- to 6-membered cycloalkyl group; in some embodiments, R D The heterocyclic group is -C≡C-CH2-3 to 8-membered, wherein the 3 to 8-membered heterocyclic group is optionally selected from halogens, C 1-6 Alkyl, C 1-6 It is substituted with one or more of the haloalkyl and cyclopropyl groups.

[0074] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or (II-Q) or a pharmaceutically acceptable salt thereof.

[0075] in:

[0076] q1 can be 0, 1, 2, 3, 4, 5, or 6;

[0077] The dashed line indicates whether the ring is aromatic or non-aromatic.

[0078] R 2D Selected from cycloalkylalkyl, heterocycloalkyl, arylalkyl, and heteroarylalkyl, wherein the cycloalkylalkyl, heterocycloalkyl, arylalkyl, and heteroarylalkyl are optionally substituted with one or more R*;

[0079] Ring Q, R L1 R * R B , q, G 1 G 2 G, Y, Z, L 2 R A , n, ring C, R C p and L are as defined in general formula (I).

[0080] In some embodiments of this disclosure, ring C is selected from phenyl, 5- or 6-membered heterocyclic groups, and 5- or 6-membered heteroaryl groups; in some embodiments, ring C is phenyl or 5- or 6-membered heteroaryl; in some embodiments, ring C is a 6-membered heterocyclic group; in some embodiments, ring C is morpholino; in some embodiments, ring C is thiazolyl or morpholino; in some embodiments, ring C is... In some implementations, ring C is In some embodiments, ring C is a 5-membered heteroaryl group; in some embodiments, ring C is phenyl or thiazolyl; in some embodiments, ring C is thiazolyl, thiophene, furanyl, oxazolyl, pyrazolyl, and imidazolyl; in some embodiments, ring C is thiazolyl; in some embodiments, ring C is... In some implementations, ring C is In some implementations, ring C is *The end is connected to a phenyl group. Terminal with cyclopropyl or L 1 Connected.

[0081] In some embodiments disclosed herein, L 2 C 1-6 Alkylene; in some embodiments, L 2 For optional C 1-6 Alkyl-substituted propylene; in some embodiments, L 2 It is CH2C(CH3)2CH2.

[0082] In some embodiments disclosed herein, L 2 C 1-6 Alkylene, the C 1-6 Alkylenes are optionally subjected to one or more R L2 Replace, two R L2 Together with the attached atoms, it forms a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group; in some embodiments, L 2 For being two R L2 Substituted propylidene, two R L2 Together with the attached atoms, it forms a 3- to 6-membered cycloalkyl group; in some embodiments, L 2 For being two R L2Substituted propylidene, two R L2 Together with the attached atom, it forms a cyclopropyl group; in some embodiments, L 2 for In some implementations, L 2 for In some implementations, L 2 for End and R 2 (In general formula I) or O (in general formula II) are connected, and the * end is connected to the pyrrole ring.

[0083] In some embodiments disclosed herein, G 1 For CR 6 or NR N 、N,R N R 6 As defined in general formula (I); in some implementations, G 1 For CR 6 Or N, R 6 As defined in general formula (I); in some implementations, G 1 For CR 6 Or N, R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, G 1 For N; in some implementations, G 1 For N, NH or NC 1-6 Alkyl; in some embodiments, G 1 It is N, NH or N-methyl; in some embodiments, G 1 It can be N or NH.

[0084] In some embodiments of this disclosure, G is CR 6 C(O) or N, R 6 As defined in general formula (I); in some implementations, G is CR 6 Or N, R 6 As defined in general formula (I); in some implementations, G is CR 6 Or N, R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, G is CR 6 R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, G is CH; in some embodiments, G is C-OH or C(O).

[0085] In some embodiments disclosed herein, R 6 It is a hydrogen atom, a hydroxyl group, or an oxo group; in some embodiments, R 6 It is either hydroxyl or oxidized.

[0086] In some embodiments disclosed herein, G 2 For CR 6 Or N, R 6 As defined in general formula (I); in some implementations, G 2 For CR 6 Or N, R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, G 2 For CR 6 R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, G 2 For CH.

[0087] In some implementation schemes disclosed herein, for R N As defined in general formula I; in some implementations, for In some implementation schemes, for In some implementation schemes, for R N It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, for R N It is a hydrogen atom or a methyl group; in some embodiments, it is... R N It is a methyl group; the * end is attached to Y.

[0088] In some embodiments disclosed herein, R N Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy; in some embodiments, R N It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R N It is a hydrogen atom or a methyl group; in some embodiments, R N It is a hydrogen atom.

[0089] In some embodiments disclosed herein, R 2DThe alkyl group is selected from cycloalkyl, heterocycloalkyl, arylalkyl, and heteroarylalkyl groups, each of which is optionally independently substituted by one or more R*, where R* is as defined in general formula (I); in some embodiments, R... 2D The group is selected from -CH2-3 to 12-membered cycloalkyl, -CH2-3 to 12-membered heterocyclic, -CH2-6 to 10-membered aryl, and -CH2-6 to 10-membered heteroaryl, wherein each of the 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclic, 6 to 10-membered aryl, and 6 to 10-membered heteroaryl groups is independently optionally substituted by one or more R*, where R* is as defined in general formula (I); in some embodiments, R 2D The heterocyclic group is -CH2-3 to 12-membered, wherein the 3 to 12-membered heterocyclic group is optionally selected from oxo groups, halogens, C... 1-6 Alkyl, C 1-6 The substituted group is one or more of a haloalkyl, cyano, or 3- to 6-membered cycloalkyl group; in some embodiments, R 2D The heterocyclic group is a -CH2-3 to 12-membered heterocyclic group, wherein the 3 to 12-membered heterocyclic group is optionally selected from halogens, C 1-6 Alkyl, C 1-6 The substituted group is one or more of a haloalkyl, cyano, or 3- to 6-membered cycloalkyl group; in some embodiments, R 2D The heterocyclic group is a -CH2-3 to 8-membered heterocyclic group, wherein the 3 to 8-membered heterocyclic group is optionally selected from halogens, C 1-6 Alkyl, C 1-6 The alkyl group or cyclopropyl group is substituted; in some embodiments, R 2D for In some implementation schemes, R 2D for In some implementation schemes, R 2D for

[0090] In some embodiments disclosed herein, R 2D for M represents S(O) 0-2 Carbon atoms, nitrogen atoms, or oxygen atoms;

[0091] d1 is 0, 1, 2, 3 or 4;

[0092] d2 is 0, 1, 2, 3, or 4;

[0093] d4 can be 0, 1, 2, 3, 4, 5, or 6;

[0094] R d3 It can be a hydrogen atom or R*; or two Rs. d3Together with the attached atom, it forms a cycloalkyl or heterocyclic group;

[0095] R* is defined in general formula (I).

[0096] In some embodiments disclosed herein, R 2D for M is a carbon atom, a nitrogen atom, or an oxygen atom;

[0097] d1 is 0, 1, 2, 3 or 4;

[0098] d2 is 0, 1, 2, 3, or 4;

[0099] d4 can be 0, 1, 2, 3, 4, 5, or 6;

[0100] R d3 It can be a hydrogen atom or R*; or two Rs. d3 Together with the attached atom, it forms a cycloalkyl or heterocyclic group;

[0101] R* is defined in general formula (I).

[0102] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III), (III') or (III-Q) or a pharmaceutically acceptable salt thereof.

[0103] in:

[0104] M represents S(O) 0-2 Carbon atoms, nitrogen atoms, or oxygen atoms;

[0105] d1 is 0, 1, 2, 3 or 4;

[0106] d2 is 0, 1, 2, 3, or 4;

[0107] d4 can be 0, 1, 2, 3, 4, 5, or 6;

[0108] R d3 It is a hydrogen atom or R*; or

[0109] Two Rs d3 Together with the attached atom, it forms a cycloalkyl or heterocyclic group;

[0110] q1 can be 0, 1, 2, 3, 4, 5, or 6;

[0111] The dashed line indicates whether the ring is aromatic or non-aromatic.

[0112] Ring Q, R L1 G 1 R 6 Y, Z, RA n, R B , q, R C And L is as defined in general formula (I).

[0113] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III), (III') or (III-Q) or a pharmaceutically acceptable salt thereof.

[0114] in:

[0115] M is a carbon atom, a nitrogen atom, or an oxygen atom;

[0116] d1 is 0, 1, 2, 3 or 4;

[0117] d2 is 0, 1, 2, 3, or 4;

[0118] d4 can be 0, 1, 2, 3, 4, 5, or 6;

[0119] R d3 It is a hydrogen atom or R*; or

[0120] Two Rs d3 Together with the attached atom, it forms a cycloalkyl or heterocyclic group;

[0121] q1 can be 0, 1, 2, 3, 4, 5, or 6;

[0122] The dashed line indicates whether the ring is aromatic or non-aromatic.

[0123] Ring Q, R L1 G 1 R 6 Y, Z, R A n, R B , q, R C And L is as defined in general formula (I).

[0124] In some embodiments disclosed herein, R 64 Selected from hydrogen atoms, C 1-6 Alkyl, hydroxyl and C 1-6 Alkoxy; in some embodiments, R 64 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 64 It can be a hydrogen atom or a methyl group.

[0125] In some embodiments disclosed herein, R 61 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 61 It can be a hydrogen atom or a methyl group.

[0126] In some embodiments disclosed herein, R 62 and R 63 They may be the same or different, and each is independently a hydrogen atom or a halogen; in some embodiments, R 62 and R 63 They may be the same or different, and each is independently a hydrogen atom or F; in some implementations, R 62 and R 63 Both are hydrogen atoms; in some implementations, R 62 and R 63 Both are F; in some implementations, R 62 For hydrogen atoms, R 63 It is F.

[0127] In some embodiments disclosed herein, R 7a and R 7b 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 Alkoxy C 1-6 Alkyl; in some embodiments, R 7a and R 7b They may be the same or different, and each is independently selected from hydrogen atoms, methyl, ethyl, methoxyethyl, and methoxymethyl; in some embodiments, R 7a It is a hydrogen atom or a methyl group; in some embodiments, R 7b It is methoxyethyl or methoxymethyl.

[0128] In some embodiments disclosed herein, R 9a R 9b 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 Alkoxy C 1-6 Alkyl; in some embodiments, R 9a R 9b They may be the same or different, and each is independently selected from hydrogen atoms or C atoms. 1-6 alkyl.

[0129] In some embodiments of this disclosure, R* is selected from oxo groups, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano, 3- to 8-membered heterocyclic alkyloxy, and 3- to 8-membered cycloalkyloxy; in some embodiments, R* is selected from oxo, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl and 3 to 8-membered cycloalkyloxy groups; in some embodiments, R* is an oxo group; in some embodiments, R* is a C 1-6Alkyl; in some embodiments, R* is methyl; in some embodiments, R* is cyclopropyloxy; in some embodiments, R* is tetrahydropyranoxy or oxecyclobutaneoxy; in some embodiments, R* is tetrahydro-2H-pyran-4-yloxy or oxecyclobutane-3-yloxy; in some embodiments, R* is cyano.

[0130] In some embodiments disclosed herein, each R B They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyl alkyl, cyano, 3- to 8-membered cycloalkyl, or 3- to 8-membered heterocyclic group; in some embodiments, R B They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, R B It is a hydrogen atom or a halogen; in some implementations, R B It is F.

[0131] In some embodiments of this disclosure, q is 0, 1, or 2; in some embodiments, q is 0; in some embodiments, q is 1; in some embodiments, (R B ) q It is a hydrogen atom.

[0132] In some embodiments disclosed herein, wherein Selected from Where R A and n are as defined in general formula (I); in some implementations, for Where R A and n are as defined in general formula (I); in some implementations, for In some implementation schemes, for In some implementation schemes, for

[0133] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein Selected from Where R A and n are as defined in general formula (II); in some implementations, n is... In some implementation schemes, for In some implementation schemes, for

[0134] In some embodiments disclosed herein, R d3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; or two R atoms bonded to the same carbon atom d3 Together with the attached carbon atom, it forms a 3- to 6-membered cycloalkyl group; and / or d4 is 0, 1, 2, or 3; and / or d1 is 1 or 2; and / or d2 is 1; and / or M is a nitrogen atom or an oxygen atom.

[0135] In some embodiments disclosed herein, R d3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl, or two R atoms attached to the same carbon atom d3 Together with the attached carbon atom, it forms a 3- to 6-membered cycloalkyl group; in some embodiments, R d3 Selected from hydrogen atoms or C 1-6 Alkyl group, or two R atoms attached to the same carbon atom d3 Together with the attached carbon atom, it forms a cyclopropyl group.

[0136] In some embodiments of this disclosure, d4 is 0, 1, 2, or 3; in some embodiments, d4 is 0; and in some embodiments, d4 is 3.

[0137] In some embodiments of this disclosure, d1 is 1 or 2.

[0138] In some embodiments of this disclosure, d2 is 1.

[0139] In some embodiments of this disclosure, M is a nitrogen atom or an oxygen atom.

[0140] In some implementation schemes disclosed herein, for In some implementation schemes, for In some implementation schemes, for

[0141] In some embodiments of this disclosure, Y is selected from hydrogen atoms, halogens, and C. 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl, C 1-6 Each alkoxy group is independently selected from halogens, C... 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The alkoxy group is substituted with one or more substituents in the haloalkoxy group; in some embodiments, Y is C 1-6 Alkoxy C 1-6 Alkyl-; in some embodiments, Y is CH3OCH(CH3)-; in some embodiments, Y is In some implementation schemes, Y is

[0142] In some embodiments of this disclosure, Z is C 1-6 Alkyl; and / or R B They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; and / or q is 0 or 1; and / or R C Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, cyano, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic groups.

[0143] In some embodiments disclosed herein, Z is Ring Z can be cycloalkyl, heterocyclic, aryl, or heteroaryl, R ZZ Selected from oxo, =S, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkylthio, amino, -NHalkyl, -N(alkyl)2, -alkylene-amino, -alkylene-NHalkyl, -alkylene-N(alkyl)2, amide, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclic oxy, aryloxy, and heteroaryloxy, z1 is an integer from 0 to 6.

[0144] In some embodiments, ring Z is selected from 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; in some embodiments, ring Z is a 3- to 8-membered heterocyclic or a 5- to 6-membered heteroaryl; in some embodiments, ring Z is...

[0145] In some implementation schemes, R ZZ Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, cyano, 3- to 8-membered cycloalkyl; in some embodiments, R ZZ Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano; in some embodiments, R ZZ Selected from C 1-6 Alkyl; in some embodiments, R ZZ It is a methyl group.

[0146] In some implementations, zz is 0, 1, or 2.

[0147] In some implementations, z1 is 1; in other implementations, z1 is 0, 1, or 2.

[0148] In some embodiments of this disclosure, Z is selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, 3- to 8-membered cycloalkyl groups, and 3- to 8-membered heterocyclic groups, wherein the C 1-6 Alkyl groups, 3- to 8-membered cycloalkyl groups, and 3- to 8-membered heterocyclic groups are each independently and optionally converted by one or more halogens, C 1-6 Alkyl, cyano, C 1-6 The alkyl group is replaced by a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocyclic group, a 3- to 8-membered cycloalkyloxy group, a 3- to 8-membered heterocyclic oxy group, and a 5- to 10-membered heteroaryloxy group, wherein each of the 3- to 8-membered cycloalkyl group, the 3- to 8-membered cycloalkyloxy group, the 3- to 8-membered heterocyclic oxy group, and the 5- to 10-membered heteroaryloxy group is independently optionally selected from an oxo group, =S, a halogen, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, cyano, C 1-6 Alkylthio, amino, -NH C 1- 6-alkyl, -N(C) 1-6 Alkyl)2, -C 1-6 alkylene-amino, -C 1-6 Alkylene-NH C 1-6 Alkyl, -C 1-6 Alkylene-N(C) 1-6 Alkyl)2, C 1-6 The amide group or nitro group is substituted with one or more substituents; in some embodiments, Z is selected from hydrogen atom, C 1-6 Alkyl, C1-6 Halogenated alkyl groups, 3- to 8-membered cycloalkyl groups, and 3- to 8-membered heterocyclic groups, wherein the C 1-6 Alkyl groups, 3- to 8-membered cycloalkyl groups, and 3- to 8-membered heterocyclic groups are each independently and optionally converted by one or more halogens, C 1-6 Alkyl, cyano, C 1-6 The substituted group is a haloalkyl group, a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocyclic group, a 3- to 8-membered cycloalkyloxy group, or a 3- to 8-membered heterocyclic oxy group; in some embodiments, Z is a C group substituted with a 3- to 8-membered heterocyclic oxy group. 1-6 Alkyl, or Z is the halogenated, C 1-6 Alkyl, cyano or C 1-6 A 3- to 8-membered cycloalkyl group substituted with a haloalkyl group; in some embodiments, Z is... In some implementation schemes, Z is In some implementations, Z is selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, Z is C 1-6 Alkyl or C 1-6 Halogenated alkyl; in some embodiments, Z is ethyl or CF3CH2-.

[0149] In some embodiments disclosed herein, R B They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, (R B ) q It is a hydrogen atom.

[0150] In some embodiments of this disclosure, q is 0 or 1; in other embodiments, q is 0.

[0151] In some embodiments disclosed herein, R C Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1- 6-Hydroalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyl alkyl, cyano, 3- to 8-membered cycloalkyl, or 3- to 8-membered heterocyclic group; in some embodiments, R C Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R C It is a hydrogen atom.

[0152] In some embodiments of this disclosure, p is 0, 1, or 2; in some embodiments, p is 0 or 1; in some embodiments, p is 0; in some embodiments (R C ) p It is a hydrogen atom.

[0153] In some embodiments disclosed herein, each R A They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano groups, or two R groups on the same atom A Or two R atoms on different atoms A Together with the attached atoms, it forms a 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group is optionally reacted with one or more halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano substitutions; and / or n is 0, 1 or 2.

[0154] In some embodiments disclosed herein, R A They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano groups, or two R groups on the same atom A Or two R atoms on different atoms A Together with the attached atoms, it forms a 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group is optionally reacted with one or more halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano substitution; in some embodiments, R A They may be the same or different, and each is independently selected from hydrogen atoms, halogens, or carbon atoms. 1-6 Alkyl; in some embodiments, R A They may be the same or different, and each is independently F or methyl.

[0155] In some embodiments of this disclosure, n is 0, 1, 2, or 3; in some embodiments, n is 0; in some embodiments, n is 2; in some embodiments, (R A ) n It is a hydrogen atom.

[0156] In some embodiments of this disclosure, L is a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group is optionally converted by one or more halogens, C 1-6Alkyl, C 2-6 alkenyl, C 2- 6-Alynyl, =CR 62 R 63 C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano substitution, R 62 and R 63 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; or L is Or L is In some embodiments, L is a 3- to 8-membered cycloalkyl group, which is optionally coated with one or more halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, =CR 62 R 63 C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano substitution, R 62 and R 63 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, L is a 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered heterocyclic group is optionally coated with one or more halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, =CR 62 R 63 C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano substitution, R 62 and R 63 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, L is optionally coated with one or more halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, =CR 62 R 63 C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano-substituted R 62 and R 63 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, L is... In some implementations, L is In some implementations, L is In some implementations, L is optional and C is selected. 1-6 Alkyl-substituted cyclopropyl, or L is

[0157] In some embodiments disclosed herein, L is Ring W 1 For optional use by one or more R F Substituted nitrogen-containing heterocyclic group, ring W 2 It is a cycloalkyl or heterocyclic group, R W3 For hydrogen atoms or R # w4 is 0, 1, 2, 3 or 4, R F R # R 11 and R 12 As defined in general formula (I); in some implementations, L is In some implementations, L is

[0158] In some embodiments disclosed herein, ring W 1 It is a 3- to 12-membered nitrogen-containing heterocyclic group; in some embodiments, the ring W 1 for *Ended carbonyl group; in some embodiments, W 1 for * The carbonyl group is attached to the end.

[0159] In some embodiments disclosed herein, ring W 2 It is a 3- to 12-membered heterocyclic group; in some embodiments, the ring W 2 It is a 3- to 6-membered heterocyclic group; in some embodiments, the ring W 2 for * The carbonyl group is attached to the end.

[0160] In some embodiments disclosed herein, R W3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, cyano, amino, -NH C 1-6 Alkyl, -N(C) 1-6 alkyl)2 and 3 to 6-membered cycloalkyl; in some embodiments, R W3 Selected from hydrogen atoms, halogens, C 1- 6-alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups; in some embodiments, R W3 Selected from hydrogen atoms, C 1-6 Alkyl and 3- to 6-membered cycloalkyl; in some embodiments, RW3 Selected from methyl and cyclopropyl.

[0161] In some embodiments of this disclosure, w4 is 0, 1, or 2; in some embodiments, w4 is 2.

[0162] In some embodiments of this disclosure, L is a 3- to 8-membered cycloalkyl group, wherein the 3- to 8-membered cycloalkyl group is optionally coated with one or more halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, =CR 62 R 63 C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano substitution, R 62 and R 63 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, L is selected from... In some implementation schemes, L is selected from In some implementation schemes, L is selected from In some implementation schemes, L is selected from In some implementation schemes, L is selected from In some implementations, L is

[0163] In some embodiments disclosed herein, R 12 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 12 C 1-6 Alkyl; in some embodiments, R 12 It is isopropyl.

[0164] In some embodiments disclosed herein, R L3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R L3 C 1-6 Alkyl; in some embodiments, R L3 It is a methyl group.

[0165] In some embodiments disclosed herein, R F Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, NH2, (C1- 6-alkyl)NH- and (C 1-6 alkyl)2N-; in some embodiments, R F Selected from NH2, (C 1-6 alkyl)NH- and (C 1- 6-alkyl)2N-; in some embodiments, R F For (C) 1-6 alkyl)2N-; in some embodiments, R F It is (CH3)2N-.

[0166] In some embodiments disclosed herein, R 11 C 1-6 Alkyl or 3- to 8-membered cycloalkyl; in some embodiments, R 11 It is isopropyl or cyclopentyl; in some embodiments, R 11 It is cyclopentyl.

[0167] In some embodiments disclosed herein, R 12 It is a hydrogen atom.

[0168] In some embodiments disclosed herein, L 3 For the bond or -N(CH3)C(O)-; in some implementations, L 3 For key.

[0169] In some embodiments disclosed herein, R L3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R L3 C 1-6 alkyl.

[0170] In some embodiments disclosed herein, L 4 For key.

[0171] In some embodiments disclosed herein, R L4 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R L4 C 1-6 alkyl.

[0172] In some embodiments of this disclosure, y is 0 or 1; in other embodiments, y is 0.

[0173] In some embodiments disclosed herein, R 10 Selected from 3- to 12-membered cycloalkyl groups, 3- to 12-membered heterocyclic groups, and N(C) groups. 1-6 Alkyl)2, wherein the 3- to 12-membered cycloalkyl group or the 3- to 12-membered heterocyclic group is optionally surrounded by one or more R F Replace, R F As defined in general formula (I); in some implementations, R10 Selected from 3- to 12-membered cycloalkyl groups, 3- to 12-membered heterocyclic groups, and N(C) groups. 1-6 Alkyl)2, wherein the 3- to 12-membered cycloalkyl group or the 3- to 12-membered heterocyclic group is optionally surrounded by one or more R F Replace, R F Selected from halogens, C 1-6 Alkyl and -C(O)R F1 R F1 Selected from C 2-6 alkenyl, C 2-6 Alkyne group and 3 to 8-membered heterocyclic group, the C 2-6 alkenyl, C 2-6 The alkynyl group and the 3 to 8-membered heterocyclic group are each independently and optionally constituting one or more R groups. # Replace, R # Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, amino, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl) 2- and 3- to 8-membered cycloalkyl.

[0174] In some embodiments disclosed herein, R 10 It is a 3- to 8-membered cycloalkyl group, wherein the 3- to 8-membered cycloalkyl group is optionally coated with one or more halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, =CR 62 R 63 C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano substitution, R 62 and R 63 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, R 10 For optional C 1-6 Alkyl-substituted cyclopropyl groups.

[0175] In some implementation schemes disclosed herein, Can be Among them G, G 1 G 2 R D Y, Z, R B q is as defined in general formula (I).

[0176] In some implementation schemes disclosed herein, Can be Among them G, G 1 G 2 R 2D Y, Z, R Bq is as defined in general formula (II).

[0177] In some implementation schemes disclosed herein, Can be Among them G, G 1 G 2 R 2D Y, Z, R B q is defined as in general formula (II-Q).

[0178] In some implementation schemes disclosed herein, Can be Among them, M and R d3 d4, d1, d2, Y, Z, R B q is as defined in general formula (III).

[0179] In some implementation schemes disclosed herein, Can be Among them G 1 R 6 M, R d3 d4, d1, d2, Y, Z, R B q is defined as in general formula (III-Q).

[0180] In some embodiments of this disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein the ring C is phenyl or a 5- or 6-membered heteroaryl group; L 2 For optional C 1-6 Alkyl-substituted propylene; G 1 For CR 6 Or N, R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; G is CR 6 R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; G 2 For CR 6 R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; R 2D The heterocyclic group is a -CH2-3 to 8-membered heterocyclic group, wherein the 3 to 8-membered heterocyclic group is optionally selected from halogens, C 1-6 Alkyl, C 1-6 Substituted with one or more of the haloalkyl and cyclopropyl groups; R B They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; q is 0, 1, or 2; for R A They may be the same or different, and each is independently selected from hydrogen atoms, halogens, or carbon atoms. 1- 6-alkyl; n is 0, 1, 2 or 3; L is optional. 1-6 Alkyl-substituted cyclopropyl, or L is R C Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; p is 0, 1 or 2; Y is C 1-6 Alkoxy C 1-6 Alkyl group; Z is selected from hydrogen atom, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0181] In some embodiments of this disclosure, the compound represented by the general formula (III-Q) or a pharmaceutically acceptable salt thereof, wherein R B They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; q is 0, 1, or 2; for L is a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered cycloalkyl group or the 3- to 8-membered heterocyclic group is optionally converted by one or more halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, =CR 62 R 63 C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano substitution, R 62 and R 63 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; or L is R C Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; Y is C 1-6 Alkoxy C 1-6 Alkyl group; Z is selected from hydrogen atom, C 1-6 Alkyl and C 1-6 Haloalkyl; or Z is a C substituted with a 3 to 8-membered heterocyclic alkyl group. 1-6 Alkyl, or Z is the halogenated, C 1-6 Alkyl, cyano or C 1-6 3- to 8-membered cycloalkyl groups substituted with haloalkyl groups; for Ring Q is R L1 Selected from halogens, C 1-6 Alkyl, C1-6 Haloalkyl; q1 is 0, 1 or 2; for

[0182] In some embodiments of this disclosure, the compounds represented by general formulas (III), (III'), or (III-Q), or their pharmaceutically acceptable salts, wherein R B They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; q is 0, 1, or 2; for L is a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered cycloalkyl group or the 3- to 8-membered heterocyclic group is optionally converted by one or more halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, =CR 62 R 63 C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano substitution, R 62 and R 63 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; or L is R C Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; Y is C 1-6 Alkoxy C 1-6 alkyl-; Z is for Ring Q is a 3- to 8-membered heterocyclic group; R L1 Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl; q1 is 0, 1 or 2; for

[0183] In some embodiments of this disclosure, the compounds represented by general formulas (III), (III'), or (III-Q), or their pharmaceutically acceptable salts, wherein R B They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; q is 0, 1, or 2; for L is a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered cycloalkyl group or the 3- to 8-membered heterocyclic group is optionally converted by one or more halogens, C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, =CR 62 R 63 C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano substitution, R 62 and R 63 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; or L is R C Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; Y is C 1-6 Alkoxy C 1-6 alkyl-; Z is for Ring Q is a 3- to 8-membered heterocyclic group; R L1 Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl; q1 is 0, 1 or 2; for R N It is a methyl group.

[0184] In some embodiments of this disclosure, the compounds represented by general formulas (III), (III'), or (III-Q), or their pharmaceutically acceptable salts, wherein R B They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; q is 0, 1, or 2; for L is Or L is R C Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; Y is C 1-6 Alkoxy C 1-6 Alkyl group; Z is selected from hydrogen atom, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, 3- to 8-membered cycloalkyl groups, and 3- to 8-membered heterocyclic groups, wherein the C 1-6 Alkyl groups, 3- to 8-membered cycloalkyl groups, and 3- to 8-membered heterocyclic groups are each independently and optionally converted by one or more halogens, C 1-6 Alkyl, cyano, C 1-6 Substituted with haloalkyl, 3 to 8-membered cycloalkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyloxy and 3 to 8-membered heterocyclic oxy; for Ring Q is a 3- to 8-membered heterocyclic group; R L1 Selected from halogens, C 1-6 Alkyl, C1-6 Haloalkyl; q1 is 0, 1 or 2; for

[0185] In some embodiments of this disclosure, the compounds represented by general formulas (III), (III'), or (III-Q), or their pharmaceutically acceptable salts, wherein R B They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; q is 0, 1, or 2; for L is Or L is R C Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; Y is C 1-6 Alkoxy C 1-6 Alkyl group; Z is selected from hydrogen atom, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, 3- to 8-membered cycloalkyl groups, and 3- to 8-membered heterocyclic groups, wherein the C 1-6 Alkyl groups, 3- to 8-membered cycloalkyl groups, and 3- to 8-membered heterocyclic groups are each independently and optionally converted by one or more halogens, C 1-6 Alkyl, cyano, C 1-6 Substituted with haloalkyl, 3 to 8-membered cycloalkyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyloxy and 3 to 8-membered heterocyclic oxy; for Ring Q is a 3- to 8-membered heterocyclic group; R L1 Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl; q1 is 0, 1 or 2; for

[0186] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein R B They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; q is 0, 1, or 2; for L is R C Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; Y is C 1-6 Alkoxy C 1-6 Alkyl group; Z is selected from hydrogen atom, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups; for

[0187] The following numbered embodiments are not restrictive, but exemplify several technical aspects of this disclosure:

[0188] 1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof,

[0189] in:

[0190] R D The alkynyl group is optionally selected from halogens, alkoxy groups optionally substituted with one or more R*, haloalkoxy groups, cyano groups, and -NR groups. 9a R 9b The hydroxyl group, a cycloalkyl group optionally substituted with one or more R*, a heterocyclic group optionally substituted with one or more R*, an aryl group optionally substituted with one or more R*, a heteroaryl group optionally substituted with one or more R*, a cycloalkylalkyl group optionally substituted with one or more R*, a heterocyclic alkyl group optionally substituted with one or more R*, an arylalkyl group optionally substituted with one or more R*, and a heteroarylalkyl group optionally substituted with one or more R* are substituted with one or more substituents.

[0191] Y is selected from hydrogen atom, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7a R 7b -NR 7a OR 7b -ONR 7a R 7b -NR 7c NR 7a R 7b hydroxyl group, -C(O)R 8 -C(O)OR 8 -C(O)NR 7a R 7b -S(O) w R 8 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 9a R 9b The substance is substituted by one or more substituents selected from hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0192] Z and R RThe same or different, and each independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted by one or more R*;

[0193] G 1 G 2 Whether the CR is the same as or different from G, and each is independent of the other. 6 N=O, NR N Or N;

[0194] Ring A is a heterocyclic group;

[0195] The ring carbons may be the same or different, and each is independently selected from cycloalkyl, heterocyclic, aryl or heteroaryl groups;

[0196] R A R B R C R N and R 6 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7a R 7b -NR 7a OR 7b -ONR 7a R 7b -NR 7c NR 7a R 7b hydroxyl group, -C(O)R 8 -C(O)OR 8 -C(O)NR 7a R 7b -S(O) w R 8 , Oxide group, =S, =NOR 61 =CR 62 R 63 =NR 64 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 9a R 9b The substance is substituted by one or more substituents selected from hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; or

[0197] Two Rs ATogether with the attached atoms, it forms a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. AA replace;

[0198] R 2 Selected from O, NH and N-alkyl;

[0199] L 2 The alkylene group is optionally alkylene oxide (R0) or alkylene oxide (R0) by one or more R0. L2 replace;

[0200] R L2 Same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, oxo, =S, =NOR 61 =CR 62 R 63 =NR 64 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted with one or more R* groups; or

[0201] Two Rs L2 Together with the attached atoms, it forms a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. LL2 replace;

[0202] L 1 Selected from cycloalkyl, heterocyclic and -CH(cycloQ)-, wherein each of the cycloQ, cycloalkyl and heterocyclic groups is independently optionally converted by one or more R L1 replace;

[0203] Ring Q is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0204] L is R 10 or

[0205] R 11 and R 12 The same or different, and each independently selected from hydrogen atoms, halogens, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally separated by one or more R E replace;

[0206] L 3 For key or -N(R) L3 )C(O)-;

[0207] L 4 For bonds or -(alkylene) y -N(R L4 )C(=O)-;

[0208] R 10 Selected from alkyl, cycloalkyl, heterocyclic and NR 101 R 102 The alkyl, cycloalkyl, and heterocyclic groups are each independently and optionally influenced by one or more R groups. F replace;

[0209] Each R F They may be the same or different, and each is independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7a R 7b hydroxyl group, oxo group, =S, =NOR 61 =CR 62 R 63 =NR 64 cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R F1 -C(O)OR F1 -C(O)NR F2 R F3 -S(O) w R F1 and -S(O) w OR F1 The alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally converted by one or more R groups. FF replace;

[0210] R 7a R 7b R 7c R 9a R 9b R L3 R L4 R 101 R 102 R F2 and R F3 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, heteroalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocyclic groups, wherein each of the alkyl, heteroalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocyclic groups is independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl and haloalkoxy;

[0211] Or R 7a and R 7b Together with the attached nitrogen atom, it forms a heterocyclic group, or R9a and R 9b Together with the attached nitrogen atom, it forms a heterocyclic group, or R 101 and R 102 Together with the attached nitrogen atom, it forms a heterocyclic group, or R F2 and R F3 Together with the attached nitrogen atom, a heterocyclic group is formed, wherein the heterocyclic group is optionally selected from halogens, oxo groups, =S, =NR. 64 It is substituted by one or more substituents selected from alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0212] R 8 R F1 R 61 R 62 R 63 and R 64 The same or different, and each independently selected from hydrogen atoms, halogens, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl, and heterocyclic groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups are each independently optionally selected by one or more R atoms. # Replace; or

[0213] R 62 R 63 Together with the attached atoms, they form cycloalkyl or heterocyclic groups, each of which is optionally independently bound by one or more R groups. FF replace;

[0214] Each R*, R AA R LL2 R L1 R E R FF and R #The same or different, and each independently selected from oxo, =S, =N-alkyl, =NH, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkylthio, amino, -NHalkyl, -N(alkyl)2, -alkylene-amino, -alkylene-NHalkyl, -alkylene-N(alkyl)2, amide, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclic oxy, aryloxy, and heteroaryloxy, wherein the =N-alkyl, alkyl, alkenyl, alkoxy, alkoxyalkyl, alkoxyalkyl, alkylthio, -NHalkyl, -N(alkyl)2, -alkylene-amino, -alkylene-NHalkyl, -alkylene The alkyl-N(alkyl)2, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclicalkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclicoxy, aryloxy and heteroaryloxy are each independently and optionally substituted by one or more substituents selected from oxo, =S, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkylthio, amino, -NHalkyl, -N(alkyl)2, -alkylene-amino, -alkylene-NHalkyl, -alkylene-N(alkyl)2, amide, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclicalkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclicoxy, aryloxy and heteroaryloxy;

[0215] w is 0, 1, or 2;

[0216] n is 0, 1, 2, 3, 4, 5, or 6;

[0217] p is 0, 1, 2, 3, 4, 5 or 6;

[0218] q is 0, 1, 2, or 3; and

[0219] y can be 0, 1, 2, 3, 4, 5 or 6.

[0220] 2. The compound of general formula (I) according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein L 1 It is a 3- to 6-membered cycloalkyl group.

[0221] 3. A compound of general formula (I) or a pharmaceutically acceptable salt thereof according to embodiment 1 or 2, wherein the compound is of general formula (II) or (II-Q) or a pharmaceutically acceptable salt thereof.

[0222] in:

[0223] q1 can be 0, 1, 2, 3, 4, 5, or 6;

[0224] The dashed line indicates whether the ring is aromatic or non-aromatic.

[0225] R 2D Selected from cycloalkylalkyl, heterocycloalkyl, arylalkyl, and heteroarylalkyl, wherein the cycloalkylalkyl, heterocycloalkyl, arylalkyl, and heteroarylalkyl are optionally substituted with one or more R*;

[0226] Ring Q, R L1 R * R B , q, G 1 G 2 G, Y, Z, L 2 R A , n, ring C, R C p and L are as defined in Implementation Scheme 1.

[0227] 4. The compound of general formula (I) according to any one of embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the ring C is a thiazolyl group.

[0228] 5. A compound of general formula (I) according to any one of embodiments 1 to 4, wherein the compound is a compound of general formula (III) or (III-Q) or a pharmaceutically acceptable salt thereof.

[0229] in:

[0230] M is a carbon atom, a nitrogen atom, or an oxygen atom;

[0231] d1 is 0, 1, 2, 3 or 4;

[0232] d2 is 0, 1, 2, 3, or 4;

[0233] d4 can be 0, 1, 2, 3, 4, 5, or 6;

[0234] R d3 It is a hydrogen atom or R*; or

[0235] Two Rs d3 Together with the attached atom, it forms a cycloalkyl or heterocyclic group;

[0236] q1 can be 0, 1, 2, 3, 4, 5, or 6;

[0237] The dashed line indicates whether the ring is aromatic or non-aromatic.

[0238] Ring Q, R L1 G 1 R 6 Y, Z, R A n, R B , q, R C And L as defined in Implementation Scheme 1.

[0239] 6. The compound of general formula (I) according to embodiment 1, wherein... Selected from Where R A And n is as defined in Implementation Scheme 1.

[0240] 7. A compound of general formula (I) according to any one of embodiments 5 to 6, or a pharmaceutically acceptable salt thereof, wherein R d3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; or two R atoms bonded to the same carbon atom d3 Together with the attached carbon atom, it forms a 3- to 6-membered cycloalkyl group; and / or d4 is 0, 1, 2, or 3; and / or d1 is 1 or 2; and / or d2 is 1; and / or M is a nitrogen atom or an oxygen atom.

[0241] 8. A compound of general formula (I) according to any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y is C 1-6 Alkoxy C 1-6 Alkyl group; preferably CH3OCH(CH3)-.

[0242] 9. A compound of general formula (I) according to any one of embodiments 1 to 8, wherein...

[0243] Z is C 1-6 Alkyl groups; and / or

[0244] R B They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; and / or q is 0 or 1; and / or

[0245] R C Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyl alkyl, cyano, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic groups; and / or

[0246] Ring Q is a 3- to 8-membered heterocyclic group; and / or

[0247] q1 is 0 or 1; and / or

[0248] R L1 Selected from halogens, C 1-6 Alkyl and C 1-6Halogenated alkyl groups.

[0249] 10. A compound of general formula (I) according to any one of embodiments 1 to 9, or a pharmaceutically acceptable salt thereof, wherein each R A They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano groups, or two R groups on the same atom A Or two R atoms on different atoms A Together with the attached atoms, it forms a 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group is optionally reacted with one or more halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano substitutions; and / or n is 0, 1 or 2.

[0250] 11. A compound of general formula (I) according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, wherein L is a 3- to 8-membered cycloalkyl group, said 3- to 8-membered cycloalkyl group optionally converted by one or more halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, =CR 62 R 63 C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano substitution, R 62 and R 63 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; or L is

[0251] 12. A compound of general formula (I) according to any one of embodiments 1 to 11, or a pharmaceutically acceptable salt thereof, selected from all compounds of group A or pharmaceutically acceptable salts thereof.

[0252] 13. A compound of general formula (IA) or a salt thereof,

[0253] in:

[0254] G, G 1 G 2 Y, Z, R D R 2 L 2 Ring A, R A , n, L 1 R R , ring C, R Cp, R B And q are as defined in Implementation Scheme 1.

[0255] 14. A compound or a salt thereof, selected from the following: all compounds shown in Group B or salts thereof.

[0256] 15. A method for preparing a compound of general formula (I) according to embodiment 1, comprising:

[0257] Method 1:

[0258] The compound of general formula (IA) or its salt undergoes a condensation reaction with LC(O)OH or its salt to give the compound of general formula (I) or its pharmaceutically usable salt.

[0259] in:

[0260] G, G 1 G 2 Y, Z, R D R 2 L 2 Ring A, R A , n, L 1 L, R R , ring C, R C p, R B And q as defined in Implementation Scheme 1;

[0261] Method 2:

[0262] A compound of general formula (IA) or a salt thereof undergoes a condensation reaction with L'-COOH or a salt thereof to yield L' as... The general formula (IB) or its salt, wherein R pro Amino protecting group; and / or

[0263] The product from the previous step underwent a deprotection reaction to give L' as The general formula (IB) or its salt; and / or

[0264] L' is The general formula (IB) or its salts with A condensation reaction occurs to give a compound of general formula (I) or a pharmaceutically acceptable salt thereof, wherein R LQ It can be -OLi, -ONa, -OK, OH, or a halogen;

[0265] Where L is Ring W 1 For optional use by one or more R F Substituted nitrogen-containing heterocyclic group, ring W 2 It is a cycloalkyl or heterocyclic group, RW3 For hydrogen atoms or R # w4 can be 0, 1, 2, 3, or 4.

[0266] R F R # R 11 R 12 G, G 1 G 2 Y, Z, R D R 2 L 2 Ring A, R A , n, L 1 R R , ring C, R C p, R B And q are as defined in Implementation Scheme 1.

[0267] 16. A pharmaceutical composition comprising a compound of formula (I) according to any one of embodiments 1 to 12 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0268] 17. Use of the compound of general formula (I) according to any one of embodiments 1 to 12, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 16, in the preparation of a medicament for inhibiting RAS mutant proteins.

[0269] 18. Use of the compound of general formula (I) according to any one of embodiments 1 to 12, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 16, in the preparation of a medicament for treating and / or preventing diseases or conditions mediated or dependent on RAS mutant proteins.

[0270] 19. Use of the compound of general formula (I) according to any one of embodiments 1 to 12, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to embodiment 16, in the preparation of a medicament for treating and / or preventing tumors; wherein the tumors are preferably selected from thyroid cancer, head and neck cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, brain cancer, skin cancer, testicular cancer, bile duct cancer, colorectal cancer, urothelial carcinoma, bladder cancer, breast cancer, ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, leukemia, lymphoma, myeloma, appendiceal cancer, melanoma, sarcoma, and glioblastoma; more preferably selected from gastric cancer, pancreatic cancer, colorectal cancer, and non-small cell lung cancer.

[0271] The compounds disclosed herein include, but are not limited to:

[0272] Group A:

[0273] This disclosure provides a compound of general formula (IA) or a salt thereof:

[0274] in,

[0275] G, G 1 G 2 Y, Z, R D R 2 L 2 Ring A, R A , n, L 1 R R , ring C, R C p, R B And q are as defined in general formula (I).

[0276] Furthermore, this disclosure provides a compound of general formula (IIA) or a salt thereof:

[0277] in:

[0278] R B , q, G 1 G 2 G, Y, Z, R 2D L 2 R A , n, ring C, R C p is as defined in general formula (II).

[0279] This disclosure provides a compound of general formula (IIIA) or a salt thereof:

[0280] in:

[0281] R d3 ,d1,d2,d4,M,Y,Z,R A n, R B , q, RC As defined in general formula (III).

[0282] The compounds disclosed herein include, but are not limited to:

[0283] Group B:

[0284] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, comprising:

[0285] The compound of general formula (IA) or its salt undergoes a condensation reaction with LC(O)OH or its salt to give the compound of general formula (I) or its pharmaceutically usable salt.

[0286] in:

[0287] G, G 1 G 2 L, Y, Z, R D R 2 L 2 Ring A, R A , n, L 1 R R , ring C, R C p, R B And q are as defined in general formula (I).

[0288] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, comprising:

[0289] A compound of general formula (IA) or a salt thereof undergoes a condensation reaction with L'-COOH or a salt thereof to yield L' as... The general formula (IB) or its salt, wherein R pro Amino protecting group; and / or

[0290] The product from the previous step underwent a deprotection reaction to give L' as The general formula (IB) or its salt; and / or

[0291] L' is The general formula (IB) or its salts with A condensation reaction occurs to give a compound of general formula (I) or a pharmaceutically acceptable salt thereof, wherein R LQFor -OLi, -ONa, -OK, OH, halogens;

[0292] Where L is Ring W 1 For optional use by one or more R F Substituted nitrogen-containing heterocyclic group, ring W 2 It is a cycloalkyl or heterocyclic group, R W3 For hydrogen atoms or R # w4 can be 0, 1, 2, 3, or 4.

[0293] R F R # R 11 R 12 G, G 1 G 2 Y, Z, R D R 2 L 2 Ring A, R A , n, L 1 R R , ring C, R C p, R B And q are as defined in general formula (I).

[0294] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II) or a pharmaceutically acceptable salt thereof, comprising:

[0295] The compound of general formula (IIA) or its salt undergoes a condensation reaction with LC(O)OH or its salt to give the compound of general formula (II) or its pharmaceutically usable salt.

[0296] in:

[0297] R B , q, G 1 G 2 G, Y, Z, R 2D L 2 R A , n, ring C, R C p and L are as defined in general formula (II).

[0298] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II) or a pharmaceutically acceptable salt thereof, comprising:

[0299] A compound of general formula (IIA) or its salt undergoes a condensation reaction with L'-COOH or its salt to yield L' as... The general formula (IIB) or its salt, wherein R pro Amino protecting group; and / or

[0300] The product from the previous step underwent a deprotection reaction to give L' as The general formula (IIB) or its salt; and / or

[0301] L' is general formula (IIB) or its salt with A condensation reaction occurs to give a compound of general formula (II) or a pharmaceutically acceptable salt thereof, wherein R LQ For -OLi, -ONa, -OK, OH, halogens;

[0302] Where L is Ring W 1 For optional use by one or more R F Substituted nitrogen-containing heterocyclic group, ring W 2 It is a cycloalkyl or heterocyclic group, R W3 For hydrogen atoms or R # w4 can be 0, 1, 2, 3, or 4.

[0303] R F R # R 11 R 12 R B , q, G 1 G 2 G, Y, Z, R 2D L 2 R A , n, ring C, R C p is as defined in general formula (II).

[0304] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III) or a pharmaceutically acceptable salt thereof, comprising:

[0305] The compound of general formula (IIIA) or its salt undergoes a condensation reaction with LC(O)OH or its salt to give the compound of general formula (III) or its pharmaceutically usable salt.

[0306] in:

[0307] R d3 ,d1,d2,d4,M,Y,Z,R A n, R B , q, R C And L is as defined in general formula (III).

[0308] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III) or a pharmaceutically acceptable salt thereof, comprising:

[0309] A compound of general formula (IIIA) or its salt undergoes a condensation reaction with L'-COOH or its salt to yield L' as... The general formula (IIIB) or its salt, wherein R pro Amino protecting group; and / or

[0310] The product from the previous step underwent a deprotection reaction to give L' as general formula (IIIB) or its salts; and / or

[0311] L' is general formula (IIIB) or its salts with A condensation reaction occurs to give a compound of general formula (III) or a pharmaceutically acceptable salt thereof, wherein R LQ For -OLi, -ONa, -OK, OH, halogens;

[0312] Where L is Ring W 1 For optional use by one or more R F Substituted nitrogen-containing heterocyclic group, ring W 2 It is a cycloalkyl or heterocyclic group, R W3 For hydrogen atoms or R # w4 can be 0, 1, 2, 3, or 4.

[0313] R F R # R 11 R 12 R d3 ,d1,d2,d4,M,Y,Z,R A n, R B q and R C As defined in general formula (III).

[0314] In some implementation schemes, R pro For Boc.

[0315] In some implementation schemes, R LQ For -OLi.

[0316] In some embodiments, the condensation reaction occurs under alkaline conditions in the presence of a condensing agent.

[0317] In some embodiments, the reagents providing the alkaline conditions include organic and inorganic bases. The organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium fluoride, tetrahydrofuran solution of tetrabutylammonium fluoride, or 1,8-diazabicycloundec-7-ene. The inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, cesium fluoride, and potassium hydroxide. In some embodiments, N,N-diisopropylethylamine is used.

[0318] In some embodiments, the condensing agent includes, but is not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, and O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethylurea. Hexafluorophosphate (HATU), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate, benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 1-cyano-2-ethoxy-2-oxoethyleneamino(oxy)dimethylamino-morpholino-carbomonium hexafluorophosphate (COMU) or benzotriazole-1-yl-oxytripyrrolylphosphonium hexafluorophosphate; in some embodiments, the condensing agent is HATU or COMU; in some embodiments, the condensing agent is HATU.

[0319] In some embodiments, the deprotection reaction is carried out under acidic conditions, wherein the acid includes, but is not limited to, a 1,4-dioxane solution of hydrogen chloride, hydrochloric acid, and trifluoroacetic acid.

[0320] The above synthesis is preferably carried out in a solvent, including but not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, and mixtures thereof.

[0321] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of formula (I), formula (II), formula (III) or shown in this disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0322] This disclosure further relates to the use of compounds of general formula (I), general formula (II), general formula (III) or those shown in this disclosure, or pharmaceutical compositions thereof, in the preparation of a medicament for inhibiting RAS mutant proteins.

[0323] This disclosure further relates to the use of compounds of the above general formula (I), general formula (II), general formula (III) or those shown in this disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of medicaments for the treatment and / or prevention of diseases or conditions mediated or dependent on RAS mutant proteins.

[0324] This disclosure further relates to the use of compounds of general formula (I), general formula (II), general formula (III) or those shown in this disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of medicaments for the treatment and / or prevention of tumors.

[0325] This disclosure also relates to a method of inhibiting RAS mutant proteins in a subject, comprising administering to a desired patient a compound of the above general formula (I), general formula (II), general formula (III) or the compound shown in this disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0326] This disclosure also relates to a method of treating and / or preventing diseases or conditions mediated or dependent on RAS mutant proteins, comprising administering to a desired patient a compound of the above general formula (I), general formula (II), general formula (III) or shown in this disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0327] This disclosure also relates to a method of treating and / or preventing tumors, comprising administering to a desired patient a compound of the above general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.

[0328] This disclosure further relates to a compound of the above general formula (I), general formula (II), general formula (III) or shown in this disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above, which is used as a medicine.

[0329] This disclosure further relates to a compound of the above general formula (I), general formula (II), general formula (III) or shown in this disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, which is used as a medicament for treating and / or preventing diseases or conditions mediated or dependent on the RAS mutant protein.

[0330] This disclosure further relates to compounds of general formula (I), general formula (II), general formula (III) or those shown in this disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising such compounds, for use in inhibiting RAS mutant proteins in a subject.

[0331] This disclosure further relates to compounds of the above general formula (I), general formula (II), general formula (III) or those shown in this disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for the treatment and / or prevention of diseases or conditions mediated or dependent on the RAS mutant protein.

[0332] This disclosure further relates to compounds of general formula (I), general formula (II), general formula (III) or those shown in this disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, for the treatment and / or prevention of tumors.

[0333] In some embodiments, the diseases or conditions mediated or dependent on the RAS mutant protein described in this disclosure are tumors; in some embodiments, the diseases or conditions mediated or dependent on the RAS mutant protein described in this disclosure are selected from thyroid cancer, head and neck cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, brain cancer, skin cancer, testicular cancer, bile duct cancer, colorectal cancer, urothelial carcinoma, bladder cancer, breast cancer, ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, leukemia, lymphoma, myeloma, appendix cancer, melanoma, sarcoma, and glioblastoma; in some embodiments, the diseases or conditions mediated or dependent on the RAS mutant protein described in this disclosure are selected from gastric cancer, pancreatic cancer, colorectal cancer, and non-small cell lung cancer.

[0334] In some embodiments, the tumors described in this disclosure are selected from thyroid cancer, head and neck cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, brain cancer, skin cancer, testicular cancer, bile duct cancer, colorectal cancer, urothelial carcinoma, bladder cancer, breast cancer, ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, leukemia, lymphoma, myeloma, appendix cancer, melanoma, sarcoma, and glioblastoma; in some embodiments, the tumors described in this disclosure are selected from gastric cancer, pancreatic cancer, colorectal cancer, and non-small cell lung cancer.

[0335] In some implementations, the tumor described in this disclosure is a solid tumor.

[0336] In some embodiments, the tumors described in this disclosure are hematologic malignancies.

[0337] In some embodiments, the sarcomas described in this disclosure are angiosarcomas, fibrosarcomas, rhabdomyosarcomas, liposarcomas, chondrosarcomas, Ewing's sarcoma, and Kaposi's sarcoma.

[0338] In some embodiments, the colorectal cancer described in this disclosure is colon cancer or rectal cancer.

[0339] In some embodiments, the lymphomas described in this disclosure are diffuse large B-cell lymphomas, Hodgkin's disease, and non-Hodgkin's lymphomas.

[0340] In some embodiments, the lung cancer described in this disclosure is lung adenocarcinoma; in some embodiments, the lung cancer is squamous cell lung cancer or small cell lung cancer; and in some embodiments, it is non-small cell lung cancer (NSCLC).

[0341] In some implementations, the leukemias described in this disclosure are chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and chronic myeloid leukemia.

[0342] In some embodiments, the myeloma described in this disclosure is multiple myeloma.

[0343] In some embodiments, the head and neck cancer described in this disclosure is head and neck squamous cell carcinoma (HNSCC).

[0344] In some implementations, the esophageal cancer described in this disclosure is gastric esophageal cancer.

[0345] In some implementations, the liver cancer described in this disclosure is hepatocellular carcinoma, hepatoblastoma, or hepatocellular adenoma.

[0346] In some embodiments, the RAS protein described in this disclosure is selected from K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G12A, K-Ras G12S, K-Ras G12R, K-Ras G13C, K-Ras G13D, K-Ras Q61H, K-Ras Q61R, K-Ras Q61K, or K-Ras Q61L; in some embodiments, the Ras protein is selected from N-Ras G12D, N-Ras G13D, N-Ras Q61R, N-Ras Q61K, N-Ras Q61L, N-Ras Q61H, or N-Ras Q61P; in some embodiments, the Ras protein is selected from H-Ras G12V, H-Ras G13R, H-Ras Q61R, or H-Ras Q61L.

[0347] The active compound can be formulated in a form suitable for administration via any appropriate route, in some embodiments in the form of a unit dose or in a form that a patient can self-administer as a single dose. The unit dose of the disclosed compound or composition can be expressed as a tablet, capsule, sachet, bottled liquid, powder, granule, lozenge, suppository, regenerated powder, or liquid formulation.

[0348] As a general guideline, a suitable unit dose can be 0.1–1000 mg.

[0349] 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.

[0350] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0351] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution.

[0352] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients.

[0353] The pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts.

[0354] Pharmaceutical compositions containing active ingredients may be in forms suitable for oral administration, such as tablets, sugar lozenges, tablets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide an appealing and palatable pharmaceutical formulation.

[0355] Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation, used for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.

[0356] Oral formulations can also be provided using soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil solvent.

[0357] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions for mixing. These excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweeteners.

[0358] Oil suspensions are formulated by suspending the active ingredient in vegetable or mineral oil. Oil suspensions may contain thickeners. Sweeteners and flavoring agents mentioned above may be added to provide palatable formulations. These compositions may be preserved by adding antioxidants.

[0359] The pharmaceutical compositions disclosed herein may also be in the form of an oil-in-water emulsion. The oil phase may be vegetable oil, mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain modifiers, preservatives, colorants, and antioxidants.

[0360] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable solvents or media that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, which can be injected into the patient's bloodstream via local large-volume injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compounds disclosed herein. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0361] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. The sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral acceptable non-toxic diluents or solvents. Furthermore, sterile fixative oils can be conveniently used as solvents or suspension media. Any blended fixative oil may be used for this purpose. Additionally, fatty acids may also be used to prepare injectable formulations.

[0362] The disclosed compounds can be administered in suppository form for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum, and thus dissolves in the rectum to release the drug.

[0363] 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 patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment mode, such as the treatment pattern, the daily dosage of the compound, or the type of medicinal salt can be validated based on conventional treatment protocols.

[0364] Terminology Explanation

[0365] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0366] The term "alkyl" refers to a saturated, straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkyl group). In some embodiments, the alkyl group is an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkyl groups, in some embodiments, having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6Alkyl groups). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. Alkyl groups can be substituted or unsubstituted. When substituted, they can be substituted at any usable connection point. The substituents are selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0367] The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group, as defined above, has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkylene). In some embodiments, the alkylene has 1 to 10 carbon atoms (i.e., C10). 1-10 Alkylenes), in some embodiments, alkylenes having 1 to 8 carbon atoms (i.e., C1646-C ... 1-8 Alkylenes), in some embodiments, alkylenes having 2 to 7 carbon atoms (i.e., C646-C ... 2-7 Alkylenes or alkylenes having 1, 2 or 3 carbon atoms (i.e., C14) 1-6Alkylenes. Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linking point. Substituents are selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0368] The term "heteroalkyl" refers to an alkyl group in which one or more (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms are replaced by heteroatoms selected from N, O, S, S(O), and S(O)2, and the nitrogen atom may optionally be quaternized, wherein the alkyl group is as defined above; in some embodiments, the heteroalkyl group is C 1-6 One, two, or three carbon atoms in the alkyl group are replaced by heteroatoms selected from N, O, S, S(O), and S(O)2; in some embodiments, the heteroalkyl group is a 2- to 6-membered heteroalkyl group (i.e., a total number of 2 to 6 atoms). The heteroalkyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable linker, with the substituent selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0369] The term "alkenyl" refers to an alkyl group in which the molecule contains at least one carbon-carbon double bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C atoms). 2-12 Alkenyl group). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (i.e., C10). 2-6 Alkenyl). Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, etc. Alkenyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. Substituents are selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0370] The term "alkynyl" refers to an alkyl group in a molecule that contains at least one carbon-carbon triple bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C64, C74, C84, C9 ... 2-12(Alynyl group). In some embodiments, the alkynyl group has 2 to 6 carbon atoms (i.e., C12). 2-6 (Alynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc. The alkynyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable linker. The substituent is selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0371] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy, etc. Alkoxy groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. Substituents are selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0372] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic carbocyclic (i.e., monocyclic cycloalkyl) or polycyclic system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3 to 20 membered cycloalkyl). In some embodiments, the cycloalkyl is a cycloalkyl having 3 to 12 ring atoms (i.e., 3 to 12 membered cycloalkyl) or a cycloalkyl having 4 to 11 ring atoms (i.e., 4 to 11 membered cycloalkyl), in some embodiments, a cycloalkyl having 3 to 8 ring atoms (i.e., 3 to 8 membered cycloalkyl), and in some embodiments, a cycloalkyl having 3 to 6 ring atoms (i.e., 3 to 6 membered cycloalkyl).

[0373] Non-limiting examples of the monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.

[0374] The polycyclic alkyl groups include: spirocyclic alkyl groups, fused cyclic alkyl groups, and bridged cyclic alkyl groups.

[0375] The term "spirocycloalkyl" refers to a polycyclic system in which rings share a single carbon atom (called a spiro atom), and the ring may contain one or more double bonds, or one or more heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that it contains at least one full carbon ring with a bonding point on that full carbon ring, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered spirocycloalkyl). In some embodiments, the spirocycloalkyl is a spirocycloalkyl having 6 to 14 ring atoms (i.e., 6 to 14-membered spirocycloalkyl), and in some embodiments, it is a spirocycloalkyl having 7 to 10 ring atoms (i.e., 7 to 10-membered spirocycloalkyl). The spirocycloalkyl group includes monospirocycloalkyl and polyspirocycloalkyl (such as bispirocycloalkyl, etc.). In some embodiments, it is a monospirocycloalkyl or bispirocycloalkyl group. In some embodiments, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered monospirocycloalkyl group. Non-limiting examples include:

[0376] Its connection point can be anywhere;

[0377] wait.

[0378] The term "fused cycloalkyl" refers to a polycyclic system in which two adjacent carbon atoms are shared between rings. This system is a monocyclic cycloalkyl group fused with one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl group fused with one or more heterocyclic, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic cycloalkyl group, which may contain one or more double bonds and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered fused cycloalkyl). In some embodiments, the fused cycloalkyl group is a fused cycloalkyl group having 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl), and in some embodiments, it is a fused cycloalkyl group having 7 to 10 ring atoms (i.e., 7 to 10-membered fused cycloalkyl). The fused cyclic alkyl group includes bicyclic fused cyclic alkyl groups and polycyclic fused cyclic alkyl groups (such as tricyclic fused cyclic alkyl groups, tetracyclic fused cyclic alkyl groups, etc.). In some embodiments, it is a bicyclic fused cyclic alkyl group or a tricyclic fused cyclic alkyl group. In some embodiments, it is a ternary / quadrivalent, ternary / quinary, ternary / six-membered, quadrivalent / quadrivalent, quadrivalent / five-membered, quadrivalent / six-membered, quadrivalent / quadrivalent, quadrivalent / six-membered, 5-member / tertiary, 5-member / quadrivalent, 5-member / five-membered, 5-member / six-membered, 5-member / seven-membered, 6-member / tertiary, 6-member / quadrivalent, 6-member / four-membered, 6-member / five-membered, 6-member / six-membered, 6-member / seven-membered, 7-member / five-membered, or 7-member / six-member bicyclic fused cyclic alkyl group. Non-limiting examples include:

[0379] Its connection point can be anywhere;

[0380] wait.

[0381] The term "bridged cycloalkyl" refers to a fully carbon polycyclic system in which two non-directly connected carbon atoms are shared between rings, and the ring may contain one or more double bonds and have 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., 5 to 20-membered bridged cycloalkyl). In some embodiments, the bridged cycloalkyl is a bridged cycloalkyl with 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), and in some embodiments, it is a bridged cycloalkyl with 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), and in some embodiments, it is a bicyclic bridged cycloalkyl or a tricyclic bridged cycloalkyl. Non-limiting examples include:

[0382] Its connection point can be anywhere.

[0383] The cycloalkyl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0384] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclic group) or polycyclic heterocyclic system (i.e., polycyclic heterocyclic group) containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), and having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3 to 20 membered heterocyclic groups). In some embodiments, the heterocyclic group is a heterocyclic group having 3 to 12 ring atoms (i.e., a 3 to 12-membered heterocyclic group) or a heterocyclic group having 4 to 11 ring atoms (i.e., a 4 to 11-membered heterocyclic group); in some embodiments, a heterocyclic group having 3 to 9 ring atoms (i.e., a 3 to 9-membered heterocyclic group); in some embodiments, a heterocyclic group having 3 to 8 ring atoms (i.e., a 3 to 8-membered heterocyclic group); in some embodiments, a heterocyclic group having 3 to 6 ring atoms (i.e., a 3 to 6-membered heterocyclic group); in some embodiments, a heterocyclic group having 5 or 6 ring atoms (i.e., a 5 or 6-membered heterocyclic group).

[0385] Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, etc.

[0386] The polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0387] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic system in which rings share a single atom (called a spiro atom), which may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that at least one monocyclic heterocyclic group is present and the bonding point is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered spiroheterocyclic groups). In some embodiments, the spiroheterocyclic group is a spiroheterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered spiroheterocyclic group), and in some embodiments, it is a spiroheterocyclic group having 7 to 11 ring atoms (i.e., a 7 to 11-membered spiroheterocyclic group). The spiroheterocyclic group includes monospirocyclic and polyspirocyclic groups (such as bispirocyclic groups). In some embodiments, it is a monospirocyclic or bispirocyclic group. In some embodiments, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered monospirocyclic group. Non-limiting examples include: wait.

[0388] The term "fused heterocyclic group" refers to a polycyclic heterocyclic system in which two adjacent atoms are shared between rings. The ring may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-). It is a monocyclic heterocyclic group fused with one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group fused with one or more cycloalkyl, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic heterocyclic group and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20 membered fused heterocyclic groups). In some embodiments, the fused heterocyclic group is a fused heterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), and in some embodiments, a fused heterocyclic group having 7 to 11 ring atoms (i.e., a 7 to 11-membered fused heterocyclic group). The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.). In some embodiments, it is a bicyclic or tricyclic fused heterocyclic group. In some embodiments, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples include: wait.

[0389] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic system in which two non-directly bonded atoms are shared between the rings. The rings may contain one or more double bonds, and the system contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-). The system has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered bridged heterocyclic group). In some embodiments, the bridged heterocyclic group has 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclic group), and in some embodiments, it has 7 to 10 ring atoms (i.e., a 7- to 10-membered bridged heterocyclic group). Based on the number of constituent rings, heterocyclic groups can be classified into bicyclic bridged heterocyclic groups and multicyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.). In some embodiments, they are bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups. Non-limiting examples include:

[0390] wait.

[0391] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0392] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having a conjugated π-electron system, having 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 6 to 14-membered aryl). In some embodiments, the aryl group has 6 to 10 ring atoms (i.e., 6 to 10-membered aryl). The monocyclic aryl group is, for example, phenyl. Non-limiting examples of the polycyclic aryl group include naphthyl, anthraceneyl, phenanthrene, etc. The polycyclic aryl group further includes fusion of the phenyl group with one or more heterocyclic groups or cycloalkyl groups, or fusion of the naphthyl group with one or more heterocyclic groups or cycloalkyl groups, wherein the bonding point is on the phenyl or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples including:

[0393] wait.

[0394] The aryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxyl, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0395] The term "heteroaryl" refers to a monocyclic heteroaryl ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaryl ring system (i.e., polycyclic heteroaryl) having a conjugated π-electron system, containing at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 5 to 14-membered heteroaryl). In some embodiments, the heteroaryl has 5 to 10 ring atoms (i.e., 5 to 10-membered heteroaryl), and in some embodiments, it has 5 or 6 ring atoms (i.e., 5 or 6-membered heteroaryl).

[0396] Non-limiting examples of the aforementioned monocyclic heteroaryl groups include: furanyl, thiopheneyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazonyl, pyrroleyl, N-alkylpyrroleyl, pyridyl, pyrimidinyl, pyridoneyl, N-alkylpyridone (e.g.) (etc.), pyrazinyl, pyridazinyl, etc.

[0397] Non-limiting examples of the polycyclic heteroaryl groups include: indolyl, indazole, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene, quinazolinyl, benzothiazolyl, carbazole, etc. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more aryl groups, wherein the connecting point is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more cycloalkyl or heterocyclic groups, wherein the connecting point is on the monocyclic heteroaryl ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. Non-limiting examples include: wait.

[0398] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxyl, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0399] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent ring, i.e., "cycloalkylene", "heterocyclicene", "arylene", and "heteroarylene". Non-limiting examples include: wait.

[0400] When a polycyclic system formed by the fusion of a monocyclic heterocyclic group with a cycloalkyl, aryl, or heteroaryl group is divalent, the polycyclic system is considered a "fused heterocyclic group" as long as one of the linking sites is on the monocyclic heterocyclic group; non-limiting examples include:

[0401] The term "cycloalkylalkyl" refers to an alkyl group that is substituted by one or more cycloalkyl groups, wherein the cycloalkyl and alkyl groups are as defined above.

[0402] The term "heterocyclic alkyl" refers to an alkyl group that is substituted by one or more heterocyclic groups, wherein the heterocyclic group and the alkyl group are as defined above.

[0403] The term "arylalkyl" refers to an alkyl group that is substituted with one or more aryl groups, wherein the aryl and alkyl groups are as defined above.

[0404] The term "heteroarylalkyl" refers to an alkyl group that is substituted by one or more heteroaryl groups, wherein the heteroaryl and alkyl groups are as defined above.

[0405] The term "cycloalkylalkenyl" refers to an alkenyl group that is substituted by one or more cycloalkyl groups, wherein the cycloalkyl and alkenyl groups are as defined above.

[0406] The term "heterocyclic alkenyl" refers to an alkenyl group that is replaced by one or more heterocyclic groups, wherein the heterocyclic group and alkenyl group are as defined above.

[0407] The term "aryl-alkenyl" refers to an alkenyl group that is replaced by one or more aryl groups, where the aryl and alkenyl groups are as defined above.

[0408] The term "heteroaryl-alkenyl" refers to an alkenyl group that is substituted by one or more heteroaryl groups, wherein the heteroaryl and alkenyl groups are as defined above.

[0409] The term "cycloalkylynyl" refers to an ynyl group being replaced by one or more cycloalkyl groups, wherein the cycloalkyl and ynyl groups are as defined above.

[0410] The term "heterocyclic alkynyl" refers to an alkynyl group that is replaced by one or more heterocyclic groups, wherein the heterocyclic group and the alkynyl group are as defined above.

[0411] The term "aryl-alkynyl" refers to an alkynyl group being replaced by one or more aryl groups, where the aryl and alkynyl groups are as defined above.

[0412] The term "heteroaryl-alkynyl" refers to an alkynyl group being replaced by one or more heteroaryl groups, where the heteroaryl and alkynyl groups are as defined above.

[0413] The term "cycloalkyloxy" refers to -O-cycloalkyl, where the cycloalkyl is as defined above.

[0414] The term "heterocyclic oxygen group" refers to an -O-heterocyclic group, wherein the heterocyclic group is as defined above.

[0415] The term "aryloxy group" refers to -O-aryl, where the aryl group is as defined above.

[0416] The term "heteroaryloxy" refers to -O-heteroaryl, where the heteroaryl is as defined above.

[0417] The term "aminoalkyl" refers to an alkyl group that is substituted with one or more amino groups, wherein the alkyl group is as defined above.

[0418] The term "alkoxyalkyl" refers to an alkyl group that is substituted with one or more alkoxy groups, wherein the alkoxy groups and alkyl groups are as defined above.

[0419] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0420] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0421] The term "hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0422] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0423] The term "hydroxyl group" refers to -OH.

[0424] The term "thiol" refers to -SH.

[0425] The term "amino" refers to -NH2.

[0426] The term "cyano" refers to -CN.

[0427] The term "nitro" refers to -NO2.

[0428] The term "oxo" or "oxo group" refers to "=O".

[0429] The term "carbonyl" refers to C=O.

[0430] The term "alkylthio" refers to -S-alkyl, where the alkyl group is as defined above.

[0431] The term "haloalkylthio" refers to an alkylthio group that is replaced by one or more halogens, wherein the alkylthio group is as defined above.

[0432] The term "cycloalkylthio" refers to -S-cycloalkyl, where the cycloalkyl group is as defined above.

[0433] The term "heterocyclic thio" refers to a -S-heterocyclic group, where the heterocyclic group is as defined above.

[0434] "THP" refers to 2-tetrahydropyranyl.

[0435] “TBDPS” refers to tert-butyldiphenylsilyl.

[0436] “Ms” refers to sulfonyl group.

[0437] “Cbz” refers to benzyloxycarbonyl.

[0438] “Boc” refers to tert-butyloxycarbonyl.

[0439] “Ac” refers to acetyl.

[0440] “Bn” refers to benzyl.

[0441] A "leaving group," or simply a group, is an atom or functional group that breaks off from a larger molecule in a chemical reaction. It's a term used in nucleophilic substitution and elimination reactions. In a nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks off with a pair of electrons from the substrate molecule is called the leaving group. Groups that readily accept electrons and have a strong ability to accept negative charges are desirable leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to break off from other molecules. This is because a smaller pKa means the leaving group doesn't need to bond with other atoms and has a stronger tendency to exist as an anion (or an electrically neutral leaving group). Common leaving groups include, but are not limited to, halogens, -OTs, or -OH.

[0442] The compounds disclosed herein can exist in specific stereoisomer forms. The term "stereoisomer" refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, blocked isomers, conformational isomers, and mixtures thereof (such as racemic mixtures and mixtures of diastereomers). Substituents in the compounds disclosed herein may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this disclosure. Optically active (-)- and (+)- isomers, (R)- and (S)- enantiomers, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. This disclosure discloses an isomer of a compound, which can be prepared by asymmetric synthesis or with chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, followed by diastereomer resolution using conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is typically performed by chromatography.

[0443] In the chemical structure of the compounds described in this disclosure, the bonds are... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z-type and E-type are included.

[0444] The compounds disclosed herein may exist in various tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to a structural isomer that exists in equilibrium and readily transforms from one isomer to another. This includes all possible tautomers, i.e., existing as a single isomer or as a mixture of said tautomers in any proportion. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactamimides, etc. Examples of lactam-lactamimide equilibrium are shown below:

[0445] When referring to the pyrazolyl group, it should be understood to include any one or a mixture of two tautomers of the following two structures:

[0446] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0447] The compounds disclosed herein may comprise transisomers. The term "transisomer" refers to a conformational stereoisomer resulting from restricted or significantly slowed rotation around a single bond in a molecule (as a result of spatial interactions with other parts of the molecule and asymmetric substituents at the ends of the single bond), whose interconversion is slow enough to allow separation and isolation under predetermined conditions. For example, some compounds of this disclosure may exist as mixtures of transisomers (e.g., equal-proportion mixtures, mixtures enriched with one transisomer, etc.) or as a purified transisomer. The configuration of the transisomer can be specified using nomenclature (M)- and (P)- to designate the absolute configuration (see WO2021124222A1, WO2022109242A1, etc.).

[0448] Non-limiting examples of transisomers include:

[0449] The compounds disclosed herein include all suitable isotopic derivatives thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that may be introduced into the compounds of this disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, […]. 2 H (deuterium, D) 3 H (tritium, T) 11 C 13 C 14 C 15 N、 17 O、 18 O、 32 p、 33 p、33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl、 82 Br、 123 I, 124 I, 125 I, 129 I and 131 In some implementations, I is deuterium.

[0450] Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete; partial deuterium substitution refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0451] When a site is specifically designated as deuterium D, the site should be understood as having a deuterium abundance of at least 1,000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). The compounds in the examples having a natural abundance greater than deuterium can be at least 1000 times abundant deuterium (i.e., at least 15% deuterium doping), at least 2000 times abundant deuterium (i.e., at least 30% deuterium doping), at least 3000 times abundant deuterium (i.e., at least 45% deuterium doping), at least 3340 times abundant deuterium (i.e., at least 50.1% deuterium doping), at least 3500 times abundant deuterium (i.e., at least 52.5% deuterium doping), at least 4000 times abundant deuterium (i.e., at least 60% deuterium doping), or at least 4500 times abundant deuterium (i.e., at least 67.5% deuterium doping). The abundance of deuterium is at least 5000 times (i.e., at least 75% deuterium doping), at least 5500 times (i.e., at least 82.5% deuterium doping), at least 6000 times (i.e., at least 90% deuterium doping), at least 6333.3 times (i.e., at least 95% deuterium doping), at least 6466.7 times (i.e., at least 97% deuterium doping), at least 6600 times (i.e., at least 99% deuterium doping), at least 6633.3 times (i.e., at least 99.5% deuterium doping), or higher.

[0452] "Optional" or "optional" means that the event or situation described below may but is not necessarily to occur; it includes both the possibility that the event or situation may occur or not occur. For example, "C that is optionally substituted with a halogen or cyano group..." 1-6 "Alkyl" includes cases where the alkyl group is substituted with a halogen or cyano group and cases where the alkyl group is not substituted with a halogen or cyano group.

[0453] "Substitution" or "substituted" refers to one or more hydrogen atoms in a group, in some embodiments 1 to 6, and in some embodiments 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).

[0454] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their pharmaceutically acceptable salts, along with other chemical components, such as pharmaceutically 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 its biological activity.

[0455] "Pharmacologically acceptable salt" refers to the salt of the compounds disclosed herein, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and possess the expected biological activity. They can be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include both inorganic and organic acids.

[0456] For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to the amount of a drug or agent sufficient to achieve or at least partially achieve the intended effect. The determination of the therapeutic effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate therapeutic effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0457] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0458] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0459] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and in some embodiments within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are typically given for illustrative purposes only and not as limitations. Detailed Implementation

[0460] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0461] Example

[0462] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0463] MS measurements were performed using a Finnigan LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

[0464] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 high-performance liquid chromatograph.

[0465] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0466] High performance liquid chromatography (HPLC) was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs.

[0467] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0468] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0469] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0470] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0471] Mean inhibition rate of kinases and IC50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0472] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0473] Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere.

[0474] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0475] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0476] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0477] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0478] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0479] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0480] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0481] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, D: ethyl acetate / methanol, E: dichloromethane / ethyl acetate. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0482] Example 1

[0483] M-(2S)-N-((3'S,4'S,Z)-2'-(5-(3-(1,4-oxazopentane-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1'-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazine-1-undecano]-4'-yl)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)acetamide 1-1

[0484] first step

[0485] 3-Bromo-2-((S)-1-methoxyethyl)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine 1b

[0486] (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine 1a (3 g, 8.77 mmol, prepared by the method disclosed in intermediate A on page 20 of patent application "WO2024008834"), 2-(2-propoxy)tetrahydropyran (1.84 g, 13.13 mmol, Shanghai Titan), triethylamine (2.66 g, 26.29 mmol), bis(triphenylphosphine)palladium(II) dichloride (923 mg, 1.31 mmol), and cuprous iodide (250 mg, 1.31 mmol) were dissolved in tetrahydrofuran (90 mL), purged with nitrogen, and reacted at 40 °C for 16 hours. After the reaction solution was cooled to room temperature, it was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give title compound 1b (3 g, yield: 96.5%).

[0487] MS m / z(ESI): 354.3 [M+1].

[0488] Step 2

[0489] (S)-3-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)prop-2-yn-1-ol 1c

[0490] Compound 1b (3 g, 8.47 mmol) was dissolved in methanol (30 mL) and dichloromethane (30 mL), and p-toluenesulfonic acid hydrate (8.05 g, 42.34 mmol) was added. The mixture was stirred for 3 hours. The pH of the reaction solution was adjusted to >7 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (50 mL × 3), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 1c (2.2 g, yield: 96.1%).

[0491] MS m / z(ESI):270.0[M+1].

[0492] Step 3

[0493] (S)-3-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)prop-2-yn-1-ylmethanesulfonate 1d

[0494] Compound 1c (2.2 g, 8.14 mmol) was dissolved in dichloromethane (100 mL), and triethylamine (4.12 g, 40.72 mmol) and methanesulfonic anhydride (3.54 g, 20.36 mmol) were added at 0 °C. The mixture was stirred for 1 hour. The reaction solution was extracted with saturated sodium bicarbonate solution and dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1d (2.8 g). The product was used directly in the next reaction without purification.

[0495] MS m / z(ESI):348.0[M+1].

[0496] Step 4

[0497] (S)-4-(3-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)prop-2-yn-1-yl)-1,4-oxazaheptanyl 1e

[0498] The crude compound 1d (522 mg, 5.16 mmol) was dissolved in dichloromethane (15 mL), and 1,4-oxazaheptan (450 mg, 1.29 mmol) was added. The mixture was stirred for 16 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 1e (330 mg, yield: 72.2%).

[0499] MS m / z(ESI): 353.1 [M+1].

[0500] Step 5

[0501] 1g of 2-(1-(4-bromothiazol-2-yl)cyclopropyl)-2-((tert-butoxycarbonyl)amino)acetic acid

[0502] 1f of 2-amino-2-(1-(4-bromothiazol-2-yl)cyclopropyl)acetic acid (14g, 50.51mmol, prepared by the method disclosed in Reference Example 10 on page 67 of patent application "WO2024067857") was dissolved in tetrahydrofuran (25mL) and water (10mL). Sodium bicarbonate (14.85g, 176.81mmol) and di-tert-butyl dicarbonate (13.23g, 60.62mmol) were added, and the mixture was stirred at 50°C for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1g (19g) of the crude title compound. The product was used directly in the next reaction without purification.

[0503] MS m / z(ESI): 377.3 [M+1].

[0504] Step 6

[0505] 2-(1-(4-bromothiazol-2-yl)cyclopropyl)-2-((tert-butoxycarbonyl)amino)methyl acetate 1h

[0506] (R)-2-(1-(4-bromothiazo-2-yl)cyclopropyl)-2-((tert-butoxycarbonyl)amino)methyl acetate 1h-1

[0507] (S)-2-(1-(4-bromothiazo-2-yl)cyclopropyl)-2-((tert-butoxycarbonyl)amino)methyl acetate 1h-2

[0508] 1 g (13 g, 34.46 mmol) of the crude title compound was dissolved in tetrahydrofuran (70 mL) and methanol (70 mL), and a 2 M trimethylsilyldiazomethane solution in n-hexane (34.4 mL) was added. The mixture was stirred for 16 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 1h (4.9 g, yield: 36.3%).

[0509] MS m / z(ESI): 391.3 [M+1].

[0510] Compound 1h (30 g) was resolved by a chiral column (Shimadzu LC-20AP, column: ChiralPak IG, 10 μm, 50 mm * 300 mm; mobile phase A: n-hexane, mobile phase B: isopropanol, gradient ratio: A:B = 85:15, flow rate: 80 mL / min) to give title compounds 1h-1 (13.8 g, yield: 46%) and 1h-2 (13.5 g, yield: 45%).

[0511] Single configuration compound (shorter retention time): 1 h⁻¹ (13.8 g, yield: 46%).

[0512] Chiral HPLC analysis: retention time 4.046 min, purity: 99.9% (column: ChiralPak IG, 3*100mm, 3μm; mobile phase A: n-hexane, mobile phase B: isopropanol (0.1% diethylamine), gradient ratio: A:B = 85:15, flow rate: 1.5 mL / min).

[0513] Single configuration compound (longer retention time): 1 h⁻² (13.5 g, yield: 45%).

[0514] Chiral HPLC analysis: retention time 5.895 min, purity: 99.9% (column: ChiralPak IG, 3*100mm, 3μm; mobile phase A: n-hexane, mobile phase B: isopropanol (0.1% diethylamine), gradient ratio: A:B = 85:15, flow rate: 1.5 mL / min).

[0515] MS m / z(ESI): 893.5 [M+1].

[0516] Step 7 (S)-2-(1-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazolyl-2-yl)cyclopropyl)-2-((tert-butoxycarbonyl)amino)methyl acetate 1j

[0517] Compound 1h-2 (2.06 g, 5.26 mmol) was dissolved in a mixed solvent of toluene (10 mL), 1,4-dioxane (40 mL), and water (10 mL). Then, 2,2-dimethyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1H-indol-3-yl)propyl acetate 1i (2.05 g, 5.52 mmol) was added, as described on page 81 of patent application "WO2024067857". The compound was prepared by the method disclosed in Example 9. Potassium phosphate (2.80 g, 13.19 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (385 mg, 5263 μmol) were reacted at 70 °C for 17 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system E to give the title compound 1j (2.30 g, 78.4% yield).

[0518] MS m / z(ESI): 556.7 [M+1].

[0519] Step 8 (S)-2-(1-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-2-iodo-1H-indolyl-5-yl)thiazolyl-2-yl)cyclopropyl)-2-((tert-butoxycarbonyl)amino)methyl acetate 1k

[0520] Compound 1j (1.98 g, 3.57 mmol) was dissolved in N,N-dimethylformamide (40 mL), and N-iodosuccinimide (763 mg, 3.39 mmol) was added. The mixture was stirred for 17 hours. The reaction solution was quenched with saturated sodium sulfite solution, extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The mixture was washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1k (1.69 g, 69.5% yield).

[0521] MS m / z(ESI): 682.1 [M+1].

[0522] Step 9 (S)-2-((tert-butoxycarbonyl)amino)-2-(1-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl)cyclopropyl)acetic acid 1l

[0523] Compound 1k (1.69 g, 2.48 mmol) was dissolved in tetrahydrofuran (30 mL), and a solution of lithium hydroxide monohydrate (521 mg, 12.41 mmol) in water (9 mL) was added at 0 °C. The mixture was stirred at room temperature for 16 hours. The pH of the reaction solution was adjusted to approximately 6 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude title compound 1l (1.69 g). The product was used directly in the next reaction without purification.

[0524] MS m / z(ESI): 626.1 [M+1].

[0525] Step 10 (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-2-(1-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl-2-yl)cyclopropyl)acetyl)hexahydropyridazine-3-carboxylic acid methyl ester 1m

[0526] (S)-hexahydropyridazine-3-carboxylic acid methyl ester hydrochloride (704 mg, 3.24 mmol, Shanghai Shaoyuan) was dissolved in dichloromethane (25 mL), and compound 1l (1.69 g, 2.70 mmol) was added. N,N-diisopropylethylamine (1.40 g, 10.83 mmol), n-butylphosphine anhydride (50% ethyl acetate solution) (3.89 g, 5.40 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.41 g, 7.35 mmol) were added at 0 °C. The mixture was stirred for 15 minutes while maintaining the temperature. The reaction solution was quenched with water, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 1m (986 mg, yield: 48.5%).

[0527] MS m / z(ESI): 752.3 [M+1].

[0528] Step 11 (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-2-(1-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl-2-yl)cyclopropyl)acetyl)hexahydropyridazine-3-carboxylic acid 1n

[0529] Compound 1m (986 mg, 1.31 mmol) was dissolved in tetrahydrofuran (12 mL), and a solution of lithium hydroxide monohydrate (165 mg, 3.93 mmol) in water (3 mL) was added at 0 °C. The mixture was stirred and kept at the temperature for 2 hours. The pH of the reaction solution was adjusted to <7 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1n (1.1 g). The product was used directly in the next reaction without purification.

[0530] MS m / z(ESI):738.2[M+1].

[0531] Step Twelve

[0532] ((3'S,4'S,Z)-2'-iodo-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indolia-6(1,3-pyridaziniacycloundecan]-4'-yl]tert-butyl carbamate 1o

[0533] The crude title compound 1n (1.1 g, 1.49 mmol) was dissolved in dichloromethane (80 mL), and 1-hydroxybenzotriazole (1.13 g, 7.45 mmol) and N,N-diisopropylethylamine (3.64 g, 28.2 mmol) were added. The mixture was cooled to 0 °C, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.29 g, 22.37 mmol) was added in portions. The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution, and extracted with dichloromethane (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 1o (450 mg, yield: 41.9%).

[0534] Step 13 ((3'S,4'S,Z)-10',10'-dimethyl-5',7'-dioxo-2'-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclopentan-2-yl)spiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indola-6(1,3-pyridazin-hexacycloundecan]-4'-yl) tert-butyl aminocarboxylate 1p

[0535] Compound 1o (750 mg, 1.04 mmol) was dissolved in toluene (15 mL), and 2-biscyclohexylphosphine-2',6'-dimethoxybiphenyl (129 mg, 314 μmol), tris(dibenzylacetone)dipalladium (144 mg, 157 μmol), and potassium acetate (307 mg, 3.13 mmol) were added. Pinara-borane (867 mg, 6.77 mmol) was added under 0 °C protection, followed by nitrogen purging three times. The mixture was stirred at 65 °C for 7 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 1p (750 mg, 99.9% yield).

[0536] MS m / z(ESI):720.1[M+1].

[0537] Step Fourteen

[0538] ((3'S,4'S,Z)-2'-(5-(3-(1,4-oxazopentane-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3-pyridazine-hexacycloundecanedan]-4'-yl)tert-butyl carbamate 1q

[0539] Compound 1e (330 mg, 934 μmol) was dissolved in a mixed solvent of toluene (4 mL), 1,4-dioxane (12 mL), and water (4 mL). Compound 1p (840 mg, 934 μmol), potassium phosphate (496 mg, 2.33 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (70 mg, 95 μmol) were added. The mixture was stirred at 70 °C for 16 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1q (600 mg, yield: 74.1%).

[0540] MS m / z(ESI): 866.6 [M+1].

[0541] Step 15

[0542] ((3'S,4'S,Z)-2'-(5-(3-(1,4-oxazopentane-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1'-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3-pyridazine-hexacycloundecanedan]-4'-yl)tert-butyl carbamate 1r

[0543] M-((3'S,4'S,Z)-2'-(5-(3-(1,4-oxazopentane-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1'-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indolia-6(1,3-pyridazin-hexacycloundecanedan]-4'-yl)tert-butyl carbamate 1r-1

[0544] P-((3'S,4'S,Z)-2'-(5-(3-(1,4-oxazopentane-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1'-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3-pyridazine-hexacycloundecanedan]-4'-yl)tert-butyl carbamate 1r-2

[0545] Compound 1q (600 mg, 693 μmol) was dissolved in N,N-dimethylformamide (10 mL), and cesium carbonate (1.01 g, 3.12 mmol) and iodoethane (270 mg, 1.73 mmol) were added. The mixture was stirred for 4.5 hours. The reaction solution was diluted with ethyl acetate and filtered. The filtrate was washed successively with water and saturated sodium chloride solution to separate the organic phase. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain crude title compound 1r (620 mg). The crude compound 1r was purified by preparative high performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*250 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 60%-95%, flow rate: 30 mL / min). The short retention time was collected to obtain title compound 1r-1 (70 mg, yield: 11.3%).

[0546] MS m / z(ESI): 894.6 [M+1].

[0547] Step Sixteen

[0548] M-(3'S,4'S,Z)-2'-(5-(3-(1,4-oxazopentane-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-4'-amino-1'-ethyl-10',10'-dimethylspiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazine-hexacycloundecan]-5',7'-dione hydrochloride 1s-1

[0549] Compound 1r-1 (65 mg, 73 μmol) was dissolved in dichloromethane (1 mL), and a 4 M hydrogen chloride solution of 1,4-dioxane (2 mL) was added. The mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain the crude title compound 1s-1 (60 mg). The product was used directly in the next reaction without purification.

[0550] MS m / z(ESI): 794.7 [M+1].

[0551] Step Seventeen

[0552] M-(5S)-7-((1S)-2-(((3'S,4'S,Z)-2'-(5-(3-(1,4-oxazaheptan-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1'-ethyl-10',10'-dimethyl-5',7'-dioxaspiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazine-1-4'-yl)amino)-1-cyclopentyl-2-oxoethyl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester 1t-1

[0553] (S)-2-((S)-7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]non-2-yl)-2-cyclopentylacetic acid (38 mg, 108 μmol, prepared by the method disclosed in intermediates A-3 and A-4 on page 166 of patent application "WO2023060253") was dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (142 mg, 1.10 mmol) was added at 0 °C, followed by O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (51 mg, 134 μmol). After stirring at the same temperature for 0.5 hours, crude compound 1s-1 (75 mg, 90 μmol) was added, and the reaction was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 1t-1 (90 mg, yield: 88%).

[0554] MS m / z(ESI):1128.8[M+1].

[0555] Step 18

[0556] M-(2S)-N-((3'S,4'S,Z)-2'-(5-(3-(1,4-oxazopentane-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1'-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxazo-2(4,2)-thiazo-1(5,3)-indolazo-6(1,3-pyridazine-1-cycloundecan]-4'-yl)-2-cyclopentyl-2-((S)-2,7-diazaspiro[4,4]non-2-yl)acetamide hydrochloride 1u-1

[0557] Compound 1t-1 (90 mg, 80 μmol) was dissolved in dichloromethane (1 mL), and a 4M hydrogen chloride solution of 1,4-dioxane (2 mL) was added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain the crude title compound 1u-1 (90 mg). The product was used directly in the next reaction without purification.

[0558] MS m / z(ESI):1028.5[M+1].

[0559] Step 19

[0560] M-(2S)-N-((3'S,4'S,Z)-2'-(5-(3-(1,4-oxazopentane-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1'-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazine-1-undecano]-4'-yl)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)acetamide 1-1

[0561] The crude compound 1u-1 (90 mg, 85 μmol) was dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (192 mg, 1.48 mmol) was added. At 0 °C, lithium (2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carboxylate (44 mg, 299 μmol, prepared using the method disclosed in intermediate B-1 on page 168 of patent application "WO2023060253") and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (42 mg, 110 μmol) were added. The mixture was stirred for 2 hours. The reaction mixture was filtered, and the liquid was purified by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate). C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 30mL / min) to give title compound 1-1 (19mg, yield: 22%).

[0562] MS m / z(ESI):1152.0[M+1].

[0563] 1H NMR (500MHz, CD3OD): δ8.80(d,1H),8.64(s,1H),7.93(t,1H),7.76–7.68(m,1H),7.53(d,1H),7.50(dd,1H),4.47(d,1H),4.3 5–4.13(m,3H),4.05(s,1H),3.84(t,2H),3.82–3.78(m,3H),3.75(s,2H),3.70-3.57(m,2H),3.46(t,1H),3.23(d,2H),3.08( t,1H),2.94(dt,5H),2.87(t,3H),2.76–2.54(m,3H),2.40(s,1H),2.35-2.16(m,5H),2.09–1.97(m,4H),1.79(d,5H),1.65(d dd,5H),1.57–1.45(m,7H),1.44-1.34(m,5H),1.11(dd,4H),0.96–0.80(m,4H),0.71(s,4H),0.56–0.37(m,3H),0.25(dt,1H).

[0564] Example 2

[0565] M-(1r,2R,3S)-N-((3'S,4'S,Z)-2'-(5-(3-(1,4-oxazopentane-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1'-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indola-6(1,3-pyridazin-1-cycloundecan]-4'-yl)-2,3-dimethylcyclopropane-1-carboxamide 2-1

[0566] The crude compound 1s-1 (9 mg, 11 μmol) was dissolved in N,N-dimethylformamide (0.5 mL), and N,N-diisopropylethylamine (13 mg, 100 μmol) was added. Then, (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (2.5 mg, 22 μmol) and 1-cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-morpholino-carbomony hexafluorophosphate (6 mg, 14 μmol) were added at 0 °C. The mixture was stirred at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was purified by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate). C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 30mL / min) to give title compound 2-1 (1.8mg, yield: 19%).

[0567] MS m / z(ESI): 890.5 [M+1].

[0568] 1 H NMR (500MHz, CD3OD): δ8.79(d,1H),8.59(d,1H),7.92(d,1H),7.71(dd,1H),7.49(d,2H),4.49(d, 1H),4.27(dt,2H),4.18(s,1H),4.06(dd,1H),3.84(t,2H),3.82–3.75(m,3H),3.74(s,2H),3.64( t,1H),3.24(s,3H),2.96–2.89(m,4H),2.87–2.73(m,3H),2.21(t,3H),2.10-1.93(m,6H),1.81(d ,1H),1.70-1.57(m,3H),1.47(d,3H),1.10(dt,7H),0.96–0.89(m,3H),0.87(s,3H),0.69(s,3H).

[0569] Example 3

[0570] M-(2S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)-N-((3'S,4'S,Z)-1'-ethyl-2'-(2-((S)-1-methoxyethyl)-5-(3-(4-methyl-4,7-diazaspiro[2.5]oct-7-yl)prop-1-yn-1-yl)pyridin-3-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazine-1-cycloundecan]-4'-yl)acetamide 3-1

[0571] Step 1 ((3'S,4'S,Z)-2'-(2-((S)-1-methoxyethyl)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridin-3-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3-pyridazin-cycloundecan]-4'-yl)tert-butyl carbamate 3a

[0572] Compound 1b (600 mg, 1.69 mmol) was dissolved in a mixed solvent of toluene (5 mL), 1,4-dioxane (15 mL), and water (5 mL). Compound 1p (1.5 g, 1.67 mmol), potassium phosphate (899 mg, 4.23 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (126 mg, 172 μmol) were added. The mixture was stirred at 70 °C for 16 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give title compound 3a (1 g, yield: 70%).

[0573] MS m / z(ESI): 867.6 [M+1].

[0574] Step 2

[0575] ((3'S,4'S,Z)-1'-ethyl-2'-(2-((S)-1-methoxyethyl)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridin-3-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolazo-6(1,3-pyridazinazonium]-4'-yl)tert-butyl carbamate 3b

[0576] Compound 3a (700 mg, 807 μmol) was dissolved in N,N-dimethylformamide (10 mL), and cesium carbonate (789 mg, 2.42 mmol) and iodoethane (378 mg, 2.42 mmol) were added. The mixture was stirred for 2 hours. The reaction solution was diluted with ethyl acetate and filtered. The filtrate was washed successively with water and saturated sodium chloride solution to separate the organic phase. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 3b (700 mg, yield: 96.8%).

[0577] MS m / z(ESI): 895.6 [M+1].

[0578] Step 3

[0579] ((3'S,4'S,Z)-1'-ethyl-2'-(5-(3-hydroxyprop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indola-6(1,3-pyridazin-hexacycloundecanedan]-4'-yl)tert-butyl carbamate 3c

[0580] M-((3'S,4'S,Z)-1'-ethyl-2'-(5-(3-hydroxyprop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indolia-6(1,3-pyridazin-hexacycloundecanedan]-4'-yl)tert-butyl carbamate 3c-1

[0581] P-((3'S,4'S,Z)-1'-ethyl-2'-(5-(3-hydroxyprop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indola-6(1,3-pyridazin-cycloundecanedin]-4'-yl)tert-butyl carbamate 3c-2

[0582] Compound 3b (700 mg, 782 μmol) was dissolved in methanol (8 mL) and dichloromethane (8 mL), and p-toluenesulfonic acid hydrate (744 mg, 3.91 mmol) was added. The mixture was stirred for 1 hour, and the pH of the reaction solution was adjusted to >7 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (15 mL × 3), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 3c (640 mg). The crude compound 3c was purified by preparative high performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*250 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-65%, flow rate: 30 mL / min). The short retention time was collected to obtain title compound 3c-1 (200 mg, yield: 31.2%).

[0583] MS m / z(ESI): 811.7 [M+1].

[0584] Step 4

[0585] M-3-(5-((3'S,4'S,Z)-4'-((tert-butoxycarbonyl)amino)-1'-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indolia-6(1,3-pyridaziniacycloundecan]-2'-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)prop-2-yn-1-ylmethanesulfonate 3d-1

[0586] Compound 3c-1 (200 mg, 247 μmol) was dissolved in dichloromethane (10 mL), and triethylamine (125 mg, 1.23 mmol) and methanesulfonic anhydride (107 mg, 616 μmol) were added at 0 °C. The mixture was stirred for 1 hour. The reaction solution was extracted with saturated sodium bicarbonate solution and dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 3d-1 (250 mg). The product was used directly in the next reaction without purification.

[0587] MS m / z(ESI): 889.6 [M+1].

[0588] Step 5

[0589] M-((3'S,4'S,Z)-1'-ethyl-2'-(2-((S)-1-methoxyethyl)-5-(3-(4-methyl-4,7-diazaspiro[2.5]oct-7-yl)prop-1-yn-1-yl)pyridin-3-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indolia-6(1,3-pyridazin-cycloundecan]-4'-yl)tert-butyl carbamate 3e-

[0590] The crude compound 3d-1 (219 mg, 246 μmol) was dissolved in dichloromethane (10 mL), and 4-methyl-4,7-diazaspiro[2.5]octane dihydrochloride (98 mg, 492 μmol) and N,N-diisopropylethylamine (191 mg, 1.48 mmol) were added. The mixture was stirred for 5 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 3e-1 (150 mg, yield: 66.2%).

[0591] MS m / z(ESI): 919.8 [M+1].

[0592] Step 6

[0593] P-(3'S,4'S,Z)-4'-amino-1'-ethyl-2'-(2-((S)-1-methoxyethyl)-5-(3-(4-methyl-4,7-diazaspiro[2.5]oct-7-yl)prop-1-yn-1-yl)pyridin-3-yl)-10',10'-dimethylspiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazine-cycloundecan]-5',7'-dione hydrochloride 3f-1

[0594] Compound 3e-1 (150 mg, 163 μmol) was dissolved in dichloromethane (2 mL) and methanol (2 mL), and a 1,4-dioxane solution of 4M hydrogen chloride (6 mL) was added. The mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain crude title compound 3f-1 (124 mg). The product was used directly in the next step of the reaction without purification.

[0595] MS m / z(ESI): 819.5 [M+1].

[0596] Step 7

[0597] M-(5S)-7-((1S)-1-cyclopentyl-2-(((3'S,4'S,Z)-1'-ethyl-2'-(2-((S)-1-methoxyethyl)-5-(3-(4-methyl-4,7-diazaspiro[2.5]oct-7-yl)prop-1-yn-1-yl)pyridin-3-yl)-10',10'-dimethyl-5',7'-dioxanespiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridaziniacycloundecan]-4'-yl)amino)-2-oxoethyl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester 3g-1

[0598] (S)-2-((S)-7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]non-2-yl)-2-cyclopentylacetic acid (53 mg, 145 μmol) was dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (193 mg, 1.49 mmol) was added at 0 °C. O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (71 mg, 186 μmol) was added, and the mixture was stirred at the same temperature for 0.5 hours. Then, crude compound 3f-1 (120 mg, 124 μmol) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 3 g-1 (60 mg, yield: 41.8%).

[0599] MS m / z(ESI):1153.6[M+1].

[0600] Step 8

[0601] M-(2S)-2-cyclopentyl-N-((3'S,4'S,Z)-1'-ethyl-2'-(2-((S)-1-methoxyethyl)-5-(3-(4-methyl-4,7-diazaspiro[2.5]oct-7-yl)prop-1-yn-1-yl)pyridin-3-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridaziniacycloundecan]-4'-yl)-2-((S)-2,7-diazaspiro[4.4]non-2-yl)acetamide hydrochloride 3h-1

[0602] Compound 3g-1 (60mg, 52μmol) was dissolved in dichloromethane (1mL), and a 1,4-dioxane solution of 4M hydrogen chloride (2mL) was added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain crude title compound 3h-1 (65mg). The product was used directly in the next reaction without purification.

[0603] MS m / z(ESI): 1053.6 [M+1].

[0604] Step 9

[0605] M-(2S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)-N-((3'S,4'S,Z)-1'-ethyl-2'-(2-((S)-1-methoxyethyl)-5-(3-(4-methyl-4,7-diazaspiro[2.5]oct-7-yl)prop-1-yn-1-yl)pyridin-3-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazine-1-cycloundecan]-4'-yl)acetamide 3-1

[0606] The crude compound 3h⁻¹ (58 mg, 53 μmol) was dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (136 mg, 1.05 mmol) was added. At 0 °C, lithium (2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carboxylate (31 mg, 210 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (30 mg, 79 μmol) were added. The mixture was stirred for 2 hours. The reaction mixture was filtered, and the liquid was purified by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate). C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 30mL / min) to give title compound 3-1 (18mg, yield: 29%).

[0607] MS m / z(ESI):1176.6[M+1].

[0608] 1H NMR (500MHz, CD3OD): δ8.80(d,1H),8.64(s,1H),7.94(t,1H),7.77–7.67(m,1H),7.61–7.41(m,2H),5.36(dd,2H),4.6 0(s,3H),4.48(d,2H),4.29–4.05(m,5H),3.80(d,1H),3.70–3.56(m,4H),3.47(d,2H),3.25–3.12(m,3H),3.03(d,3H), 2.91–2.75(m,5H),2.71–2.52(m,4H),2.39(d,3H),2.32(s,2H),2.30–2.17(m,4H),2.15–1.92(m,3H),1.80(s,3H),1.7 1–1.56(m,3H),1.59–1.44(m,2H),1.45–1.20(m,11H),1.23–0.84(m,6H),0.78(s,3H),0.57–0.40(m,5H),0.11(d,2H).

[0609] Example 4

[0610] M-(1r,2R,3S)-N-((3'S,4'S,Z)-1'-ethyl-2'-(2-((S)-1-methoxyethyl)-5-(3-(4-methyl-4,7-diazaspiro[2.5]oct-7-yl)prop-1-yn-1-yl)pyridin-3-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridaziniacycloundecan]-4'-yl)-2,3-dimethylcyclopropane-1-carboxamide 4-1

[0611] The crude compound 3f-1 (15 mg, 18 μmol) was dissolved in N,N-dimethylformamide (1 mL), and N,N-diisopropylethylamine (20 mg, 155 μmol) was added. Then, (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (3.5 mg, 31 μmol) and 1-cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-morpholino-carbomony hexafluorophosphate (8.6 mg, 20 μmol) were added at 0 °C. The mixture was stirred at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was purified by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate). C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 30mL / min) to give title compound 4-1 (5mg, yield: 35.1%).

[0612] MS m / z(ESI): 915.9 [M+1].

[0613] 1 H NMR (500MHz, CD3OD): δ8.80(d,1H),8.59(s,1H),8.22(d,1H),7.93(d,1H),7.78–7.69(m,1H),7.49(d,2 H),6.75(d,1H),4.49(d,1H),4.28(dq,2H),4.17(d,1H),4.05(dd,2H),3.78(d,2H),3.63(d,4H),3.24( s,3H),3.01(d,2H),2.88–2.72(m,5H),2.20(d,1H),2.06–1.95(m,1H),1.77(dd,2H),1.72–1.58(m,3H) ,1.47(d,5H),1.37–1.25(m,3H),1.19–1.02(m,9H),0.86(s,3H),0.79(s,3H),0.69(s,3H),0.58(s,2H).

[0614] Example 5

[0615] M-(2S)-N-((3'S,4'S,Z)-2'-(5-(3-(1,4-oxazopentane-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10',10'-dimethyl-5',7'-dioxo-1'-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazine-1-undecano]-4'-yl)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)acetamide 5-1

[0616] Referring to the synthetic route of Example 1, replacing iodoethane in step 15 with 2,2,2-trifluoroethyltrifluoromethane sulfonate (Shanghai Titan) yielded the title compound (45 mg, 26.9%).

[0617] MS m / z(ESI):1205.6[M+1].

[0618] 1H NMR (500MHz, CD3OD): δ8.81(s,1H),8.62(s,1H),7.87(s,1H),7.80-7.77(m,1H),7.61(s,1H), 7.60-7.58(m,1H),5.20-5.15(m,2H),4.97-4.93(m,1H),4.79-4.77(m,2H),4.48-4.45(m,1H) ,4.30-4.24(m,3H),3.85-3.82(m,2H),3.81-3.79(m,2H),3.77-3.75(m,2H),3.70-3.68(m,1H ),3.67-3.63(m,1H),3.51-3.47(m,2H),3.43-3.38(m,2H),3.29-3.27(m,2H),3.11-3.06(m,1H ),2.94-2.92(m,4H),2.88-2.83(m,2H),2.78-2.75(m,2H),2.67-2.65(m,2H),2.40-2.39(m,1 H),2.35-2.26(m,5H),2.02-1.98(m,3H),1.88-1.75(m,6H),1.68-1.62(m,4H),1.58-1.52(m, 4H),1.47-1.46(m,3H),1.44-1.42(m,1H),1.35-1.31(m,2H),1.12-1.09(m,2H),0.97(s,3H), 0.67-0.63(m,1H),0.60-0.55(m,2H),0.54-0.48(m,2H),0.45-0.41(m,1H),0.29-0.25(m,1H).

[0619] Example 6

[0620] M-(2S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)-N-((3'S,4'S,Z)-2'-(2-((S)-1-methoxyethyl)-5-(3-(4-methyl-4,7-diazaspiro[2 .5]oct-7-yl)prop-1-yn-1-yl)pyridin-3-yl)-10',10'-dimethyl-5',7'-dioxo-1'-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecanedan]-4'-yl)acetamide 6-1

[0621] Referring to the synthetic route of Example 3, the second step of iodoethane was replaced with 2,2,2-trifluoroethyltrifluoromethanesulfonate (Shanghai Titan) to obtain the title compound (30 mg, 24.9%).

[0622] MS m / z(ESI):1230.6[M+1].

[0623] 1 H NMR (500MHz, CD3OD): δ8.82(d,1H),8.63(s,1H),7.89(s,1H),7.79(d,1H),7.61(d,2H),5.18(dd,1 H),4.46(d,1H),4.29(s,2H),3.79(d,1H),3.67(d,5H),3.50(d,2H),3.15-2.55(m,14H),2.40(s,4 H),2.31(s,2H),2.29(d,2H),2.21(t,1H),2.12–1.95(m,4H),1.95–1.75(m,6H),1.73–1.51(m,10H ),1.47(d,4H),1.16–1.07(m,2H),1.01–0.87(m,5H),0.79(d,2H),0.69–0.40(m,9H),0.28(dt,1H).

[0624] Example 7

[0625] M-(2S,3S)-N-((6 4 S,3S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(4-methyl-4,7-diazaspiro[2.5]oct-7-yl)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-3-(2-oxa-6-azaspiro)

[0626] [3.3]hepta-6-methyl)-1 1 -(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)-3-methyloxacyclobutane-2-formamide 7-1

[0627] The title compound was prepared by referring to Example 27 of this disclosure and the prior art.

[0628] MS m / z(ESI): 1100.6 [M+1].

[0629] Example 8

[0630] M-(2S,3S)-N-((6 4 S,3S,4S,Z)-1 2 -(5-(3-(1,4-oxazacyclohep-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1 1 -(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)-3-methyloxacyclobutane-2-formamide 8-1

[0631] The title compound was prepared by referring to Example 27 of this disclosure and the prior art.

[0632] MS m / z(ESI):1075.6[M+1].

[0633] Example 9

[0634] M-(2S,3S)-N-((6 3 S,3S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(4-methyl-4,7-diazaspiro[2.5]oct-7-yl)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1 1 -(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-acyclohexane-4-yl)-3-methyloxacyclobutane-2-formamide 9-1

[0635] The title compound was prepared by referring to Example 27 of this disclosure and the prior art.

[0636] MS m / z(ESI):1088.6[M+1].

[0637] Example 10

[0638] M-(2S,3S)-N-((6 3 S,3S,4S,Z)-1 2 -(5-(3-(1,4-oxazacycloheptan-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1 1 -(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-acyclohexane-4-yl)-3-methyloxacyclobutane-2-carboxamide 10-1

[0639] The title compound was prepared by referring to Example 27 of this disclosure and the prior art.

[0640] MS m / z(ESI): 1063.6 [M+1].

[0641] Example 11

[0642] M-(2S,3S)-N-((6 4 S,3S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(4-methyl-4,7-diazaspiro[2.5]oct-7-yl)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-1 1 -(2-(oxecyclobutane-3-yloxy)ethyl)-5,7-dioxo-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)-3-methyloxacyclobutane-2-carboxamide 11-1

[0643] The title compound was prepared by referring to Example 27 of this disclosure and the prior art.

[0644] MS m / z(ESI): 1072.6 [M+1].

[0645] Example 12

[0646] M-(2S,3S)-N-((6 4 S,3S,4S,Z)-1 2 -(5-(3-(1,4-oxazapyridine-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-1 1 -(2-(oxecyclobutane-3-yloxy)ethyl)-5,7-dioxo-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)-3-methyloxacyclobutane-2-carboxamide 12-1

[0647] The title compound was prepared by referring to Example 27 of this disclosure and the prior art.

[0648] MS m / z(ESI): 1047.6 [M+1].

[0649] Example 13

[0650] M-(2S,3S)-N-((6 4 S,3S,4S,Z)-1 1 -((1s,3R)-3-cyanocyclobutyl)-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(4-methyl-4,7-diazaspiro[2.5]oct-7-yl)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)-3-methyloxacyclobutane-2-carboxamide 13-1

[0651] The title compound was prepared by referring to Example 27 of this disclosure and the prior art.

[0652] MS m / z(ESI): 1051.6 [M+1].

[0653] Example 14

[0654] M-(2S,3S)-N-((6 4 S,3S,4S,Z)-1 2 -(5-(3-(1,4-oxazapyridine-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -((1s,3R)-3-cyanocyclobutyl)-10,10-dimethyl-5,7-dioxo-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)-3-methyloxacyclobutane-2-formamide 14-1

[0655] The title compound was prepared by referring to Example 27 of this disclosure and the prior art.

[0656] MS m / z(ESI):1026.6[M+1].

[0657] Example 15

[0658] M-(2S)-N-((4'S,4'S,Z)-2'-(5-(3-(1,4-oxazacycloheptan-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1'-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-6] 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptanehexacycloundecaban]-4'-yl)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)acetamide 15-1

[0659] Option 1

[0660] Referring to the synthetic route of Example 1, in step 10, (S)-hexahydropyridazine-3-carboxylic acid methyl ester hydrochloride was replaced with (S)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid methyl ester di(2,2,2-trifluoroacetic acid) salt (prepared by the method disclosed in Example 8 on page 64 of the specification in patent application "WO2024067857"), to obtain the target product (126.6 mg, 29.4%).

[0661] Option 2

[0662] first step

[0663] (S)-2-((S)-2-((tert-Butoxycarbonyl)amino)-2-(1-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl)cyclopropyl)acetyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid methyl ester 15a

[0664] Methyl bis(2,2,2-trifluoroacetic acid) salt of ((S)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid (prepared by the method disclosed in Reference Example 8 on page 64 of patent application "WO2024067857") (1.24 mg, 3.24 mmol, Shanghai Shaoyuan) was dissolved in dichloromethane (25 mL), and compound 1l (1.69 g, 2.70 mmol) was added. N,N-diisopropyl Ethylamine (1.40 g, 10.83 mmol) and n-butylphosphine (50% ethyl acetate solution) (3.89 g, 5.40 mmol) were reacted at the temperature with stirring for 15 minutes. The reaction solution was quenched with water and extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 15a (986 mg, yield: 48.5%).

[0665] MS m / z(ESI): 764.5 [M+1].

[0666] Step 2

[0667] (S)-2-((S)-2-((tert-Butoxycarbonyl)amino)-2-(1-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl)cyclopropyl)acetyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid 15b

[0668] Compound 15a (986 mg, 1.31 mmol) was dissolved in tetrahydrofuran (12 mL), and a solution of lithium hydroxide monohydrate (165 mg, 3.93 mmol) in water (3 mL) was added at 0 °C. The mixture was stirred and kept at the temperature for 2 hours. The pH of the reaction solution was adjusted to <7 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 15b (1.1 g). The product was used directly in the next reaction without purification.

[0669] MS m / z(ESI): 750.4 [M+1].

[0670] Step 3

[0671] ((4'S,4'S,Z)-2'-iodo-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-6] 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaenoside]-4'-yl)tert-butyl carbamate 15c

[0672] The crude title compound 15b (1.1 g, 1.49 mmol) was dissolved in dichloromethane (80 mL), and 1-hydroxybenzotriazole (1.13 g, 7.45 mmol) and N,N-diisopropylethylamine (3.64 g, 28.2 mmol) were added. The mixture was cooled to 0 °C, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.29 g, 22.37 mmol) was added in portions. The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution, and extracted with dichloromethane (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 15c (450 mg, yield: 41.9%).

[0673] MS m / z(ESI): 732.3 [M+1].

[0674] Step 4 ((4'S,4'S,Z)-10',10'-dimethyl-5',7'-dioxo-2'-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)spiro[cyclopropane-1,3'-8-oxa-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaenoside]-4'-yl)tert-butyl carbamate 15d

[0675] Compound 15c (750 mg, 1.04 mmol) was dissolved in toluene (15 mL), and 2-biscyclohexylphosphine-2',6'-dimethoxybiphenyl (129 mg, 314 μmol), tris(dibenzylacetone)dipalladium (144 mg, 157 μmol), and potassium acetate (307 mg, 3.13 mmol) were added. Pinara-borane (867 mg, 6.77 mmol) was added under ice-water bath protection, and the mixture was purged three times with nitrogen. The mixture was stirred at 65 °C for 9 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 15d (750 mg, 99.9% yield).

[0676] MS m / z(ESI): 732.5 [M+1].

[0677] Step 5

[0678] ((4'S,4'S,Z)-2'-(2-((S)-1-methoxyethyl)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridin-3-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaenoside]-4'-yl)tert-butyl carbamate 15e

[0679] Compound 1b (1.43 g, 4.05 mmol) was dissolved in a mixed solvent of toluene (15 mL), 1,4-dioxane (45 mL), and water (15 mL). Compound 15d (2.28 g, 3.11 mmol), potassium phosphate (1.65 g, 7.78 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (228 mg, 311.9 μmol) were added. The mixture was stirred at 70 °C for 16 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give title compound 15e (2.32 g, yield: 84.6%).

[0680] MS m / z(ESI): 879.9 [M+1].

[0681] Step 6 ((4'S,4'S,Z)-1'-ethyl-2'-(2-((S)-1-methoxyethyl)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridin-3-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaenoside]-4'-yl)tert-butyl carbamate

[0682] Compound 15e (9.88 g, 11.2 mmol) was dissolved in N,N-dimethylformamide (120 mL), and cesium carbonate (12.8 g, 39.3 mmol) and iodoethane (4.38 g, 28.1 mmol) were added. The mixture was stirred for 4.5 hours. The reaction solution was diluted with ethyl acetate and filtered. The filtrate was washed successively with water and saturated sodium chloride solution to separate the organic phase. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 15f (7.90 g, yield: 77.5%).

[0683] MS m / z(ESI): 907.9 [M+1].

[0684] Step 7

[0685] ((4'S,4'S,Z)-1'-ethyl-2'-(5-(3-hydroxyprop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-6] 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptan-hexane-undecain]-4'-yl)tert-butyl carbamate 15gM-((4'S,4'S,Z)-1'-ethyl-2'-(5-(3-hydroxyprop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaenoside]-4'-yl)tert-butyl carbamate 15g-1

[0686] P-((4'S,4'S,Z)-1'-ethyl-2'-(5-(3-hydroxyprop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaenoside]-4'-yl)tert-butyl carbamate 15g-2

[0687] Compound 15f (7.9 g, 8.7 mmol) was dissolved in a mixed solvent of dichloromethane (120 mL) and methanol (120 mL), and p-toluenesulfonic acid monohydrate (7.4 g, 39 mmol) was added. The mixture was stirred for 1 hour, and a saturated sodium bicarbonate aqueous solution was added to the reaction solution to adjust the pH to greater than 7. The aqueous phase was extracted with ethyl acetate (100 mL × 3), and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 15 g, which was purified by preparative high performance liquid chromatography (Waters-2545, column: Welch Xtimate). C18, 30*250mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 60%-95%, flow rate: 30mL / min), yielded title compounds 15g-1 (1.47g, yield: 20.5%) and 15g-2 (2.10g, yield: 29.4%).

[0688] Single configuration compound 15 g-1 (shorter retention time): (1.47 g, yield: 20.5%)

[0689] HPLC analysis: retention time 1.73 min, purity: 99% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%). MS m / z (ESI): 823.8 [M+1].

[0690] Single configuration compound 15g-2 (longer retention time): (2.10g, yield: 29.4%)

[0691] HPLC analysis: retention time 1.79 min, purity: 99% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%). MS m / z (ESI): 823.8 [M+1].

[0692] Step 8

[0693] M-3-(5-((4'S,4'S,Z)-4'-((tert-butoxycarbonyl)amino)-1'-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-6] 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaenos]-2'-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)prop-2-yn-1-ylmethanesulfonate 15h-1

[0694] Compound 15 g⁻¹ (the compound with the shortest retention time, 303 mg, 368 μmol) was dissolved in dichloromethane (15 mL), and triethylamine (187 mg, 1.85 mmol) and methanesulfonic anhydride (161 mg, 924 μmol) were added. The mixture was stirred for 1 hour. Saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to greater than 7. The aqueous phase was extracted with dichloromethane (50 mL × 3), the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 15 h⁻¹. The product was used directly in the next reaction without purification.

[0695] MS m / z(ESI): 901.9 [M+1].

[0696] Step 9

[0697] M-((4'S,4'S,Z)-2'-(5-(3-(1,4-oxazacycloheptan-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1'-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-6] 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaenoside]-4'-yl)tert-butyl carbamate 15j-1

[0698] Compound 15h-1 (331 mg, 367 μmol) was dissolved in dichloromethane (5 mL), and 1,4-oxazacycloheptane (149 mg, 1.47 mmol) was added. The mixture was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 15j-1 (330 mg, yield: 99.1%).

[0699] MS m / z(ESI): 906.0 [M+1].

[0700] Step 10

[0701] M-(4'S,4'S,Z)-2'-(5-(3-(1,4-oxazacycloheptane-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-4'-amino-1'-ethyl-10',10'-dimethylspiro[cyclopropane-1,3'-8-oxaza-6] 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaphene]-5',7'-dione hydrochloride 15k-1

[0702] Compound 15j-1 (330 mg, 364 μmol) was dissolved in methanol (3 mL), and a 1,4-dioxane solution of 4 M hydrogen chloride (6 mL) was added. The mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain crude title compound 15k-1 (293 mg). The product was used directly in the next reaction without purification.

[0703] MS m / z(ESI):806.0[M+1].

[0704] Step 11

[0705] M-(5S)-7-((1S)-2-(((4'S,4'S,Z)-2'-(5-(3-(1,4-oxazacycloheptan-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1'-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-6] 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolia-6(2,4)-bicyclo[3.1.1]heptaneheptacyclo[1,4'-yl]amino)-1-cyclopentyl-2-oxoethyl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester 15l-1

[0706] (S)-2-((S)-7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]non-2-yl)-2-cyclopentylacetic acid (154 mg, 436 μmol, prepared by the method disclosed in intermediates A-3 and A-4 on page 166 of patent application "WO2023060253") was dissolved in N,N-dimethylformamide (5 mL). N,N-diisopropylethylamine (470 mg, 3.64 mmol) was added at 0 °C, followed by O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (208 mg, 547 μmol). After stirring at the same temperature for 0.5 hours, crude compound 15 k-1 (293 mg, 363 μmol) was added, and the reaction was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 15l-1 (414 mg, yield: 99%).

[0707] MS m / z(ESI):1141.1[M+1].

[0708] Step Twelve

[0709] M-(2S)-N-((4'S,4'S,Z)-2'-(5-(3-(1,4-oxazacycloheptan-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1'-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-6] 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheptacyclo[4'-yl]-2-cyclopentyl-2-((S)-2,7-diazaspiro[4.4]non-2-yl)acetamide hydrochloride 15m-1

[0710] Compound 15l-1 (573 mg, 501 μmol) was dissolved in methanol (3 mL), and a 1,4-dioxane solution of 4 M hydrogen chloride (6 mL) was added. The mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain crude title compound 15m-1 (521 mg). The product was used directly in the next reaction without purification.

[0711] MS m / z(ESI):1040.9[M+1].

[0712] Step Thirteen

[0713] M-(2S)-N-((4'S,4'S,Z)-2'-(5-(3-(1,4-oxazacycloheptan-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1'-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-6] 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptanehexacycloundecaban]-4'-yl)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)acetamide 15-1

[0714] The crude compound 15m-1 (521 mg, 500 μmol) was dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (648 mg, 5.01 mmol) was added. At 0 °C, lithium (2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carboxylate (185 mg, 1.25 mol, prepared using the method disclosed in intermediate B-1 on page 168 of patent application "WO2023060253") and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (286 mg, 547 μmol) were added. The reaction mixture was stirred for 2 hours. The reaction solution was filtered, and the liquid was purified by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate). C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 30mL / min) yielded the title compound 15-1 (130.3mg, yield: 22.4%). MS m / z (ESI): 1163.9 [M+1].

[0715] 1H NMR (500MHz, DMSO-d6): δ8.82-8.81(m,1H),8.29(s,1H),8.07-7.97(m,2H),7.87-7.86(m,1H), 7.76-7.75(m,1H),7.69-7.67(m,1H),7.59-7.57(m,1H),6.15-6.05(m,2H),5.34-5.32(m,1H), 4.61-4.59(m,2H),4.53-4.52(m,1H),4.35-4.30(m,2H),4.25-4.23(m,1H),4.08-4.04(m,2H), 3.71-3.63(m,4H),3.61-3.54(m,2H),3.49-3.47(m,1H),3.41-3.39(m,2H),3.30-3.23(m,8H), 3.13-3.09(m,1H),2.97-2.88(m,2H),2.82-2.75(m,4H),2.70-2.66(m,2H),2.61-2.59(m,1H), 2.33-2.31(m,1H),2.25-2.22(m,2H),2.18-2.08(m,2H),2.03-1.97(m,3H),1.93-1.91(m,1H), 1.87-1.81(m,2H),1.78-1.67(m,4H),1.55-1.46(m,5H),1.38-1.29(m,6H),1.05-0.99(m,1H), 0.91-0.84(m,4H),0.79-0.71(m,1H),0.63-0.47(m,3H),0.42-0.27(m,4H),0.20-0.11(m,1H).

[0716] Example 16

[0717] M-(2S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)-N-((4'S,4'S,Z)-1'-ethyl-2'-(2-((S)-1-methoxyethyl)-5-(3-(4-methyl-4,7-diazaspiro[2.5]oct-7-yl)prop-1-yn-1-yl)pyridin-3-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaphene]-4'-yl)acetamide 16-1

[0718] Referring to the synthetic route of steps nine to thirteen in Example 15, the starting material 1,4-oxazacycloheptane in step nine was replaced with 4-methyl-4,7-diazaspiro[2.5]octane dihydrochloride.

[0719] MS m / z(ESI):1188.7[M+1].

[0720] Example 17

[0721] MN-((1S)-2-(((3'S,4'S,Z)-2'-(5-(3-(1,4-oxazaheptan-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1'-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazin-hexacycloundecan]-4'-yl)amino)-1-cyclopentyl-2-oxoethyl)-1-(4-(dimethylamino)-4-methylpent-2-ynyl)-4-fluoro-N-methylpiperidin-4-carboxamide 17-1

[0722] first step

[0723] (S)-2-((tert-butoxycarbonyl)(methyl)amino)-2-cyclopentylacetate methyl ester 17b

[0724] (S)-2-((tert-butoxycarbonyl)(methyl)amino)-2-cyclopentylacetic acid 17a (900 mg, 3.50 mmol, prepared according to the method disclosed in "Organic Letters, 2023, vol. 25, #43, pp. 7822-7826") was dissolved in tetrahydrofuran (10 mL) and methanol (10 mL), and a 2M solution of (trimethylsilyl)diazomethane in n-hexane (3.5 mL) was added. The mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give title compound 17b (680 mg, yield: 71.6%).

[0725] MS m / z(ESI):172.3[M-99].

[0726] Step 2

[0727] (S)-2-cyclopentyl-2-(methylamino)acetic acid methyl ester hydrochloride 17c

[0728] Compound 17b (680 mg, 2.51 mmol) was dissolved in dichloromethane (5 mL), and a 1,4-dioxane solution of 4M hydrogen chloride (2 mL) was added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain crude title compound 17c (400 mg). The product was used directly in the next reaction without purification.

[0729] MS m / z(ESI): 172.3 [M+1].

[0730] Step 3

[0731] (S)-4-((1-cyclopentyl-2-methoxy-2-oxoethyl)(methyl)aminocarbonyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester 17d

[0732] N-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carboxylic acid (500 mg, 2.02 mmol, Shanghai Titan) was dissolved in dichloromethane (7 mL), oxalyl chloride (307 mg, 2.42 mmol) and 2 drops of N,N-dimethylformamide were added, and the mixture was stirred for 1 hour. Triethylamine (818 mg, 8.08 mmol) and crude compound 17c (400 mg, 1.92 mmol) were added, and the mixture was stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 17d (500 mg, yield: 61.7%).

[0733] MS m / z(ESI): 345.4 [M-55].

[0734] Step 4

[0735] (S)-2-cyclopentyl-2-(4-fluoro-N-methylpiperidin-4-carboxamido)methyl acetate 2,2,2-trifluoroacetate 17e

[0736] Compound 17d (500 mg, 1.25 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (4 mL) was added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain crude title compound 17e (520 mg). The product was used directly in the next reaction without purification.

[0737] MS m / z(ESI): 301.4 [M+1].

[0738] Step 5

[0739] (S)-2-cyclopentyl-2-(1-(4-(dimethylamino)-4-methylpentan-2-ynyl)-4-fluoro-N-methylpiperidin-4-carboxamido)methyl acetate 17f

[0740] The crude compound 17e (250 mg, 603 μmol), sodium 4-(dimethylamino)-4-methyl-2-pentyneate (246 mg, 1.38 mmol, Shanghai Bide), and triethylamine (402 mg, 3.97 mmol) were dissolved in N,N-dimethylformamide (4 mL). Butylphosphine anhydride (50% ethyl acetate solution) (600 mg, 833 μmol) was added under ice bath conditions. The mixture was stirred for 1 hour while maintaining the temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 17f (150 mg, yield: 41.2%).

[0741] MS m / z(ESI): 438.5 [M+1].

[0742] Step 6

[0743] (S)-2-cyclopentyl-2-(1-(4-(dimethylamino)-4-methylpentan-2-ynyl)-4-fluoro-N-methylpiperidin-4-carboxamido)acetic acid 17g

[0744] Compound 17f (150 mg, 343 μmol) was dissolved in tetrahydrofuran (4 mL) and water (4 mL). Sodium hydroxide (30 mg, 715 μmol) was added at 0 °C, and the mixture was allowed to return to room temperature with stirring for 3 hours. The reaction solution was concentrated under reduced pressure to remove the organic solvent. The residual liquid was adjusted to pH < 7 with 0.5 M hydrochloric acid, extracted with dichloromethane (10 mL × 2), and concentrated under reduced pressure in aqueous phase to obtain crude title compound 17 g (120 mg). The product was used directly in the next reaction without purification. MS m / z (ESI): 424.5 [M+1].

[0745] Step 7

[0746] MN-((1S)-2-(((3'S,4'S,Z)-2'-(5-(3-(1,4-oxazaheptan-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1'-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazin-hexacycloundecan]-4'-yl)amino)-1-cyclopentyl-2-oxoethyl)-1-(4-(dimethylamino)-4-methylpent-2-ynyl)-4-fluoro-N-methylpiperidin-4-carboxamide 17-1

[0747] The crude compound hydrochloride 1s⁻¹ (40 mg, 42.5 μmol) was dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (55 mg, 425.5 μmol) was added. At 0 °C, 17 g of the crude compound (20 mg, 47.2 μmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (24 mg, 63.1 μmol) were added. The mixture was stirred for 1 hour. The reaction solution was purified by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 30 mL / min) to obtain the title compound (26 mg, yield: 50.9%).

[0748] 1 H NMR (500MHz, CD3OD): δ8.90-8.81(m,1H),8.59(d,1H),7.98(d,1H),7.73(t,1H),7.55-7. 47(m,2H),4.76(t,1H),4.48(d,1H),4.44-3.99(m,8H),3.87(dt,4H),3.77(t,1H),3.70-3 .56(m,2H),3.31-3.12(m,11H),2.92-2.80(m,2H),2.70(d,7H),2.21(t,3H),2.17-1.96(m ,7H),1.84-1.56(m,16H),1.47(d,4H),1.12-0.99(m,4H),0.96-0.81(m,5H),0.67(d,3H).

[0749] MS m / z(ESI):1199.6[M+1].

[0750] Example 18

[0751] MN-((1S)-2-(((4'S,4'S,Z)-2'-(5-(3-(1,4-oxazacycloheptan-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1'-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-6 2 6 3-diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheptan-1-undecanoyl)-4'-yl)amino)-1-cyclopentyl-2-oxoethyl)-1-(4-(dimethylamino)-4-methylpent-2-ynyl)-4-fluoro-N-methylpiperidine-4-carboxamide 18-1

[0752] Referring to the synthetic route of Example 17, the starting material 1s-1 in step 7 was replaced with 15i-1.

[0753] MS m / z(ESI):1211.6[M+1].

[0754] Example 19

[0755] MN-((1S)-1-cyclopentyl-2-(((3'S,4'S,Z)-1'-ethyl-2'-(2-((S)-1-methoxyethyl)-5-(3-(4-methyl-4,7-diazaspiro[2.5]oct-7-yl)prop-1-yn-1-yl)pyridin-3-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazin-cycloundecan]-4'-yl)amino)-2-oxoethyl)-1-(4-(dimethylamino)-4-methylpent-2-ynyl)-4-fluoro-N-methylpiperidin-4-carboxamide 19-1

[0756] The title compound was prepared by referring to Example 17 of this disclosure and the prior art.

[0757] MS m / z(ESI):1224.6[M+1].

[0758] Example 20

[0759] MN-((1S)-1-cyclopentyl-2-(((4'S,4'S,Z)-1'-ethyl-2'-(2-((S)-1-methoxyethyl)-5-(3-(4-methyl-4,7-diazaspiro[2.5]oct-7-yl)prop-1-yn-1-yl)pyridin-3-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic[1,1]-4'-yl)amino)-2-oxoethyl)-1-(4-(dimethylamino)-4-methylpentan-2-ynyl)-4-fluoro-N-methylpiperidine-4-carboxamide 20-1

[0760] The title compound was prepared by referring to Example 18 of this disclosure and the prior art.

[0761] MS m / z(ESI):1236.6[M+1].

[0762] Example 21

[0763] M-(2S)-N-((3'S,4'S,Z)-2'-(5-(3-(1,4-oxazaheptan-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)-1'-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazine-1,3'-undecain]-4'-yl)-2-cyclopentyl-2-((5R)-7-((3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)acetamide 21-1

[0764] first step

[0765] 4-(prop-2-yn-1-yl)-1,4-oxazacycloheptane 21b

[0766] 1,4-oxazacycloheptane 21a (2 g, 19.77 mmol, BID) was dissolved in dichloromethane (50 mL), and N,N-diisopropylethylamine (3.83 g, 29.6 mmol) was added under ice bath conditions, followed by prop-2-yn-1-ylmethanesulfonate (3.183 g, 23.73 mmol, Adamas). The mixture was stirred at room temperature for 17 hours. Water was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined and concentrated under reduced pressure to obtain the crude title compound 21b (2.7 g). The product was used directly in the next reaction without purification.

[0767] Step 2

[0768] 2-Acetyl-3-bromopyridine-1-oxide 21d

[0769] Compound 21c (10 g, 49.99 mmol) was dissolved in dichloromethane (150 mL), and trifluoroacetic anhydride (21 g, 99.98 mmol, 13.9 mL, Adamas) was added dropwise at 0 °C. Urea peroxide (9.4 g, 99.98 mmol, Sinopharm) was then added in portions, and the mixture was stirred at 0 °C for 1 hour. The solution was adjusted to alkalinity with saturated sodium bicarbonate solution, washed with saturated sodium sulfite solution, and the organic phase was dried and concentrated to obtain crude title compound 21d (11 g). The product was used directly in the next reaction without purification.

[0770] MS m / z(ESI):218.1[M+2].

[0771] Step 3

[0772] 1-(3-bromo-6-hydroxypyridin-2-yl)ethyl-1-one 21e

[0773] Compound 21d (11 g, 50.92 mmol) was dissolved in N,N-dimethylformamide (100 mL), and trifluoroacetic anhydride (96.25 g, 458.26 mmol, 63.7 mL) was added under ice-water bath conditions. The reaction was carried out at 50 °C for 17 hours. The mixture was concentrated under reduced pressure, and the residue was adjusted to pH 7 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (100 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 21e (11 g). The product was used directly in the next reaction without purification.

[0774] MS m / z(ESI):218.1[M+2].

[0775] Step 4

[0776] 1-(3-bromo-6-hydroxy-5-iodopyridin-2-yl)ethyl-1-one 21f

[0777] Compound 21e (6.2 g, 28.7 mmol) was dissolved in acetonitrile (200 mL), and N-iodosuccinimide (6.46 g, 28.7 mmol) was added. The reaction was carried out at room temperature for 17 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 21f (5.88 g, yield: 59.9%).

[0778] MS m / z(ESI): 343.9 [M+2].

[0779] Step 5

[0780] 1-(3-bromo-5-iodo-6-(methoxymethoxy)pyridin-2-yl)ethyl-1-one 21g

[0781] Compound 21f (5.5 g, 16.08 mmol) was dissolved in dichloromethane (120 mL), and N,N-diisopropylethylamine (2.99 g, 23.12 mmol) and bromomethyl methyl ether (2.21 g, 17.68 mmol) were added. The mixture was stirred at room temperature for 1 hour. The reaction solution was quenched with saturated sodium bicarbonate and sodium sulfite aqueous solutions. The mixture was separated, and the aqueous phase was extracted with dichloromethane (100 mL × 2). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give compound 21f (1.95 g, yield: 31.4%).

[0782] MS m / z(ESI): 387.7 [M+2].

[0783] Step 6

[0784] (S)-1-(3-bromo-5-iodo-6-(methoxymethoxy)pyridin-2-yl)ethanol-1-ol 21h

[0785] Triethylamine (5.98 g, 59.08 mmol) was cooled to 0 °C, and formic acid (566 mg, 12.30 mmol, Adamas) was added. The mixture was purged with nitrogen three times. Then (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride (31 mg, 49 μmol, Bide) was added. The mixture was purged with nitrogen three times, and the temperature was raised to room temperature and stirred for 15 minutes. The mixture was then heated to 40 °C and reacted for 15 minutes. After cooling to room temperature, 21 g (1.9 g, 4.92 mmol) was added. The mixture was purged with nitrogen three times and heated to 40 °C and reacted for 2 hours. The reaction mixture was evaporated to dryness, and the residue was poured into water and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 21h (1.785 g, yield: 93.4%).

[0786] MS m / z(ESI): 390.1 [M+2].

[0787] Step 7

[0788] (S)-3-bromo-5-iodo-2-(1-methoxyethyl)-6-(methoxymethoxy)pyridine 21i

[0789] Compound 21h (1.785 g, 4.60 mmol) was dissolved in N,N-dimethylformamide (25 mL), sodium hydroxide (239 mg, 5.98 mmol, 60%, Adamas) was added, and the mixture was stirred at room temperature for 30 minutes. Then, methyl iodoforme (1 g, 7.05 mmol, Energetic) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated ammonium chloride aqueous solution, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with water (30 mL × 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 21i (1.55 g, yield: 84.1%).

[0790] MS m / z(ESI): 404.2 [M+2].

[0791] Step 8

[0792] (S)-4-(3-(5-bromo-6-(1-methoxyethyl)-2-(methoxymethoxy)pyridin-3-yl)prop-2-yn-1-yl)-1,4-oxazacycloheptane 21j

[0793] Under a nitrogen atmosphere, compounds 21b (805 mg, 5.78 mmol), 21i (1.55 g, 3.86 mmol), cuprous iodide (110 mg, 578 μmol), triethylamine (802 mg, 7.93 mmol), and bis(triphenylphosphine)palladium dichloride (406 mg, 578 μmol) were added to tetrahydrofuran (25 mL), and the mixture was reacted at 35 °C for 17 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 21j (1.489 g, yield: 93.4%).

[0794] MS m / z(ESI):412.9[M+1].

[0795] Step 9

[0796] ((3'S,4'S,Z)-2'-(5-(3-(1,4-oxazacyclohepta-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)-6-(methoxymethoxy)pyridin-3-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indolia-6(1,3-pyridazin-hexacycloundecanedan]-4'-yl)tert-butyl carbamate 21k

[0797] Compound 21j (287 mg, 694 μmol) was dissolved in a mixed solvent of toluene (6 mL), 1,4-dioxane (18 mL), and water (6 mL). Compound 1p (500 mg, 694 μmol), potassium phosphate (370 mg, 1.74 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (51 mg, 70 μmol) were added. The mixture was stirred at 70 °C for 16 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 21k (450 mg, yield: 69.9%).

[0798] MS m / z(ESI): 927.0 [M+1].

[0799] Step 10

[0800] M-((3'S,4'S,Z)-2'-(5-(3-(1,4-oxazacyclohepta-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)-6-(methoxymethoxy)pyridin-3-yl)-1'-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indolia-6(1,3-pyridazin-hexacycloundecanedan]-4'-yl) tert-butyl carbamate 21l-1 or

[0801] P-((3'S,4'S,Z)-2'-(5-(3-(1,4-oxazacycloheptan-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)-6-(methoxymethoxy)pyridin-3-yl)-1'-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indolia-6(1,3-pyridazin-hexacycloundecan]-4'-yl)tert-butyl carbamate 21l-2

[0802] Compound 21k (450 mg, 486 μmol) was dissolved in N,N-dimethylformamide (10 mL), and cesium carbonate (792 mg, 2.43 mmol) and iodoethane (152 mg, 0.97 mmol) were added. The mixture was stirred for 4.5 hours. The reaction solution was diluted with ethyl acetate and filtered. The filtrate was washed successively with water and saturated sodium chloride solution to separate the organic phase. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 460 mg of crude product. The crude product was purified by preparative high performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*250 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 60%-95%, flow rate: 30 mL / min). Short retention times were collected to obtain the title compounds 21l-1 (120 mg, yield: 25.9%) and 21l-2 (170 mg, yield: 36.6%).

[0803] Single configuration compound 21l-1 (shorter retention time): (120 mg, yield: 25.9%)

[0804] MS m / z(ESI): 955.0 [M+1].

[0805] HPLC analysis: Retention time 1.88 min (Column: Xtimate, C18, 1.8 μm, 2.1*50 mm; Mobile phase: Water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0806] Single configuration compound 21l-2 (longer retention time): (170 mg, yield: 36.6%)

[0807] MS m / z(ESI): 955.0 [M+1].

[0808] HPLC analysis: Retention time 1.96 min (Column: Xtimate, C18, 1.8 μm, 2.1*50 mm; Mobile phase: Water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0809] Step 11

[0810] M-(3'S,4'S,Z)-2'-(5-(3-(1,4-oxazacycloheptan-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4'-amino-1'-ethyl-10',10'-dimethylspiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazine-hexacycloundecan]-5',7'-dione hydrochloride 21m-1

[0811] Compound 21l-1 (120 mg, 126 μmol) was dissolved in methanol (2 mL), and a 4 M hydrogen chloride solution of 1,4-dioxane (4 mL) was added. The mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain crude title compound 21m-1 (100 mg). The product was used directly in the next reaction without purification.

[0812] MS m / z(ESI): 810.9 [M+1].

[0813] Step Twelve

[0814] M-(5S)-7-((1S)-2-(((3'S,4'S,Z)-2'-(5-(3-(1,4-oxazaheptan-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)-1'-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazine-1-4'-yl)amino)-1-cyclopentyl-2-oxoethyl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester 21n-1

[0815] (S)-2-((S)-7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]non-2-yl)-2-cyclopentylacetic acid (44 mg, 125 μmol, prepared by the method disclosed in intermediates A-3 and A-4 on page 166 of patent application "WO2023060253") was dissolved in N,N-dimethylformamide (3 mL). N,N-diisopropylethylamine (160 mg, 1.24 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (71 mg, 187 μmol) were added at 0 °C. After stirring at the same temperature for 0.5 hours, crude compound 21 m-1 (100 mg, 123 μmol) was added. The reaction was then stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 21n-1 (130 mg, yield: 92.0%).

[0816] MS m / z(ESI):1145.2[M+1].

[0817] Step Thirteen

[0818] M-(2S)-N-((3'S,4'S,Z)-2'-(5-(3-(1,4-oxazaheptan-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)-1'-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3-pyridazine-1,4'-undecain]-4'-yl)-2-cyclopentyl-2-((S)-2,7-diazaspiro[4,4]non-2-yl)acetamide hydrochloride 21o-1

[0819] Compound 21n-1 (130 mg, 114 μmol) was dissolved in methanol (2 mL), and a 4 M solution of 1,4-dioxane in hydrogen chloride (4 mL) was added. The mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain crude title compound 21o-1 (118 mg). The product was used directly in the next reaction without purification.

[0820] MS m / z(ESI):1044.1[M+1].

[0821] Step Fourteen

[0822] M-(2S)-N-((3'S,4'S,Z)-2'-(5-(3-(1,4-oxazaheptan-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)-1'-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazine-1,3'-undecain]-4'-yl)-2-cyclopentyl-2-((5R)-7-((3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)acetamide 21-1

[0823] The crude compound 21o-1 (118 mg, 113 μmol) was dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (147 mg, 1.13 mmol) was added. At 0 °C, lithium (2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carboxylate (32 mg, 227 μmol, prepared by the method disclosed in intermediate B-1 on page 168 of patent application "WO2023060253") and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (65 mg, 171 μmol) were added, and the reaction was stirred at room temperature for 2 hours. The reaction solution was filtered, concentrated under reduced pressure, and purified by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 30mL / min) to give the title compound 21-1 (60mg, yield: 45.5%).

[0824] MS m / z(ESI):1168.4[M+1].

[0825] 1H NMR(500MHz,CD3OD)δ8.67(s,1H),7.76(s,1H),7.71-7.68(m,1H),7.49-7.45(m,2H ),7.23(br,2H),4.52-4.48(m,1H),4.22-4.20(m,1H),4.08-4.03(m,3H),3.95-3.93 (m,1H),3.86-3.81(m,6H),3.67-3.65(m,1H),3.55-3.53(m,2H),3.47-3.39(m,2H) ,3.27-3.19(m,4H),3.08-3.06(m,6H),2.93-2.83(m,4H),2.67-2.46(m,4H),2.41(s ,1H),2.34-2.31(m,2H),2.28-2.24(m,2H),2.18-2.15(m,1H),2.05-1.96(m,4H),1 .78-1.68(m,7H),1.62-1.58(m,3H),1.49-1.48(m,2H),1.46-1.44(m,3H),1.40-1.3 6(m,2H),1.31-1.30(m,1H),1.27-1.25(m,4H),1.18-1.16(m,1H),1.03(s,3H),0.85 (s,3H),0.63-0.58(m,1H),0.51-0.44(m,2H),0.37-0.35(m,1H),0.25-0.21(m,1H).

[0826] Example 22

[0827] MN-((1S)-2-(((3'S,4'S,Z)-2'-(5-(3-(1,4-oxazaheptan-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)-1'-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazine-1-4'-yl)amino)-1-cyclopentyl-2-oxoethyl)-1-(4-(dimethylamino)-4-methylpent-2-ynyl)-4-fluoro-N-methylpiperidin-4-carboxamide 22-1

[0828] The crude compound 21m-1 (30 mg, 37 μmol) was dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (48 mg, 370 mmol) was added. Then, 17 g (16 mg, 37 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (21 mg, 56 μmol) were added at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, concentrated under reduced pressure, and purified by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 30 mL / min) to give the title compound 22-1 (15 mg, yield: 33.3%).

[0829] MS m / z(ESI):1217.1[M+1].

[0830] 1H NMR(500MHz,CD3OD)δ8.60(s,1H),7.74-7.66(m,2H),7.48-7.43(m,2H),7.10-6.99(br,3H) ,4.75-4.69(m,1H),4.60-4.59(m,1H),4.51-4.49(m,1H),4.34-4.26(m,3H),4.22-4.19(m, 1H),4.08-4.05(m,2H),3.97-3.93(m,2H),3.86-3.78(m,4H),3.73(s,2H),3.66-3.54(m,3H ),3.47-3.46(m,1H),3.26-3.19(m,3H),3.11-3.10(m,2H),3.05-3.04(m,2H),2.96-2.89(m ,5H),2.68-2.65(m,1H),2.55-2.52(m,2H),2.41-2.35(m,5H),2.28-2.26(m,1H),2.23-2.1 5(m,2H),2.06-2.03(m,1H),2.00-1.98(m,3H),1.92-1.91(m,1H),1.79-1.76(m,2H),1.69- 1.60(m,6H),1.51-1.49(m,4H),1.45-1.44(m,2H),1.36-1.31(m,4H),1.27-1.22(m,4H),1. 18-1.16(m,2H),1.04-1.03(m,2H),0.97-0.96(m,1H),0.92-0.89(m,2H),0.84-0.83(m,1H).

[0831] Example 23

[0832] M-(2S)-N-((4'S,4'S,Z)-2'-(5-(3-(1,4-oxazacycloheptan-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1'-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-6] 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolia-6(2,4)-bicyclo[3.1.1]heptanehexacycloundecaban]-4'-yl)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)acetamide 23-1

[0833] Referring to the synthetic route of steps four through seven of Example 25, the starting material 1p in step four was replaced with 15d to obtain the title compound (2.2 mg, yield: 15.4%).

[0834] MS m / z(ESI): 1193.7 [M+1].

[0835] Example 24

[0836] M-(2S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)-N-((4'S,4'S,Z)-1'-ethyl-2'-(2-((S)-1-methoxyethyl)-1-methyl-5-(3-(4-methyl-4,7-diazaspiro[2.5]oct-7-yl)prop-1-yn-1-yl)-6-oxo-1,6-dihydropyridin-3-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaphene]-4'-yl)acetamide 24-1

[0837] The title compound was prepared by referring to Example 23 of this disclosure and the prior art.

[0838] MS m / z(ESI):1218.7[M+1].

[0839] Example 25

[0840] M-(2S)-N-((3'S,4'S,Z)-2'-(5-(3-(1,4-oxazheptan-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1'-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclic] Propane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazine-1-undecano[4'-yl)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)acetamide 25-1

[0841] first step

[0842] (S)-5-bromo-3-iodo-6-(1-methoxyethyl)pyridine-2-phenol 25a

[0843] Compound 21i (1.0 g, 2.48 mmol) was dissolved in dichloromethane (8 mL), and a 1,4-dioxane solution of 4 M hydrogen chloride (8 mL) was added. The mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain crude title compound 25a (900 mg). The product was used directly in the next reaction without purification.

[0844] MS m / z(ESI): 357.9 [M+1].

[0845] Step 2

[0846] (S)-5-bromo-3-iodo-6-(1-methoxyethyl)-1-methylpyridin-2(1H)-one 25b

[0847] Compound 25a (900 mg, 2.5 mmol) was dissolved in N,N-dimethylformamide (15 mL), sodium hydrogen (193 mg, 5.03 mmol, 60% purity) was added at 0 °C, and the mixture was stirred for 30 minutes. Then, iodomethane (357 mg, 2.52 mmol) was added, and the reaction was stirred for another hour. The reaction mixture was then quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate (30 mL × 3), the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 25b (490 mg, yield: 52.4%, product with smaller Rf).

[0848] MS m / z(ESI): 371.9 [M+1].

[0849] Step 3

[0850] (S)-3-(3-(1,4-oxazacyclohep-4-yl)prop-1-yn-1-yl)-5-bromo-6-(1-methoxyethyl)-1-methylpyridin-2(1H)-one 25c

[0851] Compound 25b (490 mg, 1.31 mmol) and compound 21b (367 mg, 2.63 mmol) were dissolved in tetrahydrofuran (20 mL), and bis(triphenylphosphine)palladium dichloride (140 mg, 0.20 mmol), cuprous iodide (38 mg, 0.20 mmol), and triethylamine (400 mg, 3.95 mmol) were added sequentially. The mixture was purged with nitrogen three times and stirred at 35 °C for 17 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give title compound 25c (400 mg, 79.3% yield).

[0852] MS m / z(ESI): 383.1 [M+1].

[0853] Step 4

[0854] ((3'S,4'S,Z)-2'-(5-(3-(1,4-oxazolocyclohepta-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indolia-6(1,3-pyridazin-hexacycloundecanedan]-4'-yl)tert-butyl carbamate 25d

[0855] Compound 25c (626 mg, 1.63 mmol) was dissolved in a mixed solvent of toluene (5 mL), 1,4-dioxane (15 mL), and water (5 mL). Compound 1p (1.5 g, 2.08 mmol), potassium phosphate (866 mg, 4.08 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (121 mg, 163 μmol) were added. The mixture was stirred at 70 °C for 16 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 25d (700 mg, yield: 47.8%).

[0856] MS m / z(ESI): 896.4 [M+1].

[0857] Step 5

[0858] ((3'S,4'S,Z)-2'-(5-(3-(1,4-oxazycycloheptane-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-11 25e-Ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridaziniacycloundecan]-4'-yl) tert-butyl carbamate

[0859] M-((3'S,4'S,Z)-2'-(5-(3-(1,4-oxazycycloheptane-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1 1 25e-1 ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazin-cycloundecanedan]-4'-yl) tert-butyl carbamate

[0860] P-((3'S,4'S,Z)-2'-(5-(3-(1,4-oxazetane-hept-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1 1 25e-2-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazin-cycloundecanedan]-4'-yl) tert-butyl carbamate

[0861] Compound 25d (690 mg, 0.77 mmol) was dissolved in N,N-dimethylformamide (8 mL), and cesium carbonate (501 mg, 1.54 mmol) and iodoethane (480 mg, 3.08 mmol) were added. The mixture was stirred for 4 hours. The reaction solution was diluted with ethyl acetate and filtered. The filtrate was washed successively with water and saturated sodium chloride solution to separate the organic phase. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound 25e. The crude compound 25e was purified by preparative high performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 55%-75%, flow rate: 30 mL / min) to obtain title compounds 25e-1 (70 mg, yield: 9.8%) and 25e-2 (210 mg, yield: 29.4%, denoted as compound D).

[0862] Single configuration compound 25e-1 (shorter retention time): (70 mg, yield: 9.8%)

[0863] MS m / z(ESI): 925.0 [M+1].

[0864] HPLC analysis: Retention time 3.11 min (Column: Xtimate, C18, 1.8 μm, 2.1*50 mm; Mobile phase: Water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0865] Single configuration compound 25e-2 (longer retention time): (210 mg, yield: 29.4%)

[0866] MS m / z(ESI): 925.0 [M+1].

[0867] HPLC analysis: Retention time 3.36 min (Column: Xtimate, C18, 1.8 μm, 2.1*50 mm; Mobile phase: Water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0868] Step 6

[0869] M-(3'S,4'S,Z)-2'-(5-(3-(1,4-oxazonyl-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4'-amino-1'-ethyl-10',10'-dimethylspiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazine-hexacycloundecan]-5',7'-dione hydrochloride 25f-1

[0870] Compound 25e-1 (70 mg, 75 μmol) was dissolved in methanol (2 mL), and a 4 M hydrogen chloride solution of 1,4-dioxane (4 mL) was added. The mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain crude title compound 25f-1 (45 mg). The product was used directly in the next reaction without purification.

[0871] MS m / z(ESI):824.4[M+1].

[0872] Step 7

[0873] M-(2S)-N-((3'S,4'S,Z)-2'-(5-(3-(1,4-oxazycycloheptan-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1'-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane] [Alkyl-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indolia-6(1,3-pyridazine-cycloundecaphen]-4'-yl)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)acetamide 25-1

[0874] Referring to the synthetic route in steps 12 to 14 of Example 21, the starting material 21m-1 in step 12 was replaced with 25f-1 to obtain the title compound 25-1 (30 mg, 29.5%).

[0875] MS m / z(ESI):1181.6[M+1].

[0876] 1 H NMR (500MHz, CD3OD): δ8.68(s,1H),7.70(d,2H),7.51–7.45(m,2H),4.50(d,2H),4.21(s,2H),4.11–3.99(m,3H),3.88(s,3H),3.82(t,2H),3 .80–3.77(m,2H),3.74–3.64(m,3H),3.55(d,1H),3.41(d,1H),3.22(d ,3H),3.02(d,1H),2.93(t,3H),2.80(s,3H),2.55(d,3H),2.40(s,1H) ,2.34(s,2H),2.31–2.19(m,4H),2.17(d,1H),2.11–2.03(m,3H),1.98 (p,3H),1.75(s,3H),1.68(s,2H),1.62(d,3H),1.57(d,3H),1.48–1.4 5(m,3H),1.25(s,4H),1.16(s,1H),1.04(d,3H),0.92(t,3H),0.84(d, 3H),0.57(s,1H),0.48(td,3H),0.36–0.34(m,1H),0.28–0.19(m,2H).

[0877] Example 26

[0878] M-(2S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylazacyclopropane-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)-N-((3'S,4'S,Z)-1'-ethyl-2'-(2-((S)-1-methoxyethyl)-1-methyl-5-(3-(4-methyl-4,7) -diazaspiro[2.5]oct-7-yl)prop-1-yn-1-yl)-6-oxo-1,6-dihydropyridin-3-yl)-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3)-indolia-6(1,3)-pyridazine-cycloundecanedan]-4'-yl)acetamide 26-1

[0879] The title compound was prepared by referring to Example 25 of this disclosure and the prior art.

[0880] MS m / z(ESI): 1206.7 [M+1].

[0881] Example 27

[0882] M-(2S,3S)-N-((6 4 S,3S,4S,Z)-1 2 -(5-(3-(1,4-oxazaspirohep-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-10,10-dimethyl-5,7-dioxo-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1 1 -(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)-3-methyloxacyclobutane-2-formamide 27-1

[0883] first step

[0884] (2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)propionate methyl ester 27b

[0885] Compound 27a (660 mg, 1.47 mmol, prepared by the method disclosed in Reference Example Intermediate 2 on page 303 of patent application "WO2025080946A2") was dissolved in tetrahydrofuran (10 mL) and methanol (10 mL), and a 2M solution of trimethylsilyldiazomethane in n-hexane (2.4 mL) was added. The mixture was stirred for 4 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 27b (430 mg, yield: 63.1%).

[0886] MS m / z(ESI):462.4[M+1].

[0887] Step 2

[0888] (2S,3S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazolyl-2-yl)-2-((tert-butoxycarbonyl)amino)-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)propionate methyl 27c

[0889] Compound 27b (2.2 g, 4.76 mmol) was dissolved in a mixed solvent of toluene (10 mL), 1,4-dioxane (30 mL), and water (10 mL). Compound 1i (1.8 g, 4.85 mmol), potassium phosphate (2.6 g, 12.2 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (356 mg, 0.48 mmol) were added. The mixture was stirred at 70 °C for 17 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system E to give title compound 27c (2.2 g, 72.4% yield).

[0890] MS m / z(ESI): 627.7 [M+1].

[0891] Step 3

[0892] ((6 4 S,3S,4S,Z)-10,10-dimethyl-5,7-dioxo-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptacyclohexane-4-yl)tert-butyl carbamate 27d

[0893] Following the synthetic route of steps 8 to 13 of Example 1, starting material 1j in step 8 was replaced with 27c, and starting material (S)-hexahydropyridazine-3-carboxylic acid methyl ester hydrochloride in step 8 was replaced with (S)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid methyl ester bis(2,2,2-trifluoroacetic acid) salt (prepared by the method disclosed in Example 8 on page 64 of patent application "WO2024067857") to obtain compound 27d (250 mg, yield: 18.4%). MS m / z (ESI): 803.8 [M+1].

[0894] Step 4

[0895] M-(2S,3S)-N-((6 4 S,3S,4S,Z)-1 2 -(5-(3-(1,4-oxazaspirohep-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-10,10-dimethyl-5,7-dioxo-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1 1 -(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)-3-methyloxacyclobutane-2-formamide 27-1

[0896] Referring to the synthetic route of steps fourteen to seventeen of Example 1, the starting materials 1p and 1e in step fourteen were replaced with 27d and 25c, the starting material iodoethane in step fifteen was replaced with 2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl 4-methylbenzenesulfonate (prepared by the method disclosed in intermediate 1 on page 300 of patent application "WO2025081946"), and the starting material (S)-2-((S)-7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]non-2-yl)-2-cyclopentylacetic acid in step seventeen was replaced with (2S,3S)-3-methyloxecyclobutane-2-carboxylic acid (6 mg, 51 μmol, prepared by the method disclosed in reference example 9 on page 348 of patent application "WO2025080946A2") to obtain the title compound. MS m / z(ESI): 1105.5 [M+1].

[0897] Example 28

[0898] M-(2S,3S)-N-((6 4 S,3S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(4-methyl-4,7-diazaspiro[2.5]oct-7-yl)prop-1-yn-1-yl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-10,10-dimethyl-5,7-dioxo-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1 1 -(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolaza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecaban-4-yl)-3-methyloxacyclobutane-2-formamide 28-1

[0899] The title compound was prepared by referring to Example 27 of this disclosure and the prior art.

[0900] MS m / z(ESI): 1130.6 [M+1].

[0901] Example 29

[0902] M-(1r,2R,3S)-N-((3'S,4'S,Z)-2'-(5-(3-(1,4-oxazonyl-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1'-ethyl-10',10'-dimethyl-5',7'-dioxospiro[cyclopropane-1,3'-8-oxa-2(4,2)-thiazo-1(5,3-indolia-6(1,3-pyridazin-1-cycloundecan]-4'-yl)-2,3-dimethylcyclopropane-1-carboxamide 29-1

[0903] Referring to the synthetic route in Example 4, the starting material 3f-1 was replaced with 25f-1 to obtain the title compound 29-1 (5 mg, 22.4%).

[0904] MS m / z(ESI): 920.5 [M+1].

[0905] 1H NMR (500MHz, CD3OD): δ8.60(s,1H),7.69(d,,2H),7.46(d,2H),4.51(d,2H),4.20(q,2H),4.07(dd,2H ),3.97(d,1H),3.90–3.76(m,8H),3.70(s,2H),3.61(d,1H),3.22(s,3H),3.11–3.04(m,2H),2.94–2. 83(m,5H),2.21(t,1H),2.13(d,1H),2.05(d,1H),1.98(dt,3H),1.77(d,1H),1.67(dd,1H),1.63(s,1 H),1.56(d,3H),1.46(d,1H),1.24(t,3H),1.17–1.06(m,7H),1.02(s,2H),0.92(t,2H),0.84(s,3H).

[0906] Biological evaluation

[0907] The following test examples further describe and explain this disclosure, but these test examples are not intended to limit the scope of this disclosure.

[0908] Test Example 1: Biological Evaluation of 3D Cell Proliferation Inhibition Experiment

[0909] This experiment used the cell evaluation compounds listed in the table below to assess their inhibitory effect on the proliferation of KRAS-mutant or KRAS-amplified cells.

[0910] On the first day of the experiment, well-grown cells with 70%-80% confluence were digested, resuspended in culture medium, and the cell density was adjusted to the desired level. 90 μL of cell suspension was added to each well of a U-shaped, low-adsorption 96-well plate (Corning, 7007), with cell density as shown in the table above. The cell plates were centrifuged at 2500 rpm for 5 minutes and then incubated for 24 hours. On the second day, the 20 mM test compound dissolved in DMSO was diluted with DMSO to an initial concentration of 2 or 0.2 mM, and then serially diluted 5-fold for a total of 9 concentration points. The control wells contained DMSO. The serially diluted compounds were then further diluted 20-fold with culture medium. 10 μL of the culture medium-diluted test compound was added to each well of the cell plate. The final concentration of the compound was determined by the 9 concentration points obtained from 5-fold serial dilutions starting at 10 or 1 μM. Cell wells containing 0.5% DMSO were set as solvent control wells, and wells containing only culture medium and 0.5% DMSO were set as blank control wells. After centrifuging the cell culture plate at 2000 rpm for 3 minutes, it was placed in an incubator and cultured for 5 days. On the seventh day, the 96-well cell culture plate was removed, and 50 μL of luminescent cell viability assay reagent was added to each well. 3D Cell Viability Assay (Promega, G9683): ​​After shaking at room temperature for 25 minutes, mix thoroughly by pipetting and aspiration, and transfer 100 μL from each well to a white, opaque OptiPlate. TM In a -96-well plate (PerkinElmer, 6005290), the luminescence signal values ​​were read using a multi-functional microplate reader (PerkinElmer, EnVision2105).

[0911] Calculate the inhibition rate using the following formula: Inhibition rate = (Luminous value) / (Emitting value) 溶媒对照孔 -Luminescence value 受试化合物 ) / (luminous value) 溶 媒对照孔 -Luminescence value 空白对照孔 ()×100%. The IC50 of the compound's inhibitory activity was calculated using Graphpad Prism software. 50 The values ​​are shown in Table 1 below.

[0912] Table 1. Inhibition of 3D cell proliferation by the disclosed compounds (unit: nM)

[0913] Conclusion: The compound disclosed herein has a good inhibitory effect on the 3D proliferation of the above-mentioned cells.

[0914] Test Example 2: Biological Evaluation of 2D Cell Proliferation Inhibition Experiment

[0915] This experiment used THP-1 cells to evaluate the effects of compounds on NRAS. G12D Inhibitory effect on cell proliferation.

[0916] On day 1 of the experiment, THP-1 cells in suspension were centrifuged to remove the supernatant, then resuspended in RPMI 1640 medium containing 10% FBS and 0.05 mM 2-mercaptoethanol (Gibco, 21985023), and the cell density was adjusted to the desired level. 90 μL of cell suspension was added to each well of a white-bottomed 96-well plate (Corning, 3903), at a cell density of 2000 cells / well. The 20 mM test compound dissolved in DMSO was diluted to an initial concentration of 2 mM with DMSO, and then serially diluted 5-fold for a total of 9 concentration points. The control wells contained DMSO. The serially diluted compounds were then further diluted 20-fold with medium. 10 μL of the diluted test compound was added to each well of the cell plate. The final concentration of the compound was determined by the 9 concentration points obtained from the 5-fold serial dilutions starting at 10 μM. Wells containing 0.5% DMSO were set as solvent control wells, and wells containing only medium and 0.5% DMSO were set as blank control wells. The cell culture plates were incubated in an incubator for 5 days. On the sixth day, the 96-well cell culture plates were removed, and 50 μL of Cell Titer-Glo Luminescent Cell Viability Assay (Promega, G7573) was added to each well. The plates were then incubated at room temperature in the dark for 10 minutes. A backseal membrane (Revvity, 6005199) was attached to the bottom of the cell culture plate, and the plates were placed on a multi-functional microplate reader (PerkinElmer, EnVision 2105) to read the luminescence signal values.

[0917] Calculate the inhibition rate using the following formula: Inhibition rate = (Luminous value) / (Emitting value) 溶媒对照孔 -Luminescence value 受试化合物 ) / (luminous value) 溶 媒对照孔 -Luminescence value 空白对照孔 ()×100%. The IC50 of the compound's inhibitory activity was calculated using Graphpad Prism software. 50 The values ​​are shown in Table 2 below.

[0918] Table 2. Inhibition of 2D cell proliferation by the disclosed compounds (unit: nM)

[0919] Conclusion: The compound disclosed herein has a good inhibitory effect on the 2D proliferation of the above-mentioned cells.

[0920] Test Example 3: Biological Evaluation of ERK Phosphorylation Inhibition Experiment in AsPC-1 and AGS Cells

[0921] This experiment used the HTRF method to detect the inhibitory effect of the compound on cellular ERK phosphorylation.

[0922] AsPC-1 cells were cultured in RPMI 1640 complete medium containing 10% FBS. AGS cells were cultured in Ham's F-12K (Kaighn's) complete medium containing 10% FBS. On day 1, AsPC-1 and AGS cells were seeded in 96-well plates at densities of 20,000 and 30,000 cells per well, respectively, using complete medium, with 190 μL of cell suspension per well. The plates were incubated overnight at 37°C in a 5% CO2 incubator. On day 2, 10 μL of serially diluted test compounds prepared in complete medium were added to each well. The final concentration of the compound was determined by a 5-fold serial dilution starting from 10 μM, with nine concentration points. A blank control containing 0.5% DMSO was included. The plates were incubated at 37°C in a 5% CO2 incubator for 3 hours. After incubation, the 96-well cell culture plates were removed, the medium was aspirated, and each well was washed once with 200 μL of PBS. Remove the PBS and add 50 μL of lysis buffer (Revity, 64KL1FDF) containing blocking buffer (Revity, 64KB1AAC) to each well. Place the plate on a shaker and vortex at room temperature for 40 minutes to lyse. After lysis, mix thoroughly by pipetting. Transfer 16 μL of lysis buffer to each of two HTRF 96-well detection plates (Revity, 66PL96100). Then, add 4 μL of premixed phosphorylated ERK1 / 2 antibody solution (Revity, 64AERPEH) or 4 μL of premixed total ERK1 / 2 antibody solution (Revity, 64NRKPEH) to each well of both plates. Seal the microplate with sealing film, centrifuge for 1 minute, and incubate overnight at room temperature in the dark. On the third day, the fluorescence values ​​of excitation at 337 nm and emission at 665 nm and 620 nm were read using a multi-functional microplate reader (BMG Labtech, PHERAstar FSX).

[0923] The IC50 of the compound's inhibitory activity was calculated using Graphpad Prism software. 50 Values. See Table 3 below for the results.

[0924] Table 3. Inhibition of ERK phosphorylation in cells by the disclosed compounds (unit: nM)

[0925] Conclusion: The compound disclosed herein has a good inhibitory effect on ERK phosphorylation in the above-mentioned cells.

[0926] Test Example 4: Pharmacokinetic Evaluation

[0927] 1. Abstract

[0928] Using Balb / c nude mice as test animals, the LC / MS / MS method was used to determine the drug concentration in plasma at different time points after intragastric administration (i.g.) of the compound of the example to Balb / c nude mice, study the pharmacokinetic behavior of the compound of the present disclosure in vivo in Balb / c nude mice, and evaluate its pharmacokinetic characteristics.

[0929] 2. Test Protocol

[0930] 2.1. Test Drug

[0931] Compound 15-1.

[0932] 2.2. Test Animal

[0933] Nine female Balb / c nude mice. Provided by Vital River Laboratory Animal Technology Co., Ltd. (SCXK(Zhejiang)2024-0001).

[0934] 2.3. Drug Preparation

[0935] A certain amount of the test compound is weighed separately, added with 0.53 mL of dimethyl sulfoxide (DMSO) + 1.06 mL of PEG 400 + 0.53 mL of polyoxyethylene hydrogenated castor oil HS15 (Solutol HS15) + 3.18 mL of water, to prepare a 0.3 mg / mL clear solution.

[0936] 2.4. Administration

[0937] The administration dose is 3 mg / kg, and the administration volume is 10 mL / kg.

[0938] 3. Operation

[0939] Balb / c nude mice are administered by intragastric gavage. 0.1 mL of blood is collected from the orbital vein at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0 and 24.0 hours after administration. Blood samples are placed into EDTA-K2-containing blood collection tubes and stored on ice until centrifugation. Blood samples are centrifuged at 10,000 rpm for 1 minute (4°C), plasma is separated within 1 hour and stored at -20°C until testing.

[0940] Plasma samples at each time point after administration are analyzed by LC / MS / MS.

[0941] Table 4. Pharmacokinetic parameters of the compound of the present disclosure in vivo in Balb / c nude mice

[0942] Conclusion: The compound of the present disclosure has high plasma concentration and high exposure in vivo in Balb / c nude mice, and has pharmacokinetic advantages.

Claims

A compound of general formula (I) or a pharmaceutically acceptable salt thereof. in: R D The alkynyl group is optionally selected from halogens, alkoxy groups optionally substituted with one or more R*, haloalkoxy groups, cyano groups, and -NR groups. 9a R 9b The hydroxyl group, a cycloalkyl group optionally substituted with one or more R*, a heterocyclic group optionally substituted with one or more R*, an aryl group optionally substituted with one or more R*, a heteroaryl group optionally substituted with one or more R*, a cycloalkylalkyl group optionally substituted with one or more R*, a heterocyclic alkyl group optionally substituted with one or more R*, an arylalkyl group optionally substituted with one or more R*, and a heteroarylalkyl group optionally substituted with one or more R* are substituted with one or more substituents. Y is selected from hydrogen atom, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7a R 7b -NR 7a OR 7b -ONR 7a R 7b -NR 7c NR 7a R 7b hydroxyl group, -C(O)R 8 -C(O)OR 8 -C(O)NR 7a R 7b -S(O) w R 8 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 9a R 9b The substance is substituted by one or more substituents selected from hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; Z and R R The same or different, and each independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted by one or more R*; G 1 G 2 Whether the CR is the same as or different from G, and each is independent of the other. 6 N=O, NR N Or N; Ring A is a heterocyclic group; The ring carbons may be the same or different, and each is independently selected from cycloalkyl, heterocyclic, aryl or heteroaryl groups; R A R B R C R N and R 6 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7a R 7b -NR 7a OR 7b -ONR 7a R 7b -NR 7c NR 7a R 7b hydroxyl group, -C(O)R 8 -C(O)OR 8 -C(O)NR 7a R 7b -S(O) w R 8 , Oxide group, =S, =NOR 61 =CR 62 R 63 =NR 64 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 9a R 9b The substance is substituted by one or more substituents selected from hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; or Two Rs A Together with the attached atoms, it forms a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. AA replace; R 2 Selected from O, NH and N-alkyl; L 2 The alkylene group is optionally alkylene oxide (R0) or alkylene oxide (R0) by one or more R0. L2 replace; R L2 Same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, oxo, =S, =NOR 61 =CR 62 R 63 =NR 64 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted with one or more R* groups; or Two Rs L2 Together with the attached atoms, it forms a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. LL2 replace; L 1 Selected from cycloalkyl, heterocyclic and -CH(cycloQ)-, wherein each of the cycloQ, cycloalkyl and heterocyclic groups is independently optionally converted by one or more R L1 replace; Ring Q is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; L is R 10 or R 11 and R 12 The same or different, and each independently selected from hydrogen atoms, halogens, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally separated by one or more R E replace; L 3 For key or -N(R) L3 )C(O)-; L 4 For bonds or -(alkylene) y -N(R L4 )C(=O)-; R 10 Selected from alkyl, cycloalkyl, heterocyclic and NR 101 R 102 The alkyl, cycloalkyl, and heterocyclic groups are each independently and optionally influenced by one or more R groups. F replace; Each R F They may be the same or different, and each is independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7a R 7b hydroxyl group, oxo group, =S, =NOR 61 =CR 62 R 63 =NR 64 cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R F1 -C(O)OR F1 -C(O)NR F2 R F3 -S(O) w R F1 and -S(O) w OR F1 The alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally converted by one or more R groups. FF replace; R 7a R 7b R 7c R 9a R 9b R L3 R L4 R 101 R 102 R F2 and R F3 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, heteroalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocyclic groups, wherein each of the alkyl, heteroalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocyclic groups is independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl and haloalkoxy; Or R 7a and R 7b Together with the attached nitrogen atom, it forms a heterocyclic group, or R 9a and R 9b Together with the attached nitrogen atom, it forms a heterocyclic group, or R 101 and R 102 Together with the attached nitrogen atom, it forms a heterocyclic group, or R F2 and R F3 Together with the attached nitrogen atom, a heterocyclic group is formed, wherein the heterocyclic group is optionally selected from halogens, oxo groups, =S, =NR. 64 It is substituted by one or more substituents selected from alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; R 8 R F1 R 61 R 62 R 63 and R 64 The same or different, and each independently selected from hydrogen atoms, halogens, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl, and heterocyclic groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups are each independently optionally selected by one or more R atoms. # Replace; or R 62 R 63 Together with the attached atoms, they form cycloalkyl or heterocyclic groups, each of which is optionally independently bound by one or more R groups. FF replace; Each R*, R AA R LL2 R L1 R E R FF and R # The same or different, and each independently selected from oxo, =S, =N-alkyl, =NH, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkylthio, amino, -NHalkyl, -N(alkyl)2, -alkylene-amino, -alkylene-NHalkyl, -alkylene-N(alkyl)2, amide, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclic oxy, aryloxy, and heteroaryloxy, wherein the =N-alkyl, alkyl, alkenyl, alkoxy, alkoxyalkyl, alkoxyalkyl, alkylthio, -NHalkyl, -N(alkyl)2, -alkylene-amino, -alkylene-NHalkyl, -alkylene The alkyl-N(alkyl)2, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclicalkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclicoxy, aryloxy and heteroaryloxy are each independently and optionally substituted by one or more substituents selected from oxo, =S, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkylthio, amino, -NHalkyl, -N(alkyl)2, -alkylene-amino, -alkylene-NHalkyl, -alkylene-N(alkyl)2, amide, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclicalkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclicoxy, aryloxy and heteroaryloxy; w is 0, 1, or 2; n is 0, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, 5 or 6; q is 0, 1, 2, or 3; and y can be 0, 1, 2, 3, 4, 5 or 6. According to claim 1, the compound of formula (I) or its pharmaceutically acceptable salt, wherein L 1 It is a 3- to 6-membered cycloalkyl group. The compound of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, is a compound of general formula (II) or (II-Q) or a pharmaceutically acceptable salt thereof. in: q1 can be 0, 1, 2, 3, 4, 5, or 6; The dashed line indicates whether the ring is aromatic or non-aromatic. R 2D Selected from cycloalkylalkyl, heterocycloalkyl, arylalkyl, and heteroarylalkyl, wherein the cycloalkylalkyl, heterocycloalkyl, arylalkyl, and heteroarylalkyl are optionally substituted with one or more R*; Ring Q, R L1 R * R B , q, G 1 G 2 G, Y, Z, L 2 R A , n, ring C, R C p and L are as defined in claim 1. The compound of general formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the ring C is a thiazolyl group. The compound of general formula (I) according to any one of claims 1 to 4, or the pharmaceutically acceptable salt thereof, is a compound of general formula (III) or (III-Q) or the pharmaceutically acceptable salt thereof. in: M is a carbon atom, a nitrogen atom, or an oxygen atom; d1 is 0, 1, 2, 3 or 4; d2 is 0, 1, 2, 3, or 4; d4 can be 0, 1, 2, 3, 4, 5, or 6; R d3 It is a hydrogen atom or R*; or Two Rs d3 Together with the attached atom, it forms a cycloalkyl or heterocyclic group; q1 can be 0, 1, 2, 3, 4, 5, or 6; The dashed line indicates whether the ring is aromatic or non-aromatic. Ring Q, R L1 G 1 R 6 Y, Z, R A n, R B , q, R C And L as defined in claim 1. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Selected from Where R A and n as defined in claim 1. The compound of general formula (I) according to any one of claims 5 to 6, or a pharmaceutically acceptable salt thereof, wherein R d3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; or two R atoms bonded to the same carbon atom d3 Together with the attached carbon atom, it forms a 3- to 6-membered cycloalkyl group; and / or d4 is 0, 1, 2, or 3; and / or d1 is 1 or 2; and / or d2 is 1; and / or M is a nitrogen atom or an oxygen atom. The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y is C 1-6 Alkoxy C 1-6 Alkyl group; preferably CH3OCH(CH3)-. The compound of general formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein Z is C 1-6 Alkyl groups; and / or R B They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; and / or q is 0 or 1; and / or R C Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyl alkyl, cyano, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic groups; and / or Ring Q is a 3- to 8-membered heterocyclic group; and / or q1 is 0 or 1; and / or R L1 Selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. The compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein each R A They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano groups, or two R groups on the same atom A Or two R atoms on different atoms A Together with the attached atoms, it forms a 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group is optionally reacted with one or more halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano substitutions; and / or n is 0, 1 or 2. The compound of general formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein L is a 3- to 8-membered cycloalkyl group, said 3- to 8-membered cycloalkyl group optionally converted by one or more halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, =CR 62 R 63 C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano substitution, R 62 and R 63 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; or L is The compound of general formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, is selected from the following compounds: And all compounds shown in Group A or their pharmaceutically usable salts. A compound of general formula (IA) or a salt thereof, in: G, G 1 G 2 Y, Z, R D R 2 L 2 Ring A, R A , n, L 1 R R , ring C, R C p, R B And q as defined in claim 1. A compound or a salt thereof, selected from the following compounds: And all compounds or their salts shown in group B. A method for preparing a compound of general formula (I) according to claim 1, comprising: Method 1: The compound of general formula (IA) or its salt undergoes a condensation reaction with LC(O)OH or its salt to give the compound of general formula (I) or its pharmaceutically usable salt. in: G, G 1 G 2 Y, Z, R D R 2 L 2 Ring A, R A , n, L 1 L, R R , ring C, R C p, R B and q as defined in claim 1; Method 2: A compound of general formula (IA) or a salt thereof undergoes a condensation reaction with L'-COOH or a salt thereof to yield L' as... The general formula (IB) or its salt, wherein R pro Amino protecting group; and / or The product from the previous step underwent a deprotection reaction to give L' as The general formula (IB) or its salt; and / or L' is The general formula (IB) or its salts with A condensation reaction occurs to give a compound of general formula (I) or a pharmaceutically acceptable salt thereof, wherein R LQ It can be -OLi, -ONa, -OK, OH, or a halogen; Where L is Ring W 1 For optional use by one or more R F Substituted nitrogen-containing heterocyclic group, ring W 2 It is a cycloalkyl or heterocyclic group, R W3 For hydrogen atoms or R # w4 can be 0, 1, 2, 3, or 4. R F R # R 11 R 12 G, G 1 G 2 Y, Z, R D R 2 L 2 Ring A, R A , n, L 1 R R , ring C, R C p, R B And q as defined in claim 1. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. Use of the compound of general formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 16, in the preparation of a medicament for inhibiting RAS mutant proteins. Use of the compound of general formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, in the preparation of a medicament for the treatment and / or prevention of diseases or conditions mediated or dependent on RAS mutant proteins. The use of the compound of general formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 16, in the preparation of a medicament for treating and / or preventing tumors; wherein the tumors are preferably selected from thyroid cancer, head and neck cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, brain cancer, skin cancer, testicular cancer, bile duct cancer, colorectal cancer, urothelial carcinoma, bladder cancer, breast cancer, ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, leukemia, lymphoma, myeloma, appendiceal cancer, melanoma, sarcoma, and glioblastoma; more preferably selected from gastric cancer, pancreatic cancer, colorectal cancer, and non-small cell lung cancer.

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